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Galicia-Moreno et al. Hepatoma Res 2020;6:20 I http://dx.doi.org/10.20517/2394-5079.2019.36 Page 7 of 18

Serum alpha-fetoprotein
Produced by the fetal liver and yolk cells as well as regenerating hepatocytes. By itself, serum alpha-fetoprotein
[31]
(AFP) quantification is more sensitive than other markers. AFP has a cut off point of 10.9 ng/mL
but its sensitivity is low (25%-48%) since its concentration depends on tumor size. It is important to mention
that some patients with HCC (30% to 50%) do not have high levels of AFP even in advanced stages. Due to
[32]
this, it is not recommended as the only screening test .
Liver ultrasound
Liver ultrasound (LU) is considered the first choice screening test for HCC detection because it has a
[33]
sensitivity between 60%-80%, and its specificity is above 90% . According to international guidelines (EASL
and AASLD), a LU every six months is suggested for early detection of HCC in cirrhosis patients [34,35] . This
test is able to detect lesions larger than 1 cm in diameter, is safe, low-cost and does not have secondary
effects.

LU + alpha-fetoprotein
Together, both strategies add only 6 to 8% of cases of previously undetected HCC. Combining both markers
actually increases the number of false positive results. These diagnostic tests are suggested in subjects with a
high risk of HCC at a frequency of 6 to 12 months.

Others methods used in diagnosing HCC are as follows.

Computed tomography and magnetic resonance imaging
The diagnosis and prognosis of HCC depends on the stage at which the tumor is detected. If detected at
an early stage of HCC, long-term patient survival is more probable. Noninvasive imaging tests, including
computed tomography (CT) and magnetic resonance imaging (MR) have been recommended by several
clinical practice guidelines as the first-line diagnostic tools for the screening, diagnosis, staging and
surveillance of HCC [35-37] . One characteristic about a liver nodule that suggests dysplasia is decreased
hepatic artery flow, and the maintenance of portal venous flow. The presence of new unpaird arteries not
accompanied by bile ducts is also a classic characteristic for differentiated neoplastic nodules from typical,
regeneratiing nodules [38,39] . This, and other changes can be evaluated with current imaging techniques.
The hemodynamic alterations that occur in HCC represent pathological markers for current, noninvasive
diagnosis of HCC through CT and MR. Through the evaluation of dynamic images, the diagnosis of HCC is
established by the detection of contrast-hyperenhancement in the arterial phase, and hypoenhancement in
the portal venous phase. This response is defined as the “HCC radiological hallmark”. This vascular pattern
allows HCC diagnosis with almost 100% specificity and positive predictive value for nodules with diameters
of at least 1 cm [40-42] . According to recent meta-analyses, the sensitivity of CT and MR were 63%-73% and
77%-90% respectively, with a specificity of 87%-98% and 84%-97%, respectively [43-46] . Today, new imaging
techniques have been developed to improve the non-invasive evaluation of HCC. The most significant
techniques are diffusion weighted imaging (DWI) and hepatobiliary contrast agents.

[44]
DWI is a functional magnetic resonance technique that consists of quantifying proton diffusion in tissues .
[47]
There is cellular increase in HCC and this cellular proliferation restricts water proton diffusion . It is
important to mention that DWI quantification demonstrates restricted specificity for HCC because some
lesions can show restricted diffusion on DWI [48,49] .

On the other hand, hepatobiliary contrast agents such as gadobenate dimeglubine (Gd-BOPTA) and
gadoxetate disodium (Gd-EOB-DTPA) can provide information about tumor vasculature and hepatocyte
[50]
function in a single examination .