儿童慢性乙型肝炎肝组织HBsAg、HBcAg的表达与抗病毒疗效的关系

王丽旻; 刘树红; 朱世殊; 董漪; 徐志强; 王福川; 闫建国; 王璞; 李爱芹; 曹丽丽; 赵攀; 张敏

doi:10.3969/j.issn.1001-5256.2021.01.010

儿童慢性乙型肝炎肝组织HBsAg、HBcAg的表达与抗病毒疗效的关系

DOI: 10.3969/j.issn.1001-5256.2021.01.010

a.
解放军总医院第五医学中心肝病学部，北京 100093
b.
解放军总医院第五医学中心感染学部，北京 100093

基金项目:

首都特色课题 (Z161100000516176);

北京自然科学基金 (7202193);

国家十三五重大专项课题 (2018ZX10301-404)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突，特此声明。

作者贡献声明：王丽旻负责课题设计，资料分析，撰写论文；刘树红、朱世殊、董漪、徐志强、王福川、闫建国、王璞、李爱芹、曹丽参与收集数据，修改论文；赵攀、张敏负责拟定写作思路，指导撰写文章，并最后定稿。

详细信息

作者简介:
王丽旻(1976—)，女，副主任医师，博士，主要从事儿童肝病研究

通信作者:
张敏，gcmw2001@163.com

中图分类号: R512.62
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- 被引次数: 0
出版历程
- 收稿日期: 2020-07-07
- 录用日期: 2020-08-31
- 出版日期: 2021-01-20

Association of the expression of HBsAg and HBcAg in liver tissue with antiviral response in children with chronic hepatitis B

a.
Division of Liver Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100093, China
b.
Division of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100093, China

摘要

摘要: 目的探索性研究慢性乙型肝炎(CHB)儿童肝组织HBsAg和HBcAg不同表达与抗病毒疗效的关系。方法收集2014年1月—2017年12月在解放军总医院第五医学中心青少年肝病科住院并明确诊断为CHB的276例6月~16岁儿童患者的病例资料，比较肝组织HBsAg和HBcAg免疫组化染色阳性和阴性组(HBsAg阳性组249例, HBsAg阴性组27例; HBcAg阳性组163例，HBcAg阴性组113例)患者的临床特点，以及肝组织HBsAg和HBcAg不同表达模式下抗病毒疗效的差异。计量资料组间比较采用Mann-Whitney U检验；计数资料组间比较采用χ²检验或Fisher精确检验。以肝组织HBsAg和HBcAg染色阳性和阴性为应变量，以可能影响其表达强度有意义的相关因素为自变量，进行logistic回归分析。结果 276例患者年龄0.5~16岁，男性占60.51%(167例)。HBeAg阴性14例(5.07%)。肝脏炎症程度分级(G)：2级52.54%，2~3级6.88%，3级7.61%。肝纤维化分期(S)：3期7.25%, 3~4期1.45%，4期3.62%。肝组织HBsAg阳性组儿童年龄及血清HBsAg定量高于阴性组(Z值分别为1.854、2.447, P值均＜0.05)。肝组织HBcAg阳性组HBeAg阳性率高于阴性组(χ²=2.650)，ALT(Z=2.473)、AST(Z=1.813)、肝组织纤维化分期S≥3期的比例(χ²=2.086)均低于阴性组(P值均＜0.05)。logistic回归分析显示，影响肝组织HBsAg染色阳性的因素为血清HBsAg定量(P＜0.05)，影响肝组织HBcAg染色阳性的因素为HBeAg阴性或阳性(P＜0.05)。276患者中186例完成IFNα或单用拉米夫定抗病毒治疗停药后6个月的随访，155例(83.33%)获得HBeAg血清学转换，其中76例(40.86%)HBsAg阴转。肝组织的HBsAg阳性表达强度越高，血清HBsAg阴转率越低。肝组织的HBcAg阳性表达强度越高，HBeAg血清学转换率越低。肝组织HBsAg及HBcAg均阴性表达模式的儿童HBsAg阴转率最高(100%)，HBsAg阳性及HBcAg阴性的儿童HBsAg阴转率(32.31%)最低。结论肝组织HBsAg及HBcAg阴性的CHB儿童抗病毒治疗HBsAg阴转率最高
- 乙型肝炎, 慢性 /
- 乙型肝炎表面抗原 /
- 乙型肝炎核心抗原 /
- 儿童
Abstract: Objective To investigate the association of the expression of HBsAg and HBcAg in liver tissue with antiviral response in children with chronic hepatitis B (CHB). Methods Clinical data were collected from 276 children, aged 6 months to 16 years, who were hospitalized and diagnosed with CHB in Department of Adolescent Liver Diseases in The Fifth Medical Center of Chinese PLA General Hospital from January 2014 to December 2017, and based on the results of immunohistochemical staining for HBsAg and HBcAg, there were 249 children in the positive HBsAg group, 27 in the negative HBsAg group, 163 in the positive HBcAg group, and 113 in the negative HBcAg group. Clinical features were compared between groups, as well as the difference in antiviral response between the children with different expression patterns of HBsAg and HBcAg in liver tissue. The Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. A logistic regression analysis was performed with positive or negative staining of HBsAg and HBcAg in liver tissue as dependent variables and related significant factors affecting their expression intensity as independent variables. Results The age of 276 children ranged from 0.5 to 16 years, and there were 167 boys, accounting for 60.51%. Of all children, 14 (5.07%) had negative HBeAg. As for liver inflammation grade (G), 52.54% had G2 inflammation, 6.88% had G2-3 inflammation, and 7.61% had G3 inflammation; as for liver fibrosis stage (S), 7.25% had S3 fibrosis, 1.45% had S3-4 fibrosis, and 3.62% had S4 fibrosis. The positive HBsAg group had significantly higher age and serum HBsAg quantification than the negative HBsAg group (Z=1.854, Z=2.447, both P < 0.05). Compared with the negative HBcAg group, the positive HBcAg group had a significantly higher positive rate of HBeAg (χ²=2.650, P < 0.05) and significantly lower ALT (Z=2.473, P < 0.05), AST (Z= 1.813, P < 0.05), and proportion of children with S≥3 liver fibrosis (χ²=2.086, P < 0.05). The logistic regression analysis showed that serum HBsAg quantification was an influencing factor for positive HBsAg staining in liver tissue (P < 0.05) and negative or positive HBeAg was an influencing factor for positive HBcAg staining in liver tissue (P < 0.05). Among the 276 children, 186 completed the 6-month follow-up after antiviral therapy with IFNα or lamivudine alone, and 155 (83.33%) achieved HBeAg seroconversion, among whom 76 (40.86%) had HBsAg seroconversion. The higher the expression intensity of HBsAg in liver tissue, the lower the seroconversion rate of serum HBsAg; the higher the expression intensity of HBcAg in liver tissue, the lower the seroconversion rate of serum HBeAg. The children with negative expression of HBsAg and HBcAg in liver tissue had the highest HBsAg seroconversion rate of 100%, and the children with positive HBsAg and negative HBcAg in liver tissue had the lowest HBsAg seroconversion rate of 32.31%. Conclusion CHB children with negative HBsAg and HBcAg in liver tissue had the highest HBsAg seroconversion rate after antiviral therapy.
- Hepatitis B, Chronic /
- Hepatitis B Surface Antigens /
- Hepatitis B Core Antigens /
- Child

