ALT水平正常的慢性乙型肝炎患者的血清学特征及肝组织病理学分析

刘珊珊; 陆忠华

doi:10.12449/JCH240512

ALT水平正常的慢性乙型肝炎患者的血清学特征及肝组织病理学分析

DOI: 10.12449/JCH240512

刘珊珊¹,
陆忠华^{1, 2, , ,}

1.
南京医科大学附属无锡医学中心，江苏无锡 214000
2.
无锡市第五人民医院肝病科，江苏无锡 214000

基金项目:

无锡市医学重点学科建设项目-创新团队 (CXTD2021009);

太湖人才计划 (20200803)

伦理学声明： 本研究方案于2023年7月18日经由无锡第五人民医院伦理委员会审批，批号：2023-008-1。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：刘珊珊负责数据收集，统计数据，撰写论文；陆忠华负责设计论文框架，修改文章并最后定稿。

详细信息

通信作者:
陆忠华， lu_z_h@126.com （ORCID： 0000-0002-5388-8301）

计量
- 文章访问数: 439
- HTML全文浏览量: 114
- PDF下载量: 81
- 被引次数: 0
出版历程
- 收稿日期: 2023-08-04
- 录用日期: 2023-10-07
- 出版日期: 2024-05-25

Serological features and liver histopathology of chronic hepatitis B patients with normal alanine aminotransferase

Shanshan LIU¹,
Zhonghua LU^{1, 2
, ,
,}

1.
Wuxi Clinical Medical College Affiliated to Nanjing Medical University，Wuxi，Jiangsu 214000，China
2.
Department of Hepatology，Wuxi Fifth People’s Hospital，Wuxi，Jiangsu 214000，China

Research funding:

Wuxi Medical Key Discipline Construction Project-Innovation Team (CXTD2021009);

Taihu Talent Program (20200803)

More Information

Corresponding author: LU Zhonghua， lu_z_h@126.com （ORCID： 0000-0002-5388-8301）

摘要

摘要: 目的分析ALT水平正常的慢性乙型肝炎（CHB）患者的肝组织病理学特点及与血清学指标间的关系。方法收集2018年4月—2021年6月无锡市第五人民医院137例ALT水平正常CHB患者的临床资料，分析肝组织病理与血清学指标间的差异及相关性。计数资料组间比较采用χ²检验。采用Speraman秩相关进行相关性分析。采用Logistic回归进行多因素分析。结果 ALT水平<20 U/L、20～29 U/L、30～40 U/L患者中分别有57.4%、53.4%、75%具有显著炎症坏死（≥G2），63.8%、62.1%、75%具有显著纤维化（≥S2）。HBeAg阳性/阴性、不同水平的血清HBV DNA、不同水平的血清HBV RNA在炎症活动程度分级上差异均有统计学意义（χ²值分别为10.008、6.911、7.946，P值均<0.05）；HBeAg阳性/阴性、不同水平的血清HBV RNA在纤维化分期上差异均有统计学意义（χ²值分别为7.996、10.874，P值均<0.05）。肝脏炎症程度及纤维化分期与血清HBV DNA无明显相关性（r_s=0.024，P=0.785；r_s=0.039，P=0.652），与血清HBV RNA存在显著相关性（r_s=0.222，P=0.009；r_s=0.187，P=0.029）。多因素分析提示HBeAg阳性是CHB患者肝脏发生炎症坏死（OR=-0.302，95%CI：-1.160～0.386，P=0.002）及纤维化（OR=-0.387，95%CI：-1.160～0.386，P=0.011）的独立危险因素。结论 ALT水平正常的CHB患者的肝脏组织存在不同程度的显著炎症坏死及纤维化，HBeAg阳性是这类患者肝脏组织出现显著炎症坏死及纤维化的独立危险因素。
- 乙型肝炎病毒 /
- 丙氨酸转氨酶 /
- HBV DNA /
- HBV RNA /
- 病理学
Abstract: Objective To investigate the liver histopathological features of chronic hepatitis B （CHB） patients with normal alanine aminotransferase （ALT） and their correlation with serological markers. Methods Clinical data were collected from 137 patients with normal ALT who were treated in Wuxi Fifth People’s Hospital from April 2018 to June 2021， and the differences in liver histopathology and serological markers were analyzed， as well as the correlation between liver histopathology and serological markers. The chi-square test was used for comparison of categorical data between groups， and the Kruskal-Wallis H test was used for comparison of data between multiple groups. A Spearman rank correlation test was performed， and logistic regression was used to perform the multivariate analysis. Results In the ALT ≤20 U/L， 20‍ ‍—‍ ‍29 U/L， and 30‍ ‍—‍ ‍40 U/L groups， the patients with significant inflammatory necrosis （≥G2） accounted for 57.4%， 53.4%， and 75%， respectively， and the patients with significant fibrosis （≥S2） accounted for 63.8%， 62.1%， and 75%， respectively. There was a significant difference in the degree of inflammatory necrosis between the patients with positive or negative HBeAg， the patients with different levels of serum HBV DNA， and the patients with different levels of serum HBV RNA （χ²=10.008， 6.911， and 7.946， all P<0.05）， and there was a significant difference in fibrosis stage between the patients with positive or negative HBeAg and the patients with different levels of serum HBV RNA （χ²=7.996 and 10.874， both P<0.05）. The degree of liver inflammation and fibrosis stage were not significantly correlated with serum HBV DNA （r_s =0.024， P=0.785； r_s =0.039， P=0.652）， while they were significantly correlated with serum HBV RNA （r_s =0.222， P=0.009； r_s =0.187， P=0.029）. The multivariate analysis showed that in CHB patients， positive HBeAg was an independent risk factor for inflammatory necrosis （odds ratio ［OR］=-0.302， 95% confidence interval ［CI］： -1.160 to 0.386， P=0.002） and fibrosis （OR=-0.387， 95%CI： -1.160 to 0.386， P=0.011）. Conclusion There are varying degrees of inflammatory necrosis and fibrosis in the liver of CHB patients with normal ALT， and positive HBeAg is independent risk factor for significant inflammatory necrosis and fibrosis in liver tissue of these patients.
- Hepatitis B virus /
- Alanine Transaminase /
- HBV DNA /
- HBV RNA /
- Pathology

