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Three cut-off levels of the model score were considered, and bootstrap analysis was applied to determine the
optimal values for sensitivity and specificity [Table 3], since the diagnostic measures were calculated based
on internal validation. The cut-off level with the best sensitivity and specificity was 54, with a sensitivity of
81% (64%-94%) and a specificity of 60% (47%-71%). In the scenario of 3% prevalence of HCC risk in HCV
cirrhotic patients the best cut off value to exclude HCC is 26 [sensitivity = 100% (89%-100%); specificity = 23%
(14%-34%); PPV = 3.7%; NPV = 99.1%], and the best cut off to include HCC is 100 [sensitivity = 26% (14%-43%);
specificity = 100% (94%-100%); PPV = 44.6%; NPV = 97.7%]. When we changed the scenario prevalence to
10%, the results show better performances from the positive predictive values, from 5.8% to 18% at a cut off
level of 54, from 44.6% to 74.2% at cut off level of 100, and from 3.7% to 12.2% at cut off level of 26.

DISCUSSION
This case control study analyzed clinical and laboratory parameters used in routine daily practice, aiming to
identify patients with HCV-related cirrhosis at increased risk of HCC presence. We found that higher serum
AFP and ALT levels, and lower platelet count were independent prediction factors of HCC. Such information
could be used to develop more cost-effective screening strategies.

[26]
The median age in both groups was 59 years old. Velázquez et al. demonstrated that an age of ≥ 55 years is
an independent risk factor for HCC among patients with cirrhosis and HCV. Other published data suggest
[27]
[6]
a higher incidence of HCC from the age of 60 . Lok et al. also found that older age is a predictive factor
for HCC development. The HCC group (31 patients) had male:female ratio of 1.8:1; this finding is consistent
[24]
with data from the literature showing that the prevalence of HCC is 2 to 4 times higher in male patients .
We found no differences in liver related outcomes, such as ascites, spontaneous bacterial peritonitis,
esophageal varices, variceal bleeding or hepatic encephalopathy between groups. This suggests that HCC
does not alter the pathogenesis of the early clinical stages of HCV-related cirrhosis in more advanced stages.
A previous study showed that hepatic encephalopathy and ascites were not related to the development of
[27]
[28]
[29]
HCC, although esophageal varices were . The latter was also observed by Lok et al. . Bolondi et al.
assessed the cost-effectiveness of HCC screening by comparing 313 patients with cirrhosis and 104 patients
with cirrhosis and HCC, and identified the functional classes Child-Pugh B and C as independent risk
factors for HCC. Our results are different, possibly due to the small number of patients and also because
most of them had preserved liver function (Child-Pugh A). However they do point to the need for
identifying multiple risk factors, beyond the clinical stage of cirrhosis to allow earlier identification of risk.
This is of great importance in improving the management and prognosis of patients with HCC.

Sustained virological response (SVR) occurred in 24% of the control group, while no patients in the HCC
group exhibited SVR. Several studies have demonstrated the beneficial impact of HCV clearance with
[30]
interferon in reducing HCC occurrence . In a multiple logistic regression analysis, AFP, ALT and platelet
count were related to higher risk of HCC. In our previous cohort study of patients with cirrhosis, we found
the following risk factors for HCC; AFP > 20 ng/mL, albumin < 3.4 g/dL and patients of East Asian ethnicity
[16]
as the best of seven possible models applied to predict HCC risk . In the present study AFP > 20 ng/mL
was confirmed as a predictive risk factor for the presence of HCC. The diagnostic importance of AFP has
been the subject of much scientific debate in recent years. In some studies, a high base value of AFP has been
considered a risk factor for HCC, with a cut-off level of 20 ng/mL for determining groups of high and low
[29]
risk . AFP levels above 400 ng/mL in the presence of a hepatic nodule in imaging finding, is a conclusive
[28]
HCC diagnosis . However, small HCC tumors (< 2 cm) involve low-level secretion of AFP and thus, in most
[32]
[31]
cases the patients cannot be diagnosed using this test alone . In a prospective study, Tong et al. analyzed
31 patients with cirrhosis and hepatitis B virus or HCV who had developed HCC; they found AFP values
above 400 ng/mL in only 4(13%). It is important to note that the AFP levels may be higher in individuals