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Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60 Page 3 of 17

[14]
of malignancy . For these reasons, some additional biomarkers for the diagnosis of HCC are needed to
improve the sensitivity of AFP and solve these issues.

AFP lectin fraction (AFP-L3)
AFP exists as three glycoforms, according to its binding capability to Lens culinaris agglutinin lectin (LCA):
[15]
AFP-L1 (non-binding fraction), AFP-L2 (weak binding fraction), and AFP-L3 (binding fraction) . AFP-L1
is increased in chronic hepatitis and liver cirrhosis, whereas AFP-L3, that it´s only produced by cancer cells,
[16]
is specifically increased in HCC .

Regarding the way of measurement, “bound” and “free” AFP isoforms are separated by affinity liquid
chromatography. The concentration of bound AFP-L3 is determined fluorometrically, and results are
[17]
reported as percentage ratio of AFP-L3 to total AFP . On the other hand, the cut-off used is 10%,
observing values of 37%, 92%, 52% and 85% for sensitivity, specificity, positive and negative predictive
[4]
value, respectively . These values increase when they are combined with AFP and des-gamma-carboxy
prothrombin (DCP) to 77%, 59%, 32% and 91% respectively. However, according to a recently published
study, ROC curve analysis showed that the highest specificity and sensitivity of the studied parameters
are achieved at cut-offs of 15% as well as combining AFP-L3 and p53 improves sensitivity to 95.4% with a
[18]
specificity of 85% .
Given that the sensitivity is markedly decreased when total concentration of AFP was < 20 ng/mL (difficulty
[19]
in detection), Oda et al. found a new way of measurement based on a microchip capillary electrophoresis
and liquid-phase binding assay on a μ-ASWako i30 auto analyzer (Wako Pure Chemical Industries, Ltd.,
Osaka, Japan) that increased the sensitivity compared to the conventional measurement (12.5% vs. 44.6%),
when using a cut-off value of 5%. Also, none of the benign liver disease patients with both serum AFP
< 20 ng/mL and high sensibility-AFP-L3 < 5% developed HCC for a median follow-up of 35 months.

Finally, in a meta-analysis that included 12 studies that directly compared the diagnostic accuracy of serum
AFP-L3 and AFP in the same population, it was found that, although the specificity for AFP-L3 (0.929) was
increased vs. AFP (0.856), sensitivity also decreased significantly (0.48 vs. 0.62), with an area under the curve
[20]
(AUC) of 0.756 vs. 0.863, respectively .

In conclusion, AFP-L3 could be a complementary biomarker for the early diagnosis of HCC, but additional
studies that really confirm its usefulness are needed.

Des-γ-carboxy prothrombin
Des-γ-carboxyprothrombin (DCP), also known as prothrombin induced by vitamin K absence II (PIVKA
II), is a molecule produced during the process of hepatocytes malignant transformation due to the fact that
the vitamin K-dependent carboxylase system becomes impaired, for which it is increased in patients with
[21]
HCC .

DCP sensitivity and specificity rate at the time of diagnosis were 74% and 86%, respectively, at a cut off of
40 mAU/mL and 43% and 100%, respectively, at a cut off of 150 mAU/mL; while for AFP it was 61% and
81% at a cut off of 20 ng/mL and 22% and 100% at a cut off of 200 ng/mL. Sensitivity and specificity were
significantly reduced when determined 12 months before diagnosis, being 43% and 94%, respectively, for
[8]
DCP and 47% and 75%, respectively, for AFP .

In a case-control study, where controls were patients with compensated cirrhosis and patients with HCC, it
was evaluated DCP and AFP-L3 as biomarkers for the early diagnosis of HCC. AUC for total AFP (0.83, 95%
CI: 0.80-0.85) was similar to DCP (0.81, 95% CI: 0.78-0.84), but better than for AFP-L3 (0.72, 95% CI: 0.69-0.75).