HTML全文

表 1 肝组织病理学炎症活动程度分级、纤维化分期情况

Table 1. The result of liver Liver histopathology inflammation grading， fibrosis staging

炎症活动程度分级	例（%）	纤维化分期	例（%）
G0～1	55（40.1）	S0～1	47（34.3）
G2	69（50.4）	S2	47（34.3）
G3	13（9.5）	S3	22（16.1）
G4	0（0.0）	S4	21（15.3）

下载: 导出CSV

表 2 临床资料与炎症活动程度分级、纤维化分期的关系

Table 2. Relationship of clinical data to inflammation grading and fibrosis staging

因素	例数	炎症活动程度分级			χ²值	P值	肝纤维化分期			χ²值	P值
因素	例数	G0～G1	G2	G3～G4	χ²值	P值	S0～S1	S2	S3～4	χ²值	P值
年龄					1.814	0.404				0.711	0.701
<30岁	8	4	4	0			2	4	2
30～39岁	38	17	19	2			13	17	8
≥40岁	91	34	46	11			32	26	33
ALT					4.858	0.088				4.755	0.093
<20 U/L	47	20	23	4			17	22	8
20～29 U/L	58	27	27	4			22	16	20
30～40 U/L	32	8	19	5			8	9	15
血清HBeAg					10.008	0.040				7.996	0.046
阳性	28	8	12	8			10	6	12
阴性	109	47	57	5			37	41	31
血清HBV DNA					6.911	0.032				5.910	0.050
<10⁴ IU/mL	96	44	44	8			37	32	27
10⁴～<10⁷ IU/mL	22	3	16	3			2	17	3
≥10⁷ IU/mL	19	8	9	2			8	6	5
血清HBV RNA					7.946	0.019				10.874	0.012
<10⁴拷贝/mL	96	45	45	6			39	34	23
≥10⁴拷贝/mL	41	10	24	7			8	13	20

下载: 导出CSV

参考文献(28)

