Hepatitis viruses
肝 炎 病 毒
Hong Ling,Ph.D.
Microbiol Department,Harbin Medical University
第 37章问题
肝炎病毒有哪些？
简述 甲型肝炎病毒 的传播方式、致病特点和预防原则
简述 乙型肝炎病毒 的生物学性状,抗原抗体组成及检出的意义
乙型肝炎病毒 的传播方式和致病特点及预防原则
丙型肝炎病毒 的生物学特点和致病特点
丁型肝炎病毒 （ HDV）的概念
简述 戊型肝炎病毒 传播方式和致病特点肝炎病毒（ Hepatitis virus）
以侵害肝脏为主引起病毒性肝炎的病毒
种类：甲型肝炎病毒（ HAV）、乙型肝炎病毒（ HBV）、丙型肝炎病毒（ HCV）、丁型肝炎病毒（ HDV）、戊型肝炎病毒（ HEV）
,GBV-C/HGV,TTV
其他病毒如黄热病毒,CMV,EBV、风疹病毒等也可引起肝炎，但不列为肝炎病毒
A,Infectious”
,Serum”
Viral hepatitis
Enterically
transmitted
Parenterally
transmitted
F,G,TTV
other
E
NANB
B D C
Viral Hepatitis - Historical Perspectives
Hepatitis A virus
1973年 Feinstone应用免疫电镜技术从急性肝炎患者粪便悬液中发现
生物学性状与肠道病毒一致，故 1982年国际病毒命名委员会将它分类为小核糖核酸病毒科肠道病毒属 72型
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
Geographic Distribution of HAV infection
生物学性状
HAV为球形颗粒，直径 27～ 32nm，无包膜。
基因组为线状单正链 RNA
由 VP1～ 4四种多肽组成,VP1是主要衣壳蛋白和中和抗原，能中和所有 HAV
细胞培养,HAV可用猴肾、人胚肾细胞等进行增殖和传代，但不引起 CPE
易感动物有黑猩猩、南美洲猴、猕猴等，
接种后可出现急性肝炎
抵抗力：较强，对乙醚、酸、热（ 60oC）
稳定。高压、紫外、煮沸等可灭活致病性
传染源为患者和隐性感染者
传播方式是粪－口途径。 HAV污染食物、水源、海产品等引起暴发或散发流行
隐性感染率高，成人 HAV抗体阳性率高达
70%—90%
病毒进入机体经过两次病毒血症，到达肝脏，在肝细胞增殖致病
非溶细胞型病毒，不直接杀伤细胞，患者症状高峰是潜伏期末和症状出现初期，与病毒复制高峰时间不相符，说明病毒复制量与症状严重程度不一致，故认为免疫应答参与损伤过程
发病后期粪便中可检出 sIgA抗体。出现病毒的特异细胞免疫应答
典型的甲肝是自限过程，大约三个月，无慢性病例
Incubation period,Average 30 days
Range 15-50 days
Jaundice by <6 yrs,<10%
age group,6-14 yrs,40%-50%
>14 yrs,70%-80%
Complications,Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
Chronic sequelae,None
Hepatitis A - Clinical Features
Fecal
HAV
Symptoms
0 1 2 3 4 5 6 1
2
2
4
Hepatitis A Infection
Total anti-
HAVTitre
ALT
IgM anti-HAV
Months after exposure
Typical Serological Course
Close personal contact
(e.g.,household contact,sex contact,child day
care centers)
Contaminated food,water
(e.g.,infected food handlers,raw shellfish)
Blood exposure (rare)
(e.g.,injecting drug use,transfusion)
Hepatitis A Virus Transmission
Sources of HAV Infection
1983-93
Per
cen
tag
e o
f C
ases
Source,CDC,Viral Hepatitis Surveillance Program
Year
Personal
contact
Day care center
Foreign travel
Outbreak
Drug use
40
30
20
10
0
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993
Concentration of HAV in Various
Body Fluids
Source,Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
Feces
Serum
Saliva
Urine
100 102 104 106 108 1010
Infectious Doses per ml
Age-specific Incidence of
Hepatitis A 1983-93
Source,CDC,National Notifiable Diseases Surveillance System
Year
Rep
or
ted
C
ase
s (p
er
100
,000
)
19831984198519861987198819891990199119921993
0
5
1
0
1
5
2
0
2
5
5-14 years
15-24 years
25-39 years
0-4 years
40+ years
Endemicity
Disease
Rate
Peak Age
of Infection Transmission Patterns
High Low to
High
Early
childhood
Person to person;
outbreaks uncommon
Moderate High Late
childhood/
young adults
Person to person;
food and waterborne
outbreaks
Low Low Young adults Person to person;
food and waterborne
outbreaks
Very low Very low Adults Travelers; outbreaks
uncommon
Global Patterns of Hepatitis A Virus Transmission
诊断（ Laboratory Diagnosis）
Acute infection is diagnosed by the
detection of HAV-IgM in serum by EIA.
