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Page 8 of 11 Paranaguá-Vezozzo et al. Hepatoma Res 2018;4:11 I http://dx.doi.org/10.20517/2394-5079.2018.17

with chronic viral hepatitis (B or C), but without HCC compared with similar patients with other etiologies
of cirrhosis. This is caused by the inflammatory activity and hepatocyte regeneration in the most severe
[31]
cases of viral hepatitis. Gupta et al. conducted a systematic review evaluating AFP as an instrument for
the detection of HCC in patients with hepatitis C; they concluded that AFP has limited utility in this setting.
Most authors have found that an isolated measurement of serum AFP levels had limited success for early
HCC screening [14,33] , but even small changes in AFP levels may be a predictor for HCC [34,35] . In fact, dynamic
[36]
AFP measurement could identify patients at higher risk of HCC occurrence, as recently shown by Bird et al. .
Early HCC detection remains challenging, but novel serum biomarkers are under evaluation, such as
[39]
microRNAs (miRNAs) [37,38] , creatine/betaine ratio , the combination of chaperonin containing TCP1
[40]
complex (CCT) and IQ-motif-containing GTPase-activating protein-3 (IQGAP3) and circulating c-Myc
[41]
and p53 proteins .
The lower blood platelet count in HCC patients can be explained by a longer evolution of chronic liver
[26]
disease with subsequent advanced portal hypertension and hypersplenism. Velázquez et al. showed that
platelet count < 75,000/mm was an independent positive predictive value for HCC development. In this
3
[27]
3
analysis, the cut-off level for platelet count was 100,000/mm according to previously defined levels [42,43] . Lok et al.
also demonstrated the association of HCC risk with low platelet count through the HALT-C study cohort.
In a recent prospective study of the ANRS CO12 CirVir cohort including 1323 patients with HCV cirrhosis,
[44]
Ganne-Carrié et al. found five variables independently associated with HCC development at 1, 3, and
5 years: age > 50 years, past excessive alcohol intake, GGT above the upper limit of normal, absence of
3
SVR during follow-up and platelets < 100,000/mm . The latter was also evidenced in our work and in the
[45]
retrospective study by Noh et al. as a predictor of HCC.
This study found that serum levels of ALT, AFP and platelet count could be used to determine the risk of
small HCC with a sensitivity of 81% and specificity of 60%. The major strength of this formula is the tests are
easy to apply, and the score is simple to calculate. Therefore, this model is an auxiliary tool for identification
of patients with HCV at elevated risk of HCC by applying a formula with three serum exams used in routine
outpatient clinical practice throughout the world. An even better application of the aforementioned model
would be to rule out the presence of small HCC in the initial evaluation of the patient, since the negative
predictive value was 99.1% for those stratified as low risk (a score of 26). For example, in a patient with HCV
and cirrhosis, the presence of two abnormal variables, imply a higher risk of HCC with a score of 54. In
another hypothetical scenario with a patient score of 26, due to no abnormal variables, the patient could
be excluded from the high risk group. For maximization of the specificity of the model score, the cut-off of
100 reflects, for instance, the three abnormal variables. We tested the score performance based on a HCC
prevalence of 3% (Brazil) and in another scenario with an HCC prevalence of 10% (Japan), showing that the
higher the HCC prevalence, better the score performs in identifying individuals with HCC. Recently, El-
[34]
Serag et al. proposed models to predict HCC risk with the same variables we found (AFP > 20 ng/mL,
3
platelets < 100,000/mm and higher ALT) from the analysis of the change in AFP values according to HCC
[46]
development. Flemming et al. evaluated a risk model using six baseline clinical variables, including age,
diabetes, gender, ethnicity, etiology of cirrhosis, and severity of liver dysfunction independently associated
with HCC occurrence. The authors showed C-indices of 0.704 and 0.691 in the derivation and internal
[46]
validation cohorts, respectively . By comparison, the score proposed in this paper achieved a C-index of 0.79
[47]
(0.7-0.89). Attallah et al. reported the simplified HCC-ART score for HCC detection in chronic hepatitis
C patients from Egypt based on age, AFP, AST/ALT ratio, albumin and alkaline phosphatase. The AUROC
curve for discriminating patients with HCC (n = 227) from those with liver cirrhosis (n = 341) was 0.95. Like
our work, they used easily obtainable laboratory tests.

Our study is somewhat limited by the fact that the model score was developed only on a Brazilian HCV