[1]	World Health Organization. Progress report on HIV, viral hepatitis and sexually transmitted infections 2019. Accountability for the global health sector strategies, 2016-2021[R]. Geneva: World Health Organization, 2019.
[2]	World Health Organization. Global hepatitis report 2017[R]. Geneva: World Health Organization, 2017.
[3]	ZHU XH, CHEN ZX, ZHUANG X, et al. Comparative effectiveness of prophylactic strategies for perinatal transmission of hepatitis B virus: A network Meta-analysis of randomized controlled trials[J/CD]. Chin J Exp Clin Infect Dis(Electronic Edition), 2018, 12( 4): 316- 323. DOI: 10.3877/cma.j.issn.1674-1358.2018.04.002. 朱晓红, 陈智娴, 庄勋, 等. 不同干预措施预防乙型肝炎病毒母婴传播的网络Meta分析[J/CD]. 中华实验和临床感染病杂志(电子版), 2018, 12( 4): 316- 323. DOI: 10.3877/cma.j.issn.1674-1358.2018.04.002.
[4]	Viral Hepatitis Group, Hepatology Branch of Chinese Research Hospital Association. Expert consensus on diagnosis and treatment of chronic hepatitis B virus with persistently normal alanine aminotransferase[J]. J Clin Hepatol, 2021, 37( 10): 2286- 2291. DOI: 10.3969/j.issn.1001-5256.2021.10.007. 中国研究型医院学会肝病学分会病毒性肝炎学组. ALT持续正常的慢性HBV感染者诊疗专家共识[J]. 临床肝胆病杂志, 2021, 37( 10): 2286- 2291. DOI: 10.3969/j.issn.1001-5256.2021.10.007.
[5]	KÖCK J, THEILMANN L, GALLE P, et al. Hepatitis B virus nucleic acids associated with human peripheral blood mononuclear cells do not originate from replicating virus[J]. Hepatology, 1996, 23( 3): 405- 413. DOI: 10.1002/hep.510230303.
[6]	WANG J, SHEN T, HUANG XB, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound[J]. J Hepatol, 2016, 65( 4): 700- 710. DOI: 10.1016/j.jhep.2016.05.029.
[7]	JANSEN L, KOOTSTRA NA, van DORT KA, et al. Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa-2a and nucleos(t)ide analogues[J]. J Infect Dis, 2016, 213( 2): 224- 232. DOI: 10.1093/infdis/jiv397.
[8]	PRAKASH K, RYDELL GE, LARSSON SB, et al. High serum levels of pregenomic RNA reflect frequently failing reverse transcription in hepatitis B virus particles[J]. Virol J, 2018, 15( 1): 1- 8. DOI: 10.1186/s12985-018-0994-7.
[9]	LAM AM, REN SP, ESPIRITU C, et al. Hepatitis B virus capsid assembly modulators, but not nucleoside analogs, inhibit the production of extracellular pregenomic RNA and spliced RNA variants[J]. Antimicrob Agents Chemother, 2017, 61( 8): e00680- e00617. DOI: 10.1128/AAC.00680-17.
[10]	WOODDELL CI, YUEN MF, CHAN HLY, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg[J]. Sci Transl Med, 2017, 9( 409): eaan0241. DOI: 10.1126/scitranslmed.aan0241.
[11]	WANG J, YU YQ, LI GJ, et al. Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients[J]. J Hepatol, 2018, 68( 1): 16- 24. DOI: 10.1016/j.jhep.2017.08.021.
[12]	HUANG CL, LI Q, XU W, et al. Serum HBV RNA levels predict significant liver fibrosis in patients with chronic HBV infection[J]. Discov Med, 2020, 29( 157): 119- 128.
[13]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and therapy of hepatic fibrosis(2019)[J]. J Clin Hepatol, 2019, 35( 10): 2163- 2172. DOI: 10.3969/j.issn.1001-5256.2019.10.007. 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 肝纤维化诊断及治疗共识(2019年)[J]. 临床肝胆病杂志, 2019, 35( 10): 2163- 2172. DOI: 10.3969/j.issn.1001-5256.2019.10.007.
[14]	ODENWALD MA, PAUL S. Viral hepatitis: Past, present, and future[J]. World J Gastroenterol, 2022, 28( 14): 1405- 1429. DOI: 10.3748/wjg.v28.i14.1405.
[15]	TERRAULT NA, BZOWEJ NH, CHANG KM, et al. AASLD guidelines for treatment of chronic hepatitis B[J]. Hepatology, 2016, 63( 1): 261- 283. DOI: 10.1002/hep.28156.
[16]	TERRAULT NA, LOK ASF, MCMAHON BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance[J]. Hepatology, 2018, 67( 4): 1560- 1599. DOI: 10.1002/hep.29800.
