Email Alert | RSS

北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 920-926. doi: 10.19723/j.issn.1671-167X.2022.05.019

• 论著 • 上一篇    下一篇

慢性乙型肝炎病毒感染的自然病程特征

王雷婕1,李明蔚2,刘燕娜1,陈香梅1,赵景民3,刘树红3,*(),鲁凤民1,4,*()   

  1. 1. 北京大学基础医学院病原生物学系暨感染病中心, 北京 100191
    2. 郑州大学公共卫生学院流行病学教研室, 郑州 450001
    3. 解放军总医院第五医学中心病理科, 北京 100039
    4. 北京大学人民医院肝病研究所暨丙型肝炎和肝病免疫治疗北京市重点实验室, 北京 100044
  • 收稿日期:2022-07-04 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 刘树红,鲁凤民 E-mail:18511862409@163.com;lu.fengmin@hsc.pku.edu.cn
  • 作者简介:刘树红，解放军总医院第五医学中心病理科，副主任医师，从事病理诊断、研究与教学工作10余年，致力于肝病及其他传染病病理的临床病理诊断与鉴别诊断，擅长病毒性肝炎、酒精性肝病、非酒精性脂肪性肝炎、自身免疫性肝病、药物性肝损伤、遗传代谢性肝病以及肝脏肿瘤等肝病疾病的诊断与鉴别诊断。担任中国研究型医院学会分子诊断医学专业委员会委员，国家临床重点专科(病理科)-军队建设项目的主要骨干；参与国家“十三五”重大专项子课题、国家自然基金面上项目等课题5项；发表SCI论文20余篇，以第一作者发表在J Hepatol、Liver International、J Viral Hepatitis等期刊上，累计影响因子98.645分|鲁凤民，博士生导师，北京大学基础医学院病原生物学系主任，北京大学人民医院肝病研究所教授。
    1981—1986年就读于河南医学院临床医学专业，1986—1989年于哈尔滨医科大学接受研究生教育，1992—1994年于北京大学公共卫生学院从事博士后研究。曾先后在瑞典卡罗琳斯卡医学院、美国宾夕法尼亚大学访学，2005年回北京大学任教至今，期间曾任北京大学基础医学院副院长、国务院学位委员会基础医学学组委员。现任中国医药质量协会转化医学分会主任委员、中华医学会医学病毒学分会常委、中国微生物学会病毒学工作委员会常委、北京市微生物学会常委、北京市医学病毒学分会副主任委员等。
    长期从事乙型肝炎病毒及相关肝病、肝癌的发病机制和诊断标志物等研究，主持或参加了国家“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项、国家高技术研究发展计划(863计划)、国家重点基础研究发展计划(973计划)及国家自然科学基金面上项目等课题20余项。实验证实了乙型肝炎病毒RNA病毒样颗粒的存在，推进了血清乙型肝炎病毒RNA的临床应用。在The New England Journal of Medicine、《中华医学杂志》、Journal of Hepatology及Hepatology等期刊发表论文近200篇，被引次数超过6 000次。获得专利18项、转化7项。曾作为参加人两次获得国家科学技术进步奖二等奖
  • 基金资助:
    北京市自然科学基金(7212063)

Natural history and disease progression of chronic hepatitis B virus infection

Lei-jie WANG1,Ming-wei LI2,Yan-na LIU1,Xiang-mei CHEN1,Jing-min ZHAO3,Shu-hong LIU3,*(),Feng-min LU1,4,*()   

  1. 1. Department of Microbiology & Infectious Disease Center, Peking University School of Basic Medical Sciences, Beijing 100191, China
    2. Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
    3. Department of Pathology and Hepatology, Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing 100039, China
    4. Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Beijing 100044, China
  • Received:2022-07-04 Online:2022-10-18 Published:2022-10-14
  • Contact: Shu-hong LIU,Feng-min LU E-mail:18511862409@163.com;lu.fengmin@hsc.pku.edu.cn
  • Supported by:
    the Beijing Natural Science Foundation(7212063)

