Chronic hepatitis B (CHB) is a common chronic inflammatory disease of the liver in mainland China, which often leads to persistent damage to the liver parenchyma, followed by liver fibrosis, which can eventually lead to adverse outcomes such as liver cirrhosis, liver failure, and liver cancer. However, the relationship between different hepatitis B virus (HBV) DNA levels and liver fibrosis in immune-tolerant CHB patients is unclear. Recently, the team of Professor Wu Chao and Associate Professor Huang Rui from the Drum Tower Hospital affiliated to Nanjing University School of Medicine, together with the team of Professor Zhu Chuanwu and Professor Zhu Li of the Fifth People's Hospital of Suzhou and the team of Professor Liu Xingxiang of the Fourth People's Hospital of Huai'an City, discussed the relationship between liver fibrosis and HBV DNA levels in CHB patients with HBeAg-positive, normal alanine aminotransferase (ALT) and relatively high HBV DNA.
One
Research Methods:
研究纳入来自江苏省三家医院的622例ALT正常HBV DNA≥6 log10IU/mL的HBeAg阳性CHB患者。 根据患者HBV DNA水平高低分为三组：HBV DNA较低水平组（6-7 log10IU/mL，n = 117）、HBV DNA中等水平组（7-8 log10IU/mL，n = 324）以及HBV DNA高水平组（≥8 log10IU/mL，n = 181）。 使用APRI、FIB-4、瞬时弹性成像或肝活检评估肝纤维化。
Two
Findings:
1. Clinical features
The median age of the patients was 33.0 years, of whom 57.9% were male. The median DNA levels of ALT, HBsAg, HBeAg, and HBV were 24.0 U/L, 4.6 log10 IU/mL, 3.1 log10S/CO, and 7.7 log10 IU/mL, respectively (Table 1). The median APRI and FIB-4 were 0.27 and 0.72, respectively (Table 2). A total of 152 patients underwent transient elastography of the liver, 66 patients underwent liver biopsy, and the median LSM was 5.7 kPa, and 36.4% of patients were confirmed by liver biopsy with significant fibrosis (≥S2) (Table 2).
Table 1 Comparison of the clinical characteristics of different HBV DNA subtypes
Table 2 Comparison of liver fibrosis degree of different HBV DNA subtypes
2. Comparison of clinical features of different HBV DNA subtypes and liver fibrosis
The proportion of patients in the low-level, moderate-level and high-level HBV DNA groups was 18.8%, 52.1% and 29.1%, respectively.
Compared with patients with moderate and high levels of HBV DNA, patients with lower levels of HBV DNA were older, and the proportion of males, AST levels, alkaline phosphatase (ALP) levels, γ-glutamyl transpeptidase (GGT), and total bilirubin (Tbil) levels were higher, P<0.05. Compared with patients with moderate and high levels of HBV DNA, patients with lower levels of HBV DNA had lower levels of PLT, albumin (ALB) and HBsAg levels, P <0.05. (Table 1)
In terms of liver fibrosis, the degree of liver fibrosis in the lower level group was higher than that in the middle and high level groups, with an APRI of 0.33 in the lower group, 0.26 in the middle group, and 0.26 in the high level group, P <0.001, FIB-4 in the lower group, 0.71 in the intermediate group, 0.68 in the high level group, P <0.001, and LSM in the lower group was 7.1 kPa, 5.6 kPa in the middle group, and 5.5 kPa in the high level group, P = 0.086.
In a subgroup analysis of 66 patients who underwent liver biopsy, the proportion of patients with significant fibrosis (72.7% vs. 34.1% vs. 14.3%, P =0.009) and liver cirrhosis (18.2% vs. 2.4% vs. 2.4% vs. 0.009, P =0.009) in the low HBV DNA group was significantly higher than that in the intermediate and high levels (Table 2).
Overall, patients with low levels of HBV DNA had a higher proportion of significant liver fibrosis (24.8% vs. 9.9% vs. 3.3%, P <0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P=0.004) compared with patients with moderate and high levels of HBV DNA (Fig. 1A, B).
