Abstract
Introduction: This study evaluated the diagnostic performance of conventional blood-based biomarkers fordetecting hepatocellular carcinoma (HCC) in patients with chronic liver disease (CLD).Methods: In this prospective case-control study, adults with CLD (with and without HCC) underwent blood sampling for alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and cell-free DNA (cfDNA). Diagnostic performance was assessed individually and in combination using regression analyses, with radiological imaging as the reference standard. Pre- and post-treatment biomarker levels were analyzed in a subset of HCC patients.Results: Among 453 analyzed participants (131 HCC, 322 non-HCC controls), AUROCs for AFP, DCP, and cfDNAwere 0.84, 0.76, and 0.64, respectively. At Youden index-derived thresholds, sensitivities were 62% for AFP, 65%for DCP, and 59% for cfDNA, with corresponding specificities of 93%, 74%, and 64%. Combining biomarkers viaregression models did not improve diagnostic performance. AFP demonstrated poor sensitivity (32%) for earlystageHCC detection, and performance varied by disease etiology. Among treatment response markers, DCPshowed superior potential.Conclusion: In a real-world CLD cohort, conventional blood-based biomarkers demonstrate limited sensitivity forearly-stage HCC detection. These findings highlight the need for molecular and genetic approaches to improveearly HCC diagnosis.