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[19]
obesity, hypertension, or prediabetes . This approach enables the identification of “lean” patients with liver
steatosis who carry a risk of liver disease progression comparable to that of obese patients. Including these
patients is critical, given that they have historically been underrecognized regarding their risk and potential
to develop severe liver complications, such as advanced fibrosis or cirrhosis, without significant weight
gain . Recognizing these at-risk patients helps prevent underdiagnosis and delays in initiating treatment.
[21]
Therefore, MASLD facilitates better identification of lean patients who might otherwise be overlooked,
representing a notable advantage over MAFLD.

However, several recent studies have investigated the implications of applying MASLD for disease
diagnosis, raising serious concerns about its lack of specificity, potential for over-diagnosis, and lower
[22]
performance in detecting hepatic and extrahepatic outcomes compared to the MAFLD definition . One of
the most debated aspects of MASLD is its potential to include metabolically healthy individuals within its
diagnostic category who do not have increased hepatic fibrosis or cardiovascular risk compared to healthy
[23]
controls . It has been pointed out that various cardiometabolic risk factors may have different weights
depending on their association with insulin resistance, which is the main etiological factor of the disease.
Overdiagnosis can lead to overtreatment, which offers little to no benefit and can have significant physical,
psychological, social, and financial consequences. However, some of these patients may have a fibrosis
[24]
burden and cardiovascular risk comparable to those with manifest metabolic dysfunction . This suggests
the need for adjustments in the MASLD definition to more precisely differentiate between those with a truly
favorable metabolic profile and those at genuine risk.

In this context, some studies suggest that the MAFLD and MASLD classification may not adequately reflect
individuals with a genetic predisposition to cirrhosis and hepatocellular carcinoma (HCC) . Metabolically
[25]
healthy patients could be at risk of developing liver cancer due to genetic factors, even without meeting
traditional metabolic criteria. Several genetic variants, particularly PNPLA3, TM6SF2, GCKR, MBOAT7,
and HSD17B13, have been robustly associated with MASLD development and progression . The I148M
[26]
polymorphism of PNPLA3 is the most well-documented genetic risk factor for hepatic steatosis, fibrosis,
and HCC. Notably, individuals carrying this variant exhibit an increased risk of disease progression
regardless of metabolic status, suggesting that genetic predisposition may help identify at-risk patients who
do not meet the standard cardiometabolic criteria for MASLD. Furthermore, these genetic factors can
[27]
interact with environmental and metabolic components, influencing disease phenotype and severity . This
highlights the need for a more comprehensive evaluation that integrates not only metabolic but also genetic
and molecular factors to better identify risk in these patients.

A small proportion of lean NAFLD patients may not meet MASLD criteria and could be classified as cases
of “cryptogenic steatosis”. It is important to note that steatosis and insulin resistance can exist in the
absence of any of the five defined cardiometabolic risk factors, especially in younger individuals, and hepatic
insulin resistance may precede the development of more overt cardiometabolic abnormalities .
[28]
Additionally, hereditary metabolic diseases can contribute to hepatic steatosis in some cases . Therefore,
[29]
these patients may require advanced genetic and metabolic testing to identify possible underlying etiologies.

CHALLENGES IN ASSESSING ALCOHOL INTAKE AND ITS IMPACT ON STEATOTIC LIVER
DISEASE
As previously mentioned, MAFLD and MASLD differ in the amount of alcohol permitted in their
definitions. While the diagnosis of MAFLD can be made regardless of alcohol consumption, MASLD
excludes patients who consume more than 20 g of alcohol per day for women or 30 g per day for men. For
individuals whose alcohol intake exceeds these limits, but who also present metabolic dysfunction, the