Lifestyle modifications for nonalcohol-related fatty liver disease: a network meta-analysis

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

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

Conflict of interest statement

None known for any of the authors

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

Figures

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1
Study flow diagram
Date of search: 25 February 2021
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
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Network plots: A high resolution version of this image can be found here. The network plots showing the outcomes for which network meta‐analysis was performed. The size of the node (circle) provides a measure of the number of trials in which the particular Intervention was included as one of the intervention groups. The thickness of the line provides a measure of the number of direct comparisons between two nodes (Interventions). Abbreviations AdviceDiet: dietary advice
AdviceDiet+AerobicEx: aerobic exercise plus dietary advice
AdviceDietEx: dietary advice plus exercise advice
AerobicEx: aerobic exercise
CalRestrictDiet: calorie restricted diet
CarbRestrictDiet+AerobicEx: aerobic exercise plus carbohydrate restricted diet
FatRestrictDiet: fat restricted diet
FatRestrictDiet+AerobicEx: aerobic exercise plus fat restricted diet
MedDiet: Mediterranean diet
NoActiveIntervention: no active intervention
ResistEx: resistance exercise
SupAerobicEx: supervised aerobic exercise
SupAerobicEx+CalRestrictDiet: supervised aerobic exercise plus calorie restricted diet
SupAerobicEx+SupResistEx: supervised aerobic exercise plus resistance exercise
5
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Inconsistency factor plots: The plot shows the inconsistency factors for the only outcome (resolution of fatty liver) where direct and indirect evidence were available for one or more comparisons. Although not attaining formal levels of statistical significance, this may suggest some concern regarding the consistency of the evidence. A higher resolution image of this picture is available here. Abbreviations CalRestrictDiet: calorie restricted diet
NoActiveIntervention: no active intervention
SupAerobicEx: supervised aerobic exercise
SupAerobicEx+CalRestrictDiet: supervised aerobic exercise plus calorie restricted diet
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Effect estimates: A picture of Table 7 Effect estimates. Please see Table 7 for further details.

