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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)

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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
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ISSN 1671-167X
CN 11-4691/R
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