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

doi:10.3969/j.issn.1001-5256.2022.12.011

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

陈欣欣^{1, 2},
张海萍²,
黄春洋²,
苏建荣^1, , ,,
闫惠平^2, , ,

1.
首都医科大学附属北京友谊医院临床检验中心，北京 100050
2.
首都医科大学附属北京佑安医院临床检验中心，北京 100069

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

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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

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

Xinxin CHEN^{1, 2},
Haiping ZHANG²,
Chunyang HUANG²,
Jianrong SU^{1
, ,
,},
Huiping YAN^{2
, ,
,}

1.
Center of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
2.
Center of Clinical Laboratory, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China

Research funding:

Beijing Municipal Natural Science Foundation （7111004）

Beijing Municipal Administration of Hospitals Incubating Program （PX2019062）

More Information

Corresponding author: SU Jianrong, youyilab@163.com (ORCID: 0000-0002-0377-1711); YAN Huiping, yhp503@126.com (ORCID: 0000-0001-5980-7675)

摘要

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。
- 肝炎, 自身免疫性 /
- 乙型肝炎病毒 /
- 感染
Abstract: Objective To investigate the prevalence rate of occult HBV infection (OBI) in patients with autoimmune hepatitis (AIH) and the influence of OBI in the clinical condition and prognosis of AIH patients. Methods A total of 103 patients with a confirmed diagnosis of AIH who were admitted to Beijing YouAn Hospital from April 2012 to March 2019 were enrolled. Nested PCR and real-time PCR were used to confirm the diagnosis of OBI, and real-time PCR was used to measure HBV pgRNA. Clinical features, laboratory markers, and follow-up analysis of prognosis were compared between the OBI group with 24 patients and the non-OBI group with 79 patients. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U rank sum test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves, and the Cox regression model was used to perform univariate and multivariate analyses. Hazard ratio and its 95% confidence interval were calculated. Results The detection rate of OBI was 23.30% (24/103) in AIH patients, with an HBV DNA viral load of < 200 IU/mL, among whom 9 patients with OBI (9/24, 37.50%) were found to have HBV pgRNA in serum. Compared with the non-OBI group, the OBI group had a significantly higher positive rate of the three antibodies anti-HBs, anti-HBc, and anti-HBe (χ²=5.906, P=0.016). The univariate analysis showed that OBI, hypoproteinemia, splenomegaly, and ascites were risk factors for adverse events in AIH (all P < 0.05) and were associated with disease progression, and the multivariate Cox regression analysis showed that hypoproteinemia and ascites were independent risk factors for adverse events (all P < 0.05). Conclusion There is a relatively high detection rate of OBI in AIH patients, and the presence of OBI may accelerate the progression of AIH.
- Hepatitis, Autoimmune /
- Hepatitis B virus /
- Infection

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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

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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

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图 3 AIH患者生存曲线的比较

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

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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值
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

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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值	P值
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

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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
项目	HR	95%CI	P值	HR	95%CI	P值
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

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参考文献(25)

[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.