References

References to studies included in this review Abbate 2021 {published data only}

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Arab 2017 {published data only}
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Axley 2017 {published data only}
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De Luis 2010 {published data only}
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De Piano 2012 {published data only}
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Dynnyk 2016 {published data only}
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Eckard 2013 {published data only}
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Goss 2020 {published data only}
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Hallsworth 2011 {published data only}
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Hallsworth 2015 {published data only}
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Hickman 2013 {published data only}
    1. Croci I, Byrne NM, Chachay VS, Hills AP, Clouston AD, O'Moore-Sullivan TM, et al. Independent effects of diet and exercise training on fat oxidation in non-alcoholic fatty liver disease. World Journal of Hepatology 2016;8(27):1137-48.
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Houghton 2017 {published data only}
    1. Houghton D, Thoma C, Hallsworth K, Cassidy S, Hardy T, Burt AD, et al. Exercise reduces liver lipids and visceral adiposity in patients with nonalcoholic steatohepatitis in a randomized controlled trial. Clinical Gastroenterology and Hepatology 2017;15(1):96-102.e3.
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Johari 2019 {published data only}
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Kaliora 2016 {published data only}
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Kani 2014 {published data only}
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Katsagoni 2018 {published data only}
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Misciagna 2017 {published data only}
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Monica Dinu 2017 {published data only}
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Moradi 2020 {published data only}
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NCT02679417 {published data only}
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NCT03183193 {published data only}
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NCT03461562 {published data only}
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Nikroo 2017 {published data only}
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Nishimori 2018 {published data only}
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Nourian 2020 {published data only}
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Oh 2017 {published data only}
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Panganiban 2020 {published data only}
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Properzi 2018 {published data only}
    1. Properzi C, O'Sullivan TA, Sherriff JL, Ching H, Jeffrey GP, Tibballs J, et al. Hepatic steatosis is significantly reduced by either a low-fat or a Mediterranean-style diet in patients with non-alcoholic fatty liver disease. Journal of Gastroenterology and Hepatology 2017;32:181.
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Pugh 2014 {published data only}
    1. Pugh CJ, Cuthbertson DJ, Sprung VS, Kemp GJ, Richardson P, Umpleby AM, et al. Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease. American Journal of Physiology - Endocrinology and Metabolism 2013;305(1):e50-8.
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Ramirez 2016 {published data only}
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Ramon‐Krauel 2013 {published data only}
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Rezende 2016 {published data only}
    1. Rezende RE, Duarte SM, Stefano JT, Perandini LA, Dassouki T, Sa-Pinto AL, et al. Impact of aerobic exercise in postmenopausal women with nonalcoholic fatty liver disease: a 24 weeks randomized clinical trial. Journal of Hepatology 2015;62:S724.
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Rodriguez‐Hernandez 2011 {published data only}
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Roy 2017 {published data only}
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Schattenberg 2017 {published data only}
    1. Schattenberg JM, Schlegel L, Nier A, Huber Y, Galle PR, Bergheim I. Dietary counselling focusing only on fructose consumption improves hepatic inflammation in patients with NAFLD-a prospective, controlled, randomized open-label study (NUCES NASH). Hepatology (Baltimore, Md.) 2017;66(Suppl 1):1106a-7a.
Selezneva 2014 {published data only}
    1. Selezneva K, Kirillova O, Vorozhko I, Isakov VA, Sentsova T. Short-term effect of low-calorie diet (LCD) versus isocalorie diet (ICD) on blood aminotransferases level and lipids profile in patients with non-alcoholic steatohepatitis (NASH). Journal of Hepatology 2014;60(1 Suppl 1):S353.
Shidfar 2018 {published data only}
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Sima 2014 {published data only}
