HBV相关慢加急性肝衰竭恢复期患者肝组织HBV cccDNA水平及其临床意义

蔡哲凯; 徐龙; 刘文丽; 肖影群; 钟青梅; 张伟; 吴敏

doi:10.12449/JCH250109

HBV相关慢加急性肝衰竭恢复期患者肝组织HBV cccDNA水平及其临床意义

DOI: 10.12449/JCH250109

蔡哲凯^a,
徐龙^a, , ,,
刘文丽^b,
肖影群^b,
钟青梅^b,
张伟^a,
吴敏^a

a.
南昌市第九医院慢性肝病科，南昌 330002
b.
南昌市第九医院病理科，南昌 330002

伦理学声明：本研究方案于2023年7月3日经由南昌市第九医院伦理委员会审批，批号：［2023］伦审字（34）号。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：蔡哲凯负责研究设计，数据整理，统计分析，文章撰写；张伟、吴敏负责样本收集，数据整理；刘文丽、钟青梅负责病理诊断，实验操作，资料整理；肖影群负责病理诊断质控及论文审阅；徐龙负责研究设计指导，论文审阅。

详细信息

通信作者:
徐龙， xulong791@126.com （ORCID： 0009-0004-9918-3237）

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出版历程
- 收稿日期: 2024-05-17
- 录用日期: 2024-07-10
- 出版日期: 2025-01-25

The level of HBV cccDNA in liver tissue and its clinical significance in patients in the convalescence stage of hepatitis B virus-related acute-on-chronic liver failure

a.
Department of Chronic Liver Diseases The Ninth Hospital of Nanchang, Nanchang 330002, China
b.
Department of Pathology, The Ninth Hospital of Nanchang, Nanchang 330002, China

More Information

Corresponding author: XU Long， xulong791@126.com （ORCID： 0009-0004-9918-3237）

摘要

摘要: 目的观察HBV cccDNA在HBV相关慢加急性肝衰竭（HBV-ACLF）恢复期患者肝组织中的表达水平，并探讨其与HBV标志物、肝组织病理改变的关系。方法选取2015年1月—2023年10月在南昌市第九医院住院的HBV-ACLF恢复期患者30例为肝衰竭组，另选取同期9例性别及年龄匹配的慢性乙型肝炎患者（CHB）作为对照组，检测肝组织HBV cccDNA水平，并分析其与临床资料、实验室检查指标的关联性。计量资料两组间比较采用成组t检验或Mann-Whitney U检验；多组间比较采用单因素方差分析或Kruskal-Wallis H检验。计数资料组间比较采用Fisher精确检验。相关性分析采用Spearman相关分析。结果肝衰竭组肝组织HBV cccDNA水平显著低于对照组［（-0.92±0.70） log₁₀ copies/cell vs （-0.13±0.91） log₁₀ copies/cell，t=2.761，P=0.009］。肝衰竭组中，血清HBeAg阳性与阴性患者肝组织HBV cccDNA水平比较，差异无统计学意义（P>0.05）；肝组织炎症活动度G0～G2级、G3级、G4级患者的肝组织HBV cccDNA水平比较，差异无统计学意义（P>0.05）；肝组织纤维化程度S0～S2期、S3期、S4期患者的肝组织HBV cccDNA水平比较，差异无统计学意义（P>0.05）；血清HBV DNA阴性与血清HBV DNA阳性患者肝组织HBV cccDNA水平比较，差异无统计学意义（P>0.05）。肝衰竭组肝组织HBV cccDNA水平与肝组织HBV DNA水平呈正相关（r=0.426，P=0.043），与血清HBV DNA水平无明显相关性（P>0.05）。结论肝组织HBV cccDNA水平在HBV-ACLF恢复期明显降低，肝组织HBV cccDNA持续稳定存在，较血清及肝组织HBV DNA更能反映HBV的持续感染与复制。
- 乙型肝炎病毒 /
- 慢加急性肝功能衰竭 /
- 恢复期 /
- 共价闭合环状DNA
Abstract: Objective To investigate the expression level of HBV cccDNA in patients in the convalescence stage of hepatitis B virus-related acute-on-chronic liver failure （HBV-ACLF） and its correlation with HBV markers and liver histopathological changes. Methods A total of 30 patients in the convalescence stage of HBV-ACL who were hospitalized in The Ninth Hospital of Nanchang from January 2015 to October 2023 were enrolled as liver failure group， and 9 patients with chronic hepatitis B （CHB）， matched for sex and age， were enrolled as control group. The content of HBV cccDNA in liver tissue was measured， and its correlation with clinical data and laboratory markers was analyzed. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and a one-way analysis of variance or the Kruskal-Wallis H test was used for comparison between multiple groups； the Fisher’s exact test was used for comparison of categorical data between groups. A Spearman correlation analysis was performed. Results The liver failure group had a significantly lower content of HBV cccDNA in liver tissue than the control group （-0.92±0.70 log₁₀ copies/cell vs -0.13±0.91 log₁₀ copies/cell， t=2.761， P=0.009）. In the liver failure group， there was no significant difference in the content of HBV cccDNA in liver tissue between the HBeAg-positive patients and the HBeAg-negative patients （P>0.05）； there was no significant difference in the content of HBV cccDNA in liver tissue between the patients with different grades （G0-G2， G3， and G4） of liver inflammatory activity （P>0.05）； there was no significant difference in the content of HBV cccDNA in liver tissue between the patients with different stages （S0-S2， S3， and S4） of liver fibrosis （P>0.05）； there was no significant difference in the content of HBV cccDNA in liver tissue between the patients with negative HBV DNA and those with positive HBV DNA （P>0.05）. For the liver failure group， the content of HBV cccDNA in liver tissue was positively correlated with the content of HBV DNA in liver tissue （r=0.426， P=0.043） and was not significantly correlated with the content of HBV DNA in serum （P>0.05）. Conclusion There is a significant reduction in the content of HBV cccDNA in liver tissue in the convalescence stage of HBV-ACLF. HBV cccDNA exists continuously and stably in liver tissue and can better reflect the persistent infection and replication of HBV than HBV DNA in serum and liver tissue.
- Hepatitis B Virus /
- Acute-On-Chronic Liver Failure /
- Convalescence /
- Covalently Closed Circular DNA

