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Revisiting the Gray Zone in HBeAg-Negative Chronic Hepatitis B: Insights From a Multicenter Liver Biopsy Cohort

Publish Date: August 11, 2026
Özlem Gül ORCID Hüseyin Köseoğlu ORCID Selim Yalçın ORCID Barış Yılmaz Dilek Oğuz ORCID Sema Zergeroğlu ORCID Bilal Ergül ORCID
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Turkish Journal of Gastroenterology

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Published Online: August 11, 2026

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This work is licensed under a Creative Commons Attribution 4.0 International License.

Özlem Gül ORCID
Department of Gastroenterology, Lokman Hekim University Faculty of Medicine, Ankara, Türkiye
Hüseyin Köseoğlu ORCID
Department of Gastroenterology, Hitit University Faculty of Medicine, Çorum, Türkiye
Selim Yalçın ORCID
Department of Oncology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Barış Yılmaz
Department of Gastroenterology, Hitit University Faculty of Medicine, Çorum, Türkiye
Dilek Oğuz ORCID
Department of Oncology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Sema Zergeroğlu ORCID
Department of Pathology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Bilal Ergül ORCID
Department of Gastroenterology, Lokman Hekim University Faculty of Medicine, Ankara, Türkiye
Gül, Özlem, Köseoğlu, H., Yalçın, S., Yılmaz, B., Oğuz, D., Zergeroğlu, S., & Ergül, B. (2026). Revisiting the Gray Zone in HBeAg-Negative Chronic Hepatitis B: Insights From a Multicenter Liver Biopsy Cohort. Turkish Journal of Gastroenterology. https://doi.org/10.5152/tjg.2026.26367
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Abstract

Background/Aims: The management of patients with HBeAg-negative chronic hepatitis B (CHB) with intermediate viremia and persistently normal alanine aminotransferase (ALT) levels remains controversial. This “gray-zone” (GZ) population may harbor significant histological liver injury despite not meeting conventional treatment criteria. This study characterized the histologic features of this GZ population and compared their clinical and laboratory characteristics.

Materials and Methods: In this multicenter retrospective study, patients with HBeAg negative CHB who had hepatitis B virus (HBV) DNA levels between 2000 and 20 000 IU/mL and persistently normal ALT levels and who underwent liver biopsy between 2014 and 2022 were included. Histological assessment was performed using the modified Ishak scoring system. Significant fibrosis was defined as Ishak stage of 2 or greater. Clinical, virological, and noninvasive fibrosis parameters were analyzed.

Results: A total of 145 patients were included (mean age: 46.3 ± 12.6 years; 54.5% female). Significant fibrosis and/or moderate-tosevere necroinflammatory activity requiring antiviral therapy was identified in 109 patients (75.1%). Although ALT and aspartate aminotransferase levels remained within normal reference range, both were significantly higher in the treatment group compared than in the nontreatment group (P = .003 and P = .018, respectively). Aspartate aminotransferase-to-platelet ration index (APRI) scores were also significantly elevated among treated patients (P = .02), whereas Fibrorsis-4 (FIB-4) scores did not differ significantly. HBV DNA and quantitative Hepatitis B surface antigen (HBsAg) levels were comparable between groups.

Conclusion: A substantial proportion of patients with HBeAg-negative CHB in the GZ exhibited clinically significant histologic disease despite persistently normal ALT levels. Reliance solely on conventional biochemical thresholds may underestimate the burden of fibrosis. Early histological evaluation and more proactive treatment strategies should be considered for selected patients in the GZ.

Cite this article as: Gül Ö, Köseoğlu H, Yalçın S, et al. Revisiting the gray zone in HBeAg negative chronic hepatitis B: Insights from a multicenter liver biopsy cohort. Turk J Gastroenterol. Published online August 11, 2026. doi: 10.5152/tjg.2026.26367.

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Article Info
Published In
Journal Turkish Journal of Gastroenterology
DOI 10.5152/tjg.2026.26367
History
Published Online August 11, 2026
License
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Affiliations
Özlem Gül ORCID
Department of Gastroenterology, Lokman Hekim University Faculty of Medicine, Ankara, Türkiye
Hüseyin Köseoğlu ORCID
Department of Gastroenterology, Hitit University Faculty of Medicine, Çorum, Türkiye
Selim Yalçın ORCID
Department of Oncology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Barış Yılmaz
Department of Gastroenterology, Hitit University Faculty of Medicine, Çorum, Türkiye
Dilek Oğuz ORCID
Department of Oncology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Sema Zergeroğlu ORCID
Department of Pathology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Bilal Ergül ORCID
Department of Gastroenterology, Lokman Hekim University Faculty of Medicine, Ankara, Türkiye
Cite this Article
Gül, Özlem, Köseoğlu, H., Yalçın, S., Yılmaz, B., Oğuz, D., Zergeroğlu, S., & Ergül, B. (2026). Revisiting the Gray Zone in HBeAg-Negative Chronic Hepatitis B: Insights From a Multicenter Liver Biopsy Cohort. Turkish Journal of Gastroenterology. https://doi.org/10.5152/tjg.2026.26367
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