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表 1 儿童肝组织HBsAg与HBcAg不同分组各临床基线指标的比较

指标	HBsAg				HBcAg
指标	阳性组(n=249)	阴性组(n=27)	统计值	P值	阳性组(n=163)	阴性组(n=113)	统计值	P值
年龄(岁)	5.00(2.67~11.00)	4.25(2.08~7.00)	Z=1.854	0.041	5.00(2.50~10.00)	4.83(2.58~7.67)	Z=0.892	0.113
男性[例(%)]	151(60.64)	16(59.26)	χ²=0.140	0.890	97(59.51)	70(61.95)	χ²=0.407	0.683
母亲HBsAg阳性[例(%)]	191(76.71)	22(81.48)	χ²=0.222	0.824	123(75.46)	90(79.65)	χ²=0.815	0.417
ALT (U/L)	99.0(56.0~192.0)	98.0(64.5~153.0)	Z=0.478	0.612	95.0(61.0~175.5)	113.0(50.0~214.0)	Z=2.473	0.021
AST (U/L)	82.0(57.0~170.0)	75.0(58.0~110.5)	Z=0.876	0.239	78.0(48.0~133.0)	91.0(53.0~177.0)	Z=1.813	0.043
HBsAg定量(IU/ml)	11 155.5(4299.0~30 119.3)	3884.2(892.7~18 289.0)	Z=2.447	0.023	18 195.0(5461.0~32 602.8)	7882.5(3002.0~16 083.3)	Z=0.824	0.417
HBeAg阳性[例(%)]	223(89.56)	25(92.59)		1.000¹⁾	153(93.87)	95(84.07)	χ²=2.650	0.008
HBV DNA(lg IU/ml)	7.45 (6.83~8.65)	6.28 (5.14~8.05)	Z=0.891	0.223	7.57(6.35~8.42)	7.05(6.11~8.11)	Z=0.921	0.368
肝组织炎症分级[例(%)]			χ²=0.904	0.366			χ²=0.848	0.396
G＜2	80(32.13)	11(40.74)			57(34.97)	34(30.09)
G≥2	169(67.87)	16(59.26)			106(65.03)	79(69.91)
肝组织纤维化分期[例(%)]				0.541¹⁾			χ²=2.086	0.037
S＜3	217(87.15)	25(92.59)			148(90.80)	93(82.30)
S≥3	32(12.85)	2(7.41)			15(9.20)	20(17.70)
注：1)为Fisher精确检验。