Past Infection i.e,immunity is determined
by the detection of HAV-IgG by EIA.
防治原则
加强食品卫生管理，水源保护。但 HAV感染以隐性感染和无黄疸型病毒例占多数，故对传染源较难控制
我国已批准将减毒疫苗株 H2株和 L1株投放市场试用
应急预防可用丙种球蛋白
基因工程疫苗也正在研究之中
Many cases occur in community-wide outbreaks
no risk factor identified for most cases
highest attack rates in 5-14 year olds
children serve as reservoir of infection
Persons at increased risk of infection
travelers
homosexual men
injecting drug users
Hepatitis A Vaccination Strategies
Epidemiologic Considerations
Pre-exposure
travelers to intermediate and high HAV-endemic regions
Post-exposure (within 14 days)
Routine
household and other intimate contacts
Selected situations
institutions (e.g.,day care centers)
common source exposure (e.g.,food prepared by infected food
handler)
Hepatitis A Prevention
- Immune Globulin
Group Age
No.
Doses EL.U.* (ml)
Schedule
(months)
Children and
adolescents 2-18 years 3 360 (0.5) 0,1,6-12
Adults >18 years 2 1,440 (1.0) 0,6-12
Doses
HAVRIX?
*ELISA units
Recommended Doses & Schedules
of HAV Vaccination
Hapatitis B Virus
1963年 Blumberg在多次输血的血友病患者中发现澳抗,1968年确与血清型肝炎高度相关,1970年 Dane在电镜下看到具有传染性的 42nm病毒颗粒
HBV在亚洲广泛流行，在中国约 10%人口携带该病毒，全球约 3.5亿
1983年将 HBV及与其分子结构、生物学特性相似的土拨鼠肝炎病毒 (woodchuck hepatitis virus,WHV)、地松鼠肝炎病毒
(ground squirrel hepatitis virus,GSHV)及鸭肝炎病毒 (duck hepatits
virus,DHV)归纳起来独立命名为 嗜肝病毒科（ Hepadnaviridae
）
HBsAg Prevalence
38% - High
2-7% - Intermediate
<2% - Low
Geographic Distribution of Chronic
HBV Infection
形态与结构
电镜检查血清标本可见小球形颗粒（ 22nm）、管形颗粒（ 22nmx50—700nm）、大球形颗粒（ 42nm）
完整的 HBV颗粒亦称 Dane颗粒，颗粒直径为
42nm
具有双层衣壳结构。外壳相当于包膜，由脂质双层和乙肝表面抗原（ HBsAg）、多聚人血清白蛋白受体（ PHSA-r）和前 S抗原（
Pre-S）组成。内部有 28nm的核心，表面相当于内衣壳，含有乙型肝炎核心抗原（
HBcAg）和乙型肝炎 e抗原（ HBeAg）。内部有 HBV的 DNA和 DNA多聚酶
HBV 基因组
DNA是由 3.2KB的长链 L（ -）和短链 S（ +）
（约为 L链的 50%至 85%长）组成的不完全双链环状 DNA，长链载有病毒蛋白质的全部密码，有 4个开放读码框架 (ORF)，分别称为 S
,C,P和 X区
HBV,Replication
HBV 2.4 KB3.5 KB
Provirus
RT Replicate
Nuclear
2.1 KB
抗原组成
HBV表面抗原（ HBsAg），是机体受 HBV感染的标志。 226AA，由 S基因编码。 HBsAg有一个共同抗原决定簇 a和二组互相排斥的亚型抗原决定簇 d/y和 w/r。因此,HBsAg可分为 adr,adw,ayr和 ayw4种亚型。我国内地和沿海各省汉族主要为 adr型，欧美为 adw
HBsAg刺激机体产生的抗 HBs，能与 HBV表面结合,使其失去感染性，具有防御 HBV感染的作用
HBV核心抗原（ HBcAg），在肝细胞核中才能检出。分子量 22KD，由 C基因编码，是病毒的内衣壳蛋白。通常被 HBsAg或与抗 HBc
抗体结合成免疫复合物，一般方法在血中检测不到，只能在肝细胞内检出。是致敏
CTL作用的靶抗原
抗 HBc无中和作用，检出高效价抗 HBc，特别是抗 HBc IgM表示 HBV再肝内处于增殖状态
