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

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.