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表 1 一般资料比较

Table 1. Comparison of general information

项目	对照组（n=9）	肝衰竭组（n=30）	统计值	P值
年龄（岁）	31.33±9.75	33.40±7.50	t=-0.676	0.503
男/女（例）	9/0	28/2		>0.05
ALT（U/L）	32.47±12.86	36.65±11.16	t=-0.954	0.346
SCr（μmol/L）	77.55±13.28	78.60±11.85	t=-0.217	0.829
PTA（%）	103.25±23.17	83.23±13.56	t=2.339	0.046
血清HBV DNA（log₁₀ 拷贝/mL）	6.64（4.00～8.15）	5.70（3.78～5.70）	Z=-1.518	0.129
肝组织HBV DNA（log₁₀ 拷贝/mL）	4.83（3.86～5.72）	4.18（2.78～5.09）	Z=-1.401	0.161

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表 2 血清HBeAg阳性与HBeAg阴性HBV-ACLF恢复期患者比较

Table 2. Comparison of HBV-ACLF convalescent patients with serum HBeAg-positive and HBeAg-negative

项目	HBeAg阳性（n=15）	HBeAg阴性（n=15）	统计值	P值
年龄（岁）	31.13±6.47	35.67±7.99	t=1.708	0.099
男/女（例）	15/0	13/2		0.483
ALT（U/L）	37.53±10.25	35.77±12.30	t=-0.426	0.674
SCr（μmol/L）	82.13±10.27	75.07±12.58	t=-1.685	0.103
PTA（%）	87.40±12.94	79.07±13.27	t=-1.741	0.093
MELD评分（分）	17.90±5.74	15.11±3.55	t=-1.602	0.120
血清HBV DNA（log₁₀ 拷贝/mL）	5.70（3.91～5.70）	5.35（3.56～5.70）	Z=-0.494	0.621
肝组织HBV DNA（log₁₀ 拷贝/mL）	4.28（3.75～5.29）	3.79（2.70～5.00）	Z=-1.231	0.218
肝组织HBV cccDNA（log₁₀ copies/cell）	-0.83±0.80	-1.00±0.60	t=-0.667	0.510

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表 3 不同肝组织炎症程度HBV-ACLF恢复期患者比较

Table 3. Comparison of HBV-ACLF convalescent patients with different degrees of liver tissue inflammation

项目	G0～G2（n=9）	G3（n=10）	G4（n=11）	统计值	P值
年龄（岁）	32.22±7.61	31.90±8.58	35.73±6.42	F=0.830	0.447
男/女（例）	9/0	10/0	9/2		0.157
血清HBV DNA（log₁₀ 拷贝/mL）	5.70（4.33～5.75）	5.35（3.56～5.70）	3.35（3.65～5.70）	H=0.605	0.739
肝组织HBV DNA（log₁₀ 拷贝/mL）	4.28（2.70～5.15）	3.91（2.78～4.65）	4.20（3.01～5.10）	H=1.415	0.493
肝组织HBV cccDNA（log₁₀ copies/cell）	-0.83±0.80	-0.86±0.62	-1.04±0.72	F=0.275	0.761

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表 4 不同肝组织纤维化程度HBV-ACLF恢复期患者比较

Table 4. Comparison of HBV-ACLF convalescent patients with different degrees of liver fibrosis

项目	S0～S2（n=5）	S3（n=7）	S4（n=18）	统计值	P值
年龄（岁）	32.00±10.95	30.71±9.27	34.83±5.64	F=0.855	0.436
男/女（例）	5/0	6/1	17/1		0.593
血清HBV DNA（log₁₀ 拷贝/mL）	4.78（3.90～5.75）	5.00（3.54～5.70）	5.70（3.80～5.70）	H=0.544	0.762
肝组织HBV DNA（log₁₀ 拷贝/mL）	5.29（3.32～5.55）	3.79（3.01～4.46）	4.18（2.70～5.09）	H=1.558	0.459
肝组织HBV cccDNA（log₁₀ copies/cell）	-0.56±0.90	-1.40±0.47	-0.83±0.65	F=2.801	0.078

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表 5 血清HBV DNA阳性与HBV DNA阴性HBV-ACLF恢复期患者比较

Table 5. Comparison of HBV-ACLF convalescent patients with serum HBV DNA-positive and HBV DNA-negative

项目	HBV DNA阳性（n=14）	HBV DNA阴性（n=16）	t值	P值
年龄（岁）	33.57±7.09	33.25±8.08	-0.115	0.909
男/女（例）	13/1	15/1		0.922
ALT（U/L）	37.64±13.39	35.79±9.15	-0.437	0.666
SCr（μmol/L）	82.29±8.45	75.38±13.62	-1.640	0.112
PTA（%）	87.21±10.19	79.75±15.41	-1.540	0.135
MELD评分（分）	17.25±6.03	15.85±3.72	-0.780	0.442
抗病毒治疗时间（d）	36.00±13.87	50.75±26.54	1.866	0.073
入院时血清HBV DNA（log₁₀ 拷贝/mL）	7.32±1.53	6.60±1.44	-1.331	0.194
肝组织HBV cccDNA（log₁₀ copies/cell）	-0.85±0.83	-0.97±0.57	-0.471	0.642

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