PDF下载 ( 658 KB)
戊型肝炎病毒感染重症化和慢性化的机制
DOI: 10.3969/j.issn.1001-5256.2023.11.003
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：陈俞心负责查阅文献，起草文章；王艺瑾负责拟定课题，设计写作思路，指导撰写文章并最后定稿。
The mechanism of the severe exacerbation and chronicity of hepatitis E virus infection
-
摘要: 戊型肝炎病毒（HEV）感染是全球范围急性病毒性肝炎最常见的原因。在过去十年，HEV被发现不仅能引起急性自限性疾病，还可导致重症及慢性感染。HEV感染孕妇或基础肝病患者后易发展为肝衰竭，病死率较高；HEV感染实体器官移植患者易发展为慢性肝炎。本文介绍了HEV重症及慢性感染的诊断、临床特征、传播方式、预防和治疗，重点探讨了HEV重症化和慢性化过程中免疫反应、炎症反应以及病毒本身的特征，并总结其促进HEV病程进展的机制。然而，现有研究与临床应用之间仍然存在鸿沟，目前仍然缺乏针对重症及慢性HEV的较好的诊疗方案。临床研究人员需要不断推进戊型肝炎发病机制及系统的队列研究，同时提高临床护理水平，最终实现预防和改善戊型肝炎患者预后的目标。Abstract: Hepatitis E virus （HEV） infection is the most common cause of acute viral hepatitis worldwide， and over the past ten years， studies have shown that HEV can not only cause acute self-limiting hepatitis， but also lead to severe and chronic infection. Pregnant women or patients with underlying liver disease may progress to liver failure after HEV infection， resulting in a relatively high mortality rate， and patients receiving solid organ transplantation may progress to chronic hepatitis after HFV infection. This article introduces the diagnosis， clinical features， transmission， prevention， and treatment of severe and chronic HEV infection， discusses the features of immune response， inflammatory response， and the virus itself during the severe exacerbation and chronicity of HEV infection， and summarizes the mechanism in promoting the progression of HEV. Nevertheless， there are still large gaps between current studies and clinical application， and there is still a lack of effective diagnosis and treatment regimens for severe and chronic HEV infection. It is necessary for clinical researchers to conduct research on the pathogenesis of hepatitis E and systematic cohort studies and improve the level of clinical nursing， thereby achieving the goal of preventing hepatitis E and improving the prognosis of patients with hepatitis E.
-
Key words:
- Hepatitis E virus /
- Hepatitis E /
- Autoimmunity
-
[1] MA JX, LIU YY, LI Q, et al. Study on the safety and immunogenicity of simultaneous vaccination on both hepatitis E and hepatitis B vaccines[J]. Chin J Epidemiol, 2019, 40( 4): 451- 456. DOI: 10.3760/cma.j.issn.0254-6450.2019.04.015.马建新, 刘瑶瑶, 李倩, 等. 戊型肝炎疫苗和乙型肝炎疫苗联合接种的安全性及免疫原性研究[J]. 中华流行病学杂志, 2019, 40( 4): 451- 456. DOI: 10.3760/cma.j.issn.0254-6450.2019.04.015. [2] HUANG AD, TANG L, WANG XQ, et al. Hepatitis E incidence trends and spatial-temporal clustering in China, 2011-2021[J]. Chin J Vaccines Immun, 2022, 28( 4): 417- 421. DOI: 10.19914/j.CJVI.2022080.黄澳迪, 唐林, 王晓琪, 等. 中国2011—2021年戊型病毒性肝炎发病趋势和时空聚集性[J]. 中国疫苗和免疫, 2022, 28( 4): 417- 421. DOI: 10.19914/j.CJVI.2022080. [3] WANG W, CHEN KY, WU LM, et al. Genetic characteristics of hepatitis E in Shanghai, 2017-2020[J]. Dis Surveillance, 2022, 37( 2): 214- 219. DOI: 10.3784/jbjc.202106210349.王葳, 陈恺韵, 吴立梦, 等. 2017—2020年上海市戊型肝炎病毒基因型特征研究[J]. 