In this issue of
Clinical and Molecular Hepatology, Gofton et al. [
1] reviewed the difference between metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic fatty liver disease (NAFLD). Since 2020, MAFLD has been proposed as a term referring to fatty liver diseases associated with metabolic dysfunction, as a replacement for the term NAFLD, which is based on negative diagnostic criteria [
2]. MAFLD has subsequently been endorsed by several societies specializing in the study of liver diseases [
3,
4]. However, a consensus has not yet been reached across a significant number of key national and pan-national societies, and a consensus with broader global multi-stakeholders is required.
The change of nomenclature from NAFLD to MAFLD has several advantages; it raises awareness of the disease in patients and primary care physicians, clarifies treatment strategies, and enables a holistic approach to treating patients with liver disease [
5]. First, MAFLD allows better recognition of patients with a more advanced stage of hepatic fibrosis and greater risk of overall mortality [
6-
8]. Second, MAFLD enables improved management of patients with comorbid liver diseases other than NAFLD. In the era of NAFLD, patients with chronic hepatitis B were classified as such regardless of presence of hepatic steatosis. Thus, the importance of lifestyle modifications in these patients has been underestimated. However, there is growing evidence that comorbid hepatic steatosis worsens the prognosis in patients with chronic viral hepatitis [
9-
11]. In this regard, MAFLD enables multidisciplinary treatment for such patients. Non-alcoholic-, alcohol-associated-, and viral hepatitis-steatotic liver disease will be discussed in the planned consensus meeting. These novel terms not only acknowledge the dual etiology of fatty liver disease, but also increase awareness of the diesase [
12]. Third, MAFLD emphasizes metabolic dysfunction as the basic mechanism of fatty liver disease, both through its name and the inclusive diagnostic criteria [
2]. This change in name also would allow in tuitive explanation of causes and treatment approaches to patients. Additionally, it could reduce the time from diagnosis to treatment by omitting the need to exclude other liver diseases during diagnosis.
The change of nomenclature from NAFLD to MAFLD is more than a simple change in terminology and will have an extensive impact on research, the pharmaceutical industry, insurance companies, and government policies. The change in nomenclature to “MAFLD” requires significant changes in ongoing NAFLD clinical trial designs, primary endpoints, clinical outcomes of final approval, and therapeutic targets of treatment due to the new inclusion criteria.
There are several reasons to wait for a robust consensus on the nomenclature change among the broader body of stakeholders, including pharmaceutical companies, authorities, and various patient alliances [
13,
14]. First, the heterogeneous aspect of NAFLD is overlooked in MAFLD. In early clinical trials, researchers focused on controlling insulin resistance or metabolic risk factors, as NAFLD was deemed a manifestation of metabolic syndrome in the liver. However, most clinical trials with insulin sensitizers, lipid-lowering agents, and anti-obesity treatments have not been successful in NAFLD treatment. The development of fatty liver disease is based on heterogeneous mechanisms and is more complex than originally believed [
15]. Thus, an excessive focus on metabolic dysfunction could veil novel therapeutic targets and delay drug development. Genetic factors [
16], intestinal dysbiosis [
17], and sarcopenia [
18], which are not closely related to metabolic dysfunction as to NAFLD, are underestimated pathophysiologies in MAFLD [
19]. Nonetheless, these factors contribute to the development of NAFLD and are possible starting points for drug development. Second, the new definition of MAFLD may increase the heterogeneity of the target population during phase III clinical trials, as it also includes individuals with viral hepatitis or alcoholic liver disease. Controlling the effects of viral hepatitis and alcohol consumption is a complex problem. Third, the use of MAFLD resolution as a primary endpoint in clinical trials may lead to ambiguity. Currently, nonalcoholic steatohepatitis resolution without exacerbation of liver fibrosis is used as an endpoint in clinical trials for NAFLD. However, the endpoint in MAFLD would be different from the endpoint currently used in NAFLD. Therefore, long-term data are needed to determine whether improvement in metabolic dysfunction or normalization of bodyweight could be viewed as MAFLD resolution when it is achieved without histological improvement. Fourth, it may be difficult to evaluate the efficacy of candidate drugs in clinical trials when these drugs target inflammation or fibrosis without ameliorating metabolic abnormalities. A considerable number of candidate drugs under development is unrelated to metabolic improvement or weight loss.
