中文English
ISSN 1001-5256
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

自身免疫性肝炎中隐匿性HBV感染的情况及其对疾病进展的影响

陈欣欣 张海萍 黄春洋 苏建荣 闫惠平

引用本文:
Citation:

自身免疫性肝炎中隐匿性HBV感染的情况及其对疾病进展的影响

DOI: 10.3969/j.issn.1001-5256.2022.12.011
基金项目: 

北京市自然科学基金 7111004;

北京市医管局培育项目 PX2019062

伦理学声明:本研究方案于2012年5月22日和2021年12月30日经由首都医科大学附属北京佑安医院伦理委员会审批, 批号为[2012]44号和[2021]392号。患者均签署知情同意书。
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。
作者贡献声明:闫惠平、苏建荣对研究的思路、设计、论文的审阅等有关键贡献;陈欣欣参与了研究实验的设计,实验的实施、数据的获取分析解释过程,参与起草或修改文章关键内容;张海萍、黄春洋参与了实验和数据分析。
详细信息
    通信作者:

    苏建荣,youyilab@163.com

    闫惠平,yhp503@126.com

Occult HBV infection in autoimmune hepatitis and its influence on disease progression

Research funding: 

Beijing Municipal Natural Science Foundation 7111004;

Beijing Municipal Administration of Hospitals Incubating Program PX2019062

More Information
  • 摘要:   目的  了解自身免疫性肝炎(AIH) 患者中隐匿性HBV感染(OBI) 的流行率,探讨合并OBI是否影响AIH患者的临床及预后。  方法  选取2012年4月—2019年3月北京佑安医院收治的确诊AIH患者103例,利用巢式PCR和Real-time PCR法确诊OBI的诊断,Real-time PCR法检测HBV pgRNA,比较合并OBI的AIH组(n=24)和非OBI组(n=79)患者临床特征、实验室指标、随访分析预后特征。正态分布计量资料两组间比较采用独立样本t检验,非正态分布计量资料两组间比较采用Mann-Whitney U秩和检验,计数资料组间比较采用χ2检验或Fisher精确概率法,Kaplan-Meier法绘制生存曲线,采用Cox回归模型进行单因素和多因素分析,并计算风险比(HR)及95%CI  结果  AIH患者中OBI的检出率为23.30%(24/103),且HBV DNA病毒载量均<200 IU/mL,其中9例(37.50%,9/24)OBI患者血清中可以检测到HBV pgRNA。OBI组患者HBV三个抗体(抗-HBs、抗-HBc、抗-HBe)同时阳性率显著高于非OBI组(χ2=5.906,P=0.016)。单因素分析显示,OBI、低蛋白血症、脾肿大、腹水为AIH不良事件的危险因素(P值均<0.05),与疾病进展相关。进一步行多因素Cox回归分析发现,低蛋白血症、腹水为不良事件相关的独立危险因素(P值均<0.05)。  结论  AIH患者中存在较高的OBI检出率,合并OBI可能加速AIH疾病的进展。

     

  • 图  1  C、S、P、X四个阅读框的巢式PCR扩增电泳图

    注:a, C阅读框;b, S阅读框;c,P阅读框;d, X阅读框。1,阳性对照;2,阳性对照;3~6样本。

    Figure  1.  The results of nesting PCR amplification of C, S, P, X four reading frames