Fig.1 Proportion of significant fibrosis and cirrhosis among different HBV DNA subtypes
3. Factors related to significant liver fibrosis in patients with CHB in IT stage
Logistic regression analysis was used to analyze the associated factors of significant liver fibrosis in patients with CHB in IT stage (Table 3). In univariate analysis, higher levels of male, neutrophil, lymphocyte, ALP, GGT, Tbil, and lower levels of ALB and HBV DNA were associated with significant liver fibrosis. In multivariate analysis, low-level HBV DNA (OR=4.968, 95%CI 1.706~14.473, P=0.003) and moderate-level HBV DNA (OR=3.095, 95%CI 1.165~8.222, P=0.023) remained independent risk factors for significant liver fibrosis compared with high-level HBV DNA.
Table 3 Analysis of clinical parameters associated with significant liver fibrosis
4. Relationship between HBV DNA levels and liver fibrosis in different age groups
Among patients aged < 30 years, the proportions of low, medium and high HBV DNA were 11.0%, 58.1% and 31.0%, respectively. There were no significant differences in APRI, FIB-4, LSM values, and the proportion of significant liver fibrosis and cirrhosis between the three groups (Fig. 1C and D). Eight patients in the age < 30 years group underwent liver biopsy. Although the proportion of patients with significant liver fibrosis in the lower group (75.0%) was higher than that in the middle group (25.0%) and the high level group (20.0%), the difference was not statistically significant (P = 0.129).
In patients aged ≥ 30 years, compared with patients with moderate and high levels of HBV DNA, the APRI values (0.35 vs. 0.27 vs. 0.25, P<0.001) and FIB-4 values (1.16 vs. 0.79 vs. 0.71, P.) were compared with patients with moderate and high levels of HBV DNA <0.001) and LSM values (7.4 vs. 5.5 vs. 5.5, P = 0.033) were higher. Patients in the lower group also had a higher proportion of significant liver fibrosis (26.0% vs. 11.1% vs. 2.3%, P <0.001) and cirrhosis (9.0% vs. 3.0% vs. 0.8%, P = 0.003) compared with patients with moderate and high levels of HBV DNA (Fig. 1 E and F).
In the group of patients aged < 30 years, HBV DNA levels were not associated with significant fibrosis. However, in the age ≥ 30 years, moderate HBV DNA (OR 6.487, 95% CI 1.489–28.255, P = 0.013) and low HBV DNA (or 8.618, 95% CI 1.836–40.458, P = 0.006) were independent risk factors for significant fibrosis compared with high HBV DNA (Table 4).
Table 4 Analysis of clinical parameters associated with significant liver fibrosis in different age groups
Three
Conclusions of the study
In patients with HBeAg-positive CHB with normal ALT and a high viral load, lower HBV DNA levels are associated with more severe liver fibrosis, especially in patients over 30 years of age. These patients should be aggressively evaluated for fibrosis and antiviral therapy considered.
Resumes of experts
Prof. Chao Wu
- Chief physician, professor and doctoral supervisor of the Department of Infectious Diseases, Drum Tower Hospital, Nanjing University School of Medicine
- Former chairman of the Infectious Disease Branch of Jiangsu Medical Association
- He is a member of the Society of Infectious Diseases and Hepatology of the Chinese Medical Association
- Director of the Institute of Virology and Infectious Diseases, Nanjing University
- United States. Member of the European Association of Hepatology (AASLD) (EASL).
- Member of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).
- As the first person in charge, he has undertaken 4 projects of the National Natural Science Foundation of China and major projects, sub-projects of major national infectious diseases and 8 provincial and ministerial scientific research projects
- 发表SCI收录论文150余篇，包括Lancet Infect Dis、Lancet Gastroenterol Hepatol、Lancet Reg Health West Pac、JAMA Network Open、J Hepatol、Hepatology、Am J Gastroenterol、Aliment Pharmacol Ther等，其中3篇论著入选ESI高被引论文。 为10余个SCI期刊的编委及特约审稿人。
Bibliography:
Wang J, Zhu L, Zhang Z, Zhang S, Pan Y, Li Y, Cao F, Jiang C, Fan T, Xiong Y, Liu J, Chen Y, Yin S, Tong X, Zhu C, Liu X, Li J, Wu C, Huang R. Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase. Virol J. 2024 Jun 4; 21(1):127. doi: 10.1186/s12985-024-02368-0. PMID: 38835029; PMCID: PMC11151594.
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