Skip to content
DraconiticResearch
Search Sources API
223,421 studies31 sourcesUpdated 16 min ago
Peer-reviewedCC BY 4.0The Turkish Journal of Gastroenterology

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

  • Özlem Gül1
  • Hüseyin Köseoğlu2
  • Selim Yalçın3
  • Barış Yılmaz2
  • Dilek Oğuz4
  • Sema Zergeroğlu5
  • Bilal Ergül1
5 affiliations
  1. 1Department of Gastroenterology, Lokman Hekim University Faculty of Medicine, Ankara, Türkiye
  2. 2Department of Gastroenterology, Hitit University Faculty of Medicine, Çorum, Türkiye
  3. 3Department of Oncology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
  4. 4Department of Gastroenterology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
  5. 5Department of Pathology, Kırıkkale University Faculty of Medicine, Kırıkkale, Türkiye
Read full textPDFDOICite

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-to-severe 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.

Related

  1. Reply to ‘DR1-DR2 enrichment in HBeAg-negative chronic hepatitis B: integration hotspot or survivor signature?’
    Daryl T-Y Lau, Ying-Hsiu Su, Haitao Guo
    GutPeer-reviewedLicence not statedFull textEpidemiology & public healthPMC
  2. Natural History and Clinical Outcomes of HBeAg-Negative Chronic Hepatitis B Patients in the “Grey Zone”: A Longitudinal Cohort Study
    Yunling Xue, Mengyuan Liu, Guorui Wang +7
    Journal of Clinical MedicinePeer-reviewedCC BY 4.0Epidemiology & public healthCrossref
  3. Associations of social support and disease-specific quality of life with self-management among patients with chronic hepatitis B: a multicenter cross-sectional study.
    Wen-Ting Yi, Ling-Ling Li, Mao-Ting Huang +7
    Frontiers in public healthPeer-reviewedCC BYFull textEpidemiology & public healthEurope PMCCrossref
  4. Evolutionary and functional landscape of HBx mutations in genotype D1 HBV: comparative insights from acute infection, chronic hepatitis, and HCC.
    Kamyar Mazloum Jalali, Ali Sameer Alkhawaja, Ilyos Xursandov +5
    Infectious agents and cancerPeer-reviewedCC BY-NC-NDFull text1 citedEpidemiology & public healthEurope PMCPMC
  5. Revisiting brain asymmetry in schizophrenia: insights from machine learning subtypes from 1,761 patients
    Lu Jin, Zhaoyun Liu, Xiao Chang +18
    BMC MedicinePeer-reviewedCC BY-NC-ND 4.0Psychiatry & mental healthCrossref

Cite

BibTeXRIS
BibTeX
@article{gul2026revisiting,
  title = {{Revisiting the Gray Zone in HBeAg-Negative Chronic Hepatitis B: Insights From a Multicenter Liver Biopsy Cohort}},
  author = {Özlem Gül and Hüseyin Köseoğlu and Selim Yalçın and Barış Yılmaz and Dilek Oğuz and Sema Zergeroğlu and Bilal Ergül},
  journal = {The Turkish Journal of Gastroenterology},
  year = {2026},
  month = aug,
  doi = {10.5152/tjg.2026.26367},
  url = {https://doi.org/10.5152/tjg.2026.26367},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Revisiting the Gray Zone in HBeAg-Negative Chronic Hepatitis B: Insights From a Multicenter Liver Biopsy Cohort
AU  - Özlem Gül
AU  - Hüseyin Köseoğlu
AU  - Selim Yalçın
AU  - Barış Yılmaz
AU  - Dilek Oğuz
AU  - Sema Zergeroğlu
AU  - Bilal Ergül
PY  - 2026
DA  - 2026/08/11
JO  - The Turkish Journal of Gastroenterology
DO  - 10.5152/tjg.2026.26367
UR  - https://doi.org/10.5152/tjg.2026.26367
AB  - 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-to-severe 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.
SN  - 1300-4948
SN  - 2148-5607
ER  -