RICH HTML

 16   

PDF (PC)

214

摘要：

目的: 通过对单中心大样本慢性乙型肝炎病毒(hepatitis B virus, HBV)感染队列的分析, 对我国慢性HBV感染自然病程的划分提出修订建议。方法: 回顾性地纳入2014年1月至2020年10月在中国人民解放军总医院第五医学中心接受过肝组织活检的慢性HBV感染者。参考《欧洲肝病学会乙型肝炎病毒感染管理临床实践指南(2017年版)》等国内外最新版慢性乙型肝炎(chronic hepatitis B, CHB)防治指南, 将患者按乙型肝炎e抗原(hepatitis B e antigen, HBeAg)状态及肝损伤程度分为HBeAg阳性感染(免疫耐受期)、HBeAg阳性CHB(免疫清除期)、HBeAg阴性感染(免疫控制期)和HBeAg阴性CHB(再活动期)四个自然病程分期, 并重点比较了不同分期患者的人口学和实验室检验结果。两组间年龄差异采用Mann-Whitney U检验。结果: 最终纳入符合纳排标准的患者760例, 包括197例未成年(年龄 < 18岁)和563例成年感染者, 男性456例、女性304例, 纳入患者的中位年龄为29岁, (四分位间距: 16, 39岁)。上述四个自然病程分期患者分别有173、329、95和163例, 进一步比较四期患者的年龄发现: HBeAg阴性CHB的中位年龄尽管大于HBeAg阳性CHB(37岁vs. 24岁, P < 0.001), 但却小于HBeAg阴性感染者(37岁vs. 39岁, P = 0.240)。结论: 根据本研究可以推测, HBeAg阴性CHB患者并非都是由HBeAg阴性感染者进入再活动期发展而来, 也可以由仍处于持续免疫活动状态的HBeAg阳性CHB患者发生HBeAg阴转或血清学转换而来。

关键词: 慢性乙型肝炎, 自然史, 乙型肝炎e抗原

Abstract:

Objective: To better understand and revise the natural history and disease progression of chronic hepatitis B virus (HBV) infection through analysis of a single-center large-scale cohort of indivi-duals with chronic HBV infection. Methods: Patients with chronic HBV infection who had undergone liver biopsy in the Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital from January 2014 to October 2020 were retrospectively recruited. Based on patient's hepatitis B e antigen (HBeAg) states and pathologic diagnosis, they were categorized into four disease progression statuses (or phases according to the old-terminology in the updated guidelines of chronic hepatitis B (CHB), such as European Association for the Study of the Liver (EASL) 2017, Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection: HBeAg-positive chronic HBV infection (immune tolerance), HBeAg-positive CHB (immune active HBeAg positive), HBeAg-negative chronic HBV infection (inactive carrier), and HBeAg-negative CHB (immune reactive HBeAg negative). Then the demographic, laboratory tests and liver histological results of the patients in different disease progression stages were compared. Age differences between the two groups were evaluated using Mann-Whitney U test. Results: A total of 760 eligible patients with a median age of 29 (interquartile range: 16-39) years were enrolled. Among them, 197 were underage individuals (age < 18 years) and 563 were adults; and 456 were males and 304 females. According to the pathological diagnosis, the patients were classified, and in each of the above four natural disease phases there were 173, 329, 95, and 163 individuals, respectively. Further comparison of the ages of the patients of the four disease progression statuses revealed that patients of HBeAg-negative CHB had a median age at 37 years, which was reasonably higher than those with HBeAg-positive CHB in immune active phase (37 vs. 24 years, P < 0.001), but was relatively younger than those with HBeAg-negative chronic HBV infection (37 vs. 39 years, P= 0.240). Conclusion: According to this study, it could be speculated that HBeAg-negative CHB patients probably not all reactivate from individuals of HBeAg-negative chronic HBV infection. Instead, certain HBeAg-negative CHB patients may also come from HBeAg-positive CHB patients who have undergone HBeAg clearance or seroconversion and still remain in the immune active state.