    1. Sima HR, Nikroo H, Nematy M, Attarzade-Hosseini SR, Mohammadian-Damasaki M, Rad MP, et al. Effect of aerobic exercise added to calorie-restricted diet on non-alcoholic steatohepatitis, a randomized clinical trial. Gastroenterology 2014;146(5 Suppl 1):S-945.
Sullivan 2012 {published data only}
    1. Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Effect of endurance exercise on nonalcoholic fatty liver disease. Clinical and Translational Science 2012;5(2):154.
    1. Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) 2012;55(6):1738-45.
Tutino 2018 {published data only}
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Wang 2008 {published data only}
    1. Wang CL, Liang L, Fu JF, Zou CC, Hong F, Xue JZ, et al. Effect of lifestyle intervention on non-alcoholic fatty liver disease in Chinese obese children. World Journal of Gastroenterology 2008;14(10):1598-602.
Wang 2016 {published data only}
    1. Wang XG, Huang LH. Therapeutic effect of fasted exercise on nonalcoholic fatty hepatitis. World Chinese Journal of Digestology 2016;24:3417-21.
Wong 2013 {published data only}
    1. Shen J, Wong GL, Chan HL, Chan RS, Chan HY, Chu WC, et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. Journal of Gastroenterology and Hepatology 2015;30(1):139-46.
    1. Wong VW, Chan RS, Wong GH, Cheung BK, Chu WW, Chan HY, et al. Low glycaemic index dietary intervention for patients with non-alcoholic fatty liver disease in the general population-a randomised controlled trial. Gut 2012;61:A417.
    1. Wong VW, Chan RS, Wong GL, Cheung BH, Chu WC, Yeung DK, et al. Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial. Journal of Hepatology 2013;59(3):536-42.
    1. Wong VW, Wong GL, Chan RS, Shu SS, Cheung BH, Li LS, et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. Journal of Hepatology 2018;22:22.
Yao 2018 {published data only}
    1. Yao JL, Meng MM, Yang SN, Li F, Anderson RM, Liu C, et al. Effect of aerobic and resistance exercise on liver enzyme and blood lipids in Chinese patients with nonalcoholic fatty liver disease: a randomized controlled trial. International Journal of Clinical and Experimental Medicine 2018;11(5):4867-74.
Zade 2016 {published data only}
    1. Zade MR, Telkabadi MH, Bahmani F, Salehi B, Farshbaf S, Asemi Z. The effects of dash diet on weight loss and metabolic status in adults with non-alcoholic fatty liver disease: a randomized clinical trial. Liver International 2016;36(4):563-71.
Zelber‐Sagi 2014 {published data only}
    1. Zelber-Sagi S, Buch A, Yeshua H, Vaisman N, Webb M, Harari G, et al. Effect of resistance training on non-alcoholic fatty-liver disease a randomized-clinical trial. World Journal of Gastroenterology 2014;20(15):4382-92.
Zhang 2016 {published data only}
    1. Zhang H, Pan LL, Ma ZM, Chen Z, Lu Y, Li XY. The long-term effect of exercise intervention on improving fatty liver and cardiovascular risk factors in obese adults: a one-year follow-up study. Diabetologia 2016;1(Suppl 1):S150.
    1. Zhang HJ, He J, Pan LL, Ma ZM, Han CK, Chen CS, et al. Effects of moderate and vigorous exercise on nonalcoholic fatty liver disease: a randomized clinical trial. JAMA Internal Medicine 2016;176(8):1074-82.
    1. Zhang HJ, Pan LL, Ma ZM, Chen Z, Huang ZF, Sun Q, et al. Long-term effect of exercise on improving fatty liver and cardiovascular risk factors in obese adults: a 1-year follow-up study. Diabetes, Obesity and Metabolism 2017;19(2):284-9.
References to studies excluded from this review Aller 2014 {published data only}
    1. Aller R, De Luis DA, Izaola O, De la Fuente B, Bachiller R. Effect of a high monounsaturated vs high polyunsaturated fat hypocaloric diets in nonalcoholic fatty liver disease. European Review for Medical and Pharmacological Sciences 2014;18(7):1041-7.
An 2015 {published data only}
    1. An YM, Jun DW, Lee SM. Development and application of low-carbohydrates and low-simple sugar nutrition education materials for non-alcoholic fatty liver disease patients. Clinical Nutrition Research 2015;4(4):250-8.
Arefhosseini 2011 {published data only}
    1. Arefhosseini SR, Ebrahimi-Mameghani M, Farsad Naeimi A, Khoshbaten M, Rashid J. Lifestyle modification through dietary intervention: health promotion of patients with non-alcoholic fatty liver disease. Health Promotion Perspectives 2011;1(2):147-54.
Austin 2020 {published data only}
    1. Austin PW, Nachum R, Jackson K, Escheik C, Duric Z, Weinstein AA, et al. Personalized intervention increases free-living physical activity in sedentary individuals with nonalcoholic fatty liver disease (NAFLD). Hepatology (Baltimore, Md.) 2020;72(1 Suppl):986a.
Baldry 2017 {published data only}
    1. Baldry E, Aithal GP, Kaye P, Idris I, Leeder P, Bennett A, et al. Effects of short term very low energy diets prior to bariatric surgery on liver histology and circulating biomarkers: results of a randomised controlled trial (RCT). Journal of Hepatology 2015;62:S716.
    1. Baldry EL, Aithal GP, Idris I, Kaye P, Leeder P, Bennett A, et al. Effects of short-term energy restriction prior to bariatric surgery on liver fat, inflammation and systemic metabolic parameters. Diabetic Medicine 2015;32:52.
    1. Baldry EL, Aithal GP, Kaye P, Idris IR, Bennett A, Leeder PC, et al. Effects of short-term energy restriction on liver lipid content and inflammatory status in severely obese adults: results of a randomized controlled trial using 2 dietary approaches. Diabetes, Obesity and Metabolism 2017;19(8):1179-83.
