Dynamic Changes in Serum Markers and Their Utility in the Early Diagnosis of All Stages of Hepatitis B-Associated Hepatocellular Carcinoma

Abstract

Objective: This study aimed to evaluate the individual and combined diagnostic values of serum alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP), glypican-3 (GPC3) and golgi protein 73 (GP73) in diagnosing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).

Methods: Participants from Beijing YouAn Hospital were enrolled and divided into seven groups. Serum was collected and the levels of AFP, GPC3, GP73 and DCP were simultaneously measured with a protein array. Pearson's χ² test was applied to compare the clinicopathological characteristics. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic performance of the four markers.

Results: As a single biomarker for differentiating HCC from all controls, AFP had a larger area under the curve (AUC) (0.798, 95% CI (0.754-0.838) than the other biomarkers, with a sensitivity of 77.3% and a specificity of 71.1%. Among the other combinations, AFP plus GPC3 and DCP (0.871, 95% CI (0.833-0.903)) was the best at differentiating HCC from all controls. In discriminating very early stage and early stage HCC from all controls, the AUC of GPC3 (0.744, 95% CI (0.690-0.793); sensitivity 62.8%; specificity 83.3%) was better than that of AFP (0.723, 95% CI (0.668-0.774); sensitivity 67.3%; specificity 71.7%). Among all biomarker combinations, the combination of AFP, GPC3 and GP73 had the largest AUC (0.843, 95% CI (0.796-0.883); sensitivity 84.1%; specificity 71.7%). AFP (AUC 0.726, 95% CI (0.662-0.784)) showed the best performance in the very early diagnosis of HBV-related HCC.

Conclusion: As a single biomarker, AFP has an advantage in the very early and early diagnosis of HBV-related HCC. The combination of AFP, GPC3 and GP73 is the most suitable marker for the early diagnosis of HBV-related HCC. However, AFP remains the best biomarker for the very early diagnosis of HBV-related HCC, and the adding of one or more markers does not significantly improve the diagnostic accuracy.

Keywords: diagnosis; hepatitis B virus; hepatocellular carcinoma; protein array.

Figure 1

The levels of serum AFP, GPC3, GP73 and DCP in each subgroup. (A) AFP. (B) GPC3. (C) GP73. (D) DCP. (E) Representative image of each subgroup. *P<0.05,  **P <0.01. Abbreviations: HCC, hepatocellular carcinoma; LC, liver cirrhosis; CHB, chronic hepatitis B virus infection; HC, healthy controls; AFP, α-fetoprotein; GPC3, glypican 3; GP73, golgi protein 73; DCP, des-γ-carboxy prothrombin; ns, no significance; int, intensity.

Figure 2

Assessment of the diagnostic value of serum AFP, GPC3, GP73 and DCP in differentiating HBV-related HCC from controls. (A) All HCC vs LC, CHB, HC. (B) All HCC vs LC, CHB. (C) All HCC vs LC. (D) Very early and early stage HCC vs LC, CHB, HC. (E) Very early and early stage HCC vs LC, CHB. (F) Very early and early stage HCC vs LC. Abbreviations: HCC, hepatocellular carcinoma; LC, liver cirrhosis; CHB, chronic hepatitis B virus infection; HC, healthy controls; AFP, α-fetoprotein; GPC3, glypican 3; GP73, golgi protein 73; DCP, des-γ-carboxy prothrombin.

Figure 3

The value of serum AFP, GPC3, GP73 and DCP in the very early diagnosis of HBV-related HCC. (A) Very early stage HCC vs LC, CHB, HC. (B) Very early stage vs LC, CHB. (C) Very early stage vs LC. Abbreviations: HCC, hepatocellular carcinoma; LC, liver cirrhosis; CHB, chronic hepatitis B virus infection; HC, healthy controls; AFP, α-fetoprotein; GPC3, glypican 3; GP73, golgi protein 73; DCP, des-γ-carboxy prothrombin.