# Liver histological study of patients with chronic hepatitis B virus infection in the grey zone

## TL;DR

This study examines liver tissue in patients with chronic hepatitis B virus infection who fall into an ambiguous 'grey zone' classification, aiming to guide treatment decisions.

## Contribution

The study identifies liver histological patterns in 'grey zone' hepatitis B patients to inform antiviral therapy recommendations.

## Key findings

- 46.7% of grey zone patients showed significant liver histological changes.
- Age ≤30 years was associated with significant liver changes in certain grey zone subgroups.
- Antiviral therapy is recommended for HBeAg-negative patients with specific viral and age criteria.

## Abstract

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.

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.

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%.

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.

The online version contains supplementary material available at 10.1186/s12879-025-10790-0.