In conclusion, we propose a cautious and in-depth discussion to reach a consensus among all stakeholders before the terminology is changed from NAFLD to MAFLD.
FOOTNOTES
-
Authors’ contributions
YEL, first drafting and revision of the manuscript; JDW, organized and supervised the manuscript. All the authors approved the final manuscript.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
metabolic dysfunction-associated fatty liver disease
non-alcoholic fatty liver disease
nonalcoholic steatohepatitis
REFERENCES
- 1. Gofton C, Upendran Y, Zheng MH, George J. MAFLD: How is it different from NAFLD? Clin Mol Hepatol 2023;29(Suppl):S17-S31.
- 2. Eslam M, Sanyal AJ, George J; International Consensus Panel. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 2020;158:1999-2014 e1.
- 3. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020;14:889-919.
- 4. Méndez-Sánchez N, Bugianesi E, Gish RG, Lammert F, Tilg H, Nguyen MH, et al.; Global multi-stakeholder consensus on the redefinition of fatty liver disease. Global multi-stakeholder endorsement of the MAFLD definition. Lancet Gastroenterol Hepatol 2022;7:388-390.
- 5. Kawaguchi T, Tsutsumi T, Nakano D, Eslam M, George J, Torimura T. MAFLD enhances clinical practice for liver disease in the Asia-Pacific region. Clin Mol Hepatol 2022;28:150-163.
- 6. Kim M, Yoon EL, Cho S, Lee CM, Kang BK, Park H, et al. Prevalence of advanced hepatic fibrosis and comorbidity in metabolic dysfunction-associated fatty liver disease in Korea. Liver Int 2022;42:1536-1544.
- 7. Lee H, Lee YH, Kim SU, Kim HC. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: A nationwide cohort study. Clin Gastroenterol Hepatol 2021;19:2138-2147.e10.
- 8. Wong VW, Wong GL, Woo J, Abrigo JM, Chan CK, Shu SS, et al. Impact of the new definition of metabolic associated fatty liver disease on the epidemiology of the disease. Clin Gastroenterol Hepatol 2021;19:2161-2171.e5.
- 9. Choi HSJ, Brouwer WP, Zanjir WMR, de Man RA, Feld JJ, Hansen BE, et al. Nonalcoholic steatohepatitis is associated with liverrelated outcomes and all-cause mortality in chronic hepatitis B. Hepatology 2020;71:539-548.
- 10. Huang SC, Liu CJ. Chronic hepatitis B with concurrent metabolic dysfunction-associated fatty liver disease: Challenges and perspectives. Clin Mol Hepatol 2023 Feb 1. doi: 10.3350/cmh.2022.0422.
- 11. Zheng Q, Zou B, Wu Y, Yeo Y, Wu H, Stave CD, et al. Systematic review with meta-analysis: prevalence of hepatic steatosis, fibrosis and associated factors in chronic hepatitis B. Aliment Pharmacol Ther 2021;54:1100-1109.
- 12. Ng CH, Chan KE, Muthiah M, Tan C, Tay P, Lim WH, et al. Examining the interim proposal for name change to steatotic liver disease in the US population. Hepatology 2023 Jan 3. doi: 10.1097/HEP.0000000000000043.
- 13. Yoon EL, Jun DW. Waiting for Multi-Stakeholders’ consensus position statement on new nonalcoholic fatty liver disease nomenclature. Gut Liver 2022;16:319-320.
- 14. Younossi ZM, Rinella ME, Sanyal AJ, Harrison SA, Brunt EM, Goodman Z, et al. From NAFLD to MAFLD: Implications of a premature change in terminology. Hepatology 2021;73:1194-1198.
- 15. Ko E, Yoon EL, Jun DW. Risk factors in nonalcoholic fatty liver disease. Clin Mol Hepatol 2023;29(Suppl):S79-S85.
