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Page 2 of 6 Best et al. Hepatoma Res 2021;7:32 https://dx.doi.org/10.20517/2394-5079.2021.52

with an annual incidence of 0.8%-2.3% per year. Of note, prevalence of type II diabetes mellitus (T2DM)
and obesity appear to be independent HCC-predisposing risk factors in the context of NASH-associated
metabolic syndrome. Furthermore, in NASH patients, initial HCC diagnosis is frequently made at later
[8]
tumor stages because they are monitored less intensively due to the absence of, or less advanced, cirrhosis .

Human hepatocarcinogenesis is always a multifactorial event. Environmental influences (e.g., alcohol and
smoking) and host factors (age, gender, familial predisposition, obesity, diabetes, and fibrosis) interact with
genetic, immunological, and viral factors in a complex interplay in HCC development. In the context of
DNA sequence changes in the form of mutations, resistance of proliferating hepatocytes to programmed
cell death (apoptosis) occurs, allowing mutant cells to proliferate [Figure 1]. In addition, in NASH,
[9]
chronic hepatic inflammation represents a cirrhosis-independent trigger of hepatocarcinogenesis. It is a
complex, multifactorial process involving various risk factors (genomic instability, obesity, and T2DM). An
understanding of the various key molecular initiation and progression mechanisms of hepatocarcinogenesis
is essential to define etiology-adapted therapeutic targets in the future.

Routine ultrasound (US) of the liver for HCC screening exhibits distinct limitations in terms of diagnostic
value. Smaller lesions show limited detectability in the cirrhotically remodeled or steatotic liver.
Determination of HCC biomarkers, such as alpha-fetoprotein (AFP), has the advantage of being
investigator independent and to provide reproducible results. However, not all international guidelines
recommend AFP determination in addition to US, since sensitivity of AFP in HCC detection ranges from
39% to 65% only . To facilitate sensitivity superior to the combination of US and AFP while maintaining
[10]
good specificity in early HCC detection, a large number of studies investigated the suitability of different
biomarkers, such as osteopontin, glypican-3, the AFP variant binding to the lectin molecule “Lens culinaris
agglutinin” (AFP-L3), and Des-gamma-carboxy prothrombin (DCP) for HCC surveillance [11-14] . As s result,
a statistics-based model called GALAD score, including patients gender, age, AFP, AFP-L3, and DCP, was
developed. It clearly demonstrated superior sensitivity and specificity compared to assessment of
biomarkers individually and was extensively validated in international studies [15,16] . In addition, GALAD
scores’ utility in HCC early detection was specifically tested in an international multicenter trial in a NASH
population; it was able to detect HCC even at early stages (BCLC 0/A) and achieved an AUC of 0.91.
Furthermore, in a prospective NASH pilot trial, it could be demonstrated that GALAD was already elevated
up to 1.5 years before the initial diagnosis of HCC was made by imaging procedures. Those encouraging
results implicate that the GALAD model is suitable for HCC early detection of all etiologies, including
[17]
NASH . Only earlier HCC detection, predominantly in the emerging high-risk cohort of patients with
NASH, T2DM, and obesity, can facilitate curative treatment options for this population. Further phase IV
prospective trials are urgently warranted to determine whether GALAD has potential as an integral part of
HCC screening algorithms in the near future.

Currently, HCCs are frequently diagnosed at advanced stages when curative therapy options such as liver
resection or transplantation are unavailable. In addition to established palliative, locoregional therapies,
such as conventional transarterial chemoembolization (TACE), alternative transarterial procedures such as
selective internal radiotherapy (SIRT) are also available [Figure 2]. Recent randomized clinical trials (RCT)
showed no survival benefit for SIRT over systemic therapy in patients with advanced HCC . A meta-
[18]
analysis on the latest RCTs in contrast could demonstrate that SIRT is non-inferior to standard of care
systemic therapy in terms of overall survival (OS) while offering an adequate safety profile with fewer side
effects. Furthermore, patients with advanced HCCs arising in NAFLD may not be suitable for systemic
therapy due to metabolic syndrome-related diseases. Here, SIRT exhibited similar survival outcomes at a
comparable toxicity profile in HCC patients with NAFLD and HBV, implicating that NAFLD-associated