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ensure a comprehensive and transparent analysis, we conducted a structured literature search in PubMed
focusing on studies published between 2000 and 2024 related to the evolving nomenclature and its
implications.

ENHANCED RISK STRATIFICATION THROUGH THE MASLD FRAMEWORK
The transition to MASLD is rooted in a proactive approach centered on identifying metabolic dysfunction.
This new nomenclature classifies patients by the coexistence of hepatic steatosis with at least one
[6]
cardiometabolic factor, such as obesity, T2DM, arterial hypertension, or dyslipidemia . These
comorbidities are well-established not only for their role in liver disease progression but also for increasing
cardiovascular risk, one of the leading causes of mortality in these patients . A major advantage of MASLD
[8]
[9]
lies in its ability to identify patients at elevated risk of developing liver fibrosis , the main risk factor for
disease progression and adverse outcomes . Supporting this, a recent study analyzing data from over
[10]
230,000 patients with T2DM in Sweden demonstrated that accumulating MetS traits significantly increased
the risk of major adverse liver outcomes (MALOs), including cirrhosis and its complications . Compared
[11]
to patients with only T2DM, those with multiple MetS traits had a more than twofold higher risk of
developing MALOs [adjusted hazard ratio (aHR) 2.33, 95%CI: 1.53-3.54]. Moreover, the risk of liver disease
progression increased progressively with the number of metabolic traits present, with hypertension
emerging as the most strongly associated risk factor (aHR 2.06, 95%CI: 1.57-2.71). These findings further
support the rationale behind MASLD’s emphasis on cardiometabolic dysfunction as a key determinant of
liver disease progression and long-term outcomes.

By including cardiometabolic factors as a diagnostic criterion for MASLD, a more accurate assessment of
mortality risk from both hepatic and non-hepatic causes is enabled. A recent study analyzing data from the
third National Health and Nutrition Examination Survey (NHANES III) and its linked mortality data over a
26.9-year median follow-up found that MASLD was associated with a significantly higher risk of all-cause
mortality (aHR 1.19, 95%CI: 1.06-1.34), particularly in individuals who met MASLD criteria but did not
fulfill the NAFLD definition. Notably, NAFLD alone was not significantly associated with all-cause
mortality, whereas MASLD and MAFLD identified a broader group of at-risk individuals, reinforcing the
clinical relevance of metabolic dysfunction in risk stratification . Consequently, the MASLD framework
[12]
extends beyond liver involvement, incorporating the systemic impact of metabolic dysfunctions such as
insulin resistance and MetS, both of which are associated with increased overall mortality [13,14] .

Previous classifications often adopted a binary approach to comorbidities like T2DM, without
distinguishing between complicated and uncomplicated cases. It is essential, however, to recognize that
T2DM with macroangiopathy or microangiopathy profoundly impacts liver disease progression compared
[15]
to uncomplicated cases . Similarly, the severity and control of arterial hypertension and dyslipidemia must
be considered, as these factors can differently influence liver disease progression [16,17] . The current
classification also highlights the need for a more nuanced approach to obesity. While body mass index
(BMI) is commonly used, metrics such as circumference or the waist-to-hip ratio are more accurate
[18]
predictors of cardiovascular risk . Incorporating these distinctions into the MASLD classification is
essential for more precise risk stratification.

DEFINITIONAL CHALLENGES OF MASLD: BALANCING OVERDIAGNOSIS AND
UNDERDIAGNOSIS
The main differences between the definitions of MAFLD and MASLD are the amount of permitted alcohol
consumption and the number of cardiometabolic factors required for diagnosis, particularly in normal-
weight individuals [Figure 1]. MAFLD includes any condition of liver steatosis when associated with one of