疾病监测, 2022, 37( 2): 214- 219. DOI: 10.3784/jbjc.202106210349. [4] NAIR VP, ANANG S, SUBRAMANI C, et al. Endoplasmic reticulum stress induced synthesis of a novel viral factor mediates efficient replication of genotype-1 hepatitis E virus[J]. PLoS Pathog, 2016, 12( 4): e1005521. DOI: 10.1371/journal.ppat.1005521. [5] PÉREZ-GRACIA MT, SUAY-GARCÍA B, MATEOS-LINDEMANN ML. Hepatitis E and pregnancy: Current state[J]. Rev Med Virol, 2017, 27( 3): e1929. DOI: 10.1002/rmv.1929. [6] LHOMME S, MARION O, ABRAVANEL F, et al. Clinical manifestations, pathogenesis and treatment of hepatitis E virus infections[J]. J Clin Med, 2020, 9( 2): 331. DOI: 10.3390/jcm9020331. [7] ZHOU XY, HUANG F, XU L, et al. Hepatitis E virus infects neurons and brains[J]. J Infect Dis, 2017, 215( 8): 1197- 1206. DOI: 10.1093/infdis/jix079. [8] WENTER C, BORENA W, OBERHUBER G, et al. Acute liver failure in immunocompetent patients infected with hepatitis E[J]. Wien Klin Wochenschr, 2019, 131( 17-18): 442- 445. DOI: 10.1007/s00508-019-01547-2. [9] WANG YJ, LIU SH, PAN QW, et al. Chronic hepatitis E in an immunocompetent patient[J]. Clin Res Hepatol Gastroenterol, 2020, 44( 3): e66- e68. DOI: 10.1016/j.clinre.2019.08.001. [10] DALTON HR, STABLEFORTH W, THURAIRAJAH P, et al. Autochthonous hepatitis E in Southwest England: Natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease[J]. Eur J Gastroenterol Hepatol, 2008, 20( 8): 784- 790. DOI: 10.1097/MEG.0b013e3282f5195a. [11] LI JX, LI YQ, LI J. Clinical analysis for 46 hepatitis E cases in elderly people[J]. Med J Chin People’s Heath, 2010, 22( 16): 2064- 2065. DOI: 10.3969/j.issn.1672-0369.2010.16.012.李君熹, 李玉琴, 李晶. 老年戊型病毒性肝炎46例临床分析[J]. 中国民康医学, 2010, 22( 16): 2064- 2065. DOI: 10.3969/j.issn.1672-0369.2010.16.012. [12] MA XX, JI YP, JIN L, et al. Prevalence and clinical features of hepatitis E virus infection in pregnant women: A large cohort study in Inner Mongolia, China[J]. Clin Res Hepatol Gastroenterol, 2021, 45( 4): 101536. DOI: 10.1016/j.clinre.2020.08.012. [13] RAYIS DA, JUMAA AM, GASIM GI, et al. An outbreak of hepatitis E and high maternal mortality at Port Sudan, Eastern Sudan[J]. Pathog Glob Health, 2013, 107( 2): 66- 68. DOI: 10.1179/2047773213Y.0000000076. [14] QIAN ZY, LI TY, XIA YP, et al. Genotype 4 hepatitis E virus replicates in the placenta, causes severe histopathological damage, and vertically transmits to fetuses[J]. J Infect, 2023, 87( 1): 34- 45. DOI: 10.1016/j.jinf.2023.05.003. [15] WANG YJ, LIU HY, JIANG YY, et al. Poor outcomes of acute hepatitis E in patients with cirrhotic liver diseases regardless of etiology[J]. Open Forum Infect Dis, 2020, 7( 4): ofaa107. DOI: 10.1093/ofid/ofaa107. [16] WANG YJ, LIU HY, LIU SH, et al. Incidence, predictors and prognosis of genotype 4 hepatitis E related liver failure: A tertiary nested case-control study[J]. Liver Int, 2019, 39( 12): 2291- 2300. DOI: 10.1111/liv.14221. [17] KUMAR A, SARASWAT VA. Hepatitis E and acute-on-chronic liver failure[J]. J Clin Exp Hepatol, 2013, 3( 3): 225- 230. DOI: 10.1016/j.jceh.2013.08.013. [18] FRIAS M, LÓPEZ-LÓPEZ P, RIVERO A, et al. Role of hepatitis E virus infection in acute-on-chronic liver failure[J]. Biomed Res Int, 2018, 2018: 9098535. DOI: 10.1155/2018/9098535. [19] KUMAR ACHARYA S, KUMAR SHARMA P, SINGH R, et al. Hepatitis E virus(HEV) infection in patients with cirrhosis is associated with rapid decompensation and death[J]. J Hepatol, 2007, 46( 3): 387- 394. DOI: 10.1016/j.jhep.2006.09.016. [20] FANG L, ZHANG JL, CHEN HY, et al. Epidemiological characteristics and clinical manifestations of hepatitis E in a tertiary hospital in China: A retrospective study[J]. Front Microbiol, 2022, 12: 831968. DOI: 10.3389/fmicb.2021.831968. [21] KAMAR N, ROSTAING L, LEGRAND-ABRAVANEL F, et al. How should hepatitis E virus infection be defined in organ-transplant recipients?