Serum IGFBP-3 is a more effective predictor than IGF-1 and IGF-2 for the development of hepatocellular carcinoma in patients with chronic HCV infection

Abstract

Hepatocellular carcinoma (HCC) contributes to 14.8% of all cancer mortality in Egypt, which has a high prevalence of hepatitis C virus (HCV). We have previously shown alterations in the insulin-like growth factor-1 (IGF-1) receptor signalling pathway during experimental hepatocarcinogenesis. The aim of this study was to determine whether serum levels of IGF-1, IGF-2 and IGFBP-3 can be used to discriminate between HCC and the stages of hepatic dysfunction in patients with liver cirrhosis assessed by the Child-Pugh (CP) score, and to correlate these levels with HCC stages. We recruited 241 subjects to the present study; 79 with liver cirrhosis, 62 with HCV-induced HCC and 100 age-matched controls. Results showed that serum levels of IGF-1, IGF-2 and IGFBP-3 were reduced significantly in cirrhosis and HCC patients in comparison to the controls, and that this reduction negatively correlated with the CP scores. However, only IGFBP-3 levels showed significant negative correlation with α-fetoprotein levels. The reduction in IGF-1 and IGFBP-3 but not IGF-2 levels was significant in HCC in comparison to patients with cirrhosis. None of the parameters significantly correlated with the HCC stage. IGFBP-3 levels discriminated between cirrhosis and HCC at a sensitivity of 87%, a specificity of 80% and a cut-off value of <682.6 ng/ml. In conclusion, although our results showed that serum IGF-1, IGF-2 and IGFBP-3 are reduced with the progression of hepatic dysfunction, only IGFBP-3 may be considered as the most promising serological marker for the prediction of the development of HCC in the chronic HCV patients with liver cirrhosis.

Figure 1

Mean serum levels of (A) IGF-1, (B) IGF-2 and (C) IGFBP-3 decrease in cirrhosis and in HCC patients in comparison to those of healthy subjects.

Figure 2

Significant negative correlation between Child-Pugh score and (A) IGF-1, (B) IGF-2 and (C) IGFBP-3 levels in patients with liver cirrhosis (p≤0.05). (D) Significant negative correlation between IGFBP-3 and α-fetoprotein (AFP) in patients with liver cirrhosis.

Figure 3

Receiver-operating characteristic (ROC) curves for serum (A) IGFBP-3, (B) IGF-1 and IGF-2, (C) IGF-1 and IGFBP-3 and (D) IGF-2 and IGFBP-3 levels to establish the optimal cut-off values for the prediction of the development of HCC in patients with liver cirrhosis. The areas under the ROC curves are 0.93, 0.78, 0.93 and 0.9 for (A) IGFBP-3, (B) IGF-1 and IGF-2, (C) IGF-1 and IGFBP-3 and (D) IGF-2 and IGFBP-3 levels, respectively.