Despite the advent of newer imaging modalities for accurate and earlier
hepatocellular carcinoma (HCC) detection, no method is sensitive enough. Here, we aimed to evaluate the accuracy of B7-H4 and dickkopf-1 (DKK1) combination for early HCC differentiating from premalignant liver cirrhosis or fibrosis. A total of 210 chronic hepatitis C (CHC) patients (110 with HCC and 100 were non-HCC patients (45 cirrhosis and 55 fibrosis) were included. Both B7-H4 and DKK1 were screened for all cases. HCC patients were distinctly (P<0.05) associated with high B7-H4 (44.8±5.3) and DKK1 (5.4±2.1) levels (ng/mL) compared to cirrhotic (38.9±4.6, 2.6±0.8, respectively) and fibrotic (33.5±6.6, 2.2±0.6, respectively) controls. For separating HCC, both B7-H4 (AUC=0.863) and DKK1 (AUC=0.852) had a good diagnostic power superior to AFP (AUC=0.802). Multiplying B7-H4 with DKK1 exhibited values that significantly (P=0.0001) increased in HCC patients (192.3 (120.2-380.1)) versus patients with hepatic cirrhosis (99.9 (85.6-111.2)) and fibrosis (77.2 (63.1-100.1)). This index improves HCC diagnostic performances [AUC=0.892; sensitivity 80.9%, specificity 77%, PPV 79.5%, NPV 78.6% and efficiency 79.1%]. Elevated B7-H4×DKK1 values were strongly correlated with aggressive features including multiple lesions, large size, Child-Pugh and BCLC late stages. In conclusion, B7-H4×DKK1 is reliable, feasible and simple HCC diagnostic blood based method that could improve diagnostic sensitivity and accuracy and could represent an addition in follow up and management of cases with premalignant liver disorders.