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Rojas et al. Hepatoma Res 2018;4:31 I http://dx.doi.org/10.20517/2394-5079.2018.60 Page 11 of 17

subjects with only liver cirrhosis or healthy livers (P < 0.01). An additional interesting finding of this study
was the association between HepPar1+ MPs and the early recurrence of HCC after liver resection. HepPar1+
MPs, measured before liver resection, were significantly more numerous in the blood of subjects which
[135]
displayed recurrence (P = 0.021) .
Additionally, other study reported that MPs profiling for distinct MPs populations that are associated with
chronic liver diseases robustly discriminates between chronic HCV infection and non-alcoholic fatty liver
disease [136] . Julich-Haertel et al. [137] successfully differentiated HCC and cholangiocarcinoma (CCA) from
chronic diseases without liver tumours base on MPs profile. AnnexinV+ EpCAM+ CD147+ taMPs were
increased in HCC and CCA. Moreover, AnnexinV+ EpCAM+ ASGPR1+ taMPs allowed to differentiate
between liver cancer (HCC or CCA) and cirrhosis from tumour-free individuals (sensitivity 75% and
specificity 47%) [137] . AnnexinV+ EpCAM+ ASGPR1+ taMPs were increased in liver cancer and decreased
after liver resection indicating the powerful diagnostic accuracy (P < 0.05) and these MPs were correlated
“moderately” with liver tumos diameters (r = 0.56, P > 0.001). However, no significant correlation between
AFP levels, tumour diameter and AnnexinV+ EpCAM+ ASGPR1+ taMPs was found [137] .

The evidence about the hypothesis that taMPs populations could be used as a novel liquid biopsy tool to
identify and discriminate liver tumours in patients with cirrhosis and their use as diagnostic and responder
biomarkers need further studies.

CONCLUSIONS
In conclusion, nowadays the early diagnosis of HCC is difficult, despite being of vital importance for an
adequate treatment and the consequent improvement of survival in these patients. However, no single
biomarker represents an optimum sensitive and specific tool for this purpose.

Therefore, a study has been recently published in which several biomarkers (AFP, AFP-L3 and DCP)
were combined to validate two statistical models for the early diagnosis and prognosis of HCC (GALAD
and BALAD-2, respectively). Thus, GALAD discriminated patients with HCC from those with other
hepatobiliary cancers with an area under the ROC curve (AUROC) value of 0.95, lower in case of small
unifocal HCC (0.85-0.95). On the other hand, BALAD-2 established 4 different groups depending on the
prognosis [138] . In addition, there are many other biomarkers that are under study to check their utility in the
management of this disease, such as golgi protein-73, osteopontin, soluble urokinase plasminogen receptor
activator, etc.

The utility of the current blood molecular biomarkers included in the context of liquid biopsy, are promising
as diagnostic, therapeutic and/or prognostic markers for HCC. Regarding this, a liquid biopsy could give us
information about the genetics and epigenetics alterations present in the tumor showing great advantages
compared to tissue biopsies; it is a non-invasive method to determine the molecular biology of the tumor
as well as the feasibility of taking samples in order to monitorize the tumor state in real time. However,
due to the lack of standardized technical approach, data is quite different among various studies. With the
standardization of effective methods, liquid biopsy biomarkers alone or in combination with conventional
serum biomarkers might serve as promising diagnostic, prognostic, therapeutic monitoring and risk
assessment of HCC.

DECLARATIONS
Authors’ contributions
Substantial contributions to the conception, the acquisition, analysis, and interpretation of data: Rojas Á,
Sánchez-Torrijos Y, Gil-Gómez A, Liu CH, Rodríguez-Rivas C