Omari Y, Almeqdadi M. Phase-dependent interpretation of quantitative hepatitis B surface antigen and hepatocellular carcinoma risk in chronic hepatitis B infection. World J Hepatol 2026; 18(6): 119837 [DOI: 10.4254/wjh.119837]
Corresponding Author of This Article
Yazan Omari, MD, Internal Medicine, Henry Ford Health, 16001 West 9 Mile Road, Southfield, MI 48075, United States. yazanomari12@gmail.com
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Gastroenterology & Hepatology
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review-article
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Omari Y, Almeqdadi M. Phase-dependent interpretation of quantitative hepatitis B surface antigen and hepatocellular carcinoma risk in chronic hepatitis B infection. World J Hepatol 2026; 18(6): 119837 [DOI: 10.4254/wjh.119837]
World J Hepatol. Jun 27, 2026; 18(6): 119837 Published online Jun 27, 2026. doi: 10.4254/wjh.119837
Phase-dependent interpretation of quantitative hepatitis B surface antigen and hepatocellular carcinoma risk in chronic hepatitis B infection
Mohammad Almeqdadi, Yazan Omari
Yazan Omari, Internal Medicine, Henry Ford Health, Southfield, MI 48075, United States
Mohammad Almeqdadi, Department of Transplant and Hepatobiliary Disease, Tufts Medical Center, Boston, MA 02111, United States
Author contributions: Omari Y performed the literature search and wrote the original draft; Almeqdadi M reviewed and edited the manuscript; Omari Y and Almeqdadi M conceptualized the minireview; all authors have read and approved the final manuscript.
AI contribution statement: No AI tools, including ChatGPT, Grammarly, DeepL, or any other generative AI systems, were used in the preparation of this response to reviewers document and this manuscript. No portion of the manuscript or our response document was AI-generated. No AI tools were used for language polishing, translation, data analysis, or writing assistance. No AI tools participated in the design of the study, data interpretation, or scientific analysis. No images included in the manuscript were generated by AI.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Corresponding author: Yazan Omari, MD, Internal Medicine, Henry Ford Health, 16001 West 9 Mile Road, Southfield, MI 48075, United States. yazanomari12@gmail.com
Received: February 7, 2026 Revised: March 17, 2026 Accepted: May 26, 2026 Published online: June 27, 2026 Processing time: 134 Days and 9.8 Hours
Abstract
Quantitative hepatitis B surface antigen (qHBsAg) is one of the known and commonly utilized blood tests that shows the total hepatitis B virus (HBV) antigen production from 2 distinct sources: (1) Transcriptionally active covalently closed circular DNA; and (2) The HBV DNA that is already integrated to the host genome. Its use has resulted in inconsistent results across patients with different stages of hepatitis B and therefore has limited its clinical utility. For this reason, this marker is yet to be adopted on a larger scale for routine hepatocellular carcinoma (HCC) cancer prediction. Emerging evidence suggests that the prognostic meaning of qHBsAg is heavily impacted by the phase of HBV infection and the underlying source of the antigen presence. For instance, in patients with hepatitis B e antigen+ chronic infection, elevated qHBsAg levels do indicate a state of active covalently closed circular DNA transcription and active viral replication, and higher HBsAg levels (> 10000 IU/mL) are paradoxically associated with delayed HCC development. In contrast, in patients with negative hepatitis B e antigen and a low viral load (< 2000 IU/mL), high qHBsAg (> 1000 IU/mL) suggests replication-independent HBsAg production from the integrated HBV DNA and is strongly associated with increased risk of HCC with an adjusted hazard ratio of 13.7 (95%CI: 4.8-39.3). This minireview analyzes the current data and presents a phase-dependent framework for interpreting qHBsAg in untreated chronic hepatitis B virus patients. We also discuss how it can be used in clinical practice as a complementary test to stratify the risk of developing HCC in those patients.
Core Tip: Quantitative hepatitis B surface antigen can serve as a complementary predictor of development of hepatocellular carcinoma among chronic hepatitis B patients. However, its interpretation is largely dependent on the phase of chronic hepatitis B at which it was measured. This phase-dependence arise from inherent differences in the pathophysiology of viral replication (from covalently closed circular DNA in early stages to integration-driven antigen production in later stages) and evolving host immune control. Clinically, quantitative hepatitis B surface antigen offers the most predictive value in hepatitis B e antigen negative patients with low viremia (< 2000 IU/mL). In this group, persistently elevated marker level (> 1000 IU/mL) can identify patients with significantly increased risk of developing hepatocellular carcinoma who warrant closer monitoring or earlier treatment discussion. Recognizing this in context is essential for appropriate clinical use.
