Ultrasound and Biomarker-Based Surveillance for Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Infection: A Review

Abstract

Six-monthly ultrasound, with or without alpha-fetoprotein, is the surveillance strategy recommended worldwide for patients at risk of hepatocellular carcinoma. Its purpose is to find tumours while they are still curable. Pooled across the literature, ultrasound alone finds fewer than half of them at that stage. Objectives: To review the published evidence on ultrasound and serum biomarker surveillance for hepatocellular carcinoma, with particular reference to chronic hepatitis B: what ultrasound detects and at what stage, what alpha-fetoprotein adds, how multi-marker panels compare, and what determines whether a surveillance ultrasound is interpretable at all.
Material and Methods: Narrative review of diagnostic accuracy meta-analyses, biomarker validation cohorts, imaging quality studies and society guidance indexed in PubMed and the major hepatology journals. Studies were eligible if they reported the accuracy of surveillance imaging or serum markers for hepatocellular carcinoma in a defined at-risk population, or factors affecting the performance of either. No new patient data were generated; every accuracy estimate quoted is one published by the original investigators. Results: Pooling 32 studies, ultrasound detected hepatocellular carcinoma at any stage with 84 per cent sensitivity but early-stage disease with only 47 per cent, and the area under the curve fell from 0.96 for any stage to 0.88 for early stage. Adding alpha-fetoprotein raised early-stage sensitivity from 45 to 63 per cent, a significant gain (p = 0.002) at a small cost in specificity. Multi-marker panels performed better: a serum score combining sex, age, alpha-fetoprotein, its L3 isoform and des-gamma-carboxy prothrombin achieved an area under the curve of 0.95 against 0.82 for ultrasound (p < 0.01), rising to 0.98 when combined with ultrasound. In a European cohort of patients with chronic hepatitis B, the same score reached 0.96, and 0.94 for early-stage disease against 0.86 for alpha-fetoprotein alone. Conclusion: The evidence does not support ultrasound alone as an adequate surveillance test. Alpha-fetoprotein should be added, and serum panels outperform both in reported cohorts, though they have been validated largely in populations with high disease prevalence and prospective surveillance data remain limited. Ultrasound quality is a further modifiable determinant that is rarely reported. Abbreviations: HCC – Hepatocellular Carcinoma, HBV – Hepatitis B Virus, CHB – Chronic Hepatitis B, AFP – Alpha-Fetoprotein, AFP-L3 – Lens Culinaris Agglutinin-Reactive AFP, DCP – Des-Gamma-Carboxy Prothrombin, GALAD – Gender, Age, AFP-L3, AFP and DCP model, US – Ultrasound, MRI – Magnetic Resonance Imaging, AUC – Area Under the Receiver Operating Characteristic Curve, BCLC – Barcelona Clinic Liver Cancer, NPV – Negative Predictive Value.