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present in normal-weight individuals, a recent Indian study evaluated which definition performed better in
[87]
this patient population . The Authors included 170 patients with lean NAFLD. Among them, 142 (83.5%)
fulfilled the MASLD definition, while only 84 (49.4%) patients satisfied the MAFLD criteria (even though
data on HOMA-IR and hs-CRP were not available for most patients). According to the MAFLD definition,
half of all lean NAFLD patients could not receive a specific diagnosis, while according to the recent Delphi
consensus, 16.5% would be diagnosed with cryptogenic SLD. Unfortunately, genetic data were not available
in this study. While the Authors carefully excluded patients with drug-induced liver injury, chronic viral
hepatitis, malnutrition, celiac disease, and Wilson’s disease, potential other etiologies were not evaluated.
Nonetheless, it is unlikely that rare genetic metabolic disorders could account for all the remaining cases
and the underlying pathophysiology of SLD in this small subgroup remains elusive.

On the opposite side, patients in the MAFLD-only group have a higher alcohol intake in the presence of
metabolic dysfunction; this group should be characterized by a higher risk of liver-related events and
[88]
probably cardiovascular outcomes, as suggested by a recent population-based study . It should be noted,
however, that by looking at the definitions, one can expect a high degree of overlap between this MAFLD-
only group and patients with MetALD.

THE HURDLES OF DEFINING METABOLIC DYSFUNCTION
[89]
As recently reviewed , the history of the debate about metabolic health and metabolic dysfunction dates
back at least to the 1988 Banting Lecture by Gerald Reaven, discussing the insulin resistance syndrome .
[90]
Several definitions of the metabolic syndrome have been proposed. While they all focus on the same cluster
of variables (i.e., waist circumference, triglycerides, HDL-cholesterol, blood pressure and blood glucose
levels), the number of alterations needed to make a diagnosis and the specific threshold to be applied for
each component varied. The most frequently cited are the recommendations from the National Cholesterol
[92]
Education Program (NCEP)-ATP III published in 2001, later harmonized by Alberti et al. . According
[91]
to these definitions, metabolic syndrome can be diagnosed when the patient meets at least three of the five
considered components. While the effort to achieve a global consensus on the definition of this prevalent
condition is commended, relevant criticisms of the definition have been put forward by eminent Authors.
First, this definition does not include any measure of insulin resistance, which is believed to be the
pathophysiological defect underlying this cluster of manifestations . Indeed, accurate measurement of
[93]
insulin resistance would require performing the gold standard euglycemic, hyperinsulinemic clamp ,
[94]
which is time-consuming and elaborate and not well suited for large-scale application. Nonetheless, several
easier-to-perform biomarkers based on fasting insulin and fasting glucose levels, such as HOMA-IR,
QUICKI, and their variations, have been proposed [95-98] . They exhibit moderate performance compared to
[99]
the glucose clamp technique , but still need measurement of insulin levels, which are somewhat assay-
dependent ; consequently, measurement of insulin resistance is not recommended by most international
[100]
guidelines in any specific condition. Second, while metabolic syndrome needs three metabolic alterations to
be present and define a yes/no condition, evidence shows that the risk for cardiovascular disease and
mortality increases progressively with the increasing number of metabolic alterations present, without a
specific cut-off . Another interesting aspect is related to the impact of different metabolic risk factors on
[101]
liver-related outcomes. In a recent large cohort study conducted in patients with T2D, the comorbidity with
the largest association with incident major adverse liver outcomes (MALOs) was hypertension (aHR 2.06,
95%CI: 1.57–2.71), while dyslipidemia, obesity, and albuminuria contributed to a lesser extent . The study
[102]
confirmed that the higher the number of traits of metabolic syndrome present, the higher the risk of
MALOs.