Treatment of NAFLD: Diet, Physical Activity, and Potential Pharmacological Options
DOI:
https://doi.org/10.12775/QS.2024.16.52219Keywords
non-alcoholic fatty liver disease, metabolic-associated fatty liver disease, NAFLD, MAFLD, NAFLD treatment, MAFLD treatmentAbstract
Introduction and purpose
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, and according to current data, it affects 38% of the global population. NAFLD includes non-alcoholic fatty liver and the progressive form called non-alcoholic steatohepatitis, which is characterized by damage, inflammation of hepatocytes, and fibrosis. NASH can lead to cirrhosis and hepatocellular carcinoma. Moreover, it increases the risk of diabetes mellitus type 2, lipid disorders, and death due to cardiovascular causes. Currently, no cure is aimed at reducing the severity of NALFD and liver fibrosis. The aim of this study was to provide a total review of the current state of knowledge regarding NAFLD treatment and to identify potential areas for further evaluation.
Materials and method
The PubMed and Google Scholar databases were thoroughly searched to select appropriate sources for this article.
A brief description of the state of knowledge
Diet, weight management, and physical activity constitute fundamental elements of every treatment regimen for NAFLD. Regarding pharmacological treatment, European guidelines recommend the use of vitamin E or pioglitazone in certain patients. Recently, the topic of NAFLD treatment has been a popular subject among scientists who are striving to discover new therapeutic options. A lot of recent research has exhibited promising outcomes for GLP-1 agonists, metformin, SGLT2 inhibitors, FXR, and PPAR ligands.
Summary
The findings of the conducted studies so far are encouraging and offer promise for novel pharmacological interventions in the treatment of NAFLD. Nonetheless, before implementation, further research in this area will be imperative to comprehensively evaluate the efficacy and safety profiles of these pharmaceuticals.
References
Nassir F. NAFLD: Mechanisms, Treatments, and Biomarkers. Biomolecules. 2022 Jun 13;12(6):824. doi: 10.3390/biom12060824. PMID: 35740949; PMCID: PMC9221336.
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018 Jul;24(7):908-922. doi: 10.1038/s41591-018-0104-9. Epub 2018 Jul 2. PMID: 29967350; PMCID: PMC6553468.
https://www.mp.pl/interna/chapter/B16.II.7.11. (access 28.05.2024 r.)
Vaz K, Clayton-Chubb D, Majeed A, Lubel J, Simmons D, Kemp W, Roberts SK. Current understanding and future perspectives on the impact of changing NAFLD to MAFLD on global epidemiology and clinical outcomes. Hepatol Int. 2023 Oct;17(5):1082-1097. doi: 10.1007/s12072-023-10568-z. Epub 2023 Aug 9. PMID: 37556065; PMCID: PMC10522780.
Ding L, Oligschlaeger Y, Shiri-Sverdlov R, Houben T. Nonalcoholic Fatty Liver Disease. In: von Eckardstein A, Binder CJ, eds. Prevention and Treatment of Atherosclerosis: Improving State-of-the-Art Management and Search for Novel Targets. Cham (CH): Springer; March 18, 2020.233-269.
Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol. 2017;42(2):92-108. doi:10.23736/S0391-1977.16.02563-3
European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. doi:10.1016/j.jhep.2015.11.004
Kim DY, Park JY. Genetic risk factors associated with NAFLD. Hepatoma Res 2020;6:85. http://dx.doi.org/10.20517/2394-5079.2020.96
Huang Y, Cohen JC, Hobbs HH. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease. J Biol Chem. 2011 Oct 28;286(43):37085-93. doi: 10.1074/jbc.M111.290114. Epub 2011 Aug 30. PMID: 21878620; PMCID: PMC3199456.
Antunes C, Azadfard M, Hoilat GJ, Gupta M. Fatty Liver. In: StatPearls. Treasure Island (FL): StatPearls Publishing; January 1, 2023.
