BACKGROUND AND AIM: The natural history of chronic hepatitis B virus (HBV) infection is usually divided into four phases: immune tolerant (IT), immune active (IA), immune carrier (IC), and immune reactive (IR). Many patients still cannot be classified into the four phases, called "Grey Zone (GZ)". This study aimed to analyze the liver histological features of the GZ patients to guide antiviral therapy. METHODS: We retrospectively analyzed the 1454 patients with chronic HBV infection who underwent liver biopsy. GZ patients with identical serum hepatitis Be antigen (HBeAg) and alanine aminotransferase (ALT) levels as those in the IT, IA, IC, and IR phases were categorized into the IT-GZ, IA-GZ-1, IA-GZ-2, IC-GZ, and IR-GZ groups, respectively. We analyzed and compared the histological distribution of liver in these patients. We evaluated independent influencing factors for significant liver histological changes (SLHC) in patients in the GZ subgroups. RESULTS: Among the 1454 patients, 690(47.5%) patients in GZ. Among the 690 patients of the GZ, 322(46.7%) patients for whom histological examinations indicated SLHC. The proportion of SLHC within the GZ subgroups was as follows: IT-GZ (50.5%), IA-GZ-1 (75.0%), IA-GZ-2 (48.4%), IC-GZ (32.1%), and IR-GZ (59.6%). In the IT-GZ group, the proportion of patients aged ≤ 30 years with SLHC was 47.1%, and in the IC-GZ group, this proportion was 42.1%. CONCLUSIONS: 46.7% of GZ patients had significant liver histological changes. For HBeAg-negative patients with ALT ≤ 40U/L, HBV DNA ≥ 2000IU/mL, and an age of ≤ 30 years old, antiviral therapy was recommended
if they expressed concern, a liver biopsy was suggested.