Key words: Chronic hepatitis B, Natural history, Hepatitis B e antigen

中图分类号: 

  • R373.2

表1

HBeAg阳性和阴性患者的临床特征"

Items HBeAg positive(n=502) HBeAg negative(n=258) P value
Age/yearsa 25 (11, 33) 39 (30, 46) < 0.001
Gender，n(%)
  Male, 307 (61.2) 149 (57.8)
  Female 195 (38.8) 109 (42.2) 0.364
Serum indicators of virological
  HBV DNA/(lg IU/mL)a 7.95 (7.16, 8.34) 3.50 (2.57, 4.68) < 0.001
  HBsAg/(lg IU/mL)a 4.26 (3.79, 4.68) 3.32 (2.76, 3.68) < 0.001
Serum biochemical indicators
  ALT/(U/L)a 72 (37, 170) 27 (17, 52) < 0.001
  AST/(U/L)a 53 (31, 105) 26 (20, 41) < 0.001
  ALP/(U/L)a 100 (73, 228) 77 (63, 98) < 0.001
  GGT/(U/L)a 20 (14, 38) 20 (14, 29) 0.121
Serum indicators of liver function
  ALB/(g/L)a 41 (38, 43) 42 (40, 44) < 0.001
  PA/(mg/L)b 166±50 197±52 < 0.001
  PT/sa 11 (11, 12) 11 (11, 12) 0.025
  PLT/(×109/L)a 210 (177, 254) 186 (154, 224) < 0.001
Histological assessment
  Inflammation Grade, n (%)c
    G0-G1 228 (45.4) 182 (70.5)
    G2-G4 274 (54.6) 76 (29.5) < 0.001
  Fibrosis stage, n (%)c
    S0-1 260 (51.8) 107 (41.5)
    S2-4 242 (48.2) 151 (58.5) 0.007

表2

乙型肝炎病毒感染自然病程不同分期患者的临床特征"

Stages HBeAg positive HBeAg negative P value
Chronic HBV carrier statusa(n=173) Chronic hepatitisb(n=329) Inactive HBsAg carrier statusc(n=95) Chronic hepatitisd(n=163)
Age/yearse 25 (11, 34)△▲ 24 (12, 33)△▲ 39 (32, 47)*# 37 (29, 46)*# < 0.001
Gender, n(%)f
  Male, 106 (61.3) 201 (61.1) 53 (55.8) 96 (58.9) 0.785
  Female 67 (38.7) 128 (38.9) 42 (44.2) 67 (41.1)
Serum indicators of virological
  HBV DNA/(lg IU/mL)e 8.00 (7.56, 8.54)#△▲ 7.77 (6.89, 8.24)*△▲ 3.12 (2.40, 4.00)*# 3.97 (2.72, 5.32)*# < 0.001
  HBsAg/(lg IU/mL)e 4.61 (4.06, 4.85)#△▲ 4.09 (3.66, 4.52)*△▲ 3.21 (2.60, 3.60)*# 3.39 (2.95, 3.72)*# < 0.001
Serum biochemical indicators
  ALT/(U/L)e 41 (25, 65)#△ 112 (50, 263)*△▲ 22 (16, 38)*▲ 31 (20, 71)#△ < 0.001
  AST/(U/L)e 32 (24, 49)#△ 77 (40, 149)*△▲ 23 (19, 30)* #▲ 30 (21, 52)#△ < 0.001
  ALP/(U/L)e 89 (66, 211)#△▲ 108 (78, 235)*△▲ 75 (61, 91)* # 79 (64, 103)*# < 0.001
  GGT/(U/L)e 15 (12, 20)#▲ 29 (16, 51)*△▲ 17 (13, 24)#▲ 21 (15, 38)*#△ < 0.001
Serum indicators of liver function
  ALB/(g/L)e 41 (38, 44) 40 (38, 43)△▲ 43 (40, 45)# 42 (39, 44)# < 0.001
  PA/(mg/L)g 195±46#△ 151±46*△▲ 215±48*#▲ 187±52#△
  PT/se 11.1 (10.6, 11.7)# 11.4 (10.8, 11.9)*△ 10.8 (10.3, 11.4)#▲ 11.3 (10.7, 11.9)△ < 0.001
  PLT/(×109/L)e 218 (190, 260)△▲ 206 (172, 252)▲ 196 (164, 234)* 180 (145, 220)*#
Histological assessment
  Inflammation grade, n (%)f
    G0-G1 173 (100.0) 55 (16.7) 95 (100.0) 87 (53.4)
    G2-G4 0 (0.0) 274 (83.3) 0 (0.0) 76 (46.6)
  Fibrosis Stage, n (%)f
    S0-1 173 (100.0) 87 (26.4) 95 (100.0) 12 (7.4)
    S2-4 0 (0.0) 242 (73.6) 0 (0.0) 151 (92.6)