Haufe S, Engeli S, Kast P, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology. 2011;53(5):1504-1514. doi:10.1002/hep.24242
Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction [published correction appears in Gastroenterology. 2009 Jul;137(1):393. Mayurranjan, Mitra S [corrected to Mayurranjan S Mitra]]. Gastroenterology. 2009;136(5):1552-1560. doi:10.1053/j.gastro.2009.01.048
Lazo M, Solga SF, Horska A, et al. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care. 2010;33(10):2156-2163. doi:10.2337/dc10-0856
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-e15. doi:10.1053/j.gastro.2015.04.005
Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: Beyond the obvious. Liver Int. 2021;41(10):2249-2268. doi:10.1111/liv.15024
Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J Hepatol. 2016;65(4):791-797. doi:10.1016/j.jhep.2016.05.026
Zhang HJ, He J, Pan LL, et al. Effects of Moderate and Vigorous Exercise on Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial. JAMA Intern Med. 2016;176(8):1074-1082. doi:10.1001/jamainternmed.2016.3202
Mascaró CM, Bouzas C, Montemayor S, et al. Effect of a Six-Month Lifestyle Intervention on the Physical Activity and Fitness Status of Adults with NAFLD and Metabolic Syndrome. Nutrients. 2022;14(9):1813. Published 2022 Apr 26. doi:10.3390/nu14091813
European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402. doi:10.1016/j.jhep.2015.11.004
Jiang Q. Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy. Free Radic Biol Med. 2014;72:76-90. doi:10.1016/j.freeradbiomed.2014.03.035
Niki E. Role of vitamin E as a lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence. Free Radic Biol Med. 2014;66:3-12. doi:10.1016/j.freeradbiomed.2013.03.022
Nor Azman NHE, Goon JA, Abdul Ghani SM, Hamid Z, Wan Ngah WZ. Comparing Palm Oil, Tocotrienol-Rich Fraction and α-Tocopherol Supplementation on the Antioxidant Levels of Older Adults. Antioxidants (Basel). 2018;7(6):74. Published 2018 May 28. doi:10.3390/antiox7060074
Ahsan H, Ahad A, Iqbal J, Siddiqui WA. Pharmacological potential of tocotrienols: a review. Nutr Metab (Lond). 2014;11(1):52. Published 2014 Nov 12. doi:10.1186/1743-7075-11-52
Vogli S, Naska A, Marinos G, Kasdagli MI, Orfanos P. The Effect of Vitamin E Supplementation on Serum Aminotransferases in Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic Review and Meta-Analysis. Nutrients. 2023;15(17):3733. Published 2023 Aug 25. doi:10.3390/nu15173733
Sato K, Gosho M, Yamamoto T, et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition. 2015;31(7-8):923-930. doi:10.1016/j.nut.2014.11.018
Pioglitazone. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; June 6, 2018.
Lian J, Fu J. Pioglitazone for NAFLD Patients With Prediabetes or Type 2 Diabetes Mellitus: A Meta-Analysis. Front Endocrinol (Lausanne). 2021 Apr 28;12:615409. doi: 10.3389/fendo.2021.615409. Erratum in: Front Endocrinol (Lausanne). 2022 Feb 16;13:840299. PMID: 33995271; PMCID: PMC8115121.
Della Pepa G, Russo M, Vitale M, Carli F, Vetrani C, Masulli M, Riccardi G, Vaccaro O, Gastaldelli A, Rivellese AA, Bozzetto L. Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: clinical and pathophysiological insights from a subgroup of the TOSCA.IT randomised trial. Diabetes Res Clin Pract. 2021 Aug;178:108984. doi: 10.1016/j.diabres.2021.108984. Epub 2021 Jul 24. PMID: 34311022.
Mazhar IJ, Yasir M, Sarfraz S, Shlaghya G, Narayana SH, Mushtaq U, Shaman Ameen B, Nie C, Nechi D, Penumetcha SS. Vitamin E and Pioglitazone: A Comprehensive Systematic Review of Their Efficacy in Non-alcoholic Fatty Liver Disease. Cureus. 2023 Aug 17;15(8):e43635. doi: 10.7759/cureus.43635. PMID: 37719477; PMCID: PMC10504864.
Xie Y, Bowe B, Xian H, Loux T, McGill JB, Al-Aly Z. Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records. Lancet Diabetes Endocrinol. 2023;11(9):644-656. doi:10.1016/S2213-8587(23)00171-7
Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes Management in Chronic Kidney Disease: Synopsis of the KDIGO 2022 Clinical Practice Guideline Update. Ann Intern Med. 2023;176(3):381-387. doi:10.7326/M22-2904
Dalsgaard NB, Vilsbøll T, Knop FK. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: A narrative review of head-to-head comparisons. Diabetes Obes Metab. 2018;20(3):508-519. doi:10.1111/dom.13128
Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. doi:10.1016/j.molmet.2019.09.010
Cusi K. Incretin-Based Therapies for the Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes. Hepatology. 2019;69(6):2318-2322. doi:10.1002/hep.30670
Newsome PN, Buchholtz K, Cusi K, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395
Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-690. doi:10.1016/S0140-6736(15)00803-X
Bouchi R, Nakano Y, Fukuda T, et al. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: a randomized control trial. Endocr J. 2017;64(3):269-281. doi:10.1507/endocrj.EJ16-0449
Corcoran C, Jacobs TF. Metformin. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 17, 2023.
de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, Huttenlocher A. Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J Hepatol. 2019 Apr;70(4):710-721. doi: 10.1016/j.jhep.2018.11.034. Epub 2018 Dec 18. PMID: 30572006; PMCID: PMC6436385.
