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Best et al. Hepatoma Res 2020;6:62 I http://dx.doi.org/10.20517/2394-5079.2020.56 Page 7 of 13

HCC SURVEILLANCE BASED ON COMBINATION OF BIOMARKERS AND ULTRASOUND
Combination of AFP and ultrasound
The latest HCC guidelines have recently shown a tendency to omit biomarker-based diagnostics in favor
of sole ultrasound examinations. In a large American meta-analysis of US, the sensitivity and specificity
of US in HCC detection was analyzed with and without additional AFP determination in an HCC high-
risk patient group (32 trials/13,367 patients). Ultrasound alone detected an HCC across all stages with
a sensitivity of 84% when carried out in accordance with regional guidelines, but there was a dramatic
drop in sensitivity to 47% in early stage HCC. The combination of US with AFP was able to improve the
[21]
sensitivity in the early detection of HCC to at least 63% . This clearly indicates that ultrasound alone
has low sensitivity in detecting early stage HCC in patients with cirrhosis. Hence, the addition of AFP to
ultrasound may significantly increase the sensitivity of early HCC detection in future.

Combination of GALAD and ultrasound
Recently, the GALAD model has also been validated in an American US cohort study [single-center cohort
of 111 HCC and 180 controls and a multi-center cohort of 233 early HCC and 412 cirrhosis patients from
the Early Detection Research Network (EDRN) Phase 2 HCC Study] and the performance has been shown
to be clearly superior to sonography for HCC detection. Here the AUROC of GALAD for HCC detection
was 0.95, which was clearly superior to the AUROC of ultrasound (0.82). The combination of GALAD and
[70]
ultrasound (GALADUS score) achieved an AUC of 0.98, clearly superior to US or GALAD used solely .
These very promising data indicate that a combination of ultrasound and biomarker-based scores can
significantly improve the performance of current surveillance strategies.

MECHANISMS OF NASH-RELATED HEPATOCARCINOGENESIS AS POTENTIAL TARGETS FOR
SURVEILLANCE
Understanding the sequence from NAFLD to HCC and the impact of additive risks such as type II diabetes
mellitus [Figure 1], genetic polymorphisms, and stool microbiome are increasingly becoming the focus of
current research.

Inflammation per se, which defines NASH, is a clinically relevant trigger of carcinogenesis, even without
the basis of cirrhosis of the liver. While an altered lipid and glucose metabolism contributes to hepatic
steatosis in the context of the metabolic syndrome, the interplay of genetic variations, mitochondrial
dysfunction, altered immune response, and an imbalance of the microbiome cause a progression of simple
fatty liver to NASH, and in the “worst case” scenario, HCC.

GENETIC FACTORS
For certain gene polymorphisms, there is a direct relationship between the prevalence of NAFLD and the
risk of progression to advanced NASH fibrosis.

The polymorphism of the patatin-like-phospholipase-domain-containing-3 (PNPLA3) gene leads to
increased hepatic lipid accumulation and an alteration in retinol storage in the liver. Independent of
potential disruptive factors such as body mass index (BMI), diabetes, and advanced fibrosis, there is a
3-fold increased HCC risk due to PNPLA3 .
[71]
The polymorphism of the transmembrane 6-superfamily member 2 (TM6SF2) gene manifests itself as
a transport disorder of pre-VLDL (very low-density lipoprotein) particles. There is a correlation with
the extent of steatosis and progression of fibrosis in NASH, regardless of obesity, diabetes, and PNPLA3
genotype. The direct role of this TM6SF2 variant in hepatocarcinogenesis has not yet been fully elucidated;
[72]
it is possibly the profibrogenic effect that indirectly promotes progression to HCC .