HBVe抗原（ HBeAg），由 PreC和 C基因共同编码,15KD，是 HBcAg在细胞经蛋白酶降解形成。是 HBV复制及血清有传染性的标志
抗 HBe对 HBV感染有一定保护作用
前 S抗原（ Pre-S Ag），目前认为,HBsAg由三种蛋白组成。病毒小球颗粒只有主要蛋白，而大球形颗粒和管形颗粒里则有 300—
400分子的主要蛋白和 40—80分子的中等蛋白和大分子蛋白
主要蛋白,S基因编码,226AA
中等蛋白,S + PreS2编码,226 + 55=281AA，称前 S2蛋白或抗原
大分子蛋白,S + PreS2 + PreS1编码,226 + 55 +
119 = 400AA，称前 S1蛋白或抗原
Pre-S2抗原和人肝细胞表面都具有 PHSA受体，通过 PHSAr搭桥,HBV病毒易吸附于肝细胞表面，这也可以部分解释为什么 HBV具有嗜肝细胞性
Pre-S抗原的出现与 HBsAg,HBV DNA的检出意义相同，都说明病毒在复制
抗前 S1和抗前 S2抗体具有中和血循环内的
HBV作用，故具有阻止 HBV侵入肝细胞的免疫防御作用
易感动物和细胞培养：只有黑猩猩对 HBV易感，体外细胞培养尚未成功
抵抗力：认为抵抗力相当强
对低温、干燥,UV、醚、氯仿、酚等均有抵抗性
高压蒸汽灭菌,0.5%过氧乙酸,5%次氯酸钠,3%漂白粉液,0.2%新洁尔灭均可灭活病毒，但处理时间要稍长
Incubation period,Average 60-90 days
Range 45-180 days
Clinical illness (jaundice),<5 yrs,<10%
5 yrs,30%-50%
Acute case-fatality rate,0.5%-1%
Chronic infection,<5 yrs,30%-90%
5 yrs,2%-10%
Premature mortality from
chronic liver disease,15%-25%
Hepatitis B - Clinical Features
Spectrum of Chronic Hepatitis B Diseases
Chronic Persistent Hepatitis - asymptomatic
Chronic Active Hepatitis - symptomatic
exacerbations of hepatitis
Cirrhosis of Liver
Hepatocellular Carcinoma
High (>8%),45% of global population
lifetime risk of infection >60%
early childhood infections common
Intermediate (2%-7%),43% of global population
lifetime risk of infection 20%-60%
infections occur in all age groups
Low (<2%),12% of global population
lifetime risk of infection <20%
most infections occur in adult risk groups
Global Patterns of Chronic HBV Infection
High Moderate Low/NT
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk
Concentration of Hepatitis B Virus
in Various Body Fluids
Sexual
sexual and homosexuals are particular at risk.
Parenteral
Intravenous drug abuse (IVDA),Health Workers
are at increased risk.
Perinatal
Mothers who are HBeAg positive are much more
likely to transmit to their offspring than those
who are not,Perinatal transmission is the main
means of transmission in high prevalence
populations.
Modes of Transmission of HBV
传染源：急、慢性乙肝患者及无症状携带者
传播途径：非胃肠道途径
血液、血制品传播：输血、丙种球蛋白
医源性传播：注射（吸毒）、手术、采血、针刺、拨牙、内窥镜检查、纹身等
母婴传播：发生在围产期，通过产道或吞入羊水等因素。宫内感染相对少（ <10%）。母亲
HBeAg阳性婴儿感染机会大（ 90%）,HBeAg阴性、抗 HBe阳性婴儿感染机率小（ 10%—15%）
接触传播：公共卫生洁具、剃刀、吸血昆虫
* Includes sexual contact with acute cases,carriers,and multiple partners.