    图  2  AIH合并OBI患者血清的HBV pgRNA水平

    Figure  2.  HBV pgRNA in serum of patients with AIH combined with OBI infection

    图  3  AIH患者生存曲线的比较

    Figure  3.  Predicting clinical outcomes of AIH patients stratified by OBI

    表  1  AIH患者(是/否)合并OBI的生化免疫指标比较

    Table  1.   Biochemical and immunological characteristics of OBI patients

    项目 总计(n=103) 合并OBI组(n=24) 无OBI组(n=79) 统计值 P
    男/女(例) 10/93 2/22 8/71 χ2=0.068 0.796
    年龄(岁) 52(8~83) 54.19±13.19 49.53±13.18 t=-0.328 0.722
    AST(U/L) 195.70(20.80~1898.50) 196.00(23.30~1129.20) 195.40(20.80~1898.50) Z=-0.068 0.946
    ALT(U/L) 199.10(9.40~2236.10) 205.80(23.90~1372.40) 196.10(9.40~2236.10) Z=-0.368 0.713
    TBil(μmol/L) 107.60(7.20~567.50) 141.24(9.30~535.00) 97.80(7.20~567.50) Z=-1.305 0.192
    Alb(g/L) 36.13(17.90~48.90) 35.23(18.60~45.80) 36.40(17.90~48.90) Z=-0.717 0.474
    GGT(U/L) 193.89(11.90~1282.60) 221.91(23.10~878.30) 185.94(11.90~1282.60) Z=-0.646 0.518
    ALP(U/L) 171.32(61.70~1094.90) 217.87(61.70~1029.50) 158.10(62.80~1094.90) Z=-1.126 0.260
    PLT(×109/L) 162.25(23.00~459.00) 165.48(51.00~399.00) 161.38(23.00~459.00) Z=-0.557 0.578
    IgG(g/L) 21.3(17.00~54.40) 20.3(17.00~35.40) 22.75(17.10~54.40) Z=-1.182 0.237
    IgM(g/L) 1.56(0.57~7.24) 1.69(0.68~4.52) 1.47(0.57~7.24) Z=-0.611 0.541
    IgA(g/L) 3.11(0.31~9.96) 3.2(0.87~9.96) 3.02(0.31~7.36) Z=-1.251 0.211
    ANA[例(%)] 95(92.23) 23(95.83) 72(91.14) χ2=0.566 0.454
    SMA[例(%)] 43(41.75) 8(33.33) 35(44.30) χ2=0.911 0.340
    SLA/LP[例(%)] 14(13.59) 3(12.50) 11(13.92) χ2=0.032 0.859
    LKM-1[例(%)] 4(3.88) 1(4.17) 3(3.80) χ2=0.007 0.935
    LHC-1[例(%)] 1(0.97) 0 1(1.27) χ2=0.307 0.582
    注:LKM-1,抗肝肾微粒体抗体1型;LC-1,抗肝细胞溶质1型
    下载: 导出CSV

    表  2  AIH患者是/否合并OBI的HBV血清标志物比较

    Table  2.   The comparison of HBV serum markers in AIH patients with or without occult HBV infection

    项目 总计(n=103) 合并OBI组(n=24) 无OBI组(n=79) χ2 P
    抗-HBc(+)[例(%)] 44(42.72) 12(50.00) 32(40.51) 0.678 0.410
    抗-HBc(+)[例(%)] 3(2.91) 1(4.17) 2(2.53) 0.174 0.677
    抗-HBc(+)/抗-HBs(+)[例(%)] 9(8.74) 0 9(11.39) 2.996 0.083
    抗-HBc(+)/抗-HBe(+)[例(%)] 8(7.77) 1(4.17) 7(8.86) 0.566 0.454
    抗-HBc/抗-HBs/抗-HBe(+)[例(%)] 24(23.30) 10(41.67) 14(17.72) 5.906 0.016
    抗-HBs(+)[例(%)] 14(13.59) 3(12.50) 11(13.92) 0.032 0.859
    HBV血清标志物(-)[例(%)] 45(43.69) 9(37.50) 36(45.57) 0.487 0.485
    下载: 导出CSV

    表  3  AIH患者产生不良事件的单因素和多因素分析

    Table  3.   Univariate and multivariate analysis of adverse events in patients with AIH