[J]. Am J Transplant, 2013, 13( 7): 1935- 1936. DOI: 10.1111/ajt.12253. [22] von FELDEN J, ALRIC L, PISCHKE S, et al. The burden of hepatitis E among patients with haematological malignancies: A retrospective European cohort study[J]. J Hepatol, 2019, 71( 3): 465- 472. DOI: 10.1016/j.jhep.2019.04.022. [23] DI BARTOLOMEO S, CARUBBI F, CIPRIANI P. Hepatitis E virus and rheumatic diseases: What do rheumatologists need to know?[J]. BMC Rheumatol, 2020, 4: 51. DOI: 10.1186/s41927-020-00149-0. [24] MA ZR, de MAN RA, KAMAR N, et al. Chronic hepatitis E: Advancing research and patient care[J]. J Hepatol, 2022, 77( 4): 1109- 1123. DOI: 10.1016/j.jhep.2022.05.006. [25] DALTON HR, BENDALL RP, KEANE FE, et al. Persistent carriage of hepatitis E virus in patients with HIV infection[J]. N Engl J Med, 2009, 361( 10): 1025- 1027. DOI: 10.1056/NEJMc0903778. [26] PRABHU SB, GUPTA P, DURGAPAL H, et al. Study of cellular immune response against Hepatitis E virus(HEV)[J]. J Viral Hepat, 2011, 18( 8): 587- 594. DOI: 10.1111/j.1365-2893.2010.01338.x. [27] NAIK A, GOEL A, AGRAWAL V, et al. Changes in gene expression in liver tissue from patients with fulminant hepatitis E[J]. World J Gastroenterol, 2015, 21( 26): 8032- 8042. DOI: 10.3748/wjg.v21.i26.8032. [28] KRAIN LJ, NELSON KE, LABRIQUE AB. Host immune status and response to hepatitis E virus infection[J]. Clin Microbiol Rev, 2014, 27( 1): 139- 165. DOI: 10.1128/CMR.00062-13. [29] DAVIS MM, BJORKMAN PJ. T-cell antigen receptor genes and T-cell recognition[J]. Nature, 1988, 334( 6181): 395- 402. DOI: 10.1038/334395a0. [30] LUCKHEERAM RV, ZHOU R, VERMA AD, et al. CD4⁺T cells: Differentiation and functions[J]. Clin Dev Immunol, 2012, 2012: 925135. DOI: 10.1155/2012/925135. [31] WU J, GUO YR, LU X, et al. Th1/Th2 cells and associated cytokines in acute hepatitis E and related acute liver failure[J]. J Immunol Res, 2020, 2020: 6027361. DOI: 10.1155/2020/6027361. [32] SRIVASTAVA R, AGGARWAL R, JAMEEL S, et al. Cellular immune responses in acute hepatitis E virus infection to the viral open reading frame 2 protein[J]. Viral Immunol, 2007, 20( 1): 56- 65. DOI: 10.1089/vim.2006.0053. [33] SRIVASTAVA R, AGGARWAL R, SACHDEVA S, et al. Adaptive immune responses during acute uncomplicated and fulminant hepatitis E[J]. J Gastroenterol Hepatol, 2011, 26( 2): 306- 311. DOI: 10.1111/j.1440-1746.2010.06356.x. [34] WU J, LING B, GUO NZ, et al. Immunological manifestations of hepatitis E-associated acute and chronic liver failure and its regulatory mechanisms[J]. Front Med, 2021, 8: 725993. DOI: 10.3389/fmed.2021.725993. [35] WANG WS, XU L, BRANDSMA JH, et al. Convergent transcription of interferon-stimulated genes by TNF-α and IFN-α augments antiviral activity against HCV and HEV[J]. Sci Rep, 2016, 6: 25482. DOI: 10.1038/srep25482. [36] LI Y, YU PF, KESSLER AL, et al. Hepatitis E virus infection activates NOD-like receptor family pyrin