Source,CDC Sentinel Counties Study of Viral Hepatitis
Heterosexual*
(41%)
Homosexual Activity
(9%)
Household Contact (2%)
Health Care Employment (1%)
Other (1%)Unknown (31%)
Injecting
Drug Use
(15%)
Risk factors for Acute Hepatitis B
1992-1993 USA
Source,CDC Viral Hepatitis Surveillance Program
0-14 15-19 20-29 30-39 40+
0
5
10
15
20
25
Rate of Reported Hepatitis B by Age Group
USA 1990
Age Group (years)
Rate
(/100,000)
Exposure
Infection
Death 1%
Fulminant
hepatitis
Recovery
90% - 95% Immune
Asymptomatic Carrier
Persistent Infection
Chromic hepatitis
Chronic active hepatitis
Cirrhosis
Hepatocellular carcinoma
致病机理
尚未完全明了。一般认为 HBV不直接损害肝细胞，而产通过宿主的免疫应答引起肝细胞的损伤和破坏，出现相应临床表现
细胞免疫损伤：以抗原特异 CTL为主。直接杀伤或释放淋巴因子间接杀伤肝细胞。细胞免疫强弱与临床过程轻重与转归密切相关。免疫力过强可出现重症肝炎，过低则是慢性肝炎
体液免疫损伤：并不十分重要，因为先天性无丙种球蛋白血症患者的乙肝仍表现为典型的肝炎病变。抗原抗 体复合物导致的超敏反应，造成了肝外症状表现，如关节炎、皮疹、肾小球肾炎等
自身免疫损伤,HBV感染后，肝细胞自身表面抗原 —肝特异性脂蛋白抗原（ Liver specific
protein,LSP）暴露，自身抗体加重肝细胞损伤
HBV与原发性肝细胞癌
乙肝患者原发性肝癌发生率比对照高。原发性肝癌患者血清中，有 HBV感染标志者比自然人群多。 HBV感染者比阴性者发生原发性肝癌的危险性高 217倍
与 HBV分子生物学相似的 WHV在其宿主土拨鼠中可诱导肝硬化及原发性肝癌。新生土拨鼠感染 WHV三年后 100%发生肝癌，未感染鼠则无一只发生肝癌
肝癌细胞 DNA整合有 HBV-DNA
免疫性
体液免疫：有免疫防御作用的有抗 HBs和抗
Pre-S2，是 HBV的中和抗体
细胞免疫,CTL是清除细胞内病毒的主要机制，如细胞免疫处于较低水平则易转为慢性微生物学检查法
病毒核酸的检测：斑点杂交法,PCR，极敏感的方法，临床常规。对血清病毒 DNA浓度可做动态监测
HBV抗原、抗体的检测
最敏感方法是 RIA,ELISA
检测的项目主要是 HBsAg和抗 -HBs、
HBeAg和抗 -HBe、以及抗 -HBcIgM和抗 HBc-
IgG
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Typical Serologic Course
Weeks after Exposure
Titre
Acute Hepatitis B Virus Infection with
Recovery
IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52
YearsWeeks after
Exposure
Titre
Progression to Chronic Hepatitis B Virus
Infection Typical Serologic
Course
HBsA：表示机体感染了 HBV。阳性见于
急性乙型肝炎潜伏期和急性期（ 70%）
HBV所致的慢性肝病如慢性乙型肝炎、
肝硬化和原发性肝炎
无症状 HBsAg携带者
抗 HBs：表示机体曾感染过 HBV，并获得对 HBV的免疫力
HBcAg：常规方法难以检出，临床不做
抗 HBc
抗 HBc IgM出现于急性乙型肝炎急性期
抗 HBc IgG阳性表示过去感染过 HBV，少数也可能仍有 HBV感染
HBeAg,HBeAg阳性是体内有 HBV复制和血液传染性强的标志
急性乙肝 HBeAg呈短暂阳性，如持续阳性提示转为慢性，预后不良
孕妇 HBeAg阳性，新生儿感染率高
抗 Hbe：见于急性乙肝的恢复期，可持续较长时间，表示机体获得一定免疫力
Pre-S1,Pre-S2和 PHSA受体,HBV新感染的标志，检出表示 HBV正在复制
抗 Pre-S1、抗 Pre-S2：有中和病毒作用，
