Hepatocyte Proliferation and Risk of Hepatocellular Carcinoma in Cirrhotic Patients

High hepatocyte proliferation has been recently proposed as a risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess whether hepatocyte proliferation is an independent risk factor for HCC when considered together with clinical and demographic characteristics. We retrospectively evaluated 97 consecutive patients with a histological diagnosis of cirrhosis and preserved liver function, enrolled in a surveillance program for early diagnosis of HCC. Hepatocyte proliferation was evaluated by flow-cytometric analysis in liver samples collected at the time of histological diagnosis of cirrhosis. All patients were followed with abdominal US and serum α-fetoprotein (AFP) assays every 6 months. During a mean follow-up of 53 months (range, 12–120 months), 12 patients developed HCC, giving an annual incidence of 2.8%. The mean S-phase fraction was 2.5%± 1.6 in patients who developed HCC and 0.9%± 0.6 in those who did not (p < 0.0001). By univariate analysis, S-phase fraction 1.8% or higher and AFP higher than 20 ng/ml were the only two variables significantly correlated with the development of HCC (p < 0.0001, p < 0.0001). Multivariate analysis found that both variables were independently associated with HCC development (p < 0.003 and p < 0.005, respectively), with hazard ratios of 8.0 and 7.3 (confidence intervals, 2.1–31.2 and 1.8–29.2). Among patients with high AFP and/or high S-phase fraction, 11 (39%) developed HCC, compared with only one (1%) with a low S-phase fraction and normal AFP, corresponding to HCC yearly incidences of 9.5% and 0.3% (p < 0.00009). Patients with high S-phase fraction and/or above-normal serum AFP are at higher risk of developing HCC and should be offered a close surveillance program.