The independent effect of exercise on biopsy proven non-alcoholic fatty liver disease: A systematic review

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Clin Mol Hepatol. 2023;29(2):414-416
Publication date (electronic) : 2023 February 28
doi : https://doi.org/10.3350/cmh.2023.0055
Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
Corresponding 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
Received 2023 February 10; Revised 2023 February 21; Accepted 2023 February 22.

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.

Notes

Conflicts of Interest

The authors have no conflicts to disclose.

Acknowledgements

This was supported by Inha University Research Grant.

Abbreviations

NAFLD

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

References

1. De Minicis S, Day C, Svegliati-Baroni G. From NAFLD to NASH and HCC: pathogenetic mechanisms and therapeutic insights. Curr Pharm Des 2013;19:5239–5249.
2. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
3. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15:11–20.
4. Le MH, Yeo YH, Zou B, Barnet S, Henry L, Cheung R, et al. Forecasted 2040 global prevalence of nonalcoholic fatty liver disease using hierarchical bayesian approach. Clin Mol Hepatol 2022;28:841–850.
5. Ng CH, Huang DQ, Nguyen MH. Nonalcoholic fatty liver disease versus metabolic-associated fatty liver disease: Prevalence, outcomes and implications of a change in name. Clin Mol Hepatol 2022;28:790–801.
6. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328–357.
7. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al, ; Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: Management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27:363–401.
8. Hydes TJ, Ravi S, Loomba R, E Gray M. Evidence-based clinical advice for nutrition and dietary weight loss strategies for the management of NAFLD and NASH. Clin Mol Hepatol 2020;26:383–400.
9. Chen G, Banini B, Do A, Lim J. The independent effect of exercise on biopsy-proven non-alcoholic fatty liver disease: a systematic review. Clin Mol Hepatol 2022 Dec 14. doi: 10.3350/cmh.2022.0366.
10. Hickman IJ, Byrne NM, Croci I, Chachay VS, Clouston AD, Hills AP, et al. A pilot randomised study of the metabolic and histological effects of exercise in non-alcoholic steatohepatitis. J Diabetes Metab 2013;4:1000300.
11. Eckard C, Cole R, Lockwood J, Torres DM, Williams CD, Shaw JC, et al. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol 2013;6:249–259.
12. Naimimohasses S, O’Gorman P, Wright C, Ni Fhloinn D, Holden D, Conlon N, et al. Differential effects of dietary versus exercise intervention on intrahepatic MAIT cells and histological features of NAFLD. Nutrients 2022;14:2198.
13. O’Gorman P, Naimimohasses S, Monaghan A, Kennedy M, Melo AM, Ní Fhloinn D, et al. Improvement in histological endpoints of MAFLD following a 12-week aerobic exercise intervention. Aliment Pharmacol Ther 2020;52:1387–1398.
14. Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB, ; NASH CRN Research Group. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol 2011;106:460–468. quiz 469.
15. Lahelma M, Luukkonen PK, Qadri S, Ahlholm N, Lallukka-Brück S, Porthan K, et al. Assessment of lifestyle factors helps to identify liver fibrosis due to non-alcoholic fatty liver disease in obesity. Nutrients 2021;13:169.
16. Hallsworth K, Fattakhova G, Hollingsworth KG, Thoma C, Moore S, Taylor R, et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 2011;60:1278–1283.
17. Rezende RE, Duarte SM, Stefano JT, Roschel H, Gualano B, de Sá Pinto AL, et al. Randomized clinical trial: benefits of aerobic physical activity for 24 weeks in postmenopausal women with nonalcoholic fatty liver disease. Menopause 2016;23:876–883.
18. Stine JG, Schreibman IR, Faust AJ, Dahmus J, Stern B, Soriano C, et al. NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH. Hepatology 2022;76:172–185.
19. 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. Clin Gastroenterol Hepatol 2017;15:96–102.e3.
20. Bonekamp S, Tang A, Mashhood A, Wolfson T, Changchien C, Middleton MS, et al. Spatial distribution of MRI-Determined hepatic proton density fat fraction in adults with nonalcoholic fatty liver disease. J Magn Reson Imaging 2014;39:1525–1532.
21. Noureddin M, Lam J, Peterson MR, Middleton M, Hamilton G, Le TA, et al. Utility of magnetic resonance imaging versus histology for quantifying changes in liver fat in nonalcoholic fatty liver disease trials. Hepatology 2013;58:1930–1940.
22. Yokoo T, Shiehmorteza M, Hamilton G, Wolfson T, Schroeder ME, Middleton MS, et al. Estimation of hepatic proton-density fat fraction by using MR imaging at 3.0 T. Radiology 2011;258:749–759.
23. Kang GH, Cruite I, Shiehmorteza M, Wolfson T, Gamst AC, Hamilton G, et al. Reproducibility of MRI-determined proton density fat fraction across two different MR scanner platforms. J Magn Reson Imaging 2011;34:928–934.

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