出现于急性乙肝恢复早期，消失较快
Examples of Serology Test
HBs
Ag
HBe
Ag
A nt i -
HBs
A nt i -
HBc
A nt i -
HBe
A naly s is
+ + - - - A c ut e or Ea rly
+ + - + - A c ut e or c hro nic
- - + + + re c ov ry f rom a c ut e
ph a s e
- - - + + pas t infec t ion
- - - + - had bee n Inf e c t e d
- - - - + H a d bee n inf e c t e d
or ino c ulation
预防原则
要采取切断传播途径为主的综合性措施
自动免疫,HBsAg疫苗（血源或重组）
被动免疫：乙肝免疫球蛋白 (HBIg)。接种者,
医务人员或实验室工作人员
HBsAg,HBeAg阳性母亲的新生儿
发现已误用 HBsAg阳性的血液或血制品者
与 HBsAg,HBeAg阳性者有密切性接触者
Prevent perinatal HBV transmission
Routine vaccination
all infants
children in high-risk groups
adolescents
–all unvaccinated children at 11-12 years
adults in high-risk groups
Strategy
Elimination of HBV Transmission
Vaccine
licensed
HBsAg screening
of pregnant
women
recommended
Infant
immunization
recommende
d
Adolescent
immunization
recommende
d
Decline
among
homosexual
men & HCWs
Decline
among
injecting
drug users
80
70
60
50
40
30
20
10
0
78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95
Year
Cas
es
per
100,
000
Populat
ion
Estimated Incidence of Acute Hepatitis
B,USA 1978-1995
Hepatitis C virus
1978年 WHO将非甲非乙型肝炎病毒按传播途径分为肠道传播的非甲非乙型病毒和肠道外传播的非甲非乙型肝炎病毒
1989年进一步将前者命名为戊型肝炎病毒
（ HEV），将后者命名为丙型肝炎病毒（
HCV）
目前拟将 HCV和庚型肝炎病毒（ HGV）列入黄病毒科（ Flavivurus） Hepacivirus属生物学性状
HCV属于黄病毒科，电镜照片不清晰，似球形，直径 55～ 65 nm，有脂蛋白包膜，包膜上有短突起。核酸为 +ssRNA,9.4Kb
由于不能培养，故尚不能进行血清分型。
据基因序列同源性，现分为 I — VI六个基因型。中国和亚洲流行多 Ⅱ 型，欧美为 I 型
细胞培养未成功。黑猩猩是唯一易感动物
hypervariabl
e
region
capsi
d envelop
e
protein
protease/helica
se RNA polymerase
c22
5’
cor
e
E1 E2 NS
2
NS
3
33c
NS
4
c-100
NS
5
3’
Hepatitis C Virus
Genome
Hepatitis C - Clinical Features
潜伏期 平均 6-7周（ 2-26周）
急性表现（黄疸） 轻微 (<20%)
急性期死亡率 低慢性感染率 75%-85%
慢性肝炎 70%
肝硬化 10%-20%
慢性肝脏疾病导致死亡 1%-5%
Chronic Hepatitis C Infection
The spectrum of chronic hepatitis C infection is
essentially the same as chronic hepatitis B
infection.
All the manifestations of chronic hepatitis B
infection may be seen,albeit with a lower
frequency i.e,chronic persistent hepatitis,chronic
active hepatitis,cirrhosis,and hepatocellular
carcinoma.