- 16. Sookoian S, Pirola CJ. Genetics in non-alcoholic fatty liver disease: The role of risk alleles through the lens of immune response. Clin Mol Hepatol 2023;29(Suppl):S184-S195.
- 17. Jennison E, Byrne CD. The role of the gut microbiome and diet in the pathogenesis of non-alcoholic fatty liver disease. Clin Mol Hepatol 2021;27:22-43.
- 18. Joo SK, Kim W. Interaction between sarcopenia and nonalcoholic fatty liver disease. Clin Mol Hepatol 2023;29(Suppl):S68-S78.
- 19. Jun DW. An analysis of polygenic risk scores for non-alcoholic fatty liver disease. Clin Mol Hepatol 2021;27:446-447.
Citations
Citations to this article as recorded by
- Identification of EGR1 as a Key Diagnostic Biomarker in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Through Machine Learning and Immune Analysis
Xuanlin Wu, Tao Pan, Zhihao Fang, Titi Hui, Xiaoxiao Yu, Changxu Liu, Zihao Guo, Chang Liu
Journal of Inflammation Research.2025; Volume 18: 1639. CrossRef - Molecular Clustering of Metabolic Dysfunction-Associated Steatotic Liver Disease Based on Transcriptome Analysis
Gina Ryu, Eileen Laurel Yoon, Wankyu Kim, Dae Won Jun
Diagnostics.2025; 15(3): 342. CrossRef - Metabolic Dysfunction-Associated Steatotic Liver Disease, Recent Revision of Terminology and Its Implications
Hyo Young Lee, Eileen L. Yoon
The Korean Journal of Gastroenterology.2025; 85(2): 126. CrossRef - Association of elevated Alpha-1-Acid glycoprotein with MAFLD prevalence in young and middle-aged women: a cross-sectional study based on NHANES 2017–2020
Yi Xiao, Xian Luo, Yinghao Fu, Haijuan Huang, Qiaoping Gao, Jiansong Liu, Daxin Pang, Xiaolu Liang, Huadi Chen, Hao Xu
Diabetology & Metabolic Syndrome.2025;[Epub] CrossRef - The emerging phenotype of nonalcoholic fatty liver disease in lean individuals: what’s different?
Priyankar Dey
Frontiers in Endocrinology.2025;[Epub] CrossRef - Laboratory monitoring in patients with moderate to severe plaque psoriasis
Jonathan M. Fenkel, John A. Osborne, April W. Armstrong, Bruce Strober, Linda Stein Gold, Michael Cameron, Mark Lebwohl
Journal of Dermatological Treatment.2025;[Epub] CrossRef - Clinical impact of five cardiometabolic risk factors in metabolic dysfunction-associated steatotic liver disease (MASLD): Insights into regional and ethnic differences
Joo Hyun Oh, Dae Won Jun
Clinical and Molecular Hepatology.2024; 30(2): 168. CrossRef - Glucose‐lowering drugs and liver‐related outcomes among individuals with type 2 diabetes: A systematic review of longitudinal population‐based studies
Shaghayegh Khanmohammadi, Amirhossein Habibzadeh, A. B. M. Kamrul‐Hasan, Art Schuermans, Mohammad Shafi Kuchay
Diabetic Medicine.2024;[Epub] CrossRef - Exploring the relationship between air pollution, non-alcoholic fatty liver disease, and liver function indicators: a two-sample Mendelian randomization analysis study
Qingliang Song, Jinyue Pan, Maoxing Pan, Chuiyang Zheng, Wen Fan, Jianwei Zhen, Dajin Pi, Zheng Liang, Haiyan Shen, Yuanyou Li, Qinhe Yang, Yupei Zhang
Frontiers in Endocrinology.2024;[Epub] CrossRef - Waiting for the changes after the adoption of steatotic liver disease
Eileen L. Yoon, Dae Won Jun
Clinical and Molecular Hepatology.2023; 29(4): 844. CrossRef - Correspondence on Letter regarding “Waiting for the changes after the adoption of steatotic liver disease”
Eileen L. Yoon, Dae Won Jun
Clinical and Molecular Hepatology.2023; 30(1): 126. CrossRef
