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Page 6 of 18 Llamoza-Torres et al. Metab Target Organ Damage 2024;4:40 https://dx.doi.org/10.20517/mtod.2024.64

[59]
subgroup, late recurrence (> 4 years post-transplant) was observed in 4 patients . In contrast, Kern et al.,
analyzing data from their center at Innsbruck Medical Centre (Austria), found that patients with MASH
had a higher incidence of advanced HCC (beyond the Milan criteria) compared to those with ALD, HCV,
[58]
and other indications (P = 0.034) . Additionally, postoperative complications were significantly higher in
the MASH cohort (P = 0.048). The study highlighted cofactors such as diabetes and infections, reporting a
prevalence of T2DM in 40% of MASH patients, 31.7% of ALD patients, 14.6% of HCV patients, and 15.4%
of patients with other etiologies . However, no differences in OS were detected when transplant patients
[58]
[58]
were stratified by the presence or absence of T2DM . The accuracy of diagnosing MASH in registry studies
has been heterogeneous across different research groups [63,64] . This variability is critical because it impacts
patient outcomes due to the disease’s characteristics and the effects of its comorbidities [32,36] . Accurate
diagnosis is, therefore, essential for optimizing the treatments that patients will receive.

There are few reports on the evolution of MASH-HCC in response to locoregional therapies, with a small
number of patients being studied [60-62] . These reports have not identified any significant differences in terms
of progression time, radiological response, or complications compared to non-MASH-HCC [60-62] . The
response rate to systemic treatments for HCC has not been very high [60,61] . However, in recent years, the use
of checkpoint inhibitors and different combination strategies has increased the response rate, positively
impacting OS. Despite these advances, the improvement in response rates has yet to exceed 35% [63,64] .

MASLD-RELATED HCC IN NON-CIRRHOTIC PATIENTS
In the population with “non-cirrhotic” liver diseases, various events can trigger fibrogenesis, which may
progress or regress at different rates [65-68] . This process can ultimately lead to established cirrhosis and its
associated comorbidities [65-71] . In methodologically selected populations (such as review studies and meta-
analyses based on paired biopsies), examining the different subtypes of NAFLD (NAFL, NASH), it was
observed that the rate of fibrosis progression can vary even within each subtype, identifying both slow and
rapid fibrosis progressors [72-75] . The rates of fibrosis progression and regression differ depending on whether
the study is based on a population database or not, as well as whether it includes only histological diagnoses
or non-invasive techniques. The rate of fibrosis progression is a recognized estimator of potential
complications, including the development of HCC [76-79] . Estimates on the rates of fibrosis progression have
been fundamental for predicting the future impact of these entities, facilitating efficient resource allocation
across all areas involved in patient care [75,76] . As an independent prognostic marker of hepatic-related events
(such as decompensation in the form of ascites, variceal digestive bleeding, encephalopathy, jaundice, and
HCC), the development of significant or advanced liver fibrosis is established as a critical factor, regardless
of the presence or absence of MASH. In addition, it correlates with an increased risk of cardiovascular
events and extrahepatic cancer [74-79] . Sanyal et al., in a cohort of patients with MASH and advanced fibrosis,
confirmed that fibrosis is the key determinant of disease progression, consistent with findings from other
significant MASH cohorts . However, an interesting observation in their results was that 1 in 7 patients
[80]
developed clinical complications (such as variceal gastrointestinal bleeding) despite having a hepatic venous
pressure gradient (HVPG) of less than 10 mmHg. This challenges the commonly accepted threshold for
clinically significant complications of portal hypertension, which is typically set at HVPG levels above
10 mmHg. These findings suggest that the inflammatory processes associated with MASH may overlap early
with carcinogenic mechanisms, potentially bypassing the need for progression to cirrhosis.

Vitellius et al. recently reported on a French cohort of 354 cases of MASLD-related HCC, in which 35%
[81]
occurred in non-cirrhotic patients . These non-cirrhotic patients, despite having poor prognostic factors
(such as advanced age and greater tumor burden), demonstrated better liver function, which allowed for a
more aggressive treatment approach and, overall, better survival compared to patients with cirrhosis.