Bilirubin is a superior biomarker for hepatocellular carcinoma diagnosis and for differential diagnosis of benign liver disease

Abstract Objectives To develop a novel diagnostic model combining bilirubin, protein induced by vitamin K absence or antagonist-II (PIVKA-II), and alpha-fetoprotein (AFP) to improve HCC diagnosis. Methods The serum levels of PIVKA-Ⅱ, AFP, and bilirubin in 718 hepatocellular carcinoma (HCC) patients and 2,763 benign liver disease (BLD) patients were measured. A mathematical model was used as the combined diagnostic model (PIVKA-Ⅱ, AFP, and bilirubin: PAB combination) for improving HCC diagnosis. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic value of the individual markers, the PIVKA-II and AFP (PA) combination, and the PAB combination for HCC diagnosis. Results With the increase in bilirubin, the positive predictive value (PPV) of bilirubin in HCC diagnosis decreased (p<0.001) while the negative predictive value (NPV) increased (p<0.001). The areas under the ROC curves (AUCs) of the PAB combination were 0.935 and 0.862 for the diagnosis of HCC and HCC<3.0 cm, respectively, which were significantly higher than those of PIVKA-Ⅱ, AFP, and the PA combination (p<0.001). The AUC values for PIVKA-Ⅱ, AFP, and the PA combination were significantly decreased for the diagnosis of HCC and HCC<3.0 cm when serum levels of PIVKA-Ⅱ≥40 mAU/mL and/or AFP≥20 ng/mL were used for diagnosis, while the AUC value of the PAB combination increased. Conclusions Bilirubin is a superior biomarker for diagnosing HCC and distinguishing HCC from BLD. The combination of bilirubin with PIVKA-Ⅱ and AFP has superior diagnostic value for HCC and early-stage HCC.