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Page 4 of 7 Byrne et al. Metab Target Organ Damage 2024;4:10 https://dx.doi.org/10.20517/mtod.2024.06

For those with long memories who were part of the acrimonious MetS discussions, it is important to
remember that a person needs to have one MetS characteristic, plus the presence of hepatic steatosis, for a
diagnosis of MASLD to be entertained. The fact that there is no measure of insulin resistance is important
(not least because insulin resistance underpins the metabolic dysfunction in MASLD/MAFLD). That said,
whole-body insulin resistance (or liver insulin resistance) is not easy to measure in clinical practice. Whole-
body insulin resistance is classically measured in research studies using the hyperinsulinaemic euglycemic
clamp, with variations in this methodology including staple isotopes of glucose, to accurately assess hepatic
insulin resistance. Because euglycemic clamps are burdensome, costly, time-consuming, and inconvenient,
the use of the homeostasis model assessment-insulin resistance (HOMA-IR) score has gained traction in
NAFLD/MAFLD/MASLD research as a proxy measure to assess insulin resistance. Classically, the HOMA-
[25]
IR score is calculated by the product of the fasting insulin and fasting glucose divided by a constant and
HOMA-IR thresholds have been determined to identify subjects with insulin resistance that are validated
against euglycemic clamp measurements [26-28] .

However, further controversy surrounds the HOMA-IR thresholds that should be used to define insulin
resistance. Furthermore, plasma insulin assays are not standardized across laboratories worldwide. HOMA-
IR has been validated against hyperinsulinemic-euglycemic clamp measurements (the gold standard), and a
range of HOMA-IR measurements from > 2 to > 4 have been found (in different studies) to be the best
thresholds for identifying insulin resistance [26,28,29] . Additionally, individuals with or without metabolic
dysfunction may have fatty liver disease, not least if they have variants in the patatin-like phospholipase
domain-containing 3 (PNPLA3) gene or other genetic variants that are well-known to increase the risk of
fatty liver disease but are not causes of insulin resistance . Additionally, the evidence suggests that NAFLD
[30]
also occurs frequently in subjects with metabolically healthy obesity, and obesity is a strong risk factor for
incident NAFLD, regardless of the presence or absence of insulin resistance as shown in a Korean cohort by
[31]
Sung et al. . Using data from the same Korean cohort, Chang et al. also showed in metabolically healthy
subjects at baseline, that overweight and obesity were associated with a 2.2- and 3.6-fold increase in risk
[32]
(respectively) of incident NAFLD at follow up .
With this background of evidence, how should we interpret the current developments? How will the use of
new fatty liver disease nomenclature and the focus on metabolic dysfunction (with or without using the
word “fatty”) affect patients, clinical practice, research, and policy-making? This new initiative is probably a
step in the right direction for patients. Highlighting the importance of metabolic dysfunction is a concept
that will be familiar to many patients attending diabetes clinics. A principal concern could be that some
people with several genetic risk alleles for fatty liver disease who are normal weight could slip through the
net and not satisfy the criteria to fulfill the attribution of a MAFLD/MASLD diagnosis. Whether that
matters or not remains to be seen. The proposed diagnostic criteria of MASLD are slightly more relaxed
than those of MAFLD and, therefore, the MASLD criteria may have a slightly lower positive predictive value
for diagnosing this common fatty liver disease. However, for NAFLD and MASLD, there is now evidence of
almost 100% congruence for an affected individual meeting the NAFLD or MASLD criteria .
[33]
Consequently, it seems unlikely that recruitment to randomized clinical trials should be affected and the
body of research evidence regarding NAFLD obtained in the last 30+ years should also be relevant to
MASLD.

Regarding pharmacological treatments for MAFLD/MASLD, recently, thyroid hormone receptor-β agonist
[34]
with resmetirom has shown promise; and is safe in NAFLD . In the phase 3 MAESTRO-NASH trial, both
primary liver end points of NASH resolution, ≥ 1 stage fibrosis improvement and the secondary end point
of a decrease in LDL-C concentration, were met . Nevertheless, the future is likely to be combination
[35]