Wabitsch S, McCallen JD, Kamenyeva O, Ruf B, McVey JC, Kabat J, Walz JS, Rotman Y, Bauer KC, Craig AJ, Pouzolles M, Phadke I, Catania V, Green BL, Fu C, Diggs LP, Heinrich B, Wang XW, Ma C, Greten TF. Metformin treatment rescues CD8+ T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022 Sep;77(3):748-760. doi: 10.1016/j.jhep.2022.03.010. Epub 2022 Apr 1. PMID: 35378172; PMCID: PMC9391315.
Yue F, Shi Y, Wu S, Xing L, He D, Wei L, Qiu A, Russell R, Zhang D. Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD. iScience. 2023 Nov 22;26(12):108560. doi: 10.1016/j.isci.2023.108560. PMID: 38089577; PMCID: PMC10711470.
Doycheva I, Loomba R. Effect of metformin on ballooning degeneration in nonalcoholic steatohepatitis (NASH): when to use metformin in nonalcoholic fatty liver disease (NAFLD). Adv Ther. 2014 Jan;31(1):30-43. doi: 10.1007/s12325-013-0084-6. Epub 2014 Jan 3. PMID: 24385405.
Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; February 10, 2023.
Kahl S, Ofstad AP, Zinman B, et al. Effects of empagliflozin on markers of liver steatosis and fibrosis and their relationship to cardiorenal outcomes. Diabetes Obes Metab. 2022;24(6):1061-1071. doi:10.1111/dom.14670
Kuchay MS, Krishan S, Mishra SK, et al. Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial). Diabetes Care. 2018;41(8):1801-1808. doi:10.2337/dc18-0165
Takeshita Y, Honda M, Harada K, et al. Comparison of Tofogliflozin and Glimepiride Effects on Nonalcoholic Fatty Liver Disease in Participants With Type 2 Diabetes: A Randomized, 48-Week, Open-Label, Active-Controlled Trial. Diabetes Care. 2022;45(9):2064-2075. doi:10.2337/dc21-2049
Staels B, Butruille L, Francque S. Treating NASH by targeting peroxisome proliferator-activated receptors. J Hepatol. 2023;79(5):1302-1316. doi:10.1016/j.jhep.2023.07.004w
Westerouen Van Meeteren MJ, Drenth JPH, Tjwa ETTL. Elafibranor: a potential drug for the treatment of nonalcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020;29(2):117-123. doi:10.1080/13543784.2020.1668375
Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening [published correction appears in Gastroenterology. 2017 Jun;152(8):2084]. Gastroenterology. 2016;150(5):1147-1159.e5. doi:10.1053/j.gastro.2016.01.038
Goyal NP, Mencin A, Newton KP, et al. An Open Label, Randomized, Multicenter Study of Elafibranor in Children With Nonalcoholic Steatohepatitis. J Pediatr Gastroenterol Nutr. 2023;77(2):160-165. doi:10.1097/MPG.0000000000003796
Siddiqui MS, Parmar D, Sheikh F, et al. Saroglitazar, a Dual PPAR α/γ Agonist, Improves Atherogenic Dyslipidemia in Patients With Non-Cirrhotic Nonalcoholic Fatty Liver Disease: A Pooled Analysis. Clin Gastroenterol Hepatol. 2023;21(10):2597-2605.e2. doi:10.1016/j.cgh.2023.01.018
Ezhilarasan D. Deciphering the molecular pathways of saroglitazar: A dual PPAR α/γ agonist for managing metabolic NAFLD. Metabolism. 2024;155:155912. doi:10.1016/j.metabol.2024.155912
Gawrieh S, Noureddin M, Loo N, et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology. 2021;74(4):1809-1824. doi:10.1002/hep.31843
Lefere S, Puengel T, Hundertmark J, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆. J Hepatol. 2020;73(4):757-770. doi:10.1016/j.jhep.2020.04.025
Francque SM, Bedossa P, Ratziu V, et al. A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH. N Engl J Med. 2021;385(17):1547-1558. doi:10.1056/NEJMoa2036205
Obeticholic Acid. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; December 10, 2019.
Obeticholic Acid. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; December 10, 2019.
Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol. 2021;18(5):335-347. doi:10.1038/s41575-020-00404-2
Younossi ZM, Ratziu V, Loomba R, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial [published correction appears in Lancet. 2020 Aug 1;396(10247):312] [published correction appears in Lancet. 2021 Jun 19;397(10292):2336]. Lancet. 2019;394(10215):2184-2196. doi:10.1016/S0140-6736(19)33041-7
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial [published correction appears in Lancet. 2015 Mar 14;385(9972):946] [published correction appears in Lancet. 2016 Apr 16;387(10028):1618]. Lancet. 2015;385(9972):956-965. doi:10.1016/S0140-6736(14)61933-4
Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574-82.e1. doi:10.1053/j.gastro.2013.05.042
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Justyna Śliz, Natalia Aleksandra Popławska, Marta Skorupska, Magdalena Joanna Czeczotka, Krzysztof Woźniak, Martyna Magdalena Martka
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 132
Number of citations: 0