[17]	HUANG DQ, LI XH, LE MH, et al. Natural history and hepatocellular carcinoma risk in untreated chronic hepatitis B patients with indeterminate phase[J]. Clin Gastroenterol Hepatol, 2022, 20( 8): 1803- 1812. e 5. DOI: 10.1016/j.cgh.2021.01.019.
[18]	Chinese Society of Hepatology, Chinese Society of Infectious Diseases. Guidelines for the prevention and treatment of chronic hepatitis B(2022 version)[J]. Chin J Infect Dis, 2023, 41( 1): 3- 28. DOI: 10.3760/cma.j.cn311365-20230220-00050. 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版)[J]. 中华传染病杂志, 2023, 41( 1): 3- 28. DOI: 10.3760/cma.j.cn311365-20230220-00050.
[19]	JI LX, YANG XX. Liver histological changes and clinical features in chronic hepatitis B with normal or mildly elevated alanine amin-otransferase[J]. J Clin Hepatol, 2020, 36( 4): 778- 782. DOI: 10.3969/j.issn.1001-5256.2020.04.014. 纪林秀, 杨兴祥. ALT水平正常或轻度升高慢性乙型肝炎的肝组织学改变及临床特征分析[J]. 临床肝胆病杂志, 2020, 36( 4): 778- 782. DOI: 10.3969/j.issn.1001-5256.2020.04.014.
[20]	ZHOU WW, HUANG J, PAN FM. Research progress in epidemiological characteristics and therapeutic drugs of chronic hepatitis B[J]. J Changchun Univ Chin Med, 2022, 38( 12): 1420- 1424. DOI: 10.13463/j.cnki.cczyy.2022.12.028. 周薇薇, 黄俊, 潘发明. 慢性乙型肝炎流行病学特点和治疗药物研究进展[J]. 长春中医药大学学报, 2022, 38( 12): 1420- 1424. DOI: 10.13463/j.cnki.cczyy.2022.12.028.
[21]	ZHOU X, LI WZ, MA WT, et al. Correlation between liver histopathology and age, ALT and HBV DNA levels in chronic HBV infected patients with normal ALT[J]. Chin Hepatol, 2019, 24( 10): 1141- 1144. DOI: 10.14000/j.cnki.issn.1008-1704.2019.10.017. 周璇, 李维正, 马文婷, 等. ALT正常慢性HBV感染者肝组织病理与年龄、ALT和HBV DNA水平相关性研究[J]. 肝脏, 2019, 24( 10): 1141- 1144. DOI: 10.14000/j.cnki.issn.1008-1704.2019.10.017.
[22]	ZHOU BC. Pathological characteristics of liver biopsy in patients with chronic hepatitis B with normal or slightly increased transaminase[J]. Chin Hepatol, 2019, 24( 3): 253- 256. DOI: 10.14000/j.cnki.issn.1008-1704.2019.03.013. 周保仓. 转氨酶正常或轻度增高的慢性乙型肝炎患者肝穿刺活检病理特征[J]. 肝脏, 2019, 24( 3): 253- 256. DOI: 10.14000/j.cnki.issn.1008-1704.2019.03.013.
[23]	WANG N, TANG CC, WANG LC. Progress in pathogenesis and treatment of chronic HBV infection in immune toler-ance period[J]. Chin J Integr Tradit West Med Liver Dis, 2021, 31( 7): 596- 599. DOI: 10.3969/j.issn.1005-0264.2021.07.006. 王能, 唐骢宸, 王丽春. 慢性HBV感染免疫耐受期发生机制及治疗进展[J]. 中西医结合肝病杂志, 2021, 31( 7): 596- 599. DOI: 10.3969/j.issn.1005-0264.2021.07.006.
[24]	LIU YY, JIANG M, XUE JY, et al. Serum HBV RNA quantification: Useful for monitoring natural history of chronic hepatitis B infection[J]. BMC Gastroenterol, 2019, 19( 1): 1- 9. DOI: 10.1186/s12876-019-0966-4.
[25]	BAI L, ZHANG XN, KOZLOWSKI M, et al. Extracellular hepatitis B virus RNAs are heterogeneous in length and circulate as capsid-antibody complexes in addition to virions in chronic hepatitis B patients[J]. J Virol, 2018, 92( 24): e00798- e00718. DOI: 10.1128/JVI.00798-18.
[26]	SHEN S, XIE ZL, CAI DW, et al. Biogenesis and molecular characteristics of serum hepatitis B virus RNA[J]. PLoS Pathog, 2020, 16( 10): e1008945. DOI: 10.1371/journal.ppat.1008945.
[27]	DENG R, LIU S, SHEN S, et al. Circulating HBV RNA: From biology to clinical applications[J]. Hepatology, 2022, 76( 5): 1520- 1530. DOI: 10.1002/hep.32479.
[28]	BAI H, LIU HB, CHEN XK, et al. Influence of age and HBeAg status on the correlation between HBV DNA and hepatic inflammation and fibrosis in chronic hepatitis B patients[J]. Dig Dis Sci, 2013, 58( 5): 1355- 1362. DOI: 10.1007/s10620-012-2479-7.