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Page 4 of 9 Bose et al. Hepatoma Res 2019;5:24 I http://dx.doi.org/10.20517/2394-5079.2019.10

Serological tests
Serological biomarkers may provide crucial diagnostic hint in support of the results of ultrasound and may
provide a crucial breakthrough in detecting biochemical changes related to liver malignancy prior to the
image-based identification of hepatic nodules.

Assessment of the serum biomarker AFP has been one of the most extensively used clinical tests routinely
performed for the determination of HCC. However, sensitivity of serum AFP test in determination of HCC
ranges from 25% for nodules smaller than 3 cm to 50% for lesions larger than 3 cm in diameter . Further,
[13]
for the patients with cirrhosis of different stages AFP levels are found to be varying within a broad range and
same trend has been found in the cases with underlying liver diseases where elevated serum AFP levels must
be supported with high resolution image-based analysis to avoid false positive HCC detection .
[14]
Other informative serological tests for HCC diagnosis are protein-induced by vitamin K absence or antagonist-
II (PIVKA-II), also known as DCP, and the percentage of Lens culinaris agglutinin-reactive alpha-fetoprotein
(AFP-L3). Technically, AFP-L3 is a glycoform of AFP that exclusively originates from cancer cells and
demonstrates higher specificity for HCC in combination with AFP . However, AFP-L3 is not typically
[14]
detected when AFP levels are < 20 ng/mL and it has a low sensitivity for early stage HCC diagnosis.
[8]
DCP or abnormal prothrombin cross-reacts with prothrombin antibodies in blood but fails to generate
functional activity because it lacks γ-carboxy glutamate (GLA) unit which is crucial for binding Ca .
2+
Structural studies of HCC associated DCP revealed that it has only 5 GLA unit as compared to 10 GLA units
in native prothrombin structure. The mean level of DCP in HCC patients were often found to be as high as
900 ng/mL when it was determined for the first time in a cohort of 76 patients; a significantly 67% of those
patients had DCP levels above 300 ng/mL . However, there are evidence that DCP sometimes may be present
[15]
cases of hepatitis and metastatic carcinoma, with a lower level of less than 300 ng/mL. Notably, plasma levels
of abnormal prothrombin (DCP) in HCC could not be normalized by supplementing vitamin K, whereas,
native prothrombin levels were recorded as normal. This rule out any correlation between HCC associated DCP
production and vitamin K deficiency, but its biosynthesis in malignant hepatocyte is linked with an acquired
defect in the vitamin K-dependent carboxylase system . However, often AFP and DCP assay has found to be
[16]
poorly correlated as it is expected from the very different origin of these biomarkers; the re-expression of a
fetal antigen in the tumor tissues and an independently acquired posttranslational aberration respectively.
DCP measured in biopsy homogenates of HCCs showed a high upward trend compared to the plasma
concentration of the corresponding patients. Notably, in patients having normal plasma levels of DCP
showed no changes in DCP concentrations within biopsy homogenates and surrounding healthy hepatic
tissues. Currently, plasma DCP levels greater than 100 ng/mL on ELISA are taken as suggestive of HCC .
[17]
However, DCP levels and tumor size do not correlate well, studies found that DCP levels increased in only
20% of the HCC cases with nodules less than 3 cm . A recent French study adopting a lower cut-off of DCP
[18]
(42 ng/mL) recorded a sensitivity and specificity of 77% and 82%, respectively for early diagnosis of HCC;
however, less sensitivity and specificity (61% and 50% respectively) were registered with a lower AFP cut-off of
5.5 ng/mL . A recent study demonstrated that DCP was superior to AFP or its variant biomarker, AFP-L3
[19]
in detecting HCC and a combination of DCP with the other two mentioned tests provided in better accuracy
than DCP alone .
[20]
In current clinical practice, diagnostic methodology and surveillance program for HCC follow a sequence of
image based and serological tests as described in Figure 1. Under clinical guideline of AASLD, the European
Association for the Study of the Liver and the European Organization for Research and Treatment of Cancer
(EASL-EORTC), and the Japan Society of Hepatology (JSH), those with cirrhosis and those with chronic
HBV infection regardless of cirrhosis has been considered as the high-risk population for HCC surveillance.
However, EASL-EORTC also includes patients with chronic HCV and advanced liver fibrosis in this high-