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Page 2 of 11 Zerehpooshnesfchi et al. Metab Target Organ Damage. 2025;5:15 https://dx.doi.org/10.20517/mtod.2025.04

dysfunction and excessive alcohol intake. This review critically examines the clinical, research, and epidemiological
implications of the differing approaches of MAFLD and MASLD, offering insights into their potential to enhance the
understanding and management of multi-etiology liver diseases.

Keywords: MAFLD, NAFLD, MASLD, dual etiology, MetALD

INTRODUCTION
Fatty liver disease due to metabolic dysfunction poses a significant global health issue, primarily driven by
rising rates of metabolic disorders, obesity, diabetes, and lifestyle-related factors. A recent meta-analysis
indicates that approximately 38% of the global population are affected by this condition, highlighting its
[1,2]
health, economic, and societal burden . Beyond liver disease, dysfunction-associated fatty liver disease
(MAFLD) is strongly associated with multiple extrahepatic conditions, including CVD, CKD, type 2
[3]
diabetes (T2D), and extrahepatic cancers .
With the increasing prevalence of fatty liver due to metabolic dysfunction, many patients also present with
coexisting liver conditions, such as alcohol-related liver disease (ALD) or viral hepatitis. These overlapping
conditions complicate both diagnosis and management, emphasizing the urgent need for more inclusive
and clinically relevant classification systems of liver diseases .
[4]
For decades, the terms non-alcoholic fatty liver disease (NAFLD) and its corresponding diagnostic criteria -
defined by the exclusion of significant alcohol consumption and other identifiable causes of hepatic steatosis
[5]
- have shaped the understanding of the disease . While the concept of NAFLD was groundbreaking when
introduced, it has faced growing criticism for inadequately reflecting the multifaceted nature of fatty liver
disease and the complex interplay of contributing factors, including both metabolic and alcohol-related
elements . Furthermore, its reliance on the vague term “non-alcoholic” has sparked controversy. This
[6-8]
exclusion-based definition creates a misleading dichotomy between metabolic and other contributors to
[9]
liver disease, especially concerning alcohol, thus limiting its clinical applicability .
To address these limitations, MAFLD was introduced in 2020 as a paradigm shift, emphasizing the positive
inclusion of metabolic dysfunction as a core diagnostic criterion [10-13] . The MAFLD framework has been
widely endorsed for its diagnostic clarity and clinical relevance, particularly in its ability to encompass
overlapping etiologies and provide a more holistic understanding of disease progression [14-17] . Subsequently,
[18]
in 2023, another term was introduced: metabolic dysfunction-associated steatotic liver disease (MASLD) .
While MASLD shares many diagnostic criteria with MAFLD, it also demonstrates notable differences in its
conceptual framework and diagnostic approach, especially in how each definition addresses metabolic liver
disease coexisting with other liver conditions .
[18]

To address cases of overlap, MAFLD introduced the dual etiology framework, which allows for the
diagnosis of MAFLD to coexist with other liver diseases, such as ALD or viral hepatitis [9,12,19] . Conversely,
MASLD proposes a separate term, metabolic-alcoholic liver disease (MetALD), to specifically identify cases
where significant alcohol consumption (defined as 140 to 350 g/wk for females and 210 to 420 g/wk for
males) and metabolic dysfunction overlap [18,20] . These differing approaches raise important questions about
the optimal approach to dealing with patients with overlapping etiologies. Figure 1 illustrates this overlap
and highlights the classification differences between MAFLD and MASLD.