Unraveling Metabolic Dysfunction-Associated Fatty Liver Disease: Refining Sub-Phenotypes for Resolving Its Heterogeneity (original) (raw)

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Jung Gil Park

Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Nonalcoholic fatty liver disease (NAFLD) is a disease with a prevalence of 25% worldwide.1 However, due to its diverse clinical phenotypes, it is important to target patients with advanced liver fibrosis, which is known as the most important prognostic factor, for precise surveillance and therapeutic intervention.2 Currently, most pharmacological agents related to NAFLD are undergoing clinical trials targeting these high-risk patients, and there are no approved drugs yet. The possible reason for this is the heterogeneity of NAFLD. To address its heterogeneity, there has been a proposal to update the nomenclature and sub-phenotypes.

The current definition of metabolic dysfunction-associated fatty liver disease (MAFLD) can be broadly categorized into three subtypes: diabetes, overweight/obese, and lean metabolic disorder based on proposed inclusion criteria rather than exclusion criteria.3 Among these, diabetes has been well-studied and has established relationships with important prognostic factors such as liver fibrosis and cardiovascular disease risk, leaving little room for debate. However, ongoing debates still exist regarding non-diabetic MAFLD.4 The current issue of the Gut and Liver, Lim et al.5 have also demonstrated that the fibrotic burden in the liver is highest in patients with diabetes, but lower or inconsistent in those without among the three different subtypes. Many studies evaluating the characteristics and outcomes of lean and obese NAFLD have presented disputable conclusions.6 When dividing fatty liver disease based on body mass index alone, there is a problem of including different proportions of metabolic unhealthy lean fatty liver disease and metabolic healthy obese fatty liver disease patients, which can lead to different results. A study using NHANES III data has demonstrated that MAFLD (overweight/obesity subtype) is not associated with all-cause mortality unlike other MAFLD (diabetes and lean metabolic disorder subtype).7 Some studies have also demonstrated that non-obese patients with NAFLD may have higher mortality rates than their obese counterparts.6 Thus, dividing nondiabetic MAFLD based solely on body mass index may overestimate the risk associated with obese NAFLD while neglecting the impact of metabolic health.

There is also an issue with the definition of metabolic health itself. A study regarding the association of metabolic risk abnormalities and cardiovascular risk determined by coronary artery calcification has demonstrated that the number of metabolic risk factors in the currently suggested definition of MAFLD is not sufficient to predict the high-risk cardiovascular disease phenotype.8 Even in many large-scale studies, metabolic factors, such as Homeostatic Model Assessment for Insulin Resistance and high sensitivity C-reactive protein is not included because they are not commonly practiced.9,10 This may cause inconclusive results and raise other issues in current definition of nondiabetic lean MAFLD.

Currently, although the updated nomenclature of NAFLD may not be MAFLD, it is unlikely that NAFLD will remain unchanged. The currently proposed definition of MAFLD seems insufficient to resolve the heterogeneity of NAFLD. Revising the subtype of MAFLD based on inclusion criteria supported by robust evidences will be a crucial element in establishing effective surveillance and therapeutic strategies.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

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