Evaluating the combined diagnostic power of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II for hepatocellular carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally, largely due to delayed diagnosis. Alpha-fetoprotein (AFP), a traditional biomarker for HCC, suffers from limited sensitivity and specificity, particularly in early-stage disease. Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has emerged as a promising complementary marker. This study aimed to evaluate the diagnostic performance of AFP and PIVKA-II, individually and in combination, in HCC detection.

Methods: A total of 210 HCC patients and 270 chronic hepatitis B (CHB) patients were enrolled between June 2021 and February 2023. Additionally, 91 HCC patients and 88 CHB patients were included as a validation cohort. Serum levels of AFP and PIVKA-II were measured, and their diagnostic efficacy was assessed using receiver operating characteristic (ROC) curve analysis. A multivariate logistic regression model incorporating clinical features and biomarkers was developed and validated. A meta-analysis of relevant studies was also conducted to further confirm the diagnostic value of AFP.

Results: PIVKA-II levels were significantly higher in HCC patients compared to CHB controls and showed superior diagnostic performance [area under the curve (AUC) =0.970] compared to AFP (AUC =0.890). The combination of AFP and PIVKA-II significantly improved sensitivity (98.6%) and specificity (91.1%). A predictive model integrating AFP, PIVKA-II, age, sex, aspartate aminotransferase (AST), and albumin (ALB) demonstrated excellent diagnostic accuracy (AUC =0.995) and was successfully validated (AUC =0.986). Meta-analysis supported AFP as a reliable biomarker for HCC, although with heterogeneity across studies. PIVKA-II was also effective in monitoring treatment response, with postoperative levels markedly decreasing in patients undergoing hepatectomy.

Conclusions: PIVKA-II offers superior diagnostic accuracy for HCC and complements AFP to enhance early detection, especially in AFP-insensitive cases. The combined biomarker strategy and predictive model provide a robust framework for clinical screening and early intervention. Integration of PIVKA-II into routine diagnostic workflows could improve patient outcomes and reduce diagnostic delays in HCC.

Keywords: Hepatocellular carcinoma (HCC); alpha-fetoprotein (AFP); diagnostic biomarkers; early detection; protein induced by vitamin K absence or antagonist-II (PIVKA-II).

Figure 1

Comparison of serum AFP and PIVKA-II levels between HCC and CHB patients. (A) Serum AFP and PIVKA-II levels in HCC patients and CHB patients. (B) Serum AFP and PIVKA-II levels in the preoperative and postoperative groups. AFP, alpha-fetoprotein; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; PIVKA-II, protein induced by vitamin K absence or antagonist-II.

Figure 2

ROC curve analysis of AFP and PIVKA-II in HCC diagnosis and their correlation with tumor characteristics. (A) The AUC and diagnostic accuracy of AFP and PIVKA-II for HCC patients versus CHB patients. (B) Serum AFP and PIVKA-II levels in different tumor diameters. (C) Correlation of AFP, PIVKA-II and tumor diameter. ns, not significant (P>0.05). AFP, alpha-fetoprotein; AUC, area under the curve; CI, confidence interval; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; PIVKA-II, protein induced by vitamin K absence or antagonist-II; ROC, receiver operating characteristic.

Figure 3

Nomogram for predicting HCC incidence based on multivariate logistic regression analysis. (A) Predictive modelling of HCC based on logistic regression analysis (nomogram). (B) The AUC and diagnostic accuracy of predictors (gender, age, LnAFP, LnPIVKA-II, AST, and ALB) and predictive models. (C) The AUC and diagnostic accuracy of the validation set. (D) Goodness of fit of the nomogram model. ALB, albumin; AST, aspartate aminotransferase; AUC, area under the curve; CI, confidence interval; HCC, hepatocellular carcinoma; LnAFP, natural logarithm of alpha-fetoprotein; LnPIVKA-II, natural logarithm of protein induced by vitamin K absence or antagonist-II.

Figure 4

Diagnostic efficacy of combined HGF, AFP, and PIVKA-II in differentiating HCC from CHB patients. (A) The AUC and diagnostic accuracy of AFP, PIVKA-II, and HGF in patients with HCC and patients with CHB of the validation set. (B) Correlation of HGF with AFP, PIVKA-II, and other serum markers. γ-GGT, γ-glutamyl transpeptidase; AFP, alpha-fetoprotein; ALB, albumin; AST, aspartate aminotransferase; AUC, area under the curve; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; PIVKA-II, protein induced by vitamin K absence or antagonist-II.

Figure 5

Literature screening process and quality assessment results. (A) Flowchart of literature inclusion. (B) Summary of bias risk assessment for included studies. CNKI, China National Knowledge Infrastructure.

Figure 6

Meta-analysis of AFP in HCC diagnosis. (A) Forest plot of the meta-analysis for AFP in HCC diagnosis. (B) Sensitivity analysis forest plot for AFP in HCC diagnosis. (C) Publication bias assessment results for AFP in HCC diagnosis. AFP, alpha-fetoprotein; CI, confidence interval; HCC, hepatocellular carcinoma; MD, mean difference; SD, standard deviation.

Figure 7

Molecular mechanism of PIVKA-II, AFP, and HGF in HCC diagnosis. AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; PIVKA-II, protein induced by vitamin K absence or antagonist-II.