Dela Cruz 2012 {published data only}
    1. Dela Cruz R, Mappala HT. The efficacy of ursodeoxycholic acid, probiotics vs. diet and exercise in the treatment of NAFLD: an open-labelled prospective randomized trial. Journal of Gastroenterology and Hepatology 2012;27:223.
Dorosti 2020 {published data only}
    1. Dorosti M, Heidarloo AJ, Bakhshimoghaddam F, Alizadeh M. Whole-grain consumption and its effects on hepatic steatosis and liver enzymes in patients with non-alcoholic fatty liver disease: a randomised controlled clinical trial. British Journal of Nutrition 2020;123(3):328-36.
Dynnyk 2017 {published data only}
    1. Dynnyk N, Svintsitsky A, Solovyova G, Baka O, Chernyavskyi V, Yarmenchuk I, et al. Changing eating behavior by motivational and controlled program during 12 weeks reduce weight, cytokeratin 18 levels and steatosis in patient with NAFLD. Journal of Hepatology 2017;66(1 Suppl 1):S427.
Haidari 2020 {published data only}
    1. Haidari F, Hojhabrimanesh A, Helli B, Seyedian SS, Ahmadi-Angali K, Abiri B. A hypocaloric high-protein diet supplemented with beta-cryptoxanthin improves non-alcoholic fatty liver disease: a randomized controlled trial. BMC Gastroenterology 2020;20(1):349.
    1. Haidari F, Hojhabrimanesh A, Helli B, Seyedian SS, Ahmadi-Angali K. An energy-restricted high-protein diet supplemented with beta-cryptoxanthin alleviated oxidative stress and inflammation in nonalcoholic fatty liver disease: a randomized controlled trial. Nutrition Research 2020;73:15-26.
Lim 2020 {published data only}
    1. Lim SL, Johal J, Ong KW, Han CY, Chan YH, Lee YM, et al. Lifestyle intervention enabled by mobile technology on weight loss in patients with nonalcoholic fatty liver disease: randomized controlled trial. JMIR MHealth and UHealth 2020;8(4):e14802.
Marin‐Alejandre 2021 {published data only}
    1. Marin-Alejandre BA, Abete I, Cantero I, Galarregui C, Elorz M, Tur JA, et al. Depressive symptoms and liver fat in subjects with nonalcoholic fatty liver disease after 6-month weight loss intervention: The FLIO study. Proceedings of the Nutrition Society 2020;79(Oce2):E373.
    1. Marin-Alejandre BA, Cantero I, Perez-Diaz-Del-Campo N, Monreal JI, Elorz M, Herrero JI, et al. Effects of two personalized dietary strategies during a 2-year intervention in subjects with nonalcoholic fatty liver disease: a randomized trial. Liver International 2021 February 7 [Online ahead of print]. [DOI: doi: 10.1111/liv.14818]
Nath 2020 {published data only}
    1. Nath P, Panigrahi MK, Sahu MK, Narayan J, Sahoo RK, Patra AA, et al. Effect of exercise on NAFLD and its risk factors: comparison of moderate versus low intensity exercise. Journal of Clinical & Translational Hepatology 2020;8(2):120-6.
NCT04193982 {published data only}
    1. NCT04193982. An investigator initiated prospective, four arms randomized comparative study of efficacy and safety of saroglitazar, vitamin E and life style modification in patients with nonalcoholic fatty liver disease (NAFLD)/ non-alcoholic steatohepatitis (NASH). (First posted 11 December 2019).
NCT04383951 {published data only}
    1. NCT04383951. Safety and efficacy of ketogenic diet for promoting weight loss in obese individuals with compensated NASH cirrhosis. (First posted 12 May 2020).
NCT04520724 {published data only}
    1. NCT04520724. Functional roll for non-alcoholic fatty liver disease. (First posted 20 August 2020).
Negri 2020 {published data only}
    1. Negri R, Trinchese G, Carbone F, Caprio MG, Stanzione G, Di Scala C, et al. Randomised clinical trial: calorie restriction regimen with tomato juice supplementation ameliorates oxidative stress and preserves a proper immune surveillance modulating mitochondrial bioenergetics of t-lymphocytes in obese children affected by non-alcoholic fatty liver disease (NAFLD). Journal of Clinical Medicine 2020;9(1):141.
Nigam 2014 {published data only}
    1. Nigam P, Bhatt S, Misra A, Chadha DS, Vaidya M, Dasgupta J, et al. Effect of a 6-month intervention with cooking oils containing a high concentration of monounsaturated fatty acids (olive and canola oils) compared with control oil in male Asian Indians with nonalcoholic fatty liver disease. Diabetes Technology & Therapeutics 2014;16(4):255-61.
Nobili 2008 {published data only}
    1. Nobili V, Manco M, Devito R, Di Ciomm V, Comparcola D, Sartorelh MP, et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology (Baltimore, Md.) 2008;48(1):119-28.
    1. Nobili V, Manco M, DeVito R, PietroBattista A, Comparcola D, Sartorelli MR, et al. Lifestyle intervention and antioxidants in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Gastroenterology 2008;134(4):a781.
Promrat 2010 {published data only}
    1. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology (Baltimore, Md.) 2010;51(1):121-9.
    1. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis (NASH). Hepatology (Baltimore, Md.) 2008;48(4 Suppl):802a.
Rezaei 2019 {published data only}
    1. Rezaei S, Akhlaghi M, Sasani MR, Barati Boldaji R. Olive oil lessened fatty liver severity independent of cardiometabolic correction in patients with non-alcoholic fatty liver disease: a randomized clinical trial. Nutrition 2019;57:154-61.
