CMHClinical and Molecular HepatologyClin Mol Hepatol2287-27282287-285XThe Korean Association for the Study of the Liver10.3350/cmh.2023.0055cmh-2023-0055EditorialThe independent effect of exercise on biopsy proven non-alcoholic fatty liver disease: A systematic reviewhttp://orcid.org/0000-0002-7449-2461JinYoung-Joo
Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, KoreaCorresponding author : Young-Joo Jin Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea Tel: +82-32-890-2548, Fax: +82-32-890-2549, E-mail: jyj412@hanmail.net
Editor: Seung Up Kim, Yonsei University College of Medicine, Korea
Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases from non-alcoholic fatty liver to non-alcoholic steatohepatitis (NASH), leading to fibrosis, cirrhosis, and even to hepatocellular carcinoma [1]. The overall global prevalence of NAFLD is about 25% and steadily rising [2-5]. However, to date, no drug has been approved drug for the treatment of NAFLD. Lifestyle modification, including exercise, weight reduction, and diet control is known to be the only accepted treatment for NAFLD [6-8]. However, the independent effect of exercise on biopsy-proven NAFLD remains controversial.
This issue of the Clinical and Molecular Hepatology carried the first systemic review of published literature by Chen et al. [9] for evidence on the independent effects of exercise on histological or non-invasive test (NIT) outcomes in patients with biopsy-proven NAFLD. The systemic review [9] includes seven interventional and two observational studies. In this review, histologic endpoints were evaluated in six studies including two randomized controlled trials (RCTs), one non-RCT, one uncontrolled study, and two cross-sectional studies. Two RCTs [10,11] failed to demonstrate the independent impact of exercise on histological improvement in the absence of weight reduction or diet intervention. On the other hand, the non-randomized interventional studies showed that exercise could reduce hepatocyte ballooning and liver fibrosis [12-15]. However, these studies were limited by the absence of separate NASH-related data and by the uncontrolled study design. Moreover, Chen et al. [9] did not analyze the difference between the effects of aerobic and anaerobic exercise on NAFLD. In the previous RCT involving subjects with clinically defined NAFLD, Hallsworth et al. [16], showed that resistance exercise improves NAFLD regardless of changes in body weight. Therefore, the results would have been more meaningful if Chen et al. [9] had also confirmed an independent effect according to the type of exercise on biopsy-proven NAFLD.
With regard to NIT, three RCTs and two non-RCTs assessed the independent effect of exercise on biopsy-proven NAFLD for hepatic steatosis, steatohepatitis, and liver fibrosis [12,13,17-19]. One RCT published by Rezende et al. [17] used transient elastography as an NIT for the evaluation of the benefits of exercise in NAFLD patients with hepatic steatosis and fibrosis. Although this study is the only RCT to use transient elastography to assess the independent benefit of exercise on biopsyproven NAFLD, aerobic exercise failed to demonstrate significant improvement of hepatic steatosis or fibrosis severity in this study [17]. On the other hand, interestingly, other studies using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure outcomes have demonstrated improvement in hepatic steatosis due to exercise [18,19]. However, there were no significant changes of the serum biomarkers for liver fibrosis and steatohepatitis [12,18,19]. Given that MRI-PDFF is an accurate diagnostic method for hepatic fat over the entire liver and that it is a repeatable and reproducible quantitative examination method [20-23], this result is clinically significant.
To analyze the independent role of exercise, it is important to strictly control potential bias associated with the intensity, frequency, and type of exercise between eligible studies. However, it is not easy to completely control these variables. This would inevitably be a limitation of this study [9]. It is also regrettable that a meta-analysis was not included in this systematic review [9]. This is an area that needs to be supplemented through further research in the future.
Nonetheless, this study [9] highlights the need for additional research to assess the independent role of exercise in the improvement of histologic and clinical biomarkers in patients with biopsy-proven NAFLD.
Conflicts of Interest
The authors have no conflicts to disclose.
