Retrospective Cohort Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2023; 29(16): 2479-2494
Published online Apr 28, 2023. doi: 10.3748/wjg.v29.i16.2479
Liver histopathological lesions is severe in patients with normal alanine transaminase and low to moderate hepatitis B virus DNA replication
Su-Wen Jiang, Xiang Lian, Ai-Rong Hu, Jia-Lin Lu, Zhe-Yun He, Xiao-Jun Shi, De-Dong Zhu, Zong-Yi Wang, Guan-Cheng Huang
Su-Wen Jiang, Ai-Rong Hu, Zhe-Yun He, Xiao-Jun Shi, De-Dong Zhu, Ningbo Institute of Liver Diseases, Ningbo No. 2 Hospital, Ningbo 315020, Zhejiang Province, China
Xiang Lian, Department of Infectious Diseases, Xiangshan Hospital Affiliated to Wenzhou Medical University, Ningbo 315020, Zhejiang Province, China
Jia-Lin Lu, Zong-Yi Wang, Department of Infectious Diseases, The First Hospital of Ninghai County, Ningbo 315000, Zhejiang Province, China
Guan-Cheng Huang, Department of Infectious Diseases, The Affiliated Yang-Ming Hospital of Ningbo University, Ningbo 315400, Zhejiang Province, China
Author contributions: Hu AR contributed to the conception, design and administrative support; Jiang SW, Hu AR, Lian X, Shi XJ, Zhu DD, Wang ZY, Huang GC contributed to the provision of study materials or patients; Jiang SW, Lu JL, He ZY contributed to the collection and assembly of data; Jiang SW, Hu AR contributed to the data analysis and interpretation; and all authors final approval of manuscript.
Supported by Zhejiang Provincial Basic and Public Welfare Foundation, No. LGF22H030002; Ningbo Science and Technology Program, No.2021S182; Major Medical Scientific Research Foundation of National Health Commission of the People's Republic of China-Zhejiang Province, No. WKJ-ZJ-2341; and Zhejiang Province and Ningbo City Co-constructed Project of Leading Medical & Health Discipline, No. 2016-S04.
Institutional review board statement: The study was approved by institutional ethics/committee of Ningbo No. 2 Hospital (No: PJ-NBEY-KY-2017-069-01, PJ-NBEY-KY-2021-037-02, and PJ-NBEY-KY-2022-138-01).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: We have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ai-Rong Hu, MD, Doctor, Ningbo Institute of Liver Diseases, Ningbo No. 2 Hospital, No. 41 Xibei Street, Haishu District, Ningbo 315020, Zhejiang Province, China. huairong@ucas.edu.cn
Received: January 31, 2023
Peer-review started: January 31, 2023
First decision: February 23, 2023
Revised: March 5, 2023
Accepted: April 7, 2023
Article in press: April 7, 2023
Published online: April 28, 2023
Processing time: 82 Days and 21.5 Hours
Abstract
BACKGROUND

Chronic hepatitis B virus (HBV) infection remains a major global public health problem. Chronic hepatitis B (CHB) patients can be divided into treatment indication and non-treatment indication individuals according to alanine transaminase (ALT), HBV DNA, serum hepatitis B e antigen status, disease status [liver cirrhosis, hepatocellular carcinoma (HCC), or liver failure], liver necroinflammation or fibrosis, patients’ age, and family history of HCC or cirrhosis. For example, normal ALT patients in ‘immune-tolerant’ phase with HBV DNA higher than 107 or 2 × 107 IU/mL, and those in ‘inactive-carrier’ phase with HBV DNA lower than 2 × 103 IU/mL do not require antiviral therapy. However, is it reasonable to set the defined values of HBV DNA as the fundamental basis to estimate the disease state and to determine whether to start treatment? In fact, we should pay more attention to those who do not match the treatment indications (gray-zone patients both in the indeterminate phase and in the ‘inactive-carrier’ phase).

AIM

To analyze the correlation of HBV DNA level and liver histopathological severity, and to explore the significance of HBV DNA for CHB with normal ALT.

METHODS

From January 2017 to December 2021, a retrospective cross-sectional set of 1299 patients with chronic HBV infection (HBV DNA > 30 IU/mL) who underwent liver biopsy from four hospitals, including 634 with ALT less than 40 U/L. None of the patients had received anti-HBV treatment. The degrees of liver necroinflammatory activity and liver fibrosis were evaluated according to the Metavir system. On the basis of the HBV DNA level, patients were divided into two groups: Low/moderate replication group, HBV DNA ≤ 107 IU/mL [7.00 Log IU/mL, the European Association for the Study of the Liver (EASL) guidelines] or ≤ 2 × 107 IU/mL [7.30 Log IU/mL, the Chinese Medical Association (CMA) guidelines]; high replication group, HBV DNA > 107 IU/mL or > 2 × 107 IU/mL. Relevant factors (demographic characteristics, laboratory parameters and noninvasive models) for liver histopathological severity were analyzed by univariate analysis, logistics analysis and propensity score-matched analysis.

RESULTS

At entry, there were 21.45%, 24.29%, and 30.28% of the patients had liver histopathological severities with ≥ A2, ≥ F2, and ≥ A2 or/and ≥ F2, respectively. HBV DNA level (negative correlation) and noninvasive model liver fibrosis 5 value (positive correlation) were independent risk factors for liver histopathological severities (liver necroinflammation, liver fibrosis, and treatment indication). The AUROCs of the prediction probabilities (PRE_) of the models mentioned above (< A2 vs ≥ A2, < F2 vs ≥ F2, < A2 and < F2 vs ≥ A2 or/and ≥ F2) were 0.814 (95%CI: 0.770-0.859), 0.824 (95%CI: 0.785-0.863), and 0.799 (95%CI: 0.760-0.838), respectively. HBV DNA level (negative correlation) was still an independent risk factor when diagnostic models were excluded, the P values (< A2 vs ≥ A2, < F2 vs ≥ F2, < A2 and < F2 vs ≥ A2 or/and ≥ F2) were 0.011, 0.000, and 0.000, respectively. For the propensity score-matched pairs, whether based on EASL guidelines or CMA guidelines, the group with significant liver histology damage (≥ A2 or/and ≥ F2) showed much lower HBV DNA level than the group with non- significant liver histology damage (< A2 and < F2). Patients in the moderate replication group (with indeterminate phase) had the most serious liver disease pathologically and hematologically, followed by patients in the low replication group (with ‘inactive-carrier’ phase) and then the high replication group (with ‘immune-tolerant’ phase).

CONCLUSION

HBV DNA level is a negative risk factor for liver disease progression. The phase definition of CHB may be revised by whether the level of HBV DNA exceeds the detection low limit value. Patients who are in the indeterminate phase or ‘inactive carriers’ should receive antiviral therapy.

Keywords: Chronic hepatitis B; Hepatitis B virus DNA; Histology; Risk factors

Core Tip: According to the guidelines, for patients with normal alanine transaminase (ALT), hepatitis B virus (HBV) DNA levels were defined as ≥ 107/2 × 107 and < 2 × 103 IU/mL in the ‘immune-tolerant’ and the ‘inactive-carrier’ phase, respectively. However, it is still controversial. In this study, we analyzed the liver histopathology and the risk factors in 634 cases with positive HBV DNA and normal ALT. We found that patients with low or moderate HBV DNA level had more severe liver diseases. HBV DNA level (negative correlation) was an independent risk factor for liver histopathological severity. Therefore, we consider that the phase definition of chronic hepatitis B may be revised based on whether the level of HBV DNA exceeds the detection low limit value.