病理
HCV不直接杀伤细胞，故其致病机理被认是病理免疫和细胞凋亡是造成伤害的原因
Transmission of HCV
Percutaneous
Intravenous drug abuse
Transfusion,transplant
Therapeutic (contaminated equipment,
unsafe injection practices)
Permucosal
Perinatal
Sexual
Sources of Infection for
Persons with Hepatitis C
Sexual 15%
Other* 5%
Unknown 10%
Injecting drug use 60%
Transfusion 10%
(before screening)
*Nosocomial; Health-care work; Perinatal
Source,Centers for Disease Control and Prevention
HCV Prevalence by Selected
Groups,USA
0 10 20 30 40 50 60 70 80 90
Hemophilia
Injecting drug users
Surgeons,PSWs
Hemodialysis
Average Percent Anti-HCV Positive
Gen population adults
Military personnel
STD clients
Pregnant women
Prevalence of HCV Infection by
Age & Gender,1988-1994 USA0
1
2
3
4
5
6
6-1 1 12- 19 20- 29 30- 39 40- 49 50- 59 60- 69 70+
A g e i n Y ea rs
P
e
r
c
e
n
t A
n
ti
-H
C
V
P
os
i
ti
v
e
Males
Females
Source,CDC,NHANES III
Total
Perinatal Transmission of HCV
Transmission only from women HCV-RNA
positive at delivery
Average rate of infection 6%
Higher (17%) if woman co-infected with HIV
No association with
Delivery method
Breastfeeding
Infected infants do well
Severe hepatitis is rare
*Reported in U.S.
Household Transmission of HCV
Rare but not absent
Could occur through percutaneous/mucosal
exposures to blood
Theoretically through sharing of contaminated
personal articles (razors,toothbrushes)
Contaminated equipment used for home therapies
Injections*
Folk remedies
Serologic Pattern of Acute HCV Infection
with Recovery
Symptoms +/-
Time after Exposure
Tit
er
anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
Serologic Pattern of Chronic HCV
Infection with Progression Infection
Symptoms +/-
Time after Exposure
Tit
er
anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
Laboratory Diagnosis
HCV antibody - generally used to diagnose hepatitis C
infection,Not useful in the acute phase as it takes at least 4
weeks after infection before antibody appears.
HCV-RNA - various techniques are available e.g,PCR and
branched DNA,May be used to diagnose HCV infection in
the acute phase,However,its main use is in monitoring the
response to antiviral therapy.
HCV-antigen - an EIA for HCV antigen is available,It is
used in the same capacity as HCV-RNA tests but is much
easier to carry out.
HCV Infection Testing Algorithm
for Diagnosis of Asymptomatic Persons
EIA for Anti-HCV
Negative
(non-reactive)
STOP
Positive (repeat reactive)
OR
RIBA for Anti-HCV RT-PCR for HCV RNANegative
STOP Additional Laboratory Evaluation (e.g,PCR,ALT)
Negative PositiveIndeterminate
Medical
Evaluation
Positive
Negative PCR,
Normal ALT
Positive PCR,
Abnormal ALT
Source,MMWR 1998;47 (No,RR 19)
Routine HCV Testing Not Recommended
(Unless Risk Factor Identified)
Health-care,emergency medical,and public safety workers
Pregnant women
Household (non-sexual) contacts of HCV-positive persons
Screening of blood,organ,tissue donors
High-risk behavior modification
Blood and body fluid precautions
Prevention of Hepatitis C
Estimated Incidence of Acute
HCV Infection,1960-1999 USA0
20
40
60
80
100
120
140
1960 1965 1970 1975 1980 1985 1989 1995 1999
Y ea r
N
ew
I
nfec
ti
o
ns
/
1
0
0
,
0
0
0
Decline in
transfusion recipients
Decline in injection
drug users
Source,Hepatology 2000;31:777-82
Hepatology 1997;26:62S-65S
Posttransfusion Hepatitis C0
5
10
15
20
25
30
1965 1970 1975 1980 1985 1990 1995 2000
Y e ar
%
of
R
e
c
i
p
i
e
n
ts
I
n
f
e
c
te
d
All volunteer donors
HBsAg
Donor Screening for HIV Risk Factors
Anti-HIV
ALT/Anti-HBc
Anti-HCV
Improved
HCV Tests
Adapted from HJ Alter and Tobler and Busch,Clin Chem 1997
Treatment
Interferon - may be considered for patients
with chronic active hepatitis,The response
rate is around 50% but 50% of responders
will relapse upon withdrawal of treatment.
Ribavirin - there is less experience with
ribavirin than interferon,However,recent
studies suggest that a combination of
interferon and ribavirin is more effective
than interferon alone.