    项目 单因素分析 多因素分析
    HR 95%CI P HR 95%CI P
    OBI 3.336 1.144~9.734 0.027
    低蛋白血症 6.899 1.920~24.784 0.003 5.640 1.155~27.544 0.033
    脾大 9.694 2.607~36.074 0.001
    腹肿水 4.278 2.065~8.865 <0.001 4.641 1.689~12.750 0.003
    PLT 0.992 0.983~1.001 0.068
    下载: 导出CSV
  • [1] MANNS MP, CZAJA AJ, GORHAM JD, et al. Diagnosis and management of autoimmune hepatitis[J]. Hepatology, 2010, 51(6): 2193-2213. DOI: 10.1002/hep.23584.
    [2] GRØNBÆK L, VILSTRUP H, JEPSEN P. Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study[J]. J Hepatol, 2014, 60(3): 612-617. DOI: 10.1016/j.jhep.2013.10.020.
    [3] RAIMONDO G, ALLAIN JP, BRUNETTO MR, et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection[J]. J Hepatol, 2008, 49(4): 652-657. DOI: 10.1016/j.jhep.2008.07.014.
    [4] GEORGIADOU SP, ZACHOU K, LIASKOS C, et al. Occult hepatitis B virus infection in patients with autoimmune liver diseases[J]. Liver Int, 2009, 29(3): 434-442. DOI: 10.1111/j.1478-3231.2008.01851.x.
    [5] CHEN XX, XIANG KH, ZHANG HP, et al. Occult HBV infection in patients with autoimmune hepatitis: A virological and clinical study[J]. J Microbiol Immunol Infect, 2020, 53(6): 946-954. DOI: 10.1016/j.jmii.2019.04.009.
    [6] ALVAREZ F, BERG PA, BIANCHI FB, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis[J]. J Hepatol, 1999, 31(5): 929-938. DOI: 10.1016/s0168-8278(99)80297-9.
    [7] HENNES EM, ZENIYA M, CZAJA AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis[J]. Hepatology, 2008, 48(1): 169-176. DOI: 10.1002/hep.22322.
    [8] 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 management of autoimmune hepatitis (2015)[J]. J Clin Hepatol, 2016, 32(1): 9-22. DOI: 10.3969/j.issn.1001-5256.2016.01.002.

    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. 自身免疫性肝炎诊断和治疗共识(2015)[J]. 临床肝胆病杂志, 2016, 32(1): 9-22. DOI: 10.3969/j.issn.1001-5256.2016.01.002.
    [9] FANG Y, SHANG QL, LIU JY, et al. Prevalence of occult hepatitis B virus infection among hepatopathy patients and healthy people in China[J]. J Infect, 2009, 58(5): 383-388. DOI: 10.1016/j.jinf.2009.02.013.
    [10] YIP TC, WONG GL. Current knowledge of occult hepatitis B infection and clinical implications[J]. Semin Liver Dis, 2019, 39(2): 249-260. DOI: 10.1055/s-0039-1678728.
    [11] TORBENSON M, THOMAS DL. Occult hepatitis B[J]. Lancet Infect Dis, 2002, 2(8): 479-486. DOI: 10.1016/s1473-3099(02)00345-6.
    [12] FANG Y, TENG X, XU WZ, et al. Molecular characterization and functional analysis of occult hepatitis B virus infection in Chinese patients infected with genotype C[J]. J Med Virol, 2009, 81(5): 826-835. DOI: 10.1002/jmv.21463.
    [13] POLLICINO T, CACCIOLA I, SAFFIOTI F, et al. Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications[J]. J Hepatol, 2014, 61(2): 408-417. DOI: 10.1016/j.jhep.2014.04.041.
    [14] KIM H, LEE SA, KIM DW, et al. Naturally occurring mutations in large surface genes related to occult infection of hepatitis B virus genotype C[J]. PLoS One, 2013, 8(1): e54486. DOI: 10.1371/journal.pone.0054486.
    [15] RIDOLA L, ZULLO A, LAGANÀ B, et al. Hepatitis B (HBV) reactivation in patients receiving biologic therapy for chronic inflammatory diseases in clinical practice[J]. Ann Ist Super Sanita, 2021, 57(3): 244-248. DOI: 10.4415/ANN_21_03_08.
    [16] XIA Y, GUO H. Hepatitis B virus cccDNA:Formation, regulation and therapeutic potential[J]. Antiviral Res, 2020, 180: 104824. DOI: 10.1016/j.antiviral.2020.104824.
    [17] XIA Y, GUO H. Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential[J]. Antiviral Res, 2020, 180: 104824. DOI: 10.1016/j.antiviral.2020.104824.
    [18] SI LL, LI XD, LI L, et al. Inhibitory effect of Suduxing extracts on covalently closed circular DNA of hepatitis B virus[J/CD]. Chin J Exp Clin Infect Dis(Electronic Edition), 2020, 14(4): 265-271. DOI: 10.3877/cma.j.issn.1674-1358.2020.04.001.

