Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of liver disease worldwide. This disease affects a third of the adult population and 12% of children [1–3]. It is one of the most common causes of liver cirrhosis and hepatocellular carcinoma in Western countries, particularly in those patients with non-alcoholic steatohepatitis (NASH) and advanced fibrosis [4–8]. The causes of this condition are strongly linked pathogenically to metabolic syndrome (MS), which is a constellation of metabolic abnormalities such as overweight or obesity, type 2 diabetes mellitus (T2DM), dyslipidemia and arterial hypertension, of which the first two seem to be the strongest [9–13]. The increase in its incidence at a global level has been driven by the global obesity epidemic that affects a great percentage of the world population [14,15].

NAFLD is a relatively new condition. In 1980 Ludwig J coined the term for patients who had fatty liver disease (FLD) without any obvious secondary cause, particularly alcohol [16]. During the last four decades to date, there has been intense research on this condition which has significantly increased knowledge in many aspects of this disease.

In 2020 a group of international experts proposed the change name of this disease to metabolic- or metabolic dysfunction- associated fatty liver disease (MAFLD) [17,18]. The main purpose of the change in nomenclature was to highlight the importance of metabolic abnormalities by making this disease an inclusive instead of an exclusive entity such as NAFLD. The proposal seemed logical if one considers the close pathophysiological link that this disease has with MS. However, the change in terminology brought with it also the modification of the diagnostic criteria. NAFLD is defined as the presence of FLD in the absence of known causes of steatosis, with an emphasis on alcohol, as this is the second cause of FLD [19]. Conversely, MAFLD is defined inclusively as the presence of FLD concomitantly with the presence of overweight or obesity and/or T2DM. In the absence of these clinical parameters, the presence of at least two of 7 metabolic risk abnormalities is required [17,18] (Fig. 1). This definition does not exclude concomitant diseases such as alcohol liver disease (ALD), chronic hepatitis B or C, or autoimmunity.

Fig. 1.

Diagnostic criteria of MAFLD [17,18].

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Immediately, several associations for the study of the liver from different regions of the world published guidelines on the management of the new entity [20–24]. However, more than two years after this proposal, the use of the new nomenclature has not become widespread in the different countries or among the different scientific working groups that carry out research on this disease. Conversely, some opinion texts and editorials have been published that fuel the debate about its adoption [25–31].

A group of experts in the United States of America recently gave the opinion that the adoption of the new nomenclature is premature with the following arguments: first, the change in nomenclature may be confusing and jeopardize existing efforts to promote disease awareness among patients, policymakers and non-hepatologists physicians; second, the change in terminology "is justified when a more scientific, complete understanding of its pathogenesis, and/or risk stratification, and/or molecular phenotyping, and/or novel precision medicine-based therapeutic approaches are elucidated" and third, there are concerns that the change in terminology and definition will affect both patient recruitment and endpoint assessment, particularly resolution of NASH with no worsening of liver fibrosis, which is currently a key histological endpoint for conditional drug approval [26].

To date, several cross-sectional and longitudinal studies have been carried out in different regions of the world in which the new nomenclature and diagnostic criteria are applied to patients with FLD [32–40]. Some of these studies have used archived data obtained through the Third National Health and Nutrition Examination Survey (NHANES III), which has made it possible to expeditiously study a cohort with a large number of individuals with a follow-up greater than 25 years [34,37,38,40]. The NHANES is a population-based program of surveys conducted by the National Center for Health Statistics (NCHS), whose purpose is to monitor the health and nutritional status of civilian, noninstitutionalized individuals in the U.S. population using a complex, multistage design with data currently released in 2-year cycles.

2.1Clinical and epidemiological characteristics of MAFLD

The results of these studies indicate that the prevalence of MAFLD is about similar to the prevalence of NAFLD (24.2%−36% vs. 15.3%−34%, respectively). The clinical characteristics of patients with both entities, in general, are similar, particularly when adjusting the metabolic parameters that define MAFLD [38,40]. In some studies, patients with NAFLD were significantly younger [34,38]). The percentage of overlap between both entities is around 80%, with a high correlation (Kappa, 0.83–0.94). In the remaining 20%, there is either MAFLD without NAFLD or NAFLD without MAFLD. The definition of MAFLD+/NAFLD- includes about 8–11% more patients than the NAFLD+/MAFLD- definition [40,41] (Fig. 2). Two studies have found a higher prevalence of advanced fibrosis in patients with MAFLD+ compared to NAFLD+ by liver biopsy [38] and transitional elastography [33]. At this point, a metanalysis with 17 studies published by Ayada I et al. in 2022 with more than 9 million individuals showed that notably, MAFLD-only group was at significantly increased risk for fibrosis (RR 4.2) and had higher alanine aminotransferase (mean difference: 8.0 U/L) and aspartate aminotransferase (mean difference: 6.4 U/L), compared to NAFLD-only group [41].

Fig. 2.

Percentages of distribution of isolated and combined forms of MAFLD and NAFLD observed in clinical studies. [32- 41].

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This indicates that both entities can be considered approximately equivalent in clinical and epidemiological terms, which could be explained by the high proportion of overlapping. However, the most important differences have been observed in relation to outcomes, especially in non-combined forms such as MAFLD+/NAFLD- and MAFLD-/NAFLD+.

This clinical information generated so far could be useful for trigger evidence-based debates among true international experts supported by international scientific liver societies and non-scientific societies, providers and possibly stakeholders for assessing whether the current moment is appropriate for the change of nomenclature.

The history of medicine is full of emerging diseases whose original diagnostic criteria have been modified over time as new evidence about the pathological entity arises [43]. Based on this evidence, it might be appropriate to modify the diagnostic criteria of MAFLD, perhaps by establishing realistic thresholds in alcohol consumption and emphatically pointing out the presence or absence of comorbidities (ALD, chronic hepatitis B or C, autoimmunity, etc.), classifying the disease according to these data as a "pure" entity or a dual-etiology entity. In this context, MAFLD in patients with chronic hepatitis B has already been shown to be an independent risk factor for adverse outcomes [44]

On the other side, we believe that prospective studies (preferably multicenter) are still required, conducted in various regions of the world with different prevalence of ALD and B virus infection and with a large number of patients who are stratified into subgroups according to the type and number of comorbidities. These studies could make it possible the definition of phenotypes, the dominant pathogenic mechanisms in each phenotype and the impact of the comorbidities on outcomes. This will allow the categorization of patients with differences in severity of the disease enabling the selection of a specific treatment either based on a change in lifestyle and/or pharmacological treatment alone or in combination directed to selective targets.

The idea of changing the nomenclature of NAFLD to MAFLD to prioritize metabolic abnormalities in an inclusive diagnosis was a great idea. However, the key factor that induced the debate does not lie in why but in how to concretize this change in the most appropriate way and it is there that it will be necessary to search for effective modifications that improve the defining instrument.

With the increase in the incidence and prevalence of fatty liver (MAFLD or NAFLD) worldwide, given the epidemic of obesity and T2DM, the secondary and tertiary levels of care of these patients have been exceeded and are increasingly attended by the first contact non-hepatologist physician. In this spirit, we must offer these physicians a simple, reliable and pragmatic view for the diagnosis and effective management of these patients.