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Page 4 of 13 Best et al. Hepatoma Res 2020;6:62 I http://dx.doi.org/10.20517/2394-5079.2020.56

The limitations of ultrasound scanning have been explicitly recognized in previous AASLD guidelines
which state “performance characteristics have not been well defined in cirrhotic livers” and “some patients,
particularly the obese, are not good candidates (for surveillance) despite their risk” [21-25] . To address this
insufficiency, a recent large meta-analysis, which included thirty-two studies comprising 13,367 patients,
characterized sensitivity of imaging with or without AFP for detection of HCC in cirrhotic patients. The
authors concluded that US alone has a low sensitivity to detect early stage HCC in patients with cirrhosis
[26]
and thus the addition of AFP to US significantly increased the sensitivity of early HCC detection . The
latest AASLD guidelines emphasize the importance of determining whether other serum biomarkers
[16]
(specifically AFP-L3 and DCP) might complement AFP and US in the surveillance setting .

NASH AS MAIN RISK FACTOR OF INCREASING HCC INCIDENCE
[27]
The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated at 25% . In up to one
third of all NAFL patients, progression to NASH can occur, which in turn may lead to higher-grade
fibrosis on the basis of inflammation and, in the final stage, to cirrhosis and HCC [28,29] . A recent meta-
analysis conducted by Younossi et al. even reported a global prevalence of NASH among biopsied
[13]
NAFLD patients that was almost double the previous studies’ findings at 59.1%. According to the latest
epidemiological studies, NASH is regarded as the main cause of the steadily increasing incidence of HCC
in western industrialized nations [30,31] . An analysis of the American liver transplant registry from 2002 to
2007 showed that the prevalence of HCC patients waiting for a liver transplant increased by 15.6% in the
past 15 years, from 6.4% in 2002 to 22% in 2017. NASH became the fastest growing cause of HCC. The
proportion of NASH as the cause of HCC increased 8.5-fold during the study period, from 2.1% in 2002 to
[31]
17.9% in 2017 . It should be noted here that many cases of HCC arise due to predisposing NASH in the
absence of cirrhosis, a population that has so far not been internationally screened for the purpose of early
[32]
detection of HCC. About 20% of all NASH-associated HCC cases occurred in the absence of cirrhosis .
A German single-center study from 2015, which included 1,119 HCC patients of all etiologies, showed
that there are relevant differences between patients with HCC with underlying NASH compared to those
with other hepatopathies. Patients with NASH-related HCC were older than those with other predisposing
hepatopathies (67.6 years vs. 65 years) when they were first diagnosed. In addition, the NASH-HCC cohort
showed a higher prevalence of obesity (31.1% vs. 14.7%) and diabetes mellitus type II (T2DM) (66.7%
vs. 37.85%) [Figure 1]. Interestingly, NASH-associated HCC shows a trend towards a higher frequency
of multifocality (80% vs. 69.7%) with overall larger lesions (6 cm vs. 4.8 cm) and a tendency towards an
increased rate of extrahepatic metastasis at time of initial diagnosis. It is also important to note that the
NASH-HCC patients had better global liver function despite a higher tumor burden when diagnosed for
the first time. It can be postulated that later HCC diagnosis may be the result of less intensive screening
[33]
efforts due to lesser extent of hepatic deterioration in NASH patients compared to other liver diseases .

DO BIOMARKERS ENHANCE HCC EARLY DETECTION?
For clinical routine, the diagnostic significance of ultrasound of the liver as part of the HCC screening
may exhibit distinct limitations. This includes the comparability with preliminary examinations due to
changing investigators and ultrasound devices. Predominantly in the cirrhotic or steatotic liver, small
lesions are detected in a limited extent. Determination of HCC biomarkers such as AFP have the advantage
of being independent of the investigator. Laboratory tests are subject to strict quality guidelines and
deliver reproducible results. For this reason, the addition of AFP is recommended in some guidelines
to supplement the US. In the high-risk cohort suffering from chronic viral hepatitis B or C relevant for
HCC screening, however, the hepatic inflammation may lead to a false positive AFP value elevation which
significantly attenuates the specificity, especially in this scenario [34,35] . In contrast, if the AFP cut-off values
are set higher to improve specificity, 40% of the early stages of HCC are not detected by AFP .
[36]