Hepatitis D virus
又称 δ肝炎病毒（ Hepatitis δ virus）
从 HBV感染者中发现的
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
Taiwan
Pacific Islands
Geographic Distribution of HDV Infection
生物学性状
HDV为直径 35～ 37nm的球形颗粒，核心含有环状单股负链 RNA和 HDAg（即 δ抗原），表面为 HBV包膜蛋白（ HBsAg）包裹。 HDV
RNA全长为 1.7Kb
HBsAg
RNA
d antigen
HDV为缺陷病毒，不能独立进行复制，
必须在 HBV或其它嗜肝 DNA病毒辅助才能增殖
敏感动物黑猩猩，土拨鼠和北京鸭等
Coinfection
– severe acute disease.
– low risk of chronic infection.
Superinfection
– usually develop chronic HDV infection.
– high risk of severe chronic liver disease.
– may present as an acute hepatitis.
Hepatitis D - Clinical Features
Percutanous exposures
– injecting drug use
Permucosal exposures
– sex contact
HDV Transmission
免疫性
抗 HDV 不能清除病毒，为诊断指标
抗 HDV IgM感染 2周后产生。如 HDV IgM和
IgG持续存在，提示为 HDV慢性感染
Time after
Exposure
Ti
te
r anti-
HBs
Symptoms
ALT
Elevated
Total anti-
HDV
IgM anti-HDV
HDV RNA
HBsAg
Serological Course of Acute HDV infection
Time after
Exposure
Ti
te
r
Jaundice
Symptoms
ALT Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
Serological Course of HDV superinfection
微生物学检查法
血清学方法,ELISA检查 HDAg或抗 HDV。
HDAg在急性期可阳性，检出率低。慢性感染检不到
核酸分子杂交法
HBV-HDV Coinfection
Pre or postexposure prophylaxis to prevent
HBV infection.
HBV-HDV Superinfection
Education to reduce risk behaviors among
persons with chronic HBV infection.
Hepatitis D -
Prevention
Hepatitis E virus
戊型肝炎病毒（ Hepatitis E virus,HEV），所致的疾病称为戊型肝炎。是经肠道传播的非甲非乙型肝炎病毒
Geographic Distribution of Hepatitis E
生物学性状
HEV呈球形，直径 27～ 38nm，核酸为线形（
-） ssRNA，无包膜，表面呈现锯齿状,20面体立体对称。现分类于杯状病毒
只有一个血清型。但基因序列有差异
易感动物是非洲绿猴、恒河猴、黑猩猩致病性
主要通过粪－口途径传播，主要因水源污染造成流行，极小生活接触导致感染
多感染 20—40岁成人，潜伏期 2—9周，临床表现为急性肝炎,6周即恢复。少数重症死亡。无慢性感染病例
致病机理不明，免疫损伤是主要机制。病后有一定免疫力
Weeks after
Exposure
Ti
te
r
Symptoms
ALT
IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
Serological Course of HEV infection
微生物学检查法
免疫电镜
血清学方法，检测抗 -HEV
HEV核酸检测
Avoid drinking water (and beverages with ice) of
unknown purity,uncooked shellfish,and uncooked
fruit/vegetables not peeled or prepared by traveler.
IG prepared from donors in Western countries
does not prevent infection.
Unknown efficacy of IG prepared from donors in
endemic areas.
Vaccine?
Prevention and Control Measures
for Travelers to HEV-Endemic
Regions
庚型肝炎病毒
近年来新发现的一些肝炎病毒，研究较多的是庚型肝炎病毒（ HGV）
HGV是 1995年发现，属黄病毒科，核酸为
+ssRNA,9.4KB，编码一个 ORF。黑猩猩易感
HGV感染世界分布，主要经血或肠道外传播、垂直传播和性传播。受血者、接触血源的医务工作者和静脉注射吸毒者是高危人群
临床感染可表现为急性和慢性过程。 HGV
常与 HCV重叠感染。病后抗 HGV E2具有一定保护作用
诊断主要是血清学方法或 PCR。 HGV是否嗜肝仍不清楚，因为与疾病关系必须将 HBV、
HDV,HCV感染排除后才可确认
Source of
virus
feces blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
Route of
transmission
fecal-oral percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
Chronic
infection
no yes yes yes no
Prevention pre/post-
exposure
immunization
pre/post-
exposure
immunization
blood donor
screening;
risk behavior
modification
pre/post-
exposure
immunization;
risk behavior
modification
ensure safe
drinking
water
Summary,Type of Hepatitis
A B C D E
Question Examples
Compare HAV and HBV according to the
following criteria,classification,genome,
presence of envelope,clinical features,and
transmissions.
