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Ciardullo et al. Metab Target Organ Damage 2024;4:30 https://dx.doi.org/10.20517/mtod.2024.39 Page 9 of

Finally, some perceive metabolic syndrome as a way to medicalize people who do not fit the criteria for
well-defined conditions such as hypertension or diabetes mellitus.

Given these premises, it does not come as a surprise that the definition of metabolic dysfunction differs
between MASLD and MAFLD. The MAFLD criteria were clearly based on the metabolic syndrome criteria,
but they introduced insulin resistance (HOMA-IR) and low-grade inflammation (hs-CRP) as novel
[103]
contributors . Indeed, these two aspects play pivotal roles in the development and progression of chronic
metabolic conditions including liver steatosis and their inclusion aims at reminding clinicians of this aspect.
Nonetheless, the main criticism of this approach is related to the fact that these biomarkers are seldom (if
not never) measured in routine clinical practice.

The other aspect that has been subject to debate is whether BMI-based definitions of overweight and obesity
(which are considered by both MAFLD and MASLD) are enough to define disease. Indeed, a recent report
from Korea using magnetic resonance showed that a quarter of patients with MAFLD were “metabolically
[104]
healthy” (≤ 1 risk factor and no diabetes), and more than half did not have metabolic syndrome . The
concept of metabolically healthy obesity was fueled by several studies showing similar mortality rates in
patients with overweight/obesity without metabolic syndrome, compared to normal-weight
individuals [105-107] . Moreover, a frequently cited meta-analysis published in 2013 did not show any increased
risk of all-cause mortality in patients with grade I obesity (0.95, 95%CI: 0.88-1.01) and even a reduced risk of
death in people with overweight (HR 0.94, 95%CI: 0.91-0.96) . These results provided evidence for the so-
[108]
called “obesity paradox”, i.e., the observation that among patients with a specific health condition, those
with higher BMIs might have a prognostic benefit [109,110] . Nonetheless, these results have been questioned
more recently. For instance, a subsequent large meta-analysis including more than 10 million individuals
from > 200 studies performed across the globe showed that all-cause mortality was minimal in the 20-25
kg/m group, while both people in the overweight (1.07, 1.07–1.08 for BMI 25.0-27.5 kg/m²; 1.20, 1.18–1.22
2
for BMI 27.5–30.0 kg/m²) and those in the class I obesity (1.45, 95%CI: 1.41–1.48) groups had higher
mortality rates . Subsequent studies showed that, while the prognosis of metabolically healthy obese
[111]
(MHO) individuals might be better compared with metabolically unhealthy (MUO) patients, their overall
risk of dying is higher than that of metabolically healthy normal-weight individuals . Furthermore, it is
[112]
highly likely that the MHO phenotype, although not rare in the general population (especially among young
women), is a transient state, with many patients (especially if they do not lose significant amounts of
weight) switching to a MUO phenotype with increasing age . For this reason, even recognizing the
[113]
limitations associated with BMI as a measure of overall adiposity, we agree with the inclusion of overweight/
obesity as a diagnostic criterion.

CONCLUSION
In conclusion, we believe that the recent debate on the best terminology and diagnostic criteria in the field
of liver steatosis fueled an interesting debate and led to increased awareness of this condition among
clinicians . The major advantage of the new definitions is their acknowledgment of the strict association
[114]
between liver steatosis and metabolic factors, leading some Authors in the past to consider SLD as the
hepatic manifestation of the metabolic syndrome . While clinicians might be confused by subtle changes
[115]
in the acronyms and related disease definitions, evidence shows that several aspects should be kept in mind,
regardless of terminology. First, the higher the number of concomitant metabolic abnormalities, the higher
the risk of both liver-related and cardiovascular-related mortality. Second, whether or not it interferes with
diagnostic criteria, careful evaluation for potential coexisting chronic liver conditions is of great prognostic
importance. Third, notwithstanding the limitations related to its estimation, evaluation of alcohol intake
should be performed in all patients with SLD and alcohol intake should be limited to a minimum (if not