Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, affecting at least 25% of the global adult population.¹ It is one of the leading causes of cirrhosis and hepatocellular carcinoma (HCC) in Western countries, in particular among patients with advanced fibrosis or cirrhosis.² In 2020, a group of hepatologists proposed to rename NAFLD to metabolic- or metabolic dysfunction-associated fatty liver disease (MAFLD).³ The aim was to highlight the importance of metabolic dysfunction underlying the pathogenesis of fatty liver disease and avoid trivialisation and stigma. Apart from a name change, the proposal also suggested a change in disease definition. In the past, NAFLD was diagnosed by detecting fatty liver and excluding other liver diseases such as chronic viral hepatitis and alcohol-related liver disease. In the new paradigm, MAFLD can be diagnosed by detecting fatty liver together with metabolic risk factors. Exclusion of other liver diseases is no longer necessary, in line with the reality that MAFLD can exist together with other liver diseases and may result in faster disease progression and a higher risk of cirrhosis and HCC.⁴

Thus, the MAFLD and NAFLD definitions identify slightly different populations. Patients have MAFLD but not NAFLD because they have concomitant liver diseases. In contrast, others have NAFLD but not MAFLD because they do not fulfil the metabolic criteria of MAFLD. Early epidemiological studies based on post hoc analysis of data from the general population suggest that the vast majority of patients with fatty liver would fulfil both definitions, but up to 10%-20% might only fulfil one or the other.^{5, 6} In this issue of Liver International, Ayada and colleagues report a meta-analysis to shed light on the epidemiology and clinical characteristics of these non-overlapping cases.⁷

The authors included data from 17 studies that comprised 9 808 677 individuals.⁷ Since its proposal over a year ago,³ there has been extensive debate over the new nomenclature. However, we are enjoying increasing clarity,^{8, 9} as we see the mounting number of publications on this topic. The findings from this study will lend further support to the new term. First of all, Ayada and colleagues reaffirmed that the prevalence of MAFLD was similar, if not greater, than the prevalence of NAFLD. This is not unexpected given the relatively large number of individuals with fatty liver and metabolic syndrome who consume more than a modest amount of alcohol, have another cause of chronic liver disease, or are on medications that may cause hepatic steatosis. These patients would have been missed when using the definition of NAFLD, leading to an underestimation of the prevalence of fatty liver disease associated with the metabolic syndrome. As pointed out by the authors, the difference in background prevalence of alcohol use and other causes of chronic liver disease will influence the magnitude of such missed cases. Furthermore, these are the patients who tend to have more severe liver disease as a result of the concomitant fatty liver, which brings us to the next important finding from this study.

Ayada and colleagues clearly demonstrated that individuals who fulfilled only the MAFLD criteria but not the NAFLD criteria had significantly greater serum alanine transferase (ALT) and aspartate transferase (AST) levels and worse markers of liver fibrosis when compared with individuals who fulfilled only the NAFLD criteria but not the MAFLD criteria. Furthermore, individuals who fulfilled only the MAFLD criteria but not the NAFLD criteria had significantly greater serum ALT and AST levels when compared with individuals who fulfilled both the MAFLD and the NAFLD criteria. While these non-invasive tests have their inherent limitations, they do provide fair insight given the biological plausibility of the outcomes that were observed. It is clearly not ideal when the diagnosis of individuals at risk of more severe or progressive liver disease is obscured by the very term used to define the disease. In this context, the term MAFLD, which clearly attributes the disease to its underlying aetiology, may provide clinicians, patients, and other stakeholders better focus to tackle the disease.

Last but not least, Ayada and colleagues found that the serum ALT and AST levels of patients with NAFLD but not MAFLD were not significantly different when compared with individuals without fatty liver disease. While the authors questioned the diagnosis of fatty liver in these individuals, it is more likely that the fatty liver disease was in its mildest form before other components of the metabolic syndrome become manifest. It is logical that these patients would benefit from lifestyle intervention that can lead to remission of the fatty liver and potentially delay the onset of other components of the metabolic syndrome.¹⁰ However, whether the lead time in doing so will provide a better outcome than waiting until the diagnosis of MAFLD is established before any intervention is carried out remains to be seen.

This meta-analysis adds to the accumulating data indicating the MAFLD definition better identifies patients with severe liver disease and adverse clinical outcomes than the NAFLD definition. Apart from an association with liver fibrosis,^{6, 11} MAFLD has a stronger association with cardiovascular risk and chronic kidney disease.^12-14 If future studies confirm that people with fatty liver but a low metabolic burden have a very low risk of adverse clinical outcomes,¹⁵ such individuals may be spared from an unnecessary disease label,¹⁶ while medical resources can be spent more wisely on a true at-risk population.

The Asian Pacific Association for the Study of the Liver was the first to issue a guideline using MAFLD as the formal name of the disease and outlining its management.¹⁷ Nonetheless, it is important to note that the name change has not been universally adopted.^{18, 19} In particular, hepatologists from the United States highlighted the importance of involving other stakeholders in the decision process and potential issues surrounding disease awareness, clinical trials and ambiguity of metabolic dysfunction itself. Currently, the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases have convened a nomenclature consensus workgroup, involving hepatologists, gastroenterologists, endocrinologists, primary care physicians, as well as patient representatives and regulators. It is hoped that a consensus can be reached in 2022 so that healthcare providers from different disciplines can work together under a common disease definition and push the field forward.²⁰