图1

根据中国《慢性乙型肝炎防治指南(2019年版)》修改后的慢性乙型肝炎病毒感染自然病程的分期示意图"

表3

根据中国《慢性乙型肝炎防治指南(2019年版)》修改后的慢性乙型肝炎病毒感染自然病程各期特征"

Clinical characteristics/immune status Immune tolerant phase Immune clearance phase Immune control phase Reactivation phase
Modified corresponding staging HBeAg positive chronic HBV carrier status a HBeAg positivechronic hepatitis HBeAg negativechronic hepatitis Inactive HBsAg carrier status b HBeAg negative or positive chronic hepatitisc
HBeAg + + - - +/-
ALT Normal Intermittently or persistently elevated Intermittently or persistently elevated Normal Intermittently or persistently elevated
Histological assessment None/minimal inflammation and fibrosis Moderate to severe inflammationc/fibrosis or cirrhosis Moderate to severe inflammation/fibrosis or cirrhosisc None/minimal inflammation and fibrosis Moderate to severe inflammation/fibrosis or cirrhosisc
HBV DNA High Moderate to high Low Low or undetectable Elevated
1 GBD 2019 Hepatitis B Collaborators . Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019[J]. Lancet Gastroenterol Hepatol, 2022, 7 (9): 796- 829.
doi: 10.1016/S2468-1253(22)00124-8
2 Liu J , Liang W , Jing W , et al. Countdown to 2030: eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97 (3): 230- 238.
doi: 10.2471/BLT.18.219469
3 Rehermann B . Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells[J]. Nat Med, 2013, 19 (7): 859- 868.
doi: 10.1038/nm.3251
4 Nguyen MH , Wong G , Gane E , et al. Hepatitis B virus: advances in prevention, diagnosis, and therapy[J]. Clin Microbiol Rev, 2020, 33 (2): e00046.
5 Moreno-Otero R , Garcia-Monzon C , Garcia-Sanchez A , et al. Development of cirrhosis after chronic type B hepatitis: a clinico-pathologic and follow-up study of 46 HBeAg-positive asymptomatic patients[J]. Am J Gastroenterol, 1991, 86 (5): 560- 564.
6 Lin SM , Sheen IS , Chien RN , et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection[J]. Hepatology, 1999, 29 (3): 971- 975.
doi: 10.1002/hep.510290312
7 中华医学会肝病学分会. 扩大慢性乙型肝炎抗病毒治疗的专家意见[J]. 中华肝脏病杂志, 2022, 30 (2): 131- 136.
8 Polaris-Observatory C . Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study[J]. The Lancet Gastroenterol Hepatol, 2018, 3 (6): 383- 403.
doi: 10.1016/S2468-1253(18)30056-6
9 Chen H , Ding X , Liao G , et al. Hepatitis B surface antigen kine-tics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B[J]. J Viral Hepat, 2021, 28 (8): 1121- 1129.
doi: 10.1111/jvh.13526
