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Page 8 of 11 Zerehpooshnesfchi et al. Metab Target Organ Damage. 2025;5:15 https://dx.doi.org/10.20517/mtod.2025.04

[62]
and an increased risk of disease progression compared to MASLD criteria . This consistent identification
over time facilitates early intervention and management, potentially improving patient outcomes.

CONCLUSION
The coexistence of fatty liver disease due to metabolic dysfunction with other liver diseases is both common
and significant. This combination significantly increases the burden of both liver-specific and systemic
complications, leading to worse outcomes such as advanced fibrosis, cirrhosis, HCC, CKD, and
cardiovascular disorders. The synergistic effects of metabolic and non-metabolic factors highlight the
complex interplay that drives disease progression, creating substantial challenges for accurate diagnosis and
effective management .
[63]
The evolution of fatty liver disease terminology reflects the field’s ongoing efforts to better capture the
multifactorial and complex nature of this condition. Transitioning from the exclusionary framework of
NAFLD to the inclusive, pathophysiology-driven approaches of MAFLD and MASLD represents significant
progress.

Among the proposed definitions, MAFLD stands out as the most comprehensive and clinically relevant. By
prioritizing metabolic dysfunction as the central criterion and accommodating multiple etiologies, MAFLD
addresses the inherent limitations of exclusion-based definitions . It recognizes the dynamic interplay
[64]
between metabolic, alcohol-related, and other contributors to liver disease, providing a practical and
inclusive approach that aligns with real-world clinical and research settings. Growing evidence suggests that
MAFLD is superior in identifying both liver-related and extrahepatic outcomes of the disease [65-71] as well as
in categorizing homogeneous groups of patients [71,72] . Furthermore, its adaptability to diverse populations
and healthcare systems reinforces its utility as the preferred framework .
[73]
However, the ongoing debates surrounding these terminologies underscore the need for a unified
framework that effectively incorporates overlapping etiologies, enhances diagnostic clarity, and ultimately
improves patient outcomes. Establishing a unified definition is crucial for advancing the field. A
standardized terminology would not only enhance diagnostic precision but also standardize research
methodologies, enabling consistent data comparisons and facilitating the development of targeted
therapeutic strategies .
[74]

DECLARATIONS
Authors’ contributions
Conceptualization, investigation, writing - original draft, visualization, review and editing:
Zerehpooshnesfchi S
Writing - review and editing: Lonardo A, Fan JG, Elwakil R, Tanwandee T, Altarrah MY, Örmeci N
Conceptualization, supervision, writing - original draft, writing - review and editing: Eslam M

Availability of data and materials
Not applicable.

Financial support and sponsorship
Eslam M is supported by a National Health and Medical Research Council of Australia (NHMRC)
investigator and ideas grants (AAP2008983 and APP2001692). Fan JG is supported by the National Science
and Technology Major Project of China (2023ZD0508700) and the National Natural Science Foundation of
China (82470600; 82170593).