    思兰兰, 李晓东, 李乐, 等. 复方肃毒星提取物抑制乙型肝炎病毒cccDNA的作用[J/CD]. 中华实验和临床感染病杂志(电子版), 2020, 14(4): 265-271. DOI: 10.3877/cma.j.issn.1674-1358.2020.04.001.
    [19] TAN N, LUO H, XU XY. Significance of hepatitis B virus pregenomic RNA in the progression of chronic hepatitis B[J]. J Clin Hepatol, 2018, 34(10): 2221-2223. DOI: 10.3969/j.issn.1001-5256.2018.10.035.

    谭宁, 罗皓, 徐小元. HBV pgRNA在慢性乙型肝炎进程中的可能意义[J]. 临床肝胆病杂志, 2018, 34(10): 2221-2223. DOI: 10.3969/j.issn.1001-5256.2018.10.035.
    [20] CACCIOLA I, POLLICINO T, SQUADRITO G, et al. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease[J]. N Engl J Med, 1999, 341(1): 22-26. DOI: 10.1056/NEJM199907013410104.
    [21] GIANNINI E, CEPPA P, BOTTA F, et al. Previous hepatitis B virus infection is associated with worse disease stage and occult hepatitis B virus infection has low prevalence and pathogenicity in hepatitis C virus-positive patients[J]. Liver Int, 2003, 23(1): 12-18. DOI: 10.1034/j.1600-0676.2003.01742.x.
    [22] CHAN HL, TSANG SW, LEUNG NW, et al. Occult HBV infection in cryptogenic liver cirrhosis in an area with high prevalence of HBV infection[J]. Am J Gastroenterol, 2002, 97(5): 1211-1215. DOI: 10.1111/j.1572-0241.2002.05706.x.
    [23] FUKUDA R, ISHIMURA N, NⅡGAKI M, et al. Serologically silent hepatitis B virus coinfection in patients with hepatitis C virus-associated chronic liver disease: clinical and virological significance[J]. J Med Virol, 1999, 58(3): 201-207. DOI: 10.1002/(sici)1096-9071(199907)58:3<201::aid-jmv3>3.0.co;2-2.
    [24] BRANCO F, MATTOS AA, CORAL GP, et al. Occult hepatitis B virus infection in patients with chronic liver disease due to hepatitis C virus and hepatocellular carcinoma in Brazil[J]. Arq Gastroenterol, 2007, 44(1): 58-63. DOI: 10.1590/s0004-28032007000100013.
    [25] MIURA Y, SHIBUYA A, ADACHI S, et al. Occult hepatitis B virus infection as a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C in whom viral eradication fails[J]. Hepatol Res, 2008, 38(6): 546-556. DOI: 10.1111/j.1872-034X.2007.00316.x.
  • 加载中
图(3) / 表(3)
计量
  • 文章访问数:  1339
  • HTML全文浏览量:  908
  • PDF下载量:  64
  • 被引次数: 0
出版历程
  • 收稿日期:  2022-09-05
  • 录用日期:  2022-10-13
  • 出版日期:  2022-12-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回