Ristic‐Medic 2020 {published data only}
    1. Ristic-Medic D, Kovacic M, Takic M, Arsic A, Petrovic S, Paunovic M, et al. Calorie-restricted Mediterranean and low-fat diets affect fatty acid status in individuals with nonalcoholic fatty liver disease. Nutrients 2020;13(1):23.
Ryan 2013 {published data only}
    1. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. Journal of Hepatology 2013;59(1):138-43.
Schweinlin 2018 {published data only}
    1. Schweinlin A, Ulbrich S, Staubeta S, Teutsch M, Walle H, Basrai M, et al. Comparison of a commercially available, formula-based nutritional therapy enriched with oats fiber with a non-formula isocaloric therapy to treat non-alcoholic fatty liver disease (NAFLD) - a randomized, controlled intervention trial. Zeitschrift fur Gastroenterologie 2018;56(10):1247-56.
Simons 2021 {published data only}
    1. Simons N, Veeraiah P, Simons P, Schaper NC, Kooi ME, Schrauwen-Hinderling VB, et al. Effects of fructose restriction on liver steatosis (fruitless); a double-blind randomized controlled trial. American Journal of Clinical Nutrition 2021;113(2):391-400.
St George 2009 {published data only}
    1. St George A, Bauman A, Johnston A, Farrell G, Chey T, George J. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.) 2009;50(1):68-76.
Sun 2012 {published data only}
    1. Sun WH, Song MQ, Jiang CQ, Xin YN, Ma JL, Liu YX, et al. Lifestyle intervention in non-alcoholic fatty liver disease in Chengyang district, Qingdao, China. World Journal of Hepatology 2012;4(7):224-30.
TCTR20200411004 {published data only}
    1. TCTR20200411004. Text messaging intervention and weight loss in patients with non-alcoholic fatty liver disease: a randomized controlled study. (First received 11 April 2020).
Vilar Gomez 2009 {published data only}
    1. Vilar Gomez E, Rodriguez De Miranda A, Gra Oramas B, Arus Soler E, Llanio Navarro R, Calzadilla Bertot L, et al. Clinical trial: a nutritional supplement Viusid, in combination with diet and exercise, in patients with nonalcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics 2009;30(10):999-1009.
Whyte 2020 {published data only}
    1. Whyte MB, Shojaee-Moradie F, Sharaf SE, Cuthbertson DJ, Kemp GJ, Barrett M, et al. HDL-apoA-I kinetics in response to 16 wk of exercise training in men with nonalcoholic fatty liver disease. American Journal of Physiology - Endocrinology and Metabolism 2020;318(6):E839-47.
References to studies awaiting assessment Bahrololumi 2014 {published data only}
    1. Bahrololumi S, Shidfar F, Jazayeri S, Taghvaie T. The effects of virgin olive oil-rich diet on fasting serum glucose and lipid profile in non alcoholic fatty liver patients with weight loss diet. Iranian Journal of Endocrinology and Metabolism 2014;15(6):527-37.
Grove 2020 {published data only}
    1. Grove J, Vijay A, Astbury S, Simpson L, Bawden S, Leena KB, et al. Effect of low glycemic index carbohydrate consumption in non-alcoholic fatty liver disease: a community-based pilot randomised controlled trial and mechanistic study. Hepatology (Baltimore, Md.) 2020;72(1 Suppl):369a.
Jia 2018 {published data only}
    1. Jia GY, Han T, Gao L, Wang L, Wang SC, Yang L, et al. Effect of aerobic exercise and resistance exercise in improving non-alcoholic fatty liver disease: a randomized controlled trial. Chung Hua Kan Tsang Ping Tsa Chih 2018;26(1):34-41.
References to ongoing studies IRCT20100524004010N31 {published data only}
    1. IRCT20100524004010N31. Evaluation of the effects of Fasting Mimicking Diet (FMD) on lipid profile, glycemic, inflammatory and histologic indices in Non-Alcoholic Fatty Liver (NAFLD). (First received 19 August 2020).
NCT03354247 {published data only}
    1. NCT03354247. Lifestyle Intervention in Fatty Liver (NAFLD) (FOIEGRAS). (First received 27 November 2017).
NCT03518294 {published data only}
    1. NCT03518294. Nash fitness intervention in thrombosis trial (NASHFit). (First received 8 May 2018).
    1. Stine JG, Schreibman I, Navabi S, Kang M, Dahmus J, Soriano C, et al. Nonalcoholic steatohepatitis Fitness Intervention in Thrombosis (NASHFit): study protocol for a randomized controlled trial of a supervised aerobic exercise program to reduce elevated clotting risk in patients with NASH. Contemporary Clinical Trials Communications 2020;18:100560.
NCT04283942 {published data only}
    1. NCT04283942. Effect of intermittent calorie restriction on NAFLD patients with disorders of glucose metabolism. (First received 25 February 2020).
NCT04355910 {published data only}
    1. NCT04355910. Intermittent fasting in nonalcoholic fatty liver disease. (First received 21 April 2020).
NCT04369521 {published data only}
    1. NCT04369521. Evaluation of the effects of a low free sugar diet in patients with nonalcoholic fatty liver disease. (First received 30 April 2020).
NCT04440540 {published data only}
    1. NCT04440540. Alternation of non-alcoholic fatty liver disease (NAFLD) and cardiovascular risks after liftestyle modification: a ultrasound attenuation imaging-based study. (First received 19 June 2020).
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