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Page 4 of 15 Zacharakis et al. Hepatoma Res 2018;4:65 I http://dx.doi.org/10.20517/2394-5079.2018.76

Table 1. Cut off values for the commonly used biomarkers in the diagnosis of
hepatocellular carcinoma; specificity and sensitivity characteristics
Tumor marker Specificity (%) Sensitivity (%)
AFP
> 20 ng/mL* [80-94] [41-65]
Elevated serum AFP-L3
Range: 10%-35% [83-94] [37-75]
DCP/PVKA II
Range: 60-150 mAU/mL [70-100] [41-89]
*Higher cut off values increase specificity up to 100% and decrease sensitivity to less than 20%. AFP: alpha-fetoprotein; AFP-L3: lens culinaris
agglutinin-reactive fraction of alpha-fetoprotein; DCP: des-γ-carboxyprothrombin; PIVKA II: prothrombin induced by vitamin K absence

combined surveillance tests had better detection of early-stage HCC compared with no surveillance (OR
2.16, 95% CI 1.80-2.6). On the other hand, the use of US only compared with no surveillance showed better
detection of early stage HCC (OR 2.04, 95% CI 1.55-2.68). Also, the use of either the US alone or in combination
with AFP showed similar curative rates for the treatment (OR 2.23, 95% CI 1.83-2.71 and 2.19, 95% CI 1.89-2.53,
respectively). Unfortunately, no studies have compared US alone vs. US in combination with AFP to detect
early-stage HCC or to assess curative therapy. Regarding the improving survival, US plus AFP had a pooled
risk ratio of 1.86 (95% CI 1.76-1.97) whereas the US alone had a slightly lower pooled risk ratio of 1.75 (95% CI
1.56-1.98). At present, it is unknown whether the addition of AFP allows for improved survival and which type
of surveillance tests, US alone or in combination with AFP has a better-improved survival.

Furthermore, AFP has been incorporated in nomograms or calculators to predict the outcome of hepatic
[35]
[34]
resection and transplantation . AFP combined with SCCA might predict the risk of HCC in patients with
chronic liver disease [36,37] . AFP level has been incorporated in many staging systems for HCC patients, such as
Cancer of the Liver Italian Program, Chines University Prognostic Index, Groupe d’Etude et de Traitement
[38]
du Carcinome Hépatocellulaire, and model to estimate survival in ambulatory HCC patients score .
[39]
Changes in AFP levels can predict the outcome in patients treated with transarterial chemoembolization or
Sorafenib [40,41] .

Several limitations have been recognized in using AFP levels as a biomarker for HCC. First of all, AFP
levels as a prognostic marker cannot help in therapeutic decisions and especially for patients with normal
pretreatment AFP levels. Also, there is no consensus on when post-treatment AFP levels should be measured.
Finally, the clinical utility of AFP response in patients treated with sorafenib has not yet been validated in
prospective studies.

The limitations of AFP use highlight the need to identify novel biomarkers. Given the increasing incidence
of HCC, it is necessary to explore whether other new or old serum biomarkers or a combination of them
can compete with or complement that of the US and constitute an optimal performance in the diagnosis,
prognosis, treatment response, and surveillance of HCC [9,42] .

DCP
Other serum markers such as DCP have also been explored, alone or in combination, in the diagnosis and
surveillance of HCC.

DCP is an abnormal prothrombin molecule induced by vitamin K absence (PIVKA II) and posttranslational
carboxylation machinery is known as DCP. DCP is an abnormal prothrombin molecule overproduced in HCC
patients [43,44] .

[45]
Unfortunately, DCP did not offer substantial advantages concerning AFP . This marker is not used for early
detection of HCC. DCP levels have been associated with portal vein invasion and advanced stage of HCC as