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Page 6 of 11 Zerehpooshnesfchi et al. Metab Target Organ Damage. 2025;5:15 https://dx.doi.org/10.20517/mtod.2025.04

Relying on arbitrary thresholds risks underdiagnosing or misclassifying cases where alcohol consumption
falls below the specified limits but still exacerbates metabolic dysfunction. Emerging evidence suggests that
even low or moderate alcohol intake can amplify IR, promote lipotoxicity, and accelerate liver damage,
[46]
underscoring the shortcomings of arbitrary threshold-dependent classifications . Moreover, such
premature criteria fail to account for the complex interplay between alcohol and metabolic dysfunction,
diminishing the diagnostic precision required to address dual etiology effectively.

Additionally, the MetALD framework overlooks the growing evidence that implicates alcohol produced by
the gut microbiome as a contributor to liver injury. Endogenous ethanol production, driven by alcohol-
producing gut bacteria such as Klebsiella pneumoniae, can mirror the effects of external alcohol
[47]
consumption, leading to steatohepatitis and fibrosis .

Furthermore, relying on self-reported alcohol intake as the main measure for classifying MetALD presents
additional challenges. Self-reports are frequently unreliable due to recall bias, cultural stigma, or intentional
underreporting, particularly in regions where alcohol use is socially or culturally sensitive [47,48] . This
introduces a potential for diagnostic inaccuracies, leading to misclassification of cases or failure to capture
[48]
those in which alcohol intake exacerbates metabolic dysfunction .

Another critical challenge lies in the variability of alcohol consumption over time. Lifestyle changes,
reductions in alcohol use following medical intervention, or intermittent binge drinking complicate the
identification of MetALD. However, this aspect is completely ignored in the MetALD criteria, which focus
solely on self-reported alcohol consumption. This oversight reflects a significant gap in MASLD’s ability to
consider alternative contributors to alcohol-related liver injury, further questioning its relevance in complex
clinical scenarios.

In contrast, the MAFLD definition provides a more comprehensive framework by integrating alcohol as one
of several potential co-contributors to liver disease without imposing rigid thresholds. This inclusive
approach captures the entire spectrum of dual etiology, encompassing both exogenous and endogenous
alcohol contributors, as well as cases with variable or moderate alcohol intake. The boundaries between
MAFLD and ALD are the same as between MAFLD and any other liver disease. Thus, the MAFLD
definition ensures diagnostic accuracy across diverse populations and clinical contexts, supporting a
nuanced understanding of disease progression. Furthermore, its unified structure facilitates coordinated
management strategies, aligning with the multifactorial nature of liver disease and ensuring relevance across
global settings.

REGIONAL AND GLOBAL TRENDS IN LIVER DISEASE CO-OCCURRENCE
Globally, the coexistence of metabolic dysfunction with other liver diseases reflects distinct region-specific
epidemiological patterns. In the Asia-Pacific region, the high prevalence of HBV infection significantly
overlaps with metabolic dysfunction, particularly in countries such as China and South Korea, resulting in
complex cases of metabolic-associated steatosis and viral liver disease [49-52] . In North America and Europe,
metabolic dysfunction often coexists with HCV infection, particularly in populations with high rates of
obesity and diabetes, such as individuals undergoing antiviral therapy for chronic HCV infection . In
[53]
Africa, metabolic dysfunction frequently intersects with HBV and liver diseases driven by infectious or toxic
causes, including aflatoxin exposure , while MAFLD-HIV coexistence is also a growing concern due to
[54]
[55]
HIV-associated metabolic dysfunction, inflammation, and ART-induced dyslipidemia . Meanwhile, in
Latin America, the high prevalence of obesity and diabetes contributes to the coexistence of metabolic-
associated liver disease and ALD, closely mirroring the dual etiology concept .
[56]