domain-containing 3 inflammasome antagonizing interferon response but therapeutically targetable[J]. Hepatology, 2022, 75( 1): 196- 212. DOI: 10.1002/hep.32114. [37] WU J, ZHANG XY, LIU HY, et al. RDW, NLR and RLR in predicting liver failure and prognosis in patients with hepatitis E virus infection[J]. Clin Biochem, 2019, 63: 24- 31. DOI: 10.1016/j.clinbiochem.2018.11.012. [38] MUNOZ-SUANO A, HAMILTON AB, BETZ AG. Gimme shelter: The immune system during pregnancy[J]. Immunol Rev, 2011, 241( 1): 20- 38. DOI: 10.1111/j.1600-065X.2011.01002.x. [39] SARGENT IL, BORZYCHOWSKI AM, REDMAN CWG. NK cells and human pregnancy: An inflammatory view[J]. Trends Immunol, 2006, 27( 9): 399- 404. DOI: 10.1016/j.it.2006.06.009. [40] YU WH, HAO XH, LI Y, et al. Vertical transmission of hepatitis E virus in pregnant rhesus macaques[J]. Sci Rep, 2020, 10( 1): 17517. DOI: 10.1038/s41598-020-74461-7. [41] XU L, WANG WS, LI YL, et al. RIG-I is a key antiviral interferon-stimulated gene against hepatitis E virus regardless of interferon production[J]. Hepatology, 2017, 65( 6): 1823- 1839. DOI: 10.1002/hep.29105. [42] WANG WS, WANG YJ, QU CB, et al. The RNA genome of hepatitis E virus robustly triggers an antiviral interferon response[J]. Hepatology, 2018, 67( 6): 2096- 2112. DOI: 10.1002/hep.29702. [43] SEHGAL R, PATRA S, DAVID P, et al. Impaired monocyte-macrophage functions and defective Toll-like receptor signaling in hepatitis E virus-infected pregnant women with acute liver failure[J]. Hepatology, 2015, 62( 6): 1683- 1696. DOI: 10.1002/hep.28143. [44] JILANI N, DAS BC, HUSAIN SA, et al. Hepatitis E virus infection and fulminant hepatic failure during pregnancy[J]. J Gastroenterol Hepatol, 2007, 22( 5): 676- 682. DOI: 10.1111/j.1440-1746.2007.04913.x. [45] KUMAR A, DEVI SG, KAR P, et al. Association of cytokines in hepatitis E with pregnancy outcome[J]. Cytokine, 2014, 65( 1): 95- 104. DOI: 10.1016/j.cyto.2013.09.022. [46] SINGH S, DAGA MK, KUMAR A, et al. Role of oestrogen and its receptors in HEV-associated feto-maternal outcomes[J]. Liver Int, 2019, 39( 4): 633- 639. DOI: 10.1111/liv.13928. [47] PAL R, AGGARWAL R, NAIK SR, et al. Immunological alterations in pregnant women with acute hepatitis E[J]. J Gastroenterol Hepatol, 2005, 20( 7): 1094- 1101. DOI: 10.1111/j.1440-1746.2005.03875.x. [48] YANG C, YU W, BI Y, et al. Increased oestradiol in hepatitis E virus-infected pregnant women promotes viral replication[J]. J Viral Hepat, 2018, 25( 6): 742- 751. DOI: 10.1111/jvh.12865. [49] ZHOU XY, WANG YJ, METSELAAR HJ, et al. Rapamycin and everolimus facilitate hepatitis E virus replication: Revealing a basal defense mechanism of PI3K-PKB-mTOR pathway[J]. J Hepatol, 2014, 61( 4): 746- 754. DOI: 10.1016/j.jhep.2014.05.026. [50] BI YH, YANG CC, YU WH, et al. Pregnancy serum facilitates hepatitis E virus replication in vitro[J]. J Gen Virol, 2015, 96( Pt 5): 1055- 1061. DOI: 10.1099/vir.0.000054. [51] HE YJ, WANG F, YAO NJ, et al. Serum superoxide dismutase level is a potential biomarker of disease prognosis in patients with HEV-induced liver failure[J]. BMC Gastroenterol, 2022, 22( 1): 14. DOI: 10.1186/s12876-022-02095-2. [52] EL-MOKHTAR MA, OTHMAN ER, KHASHBAH MY, et al. Evidence of