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Llamoza-Torres et al. Metab Target Organ Damage 2024;4:40 https://dx.doi.org/10.20517/mtod.2024.64 Page 7 of 18

Reviewing the major series of reports [81-85] on MASLD-related HCC reveals that the proportion of non-
cirrhotic cases ranges from 35%-55% [Table 1]. The heterogeneity in response rates to curative treatments in
MASLD-related HCC may be attributed to various factors, including the fact that 72% of diagnoses are
[81]
incidental . This is largely because non-cirrhotic patients fall outside the target population for HCC
screening programs. Nonetheless, the average percentage of MASLD-HCC cases in non-cirrhotic patients
(40%) is higher than that observed for other causes in the published series. Tan et al., in a systematic review
and meta-analysis involving 13,577 individuals with MASLD-HCC, noted that non-cirrhotic patients were
[85]
less likely to receive liver transplantation but more likely to undergo liver resection . They had a similar
likelihood of receiving ablation, and overall, patients with MASLD-related HCC were just as likely to receive
[85]
curative therapies as those with HCC from other etiologies .

MASLD is a heterogeneous clinical and pathophysiological condition characterized by several
subphenotypes, each with varying immunoregulatory effects that are just beginning to be understood in
terms of their impact on the efficacy of new treatments for HCC [32,36] . An underlying genetic predisposition
to MASLD has been established, particularly involving alterations in patatin-like phospholipase domain-
containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), with the p.I148M and
p.E167K variants, respectively, being linked to MASLD [86-93] . Additionally, a genetic risk stratification has
been developed for entities with metabolic dysfunction [90,91] . It should be mentioned that these
polymorphisms have also been associated with the development of HCC in other liver diseases unrelated to
[91]
MASLD, such as ALD and chronic hepatitis C virus infection (HCV) , although in this study, the MASLD
population comprised around 12%. Bianco et al. demonstrated that the polygenic risk score (PRS)
associated with alleles in four genes - PNPLA3, TM6SF2, membrane-bound O-acyltransferase domain-
containing 7 (MBOAT7), and glucokinase regulatory protein (GCKR) - improves the accuracy of HCC
detection and may aid in stratifying HCC risk in individuals with dysmetabolism, including those without
severe liver fibrosis . Thomas et al. also evaluated the PRS in an Asian population with NAFLD and
[92]
assessed its association with the risk of HCC . They concluded that genetically determined NAFLD may
[93]
play a potential causal role in HCC development . Chalasani et al., evaluating data from nine centers in
[93]
North America (MASH Clinical Research Network - MASH CNR - database), demonstrated the influence
of the PNPLA3 polymorphism, along with other modifiable and non-modifiable risk factors (age, sex,
diabetes, and advanced fibrosis), on the risk of developing a major adverse liver outcome (MALO) in
MASLD . They reported a HR of up to 7.78 (95%CI: 4.39-13.81; E value: 15.04; CI: 8.25) in patients with
[94]
the PNPLA3 GG polymorphism and advanced fibrosis.

To identify phenotypes that may present worse outcomes in SLD subgroups, it is important to consider
the lean-MASLD or non-obese MASLD subgroup [94-97] . Approximately 40% of MASLD patients are non-
obese, with 20% categorized as lean. Among these, nearly 30% have MASH, and almost 30% have
significant fibrosis [96,97] . These patients also share lower OS rates with the MetALD population and
experience higher rates of extrahepatic events, such as cardiovascular mortality and cancer
development [94-103] . Sripongpun et al. recently presented their data analyzing the NHANES III cohort (the
third National Health and Nutrition Examination Survey that covers the years 1988-1994) with a
follow-up of up to 27 years, showing an association of a 16% increase in mortality in patients with
MASLD compared to people without SLD [104,105] . From their data, we highlight that the MetALD
subgroup presented an increase of 33% but in ALD of up to 75%. The authors stratified the risk of
developing complications using both FIB-4 (Fibrosis-4 index) and SAFE (steatosis-associated fibrosis
estimator) scores (the latter designed to discriminate patients with non-advanced fibrosis). In its
multivariate analysis, the SAFE score manages to differentiate an increase in mortality of 31% and 90%
in the intermediate and high-risk groups, respectively, in contrast to the FIB-4, which only detects a
significant increase in mortalityin the high-risk subgroup (FIB-4 > 2.26) of 53%. Therefore, robust