10 Hsu WF , Chen CF , Lai H C , et al. Trajectories of serum hepatitis B surface antigen kinetics in patients with chronic hepatitis B receiving long-term nucleos(t)ide analogue therapy[J]. Liver Int, 2018, 38 (4): 627- 635.
doi: 10.1111/liv.13564
11 Realdi G , Alberti A , Rugge M , et al. Seroconversion from hepatitis B e antigen to anti-HBe in chronic hepatitis B virus infection[J]. Gastroenterology, 1980, 79 (2): 195- 199.
doi: 10.1016/0016-5085(80)90130-4
12 Hoofnagle JH , Dusheiko GM , Seeff L B , et al. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis[J]. Ann Intern Med, 1981, 94 (6): 744- 748.
doi: 10.7326/0003-4819-94-6-744
13 Chu CM , Karayiannis P , Fowler MJ , et al. Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum[J]. Hepatology, 1985, 5 (3): 431- 434.
doi: 10.1002/hep.1840050315
14 Lok AS , Heathcote EJ , Hoofnagle JH . Management of hepatitis B: 2000[J]. Gastroenterology, 2001, 120 (7): 1828- 1853.
doi: 10.1053/gast.2001.24839
15 Yim HJ , Lok AS . Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005[J]. Hepatology, 2006, 43 (2 Suppl 1): 173- 181.
16 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
17 Sarin SK , Kumar M , Lau GK , et al. Asian-Pacific Clinical Practice Guidelines on the management of hepatitis B: a 2015 update[J]. Hepatol Int, 2016, 10 (1): 1- 98.
doi: 10.1007/s12072-015-9675-4
18 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
19 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]. 中华传染病杂志, 2019, 37 (12): 711- 736.
20 European Association for the Study of the Liver . EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67 (2): 370- 398.
doi: 10.1016/j.jhep.2017.03.021
21 Mason WS , Gill US , Litwin S , et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients consi-dered immune tolerant[J]. Gastroenterology, 2016, 151 (5): 986- 998.
doi: 10.1053/j.gastro.2016.07.012
22 European Association for the Study of the Liver . EASL clinical practice guidelines: management of chronic hepatitis B virus infection[J]. J Hepatol, 2012, 57 (1): 167- 185.
doi: 10.1016/j.jhep.2012.02.010
23 Martin P , Nguyen MH , Dieterich DT , et al. Treatment algorithm for managing chronic hepatitis B virus infection in the United States: 2021 update[J]. Clin Gastroenterol Hepatol, 2022, 20 (8): 1766- 1775.
doi: 10.1016/j.cgh.2021.07.036
24 中华医学会传染病与寄生虫病学分会, 肝病学分会. 病毒性肝炎防治方案[J]. 中华内科杂志, 2001, 40 (1): 62- 68.