the extrahepatic replication of hepatitis E virus in human endometrial stromal cells[J]. Pathogens, 2020, 9( 4): 295. DOI: 10.3390/pathogens9040295. [53] GOUILLY J, CHEN Q, SIEWIERA J, et al. Genotype specific pathogenicity of hepatitis E virus at the human maternal-fetal interface[J]. Nat Commun, 2018, 9( 1): 4748. DOI: 10.1038/s41467-018-07200-2. [54] YADAV KK, BOLEY PA, FRITTS Z, et al. Ectopic expression of genotype 1 hepatitis E virus ORF4 increases genotype 3 HEV viral replication in cell culture[J]. Viruses, 2021, 13( 1): 75. DOI: 10.3390/v13010075. [55] BORKAKOTI J, AHMED G, RAI A, et al. Report of novel H105R, D29N, V27A mutations in the methyltransferase region of the HEV genome in patients with acute liver failure[J]. J Clin Virol, 2017, 91: 1- 4. DOI: 10.1016/j.jcv.2017.03.017. [56] TAKAHASHI K, OKAMOTO H, ABE N, et al. Virulent strain of hepatitis E virus genotype 3, Japan[J]. Emerg Infect Dis, 2009, 15( 5): 704- 709. DOI: 10.3201/eid1505.081100. [57] KAMAR N, SELVES J, MANSUY JM, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients[J]. N Engl J Med, 2008, 358( 8): 811- 817. DOI: 10.1056/nejmoa0706992. [58] WANG YJ, CHEN GF, PAN QW, et al. Chronic hepatitis E in a renal transplant recipient: The first report of genotype 4 hepatitis E virus caused chronic infection in organ recipient[J]. Gastroenterology, 2018, 154( 4): 1199- 1201. DOI: 10.1053/j.gastro.2017.12.028. [59] KAMAR N, MANSUY JM, COINTAULT O, et al. Hepatitis E virus-related cirrhosis in kidney- and kidney-pancreas-transplant recipients[J]. Am J Transplant, 2008, 8( 8): 1744- 1748. DOI: 10.1111/j.1600-6143.2008.02286.x. [60] WANG YJ, METSELAAR HJ, PEPPELENBOSCH MP, et al. Chronic hepatitis E in solid-organ transplantation: The key implications of immunosuppressants[J]. Curr Opin Infect Dis, 2014, 27( 4): 303- 308. DOI: 10.1097/QCO.0000000000000074. [61] BREMER W, BLASCZYK H, YIN X, et al. Resolution of hepatitis E virus infection in CD8+ T cell-depleted rhesus macaques[J]. J Hepatol, 2021, 75( 3): 557- 564. DOI: 10.1016/j.jhep.2021.04.036. [62] SUNEETHA PV, PISCHKE S, SCHLAPHOFF V, et al. Hepatitis E virus(HEV)-specific T-cell responses are associated with control of HEV infection[J]. Hepatology, 2012, 55( 3): 695- 708. DOI: 10.1002/hep.24738. [63] WANG YJ, ZHOU XY, DEBING Y, et al. Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus[J]. Gastroenterology, 2014, 146( 7): 1775- 1783. DOI: 10.1053/j.gastro.2014.02.036. [64] PISCHKE S, STIEFEL P, FRANZ B, et al. Chronic hepatitis e in heart transplant recipients[J]. Am J Transplant, 2012, 12( 11): 3128- 3133. DOI: 10.1111/j.1600-6143.2012.04200.x. [65] ZHOU XY, de MAN RA, de KNEGT RJ, et al. Epidemiology and management of chronic hepatitis E infection in solid organ transplantation: A comprehensive literature review[J]. Rev Med Virol, 2013, 23( 5): 295- 304. DOI: 10.1002/rmv.1751. [66] NGUYEN HT, TORIAN U, FAULK K, et al. A naturally occurring human/hepatitis E recombinant virus predominates in serum but not in faeces of a chronic hepatitis E patient and has a growth advantage in cell culture[J]. J Gen Virol, 2012, 93( Pt 3): 526- 530. DOI: 10.1099/vir.0.037259-0. -
本文二维码
计量
- 文章访问数: 316
- HTML全文浏览量: 103
- PDF下载量: 75
- 被引次数: 0
下载:
