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Page 2 of 14 Chia et al. Hepatoma Res 2019;5:9 I http://dx.doi.org/10.20517/2394-5079.2018.112

The current clinical diagnosis of early HCC is mainly based on medical imaging, including ultrasonography,
computed tomography (CT) and magnetic resonance imaging. Early stage HCC is classified by having less
[3]
than 4 tumour nodules with less than 3 cm in diameter . The sensitivity and specificity for ultrasonography
to pick up these tumour nodules are 60% and 97%, respectively, while CT has sensitivity and specificity
[4]
of 68% and 93%, respectively . There have been several attempts to increase the sensitivity by combining
imaging with α-fetoprotein (AFP) biomarker but with limited success so far, indicating the urgent need
[5,6]
for new potential biomarkers . Many patients have no access to diagnostic imaging due to the lack of
necessary equipment and imaging specialists in local and regional hospitals.

In this review, clinically approved biomarker, such as AFP, will be discussed in detail followed by updates on
other diagnostic biomarkers under development, including AXL, thioredoxin and golgi protein-73 (GP73).
A few promising HCC targets that can be used as both a diagnostic and a therapeutic biomarkers, such as
glypican 3 (GPC3), Yes-associated protein 1 (YAP1), trophoblast cell-surface antigen 2 (Trop2) and vasorin
(VASN), will also be described. Nucleic acids-based biomarkers, such as non-coding RNA, are beyond the
scope of this review and are covered elsewhere in this special issue.

DIAGNOSTIC BIOMARKERS FOR HCC
AFP
AFP is the most well studied biomarker for HCC and is also the first biomarker approved for HCC detection
in liquid biopsy. It is a 591 amino acids glycoprotein encoded by the AFP gene on human chromosome 4
[7]
(4q13). AFP transports a variety of molecules, including fatty acids and bilirubins, across the body . It is
[8]
mainly produced by the visceral endoderm of the yolk sac and fetal liver during development . The highest
AFP plasma concentration is detected during week 12 to week 16 of a fetal life and subsequently declines to
[9]
virtually undetectable after birth . However, unusually high serum concentration of AFP is also detected in
patients with HCC [10,11] .

Nonetheless, the use of AFP as a biomarker for HCC has been controversial ever since its discovery
nearly half a century ago [12,13] . One study that evaluated AFP as a standalone HCC biomarker on 5,581
[14]
men in China exhibited sensitivity and specificity of 55.3% and 86.5%, respectively . Although more
early stage HCCs were reported in the test group than in the control group, there was no survival benefit
in the test group. Another study that evaluated 18,816 patients with chronic hepatitis B demonstrated
that combining ultrasonography with AFP test in a biannual screening scheme reduced the mortality of
[15]
HCC in the test group by 37% . However, given the high false positive rate and additional costs, some
[5]
argued the practicality of recommending such a biannual screening scheme . A systematic review of five
trials conducted on patients with hepatitis C, a high risk group, between 1999 and 2002 concluded that
[13]
AFP had limited ability to detect early HCC . The high false positive rate is not only because only 61%
[16]
of HCC expresses AFP , but also the fact that AFP expression is detected in other liver abnormalities
[18]
[17]
such as cirrhosis and acute hepatitis and other tumours, including endodermal sinus tumour and
[19]
gastrointestinal malignancies .
AFP exists in three different glycoforms, namely AFP-L1, AFP-L2 and AFP-L3. Interestingly, AFP-L3
expression only increases in HCC but not in hepatitis or cirrhosis, suggesting that it could be a better HCC
[20]
biomarker . However, a trial using AFP-L3 as the sole biomarker on 372 patients with hepatitis C virus
[21]
demonstrated sensitivity of only 37%, despite a specificity of 92% . In the same study, combining AFP-L3
with another biomarker, des-gamma-carboxy prothrombin increased the sensitivity to 61% but scarified the
specificity down to 71%. Another phase II study using the combo for early stage HCC reported sensitivity
[22]
and specificity of 78% and 62%, respectively . The very low sensitivity is probably because AFP-L3 is
[23]
minimally expressed and usually undetectable when the patients’ AFP level is below 20 ng/mL. Kagebayashi et al.
utilized a microfluidic device in an attempt to detect low level of AFP-L3 in patient serum but reported