This was supported by Inha University Research Grant.
AbbreviationsNAFLD
non-alcoholic fatty liver disease
NASH
non-alcoholic steatohepatitis
NIT
non-invasive test
RCT
randomized controlled trials
MRI-PDFF
magnetic resonance imaging-proton density fat fraction
REFERENCESDe MinicisSDayCSvegliati-BaroniGFrom NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights20131952395249YounossiZMKoenigABAbdelatifDFazelYHenryLWymerMGlobal epidemiology of nonalcoholic fatty liver disease-Metaanalytic assessment of prevalence, incidence, and outcomes2016647384YounossiZAnsteeQMMariettiMHardyTHenryLEslamMGlobal burden of NAFLD and NASH: trends, predictions, risk factors and prevention2018151120LeMHYeoYHZouBBarnetSHenryLCheungRForecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach202228841850NgCHHuangDQNguyenMHNonalcoholic fatty liver disease versus metabolic-associated fatty liver disease: Prevalence, outcomes and implications of a change in name202228790801ChalasaniNYounossiZLavineJECharltonMCusiKRinellaMThe diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases201867328357KangSHLeeHWYooJJChoYKimSULeeTHKorean Association for the Study of the Liver (KASL)KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease202127363401HydesTJRaviSLoombaRE GrayMEvidence-based clinical advice for nutrition and dietary weight loss strategies for the management of NAFLD and NASH202026383400ChenGBaniniBDoALimJThe independent effect of exercise on biopsy-proven non-alcoholic fatty liver disease: a systematic review2022 Dec 14. doi: 10.3350/cmh.2022.0366HickmanIJByrneNMCrociIChachayVSCloustonADHillsAPA pilot randomised study of the metabolic and histological effects of exercise in non-alcoholic steatohepatitis201341000300EckardCColeRLockwoodJTorresDMWilliamsCDShawJCProspective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial20136249259NaimimohassesSO’GormanPWrightCNi FhloinnDHoldenDConlonNDifferential effects of dietary versus exercise intervention on intrahepatic MAIT cells and histological features of NAFLD2022142198O’GormanPNaimimohassesSMonaghanAKennedyMMeloAMNí FhloinnDImprovement in histological endpoints of MAFLD following a 12-week aerobic exercise intervention20205213871398KistlerKDBruntEMClarkJMDiehlAMSallisJFSchwimmerJBNASH CRN Research GroupPhysical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease2011106460468quiz 469LahelmaMLuukkonenPKQadriSAhlholmNLallukka-BrückSPorthanKAssessment of lifestyle factors helps to identify liver fibrosis due to non-alcoholic fatty liver disease in obesity202113169HallsworthKFattakhovaGHollingsworthKGThomaCMooreSTaylorRResistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss20116012781283RezendeREDuarteSMStefanoJTRoschelHGualanoBde Sá PintoALRandomized clinical trial: benefits of aerobic physical activity for 24 weeks in postmenopausal women with nonalcoholic fatty liver disease201623876883StineJGSchreibmanIRFaustAJDahmusJSternBSorianoCNASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH202276172185HoughtonDThomaCHallsworthKCassidySHardyTBurtADExercise reduces liver lipids and visceral adiposity in patients with nonalcoholic steatohepatitis in a randomized controlled trial20171596102.e3BonekampSTangAMashhoodAWolfsonTChangchienCMiddletonMSSpatial distribution of MRI-Determined hepatic proton density fat fraction in adults with nonalcoholic fatty liver disease20143915251532NoureddinMLamJPetersonMRMiddletonMHamiltonGLeTAUtility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials20135819301940YokooTShiehmortezaMHamiltonGWolfsonTSchroederMEMiddletonMSEstimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T2011258749759KangGHCruiteIShiehmortezaMWolfsonTGamstACHamiltonGReproducibility of MRI-determined proton density fat fraction across two different MR scanner platforms201134928934