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Page 6 of 16 Iruzubieta et al. Metab Target Organ Damage. 2025;5:10 https://dx.doi.org/10.20517/mtod.2024.143

[7]
diagnosis of MetALD or Alcohol-Related Liver Disease (ALD) may apply .

Recognizing alcohol as a contributing factor to disease progression represents one of the most novel and
valuable aspects of the new nomenclature, with the introduction of the term MetALD. This term refers
specifically to patients with metabolic dysfunction who consume alcohol in amounts greater than those
allowed for MASLD but lower than the thresholds required for ALD. This includes alcohol consumption
[7]
between 140-350 g per week for women and 210-420 g per week for men . This new entity will significantly
enhance our understanding of the joint impact of alcohol and MetS on liver disease progression. However,
several challenges remain, including the underreporting of alcohol consumption and irregular drinking
patterns, which complicate the precise quantification of intake . To address these challenges, tools such as
[30]
the “Alcohol Use Index” (ANI score) and specific direct biomarkers of alcohol consumption may improve
detection in patients who report minimal or no alcohol intake. Ongoing research into more specific and
reliable biomarkers is expected to further enhance the identification and management of patients with
MetALD in the near future.

Another controversial aspect of this classification is considering alcohol consumption of up to 30 g per day
in men and 20 g per day in women as “moderate” . Recent studies have shown that even lower alcohol
[31]
intake than these thresholds is common in patients with MASLD and is associated with a significant risk of
hepatic fibrosis and progression to MASH. The risk of fibrosis and complications increases with the amount
[32]
of alcohol consumed weekly and the number of cardiometabolic risk factors present . Beyond the
synergistic effect between alcohol consumption and MetS [33,34] , individual susceptibility to progress into
advanced fibrosis is influenced by a combination of behavioral, environmental, genetic, and epigenetic
factors , which are not considered in the new definition. Additionally, the lack of clear evidence on the
[35]
impact of previous alcohol consumption in individuals who have since ceased drinking generates
uncertainty in clinical interpretation . It is crucial to discuss whether a history of alcohol use might still
[36]
affect the prognosis and pathogenesis of steatotic liver diseases.

Although supported by a broad majority in a Delphi process, this change is not without controversy.
Broader consensus and further studies will be required to fine-tune the alcohol consumption thresholds that
maximize diagnostic accuracy and clinical management efficacy.

THE CARDIOVASCULAR ADVANTAGE OF MASLD
MASLD not only enhances the identification of patients at risk of liver disease progression but also
improves cardiovascular risk stratification. The cardiometabolic factors that define MASLD play a central
role in the pathogenesis of CVD, making MASLD a more precise diagnostic tool for identifying patients at
risk of major cardiovascular events, such as myocardial infarction, stroke, or peripheral artery disease . In
[37]
contrast to NAFLD, which may include individuals without metabolic dysfunction and, therefore, with
lower cardiovascular risk , MASLD ensures greater precision in identifying those at high risk for
[38]
cardiovascular events.

This strong association between MASLD and CVD is largely explained by its underlying pathophysiological
mechanisms, which involve hepatic lipotoxicity, oxidative stress, and systemic inflammation. The
accumulation of intrahepatic lipids, particularly free fatty acids and toxic lipid intermediates such as
ceramides, leads to mitochondrial dysfunction, increased reactive oxygen species (ROS) production, and
[39]
endoplasmic reticulum stress, all of which promote hepatocyte injury and inflammation . Additionally,
metabolic dysregulation in MASLD is closely linked to adipose tissue dysfunction, where excess visceral fat
promotes hypoxia and oxidative stress, resulting in the release of proinflammatory cytokines (TNF-α, IL-6)