25 Morita S , Matsumoto A , Umemura T , et al. Characteristics and prediction of hepatitis B e antigen negative hepatitis following seroconversion in patients with chronic hepatitis B[J]. Hepatol Res, 2014, 44 (10): E45- E53.
doi: 10.1111/hepr.12208
26 Viola LA , Barrison IG , Coleman JC , et al. Natural history of liver disease in chronic hepatitis B surface antigen carriers. Survey of 100 patients from Great Britain[J]. Lancet, 1981, 2 (8256): 1156- 1159.
27 Stroffolini T . The changing pattern of hepatitis B virus infection over the past three decades in Italy[J]. Dig Liver Dis, 2005, 37 (8): 622- 627.
doi: 10.1016/j.dld.2005.02.010
28 Schweitzer A , Horn J , Mikolajczyk RT , et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013[J]. Lancet, 2015, 386 (10003): 1546- 1555.
doi: 10.1016/S0140-6736(15)61412-X
29 Zhang ZQ , Wang YB , Lu W , et al. Performance of hepatitis B core-related antigen versus hepatitis B surface antigen and hepatitis B virus DNA in predicting HBeAg-positive and HBeAg-negative chronic hepatitis[J]. Ann Lab Med, 2019, 39 (1): 67- 75.
doi: 10.3343/alm.2019.39.1.67
[1] 高鹏,雒艳萍,李俊峰,陈琳,毛小荣. 乙型肝炎病毒在不同丙氨酸氨基转移酶状态下对Th17、Treg细胞及其比率的影响[J]. 北京大学学报（医学版）, 2022, 54(2): 272-277.
[2] 高鹏,雒艳萍,李俊峰. B/C基因型的乙型肝炎病毒对不同免疫阶段慢性乙型肝炎患者T淋巴细胞及其亚群的影响[J]. 北京大学学报（医学版）, 2020, 52(6): 1153-1156.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] 钟金晟, 欧阳翔英, 梅芳, 邓旭亮, 曹采方. 多孔β-磷酸三钙/胶原支架与犬牙周膜细胞三维复合体的构建[J]. 北京大学学报（医学版）, 2007, 39(5): 507 -510 .
[2] 范少光. 向王志均院士学习[J]. 北京大学学报（医学版）, 2000, 32(4): 300 .
[3] 李智岗, 黄景香, 李顺宗, 赵俊京, 时高峰, 梁国庆, 王红光, 韩捧银, 王琦, 谷铁树. 肝转移瘤的血供[J]. 北京大学学报（医学版）, 2008, 40(2): 146 -150 .
[4] 冯现竹, 侯平, 朱厉, 于磊, 张宏. 转铁蛋白受体基因多态性与IgA肾病易感性及临床病理表型的相关性[J]. 北京大学学报（医学版）, 2008, 40(4): 369 -373 .
[5] 王倩, 张翼, 陆敏, 管又飞, 朱毅, 王悦. 高盐诱导的高血压大鼠模型肾组织可溶性表氧化物酶高表达及其作用初步探讨[J]. 北京大学学报（医学版）, 2010, 42(2): 126 -130 .
[6] . 书讯[J]. 北京大学学报（医学版）, 2007, 39(3): 225 -328 .
[7] 管宏, 赵慧云, 沈磊, 李五岭, 王建华, 王春荣, 徐福. 联合应用重组TPO和G-CSF对骨髓抑制性小鼠外周血小板及白细胞恢复的影响[J]. 北京大学学报（医学版）, 2001, 33(2): 181 -182 .
[8] 牟向东, 王广发, 阙呈立, 李桂莲. H3N2型人流行性感冒合并金黄色葡萄球菌败血症及金黄色葡萄球菌肺炎1例[J]. 北京大学学报（医学版）, 2007, 39(6): 663 -665 .
[9] 范蓉, 张成飞, 高岩, 李斌斌, 王晶. 核因子-κB受体活化因子配体和骨保护素在慢性根尖周炎病损组织中的表达[J]. 北京大学学报（医学版）, 2008, 40(1): 39 -42 .
[10] 徐京杭, 于岩岩, 斯崇文, 陈新月, 韩忠厚, 陈勇, 张文谨, 徐道振, 陈宇萍, 于敏, 席宏丽, 李雪迎. 拉米夫定或干扰素单药治疗及序贯治疗慢性乙型肝炎的随机对照临床研究[J]. 北京大学学报（医学版）, 2010, 42(6): 739 -745 .
ISSN 1671-167X
CN 11-4691/R
主管单位：中华人民共和国教育部
主办单位：北京大学
地址： 北京市海淀区学院路38号 北京大学医学部 《北京大学学报（医学版）》
邮编：100191
电话：010-82801551
Email： xbbjb2@bjmu.edu.cn

《北京大学学报（医学版）》
微信公众号
版权所有 © 2018 《北京大学学报（医学版）》编辑部