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表 2 186例完成治疗的儿童治疗前肝组织HBsAg、HBcAg表达不同疗效的差异

项目	例数 (n=186)	HBeAg转换 (n=155)	HBsAg阴转 (n=76)
HBsAg[例(%)]
-	21(11.29)	20(95.24)	19(90.48)
+	125(67.20)	100(80.00)	50(40.00)
++	34(18.28)	31(91.18)	6(17.65)
+++	6(8.11)	4(66.67)	1(16.67)
HBcAg[例(%)]
-	74(39.78)	64(86.49)	30(40.54)
+	101(54.30)	85(84.16)	41(40.59)
++	9(4.84)	5(55.56)	4(44.44)
+++	2(1.08)	1(50.00)	1(50.00)

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表 3 肝组织HBsAg、HBcAg 4种表达方式抗病毒疗效的差异

组别	例数 (n=186)	HBeAg转换 (n=155)	HBsAg阴转 (n=76)
HBsAg(-)HBcAg(-)[例(%)]	9(4.84)	9(100.00)	9(100.00)
HBsAg(-)HBcAg(+)[例(%)]	12(6.45)	11(91.67)	10(83.33)
HBsAg(+)HBcAg(-)[例(%)]	65(34.95)	55(84.62)	21(32.31)
HBsAg(+)HBcAg(+)[例(%)]	100(53.76)	80(80.00)	36(36.00)

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参考文献(16)

