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Page 6 of 13 Best et al. Hepatoma Res 2020;6:62 I http://dx.doi.org/10.20517/2394-5079.2020.56
[55]
0.92 and a corresponding sensitivity of 86% and specificity of 89% . A subsequent international multi-
center validation study comprising 6,834 patients of different etiologies of HCC achieved an AUROC
[56]
for GALAD of consistently > 0.90, confirming the efficacy of this model . A following German single-
center study observed that the GALAD score, even in BCLC 0/A stage HCC, achieved an AUROC of 0.92,
again demonstrating superiority in HCC detection compared to the triple biomarker combination of AFP,
[57]
AFP-L3 and DCP without considering gender and age .
To further address the inadequate performance of US-based HCC early detection in NASH, where obesity
and sound artifacts due to steatosis further attenuate the diagnostic performance, the utility of the GALAD
score in the detection of NASH-associated early HCCs had been tested specifically in this this high-risk
collective. In a retrospective German multi-center cohort (8 centers) study, the GALAD score was able
to detect NASH-HCC patients with an AUROC of 0.96, significantly better than the performance of the
biomarkers alone [AFP (AUROC 0.88), AFP-L3 (AUROC 0.86), or DCP (AUROC, 0.87)]. Even for NASH
patients in early HCC stages (within the Milan criteria), the GALAD score achieved an AUROV of 0.91.
Furthermore, in a prospective Japanese cohort study, it was demonstrated that the average GALAD score in
those patients who developed HCC during the observation period was already significantly elevated up to
1.5 years before the initial diagnosis of HCC. The GALAD scores of these HCC patients rose above the cut-
[58]
off value of 0.63 approximately 200 days before first diagnosis .

This implies that the GALAD model is quite suitable for early detection of HCC of all etiologies, even in
NASH. However, a phase IV multi-center prospective study has yet to test whether the GALAD Score can
be used in the future as an integral part of HCC screening algorithms in patients at risk.

Osteopontin
Osteopontin (OPN) is an integrin-binding phosphoprotein that is overexpressed in a variety of cancers
including lung, breast, colon cancer, and HCC [39,59] . At a low level, it is also secreted by biliary epithelial
cells. OPN mediates cell signaling that controls inflammation as it is the case in hepatitis, HCC tumor
[60]
progression, and metastasis . Hepatocarcinogenesis results in elevated OPN levels compared to those
[61]
patients with chronic liver disease in the absence of HCC . In a meta-analysis investigating the efficacy of
OPN in HCC detection, the sensitivity and specificity of elevated OPN levels have been reported between
[62]
75%-87% and 62%-82%, respectively . In a phase III validation study, OPN outperformed AFP for HCC
detection with an AUROC of 0.73 [95%CI: 0.62-0.85] vs. AUROC of 0.68 [95%CI: 0.54-0.82], respectively.
The combined utilization of AFP and OPN resulted in a sensitivity of 82% and specificity of 77% for HCC
detection; however, the number of patients at BCLC stage 0/A was limited in this study .
[63]

Glypican-3
Glypican-3 (GPC-3), is a heparin sulfate proteoglycan playing a pivotal role in cell proliferation and
tumor suppression, representing a potential biomarker for the diagnosis of HCC. GPC-3 binds to growth
[64]
factor receptors and is involved in cell proliferation and tumor suppression . In healthy hepatocytes it is
absent, but during hepatocarcinogenesis it is upregulated, and it is assumed to participate in the canonical
Wnt- signaling growth pathway [65,66] . GPC-3 is present in approximately 33% of HCC patients that were
seronegative for both DCP and AFP . A meta-analysis found that GCP-3 had a sensitivity of 55.1% and a
[67]
[68]
specificity of 97% . AFP and GCP-3 in concert achieved a sensitivity of 76% even at early stage HCC. In
light of these findings, GPC-3 has been proposed to be a complementary serologic biomarker to AFP due
to the ability of GPC-3 to accurately distinguish between patients with small, well differentiated HCC and
[69]
those with underlying cirrhosis .