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Page 2 of 17 Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60

Table 1. Serum biomarkers for early diagnosis of hepatocelular carcinoma
Biomarker Cut-off Sensibility % (95% CI) Specificity % (95% CI) AUC Other utilities Ref.
AFP 20 53 (46-59) 90 (87-93) 0.8 Prognosis [9]
AFP-L3 10 28 (22-34) 97 (93-100) 0.66 Prognosis [9]
DCP 150 61 (55-68) 70 (65-74) 0.72 Prognosis [9]
GPC3 0-003-300 53 (0.49-0.57) 77 (0.74-0.81) 0.82 Treatment [28,33]

AFP: alpha-fetoprotein; DCP: des-gamma-carboxy prothrombin; GPC3: glypican-3; AUC: area under the curve; CI: confidence interval

Conventional diagnosis methods for HCC detection include imaging and serological test with low sensitivity
and specificity . In this review we provide a briefly outline of HCC serological biomarkers [Table 1] and
[4]
highlight the recent development of circulating cancer byproducts detection: liquid biopsy.

CONVENTIONAL SERUM TUMOR MARKERS
Alpha-fetoprotein
Alpha-fetoprotein (AFP) is a glycoprotein that transports a great variety of molecules, and it is usually
produced during fetal and neonatal development by the liver, yolk sac and gastrointestinal tract. Once it
reaches its maximum concentration in the second trimester, its levels decrease until it is only detected in
small amounts in serum . Elevated levels of AFP in adulthood can be related to malignant diseases, such
[5]
as HCC and other gastrointestinal, pancreatic, biliary, nonseminomatous germ-cell testicular, and germ cell
[6]
ovarian cancers . However , an increase of serum AFP levels can be expected in non-neoplasic conditions,
[7]
such as pregnancy, cirrhosis (11%-47%) or acute hepatitis (30%-50%) .
If we use a cut-off of 20 ng/mL, the sensitivity and specificity values of AFP 12 months prior to the time of
HCC diagnosis are 47% and 75% respectively, while at the time of diagnosis, those values rise to 61% in the
[8]
case of sensitivity and 81% in the specifity variable . However, if we increase the cut-off to 200 ng/mL, we
improve the specificity to 100%, at the expense of decreasing sensitivity.

On the other hand, Marrero et al. , carried out a case-control study among patients with compensated
[9]
cirrhosis and patients with HCC [both hepatitis C virus (HCV+)], concluding that AFP had the best area
under the receiver operating characteristic (ROC), curve [0.80, 95% confidence interval (CI): 0.77-0.84], with
a cut-off of 10.9 ng/mL, for early stage HCC (BCLC stages 0 and A).

At present, AFP is used as a complementary biomarker to ultrasonography (US) for HCC surveillance,
although clinical guidelines only recommend the last one [10,11] . However, according to a recently published
[12]
meta-analysis , where 38 observational cohort studies that evaluated surveillance in patients with cirrhosis
were included, it was observed that the use of US plus AFP improves detection of early-stage HCC compared
with no surveillance [odds ratio (OR) = 2.16 (95% CI: 1.80-2.60)], while US alone had an OR of 2.04 (95%
CI: 1.55-2.68); at the same time, US plus AFP had a risk ratio for improving survival of 1.86 (95% CI: 1.76-
1.97), while US alone had a slightly lower risk ratio of 1.75 (95% CI: 1.56-1.98), although it was not statistically
significant. There were no studies that directly compared US alone versus US plus AFP, and only 4 studies
used US alone, while the rest of the studies relied on US and AFP at 6-month intervals.

Finally, in addition to early diagnosis, AFP can also predict the survival after liver transplantation (LT) in
[13]
patients with HCC, as shown by She et al. in a study conducted in 250 patients, in which survival is less
than 5 years post-LT if AFP levels are higher than 400 ng/mL [66% vs. 85% (AFP < 10 ng/mL), P = 0.029].

Serum AFP level is correlated with the tumor size. In fact, 80% of small HCC (< 2 cm) do not show high
levels of serum AFP. In the other hand, AFP levels can be increased in patients with chronic liver disease
with a degree of hepatocytes regeneration such as HCV-infection that shows a high level of AFP in absence