[1]	Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2019.12.007 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007
[2]	WU JZ, WANG LC. Comparison of clinical manifestation and hepatic pathology in patients with chronic hepatitis B with negative and positive expression of HBcAg and HBsAg in liver tissue[J]. Sichuan Med J, 2017, 38(1): 32-35. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-SCYX201701013.htm 吴家箴, 王丽春. 肝组织内HBsAg、HBcAg表达阴性与阳性的慢性乙型肝炎患者临床及肝脏病理的比较[J]. 四川医学, 2017, 38(1): 32-35. https://www.cnki.com.cn/Article/CJFDTOTAL-SCYX201701013.htm
[3]	YING S, HU AR, JIANG SW, et al. Expression intensity and clinical significance of intrahepatic hepatitis B surface antigen and hepatitis B core antigen in 994 patients with chronic hepatitis B virus infection[J]. Chin J Clin Infect Dis, 2017, 10(4): 250-256. (in Chinese) DOI: 10.3760/cma.j.issn.1674-2397.2017.04.002 应盛, 胡爱荣, 蒋素文, 等. 慢性乙型肝炎病毒感染者994例肝组织HBsAg和HBcAg表达强度的临床意义[J]. 中华临床感染病杂志, 2017, 10(4): 250-256. DOI: 10.3760/cma.j.issn.1674-2397.2017.04.002
[4]	WU JZ, HUANG RG, YANG XX, et al. Association of serum HBeAg, expression intensity of HBsAg and HBcAg in hepatic tissue with clinical characteristics in 317 chronic hepatitis B patients[J]. Chongqing Med, 2017, 46(4): 468-471. (in Chinese) DOI: 10.3969/j.issn.1671-8348.2017.04.012 吴家箴, 黄仁刚, 杨兴祥, 等. 317例慢性乙型肝炎患者血清HBeAg、肝组织内HBsAg和HBcAg表达强度与临床的关系[J]. 重庆医学, 2017, 46(4): 468-471. DOI: 10.3969/j.issn.1671-8348.2017.04.012
[5]	TAN L, WU T, LYU Y, et al. HBsAg levels normalized to the same hepatic parenchyma cell volume is correlated with pathological progression but not HBeAg status[J]. J Sun Yat-Sen Univ(Medical Sciences) 2019, 40(5): 747-753. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZSYK201905014.htm 谭雷, 吴涛, 吕艳, 等. 经相同肝实质细胞体积分摊的血清HBsAg水平与肝组织病理进展相关而与HBeAg状态无关[J]. 中山大学学报(医学版), 2019, 40(5): 747-753. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSYK201905014.htm
[6]	Chinese Society of Hepatology and Chinese Society of Infectious Diseases Chinese, Medical Association. The guideline of prevention and treatment for chronic hepatitis B: A 2015 update[J]. J Clin Hepatol, 2015, 31(12): 1941-1960. (in Chinese) DOI: 10.3969/j.issn.1001-5256.2015.12.002 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(2015年更新版)[J]. 临床肝胆病杂志, 2015, 31(12): 1941-1960. DOI: 10.3969/j.issn.1001-5256.2015.12.002
[7]	ZHU SS, DONG Y, WANG LM, et al. Early initiation of antiviral therapy contributes to a rapid and significant loss of serum HBsAg in infantile-onset hepatitis B[J]. J Hepatol, 2019, 71: 871-875. DOI: 10.1016/j.jhep.2019.06.009
[8]	ZHU SS, ZHANG HF, DONG Y, et al. Antiviral therapy in hepatitis B virus-infected children with immune-tolerant characteristics: A pilot open-label randomized study[J]. J Hepatol, 2018, 68(8): 1123-1128.
[9]	CHU CM, YEH CT, SHEEN IS, et al. Subcellular localization of hepatitis B core antigen in relation to hepatocyte regeneration in chronic hepatitis B[J]. Gastroenterology, 1995, 109(6): 1926-1932. DOI: 10.1016/0016-5085(95)90760-2
[10]	ZHU SS, DONG Y, ZHANG HF, et al. The etiology and multivariate statistical analysis of outcome of 185 children with liver failure[J]. Chin J Pract Pediatr, 2014, 29(3): 205-208. (in Chinese) https://www.cnki.com.cn/Article/CJFDTOTAL-ZSEK201403014.htm 朱世殊, 董漪, 张鸿飞, 等. 儿童肝衰竭185例病因及转归多因素分析[J]. 中国实用儿科杂志, 2014, 29(3): 205-208. https://www.cnki.com.cn/Article/CJFDTOTAL-ZSEK201403014.htm
[11]	ZHANG HF, DONG Y, WANG LM, et al. A retrospective study on pathological and clinical characteristics of 3932 children with liver diseases[J]. Chin J Pediatr, 2014, 52(8): 570-574. (in Chinese) DOI: 10.3760/cma.j.issn.0578-1310.2014.08.004 张鸿飞, 董漪, 王丽旻, 等. 儿童肝穿刺组织病理与临床诊断3932例回顾性研究[J]. 中华儿科杂志, 2014, 52(8): 570-574. DOI: 10.3760/cma.j.issn.0578-1310.2014.08.004
[12]	ZHU SS, DONG Y, XU ZQ, et al. A retrospective study on HBsAg clearance rate after anfiviral therapy in children with HBeAg-positive chronic hepatitis B aged 1-7 years[J]. Chin J Hepatol, 2016, 24(10): 738-743. (in Chinese) DOI: 10.3760/cma.j.issn.1007-3418.2016.10.005 朱世殊, 董漪, 徐志强, 等. 1~7岁慢性乙型肝炎HBeAg阳性儿童经抗病毒治疗HBsAg清除率的回顾性研究[J]. 中华肝脏病杂志, 2016, 24(10): 738-743. DOI: 10.3760/cma.j.issn.1007-3418.2016.10.005
[13]	TANG QY, HE Q, LE XH, et al. Relationships between the distribution of HBcAg in hepatocytes and the markers of HBV replication in serum in patients with chronic hepatitis B[J/CD]. Chin J Exp Clin Infect Dis (Electronic Edition), 2011, 5(1): 42-45. (in Chinese) 唐奇远, 何清, 乐晓华, 等. 慢性乙型肝炎患者肝细胞内HBcAg分布与血清病毒学指标的相关性研究[J/CD]. 中华实验和临床感染病杂志(电子版), 2011, 5(1): 42-45.
[14]	GAO M, LU CZ, WANG Y, et al. Relationship between expression of HBcAg in liver tissue and characteristics of the hepatic pathological features in patients with chronic hepatitis B virus infection[J]. J Clin Hepatol, 2012, 28(3): 201-204. (in Chinese) http://lcgdbzz.xml-journal.net/article/id/LCGD201203013 高敏, 卢诚震, 王怡, 等. 慢性乙型肝炎病毒感染者肝组织HBcAg表达与临床及病理特征的关系[J]. 临床肝胆病杂志, 2012, 28(3): 201-204. http://lcgdbzz.xml-journal.net/article/id/LCGD201203013
[15]	LIU Y, LI H, YAN X, et al. Long-term efficacy and safety of peginterferon in the treatment of children with HBeAg-positive chronic hepatitis B[J]. J Viral Hepat, 2019, 26(Suppl 1): 69-76. DOI: 10.1111/jvh.13154
[16]	CORNBERG M, WONG VW, LOCARNIMI S, et al. The role of quantitative hepatitis B surface antigen revisited[J]. J Hepatol, 2017, 66(2): 398-411. DOI: 10.1016/j.jhep.2016.08.009