What are the three important antigens in the
HBV particle?
Why is the delta agent found only in persons
infected with HBV?
肝 炎 病 毒
Hong Ling,Ph.D.
Microbiol Department,Harbin Medical University
第 37章问题
肝炎病毒有哪些？
简述 甲型肝炎病毒 的传播方式、致病特点和预防原则
简述 乙型肝炎病毒 的生物学性状,抗原抗体组成及检出的意义
乙型肝炎病毒 的传播方式和致病特点及预防原则
丙型肝炎病毒 的生物学特点和致病特点
丁型肝炎病毒 （ HDV）的概念
简述 戊型肝炎病毒 传播方式和致病特点肝炎病毒（ Hepatitis virus）
以侵害肝脏为主引起病毒性肝炎的病毒
种类：甲型肝炎病毒（ HAV）、乙型肝炎病毒（ HBV）、丙型肝炎病毒（ HCV）、丁型肝炎病毒（ HDV）、戊型肝炎病毒（ HEV）
,GBV-C/HGV,TTV
其他病毒如黄热病毒,CMV,EBV、风疹病毒等也可引起肝炎，但不列为肝炎病毒
A,Infectious”
,Serum”
Viral hepatitis
Enterically
transmitted
Parenterally
transmitted
F,G,TTV
other
E
NANB
B D C
Viral Hepatitis - Historical Perspectives
Hepatitis A virus
1973年 Feinstone应用免疫电镜技术从急性肝炎患者粪便悬液中发现
生物学性状与肠道病毒一致，故 1982年国际病毒命名委员会将它分类为小核糖核酸病毒科肠道病毒属 72型
Anti-HAV Prevalence
High
Intermediate
Low
Very Low
Geographic Distribution of HAV infection
生物学性状
HAV为球形颗粒，直径 27～ 32nm，无包膜。
基因组为线状单正链 RNA
由 VP1～ 4四种多肽组成,VP1是主要衣壳蛋白和中和抗原，能中和所有 HAV
细胞培养,HAV可用猴肾、人胚肾细胞等进行增殖和传代，但不引起 CPE
易感动物有黑猩猩、南美洲猴、猕猴等，
接种后可出现急性肝炎
抵抗力：较强，对乙醚、酸、热（ 60oC）
稳定。高压、紫外、煮沸等可灭活致病性
传染源为患者和隐性感染者
传播方式是粪－口途径。 HAV污染食物、水源、海产品等引起暴发或散发流行
隐性感染率高，成人 HAV抗体阳性率高达
70%—90%
病毒进入机体经过两次病毒血症，到达肝脏，在肝细胞增殖致病
非溶细胞型病毒，不直接杀伤细胞，患者症状高峰是潜伏期末和症状出现初期，与病毒复制高峰时间不相符，说明病毒复制量与症状严重程度不一致，故认为免疫应答参与损伤过程
发病后期粪便中可检出 sIgA抗体。出现病毒的特异细胞免疫应答
典型的甲肝是自限过程，大约三个月，无慢性病例
Incubation period,Average 30 days
Range 15-50 days
Jaundice by <6 yrs,<10%
age group,6-14 yrs,40%-50%
>14 yrs,70%-80%
Complications,Fulminant hepatitis
Cholestatic hepatitis
Relapsing hepatitis
Chronic sequelae,None
Hepatitis A - Clinical Features
Fecal
HAV
Symptoms
0 1 2 3 4 5 6 1
2
2
4
Hepatitis A Infection
Total anti-
HAVTitre
ALT
IgM anti-HAV
Months after exposure
Typical Serological Course
Close personal contact
(e.g.,household contact,sex contact,child day
care centers)
Contaminated food,water
(e.g.,infected food handlers,raw shellfish)
Blood exposure (rare)
(e.g.,injecting drug use,transfusion)
Hepatitis A Virus Transmission
Sources of HAV Infection
1983-93
Per
cen
tag
e o
f C
ases
Source,CDC,Viral Hepatitis Surveillance Program
Year
Personal
contact
Day care center
Foreign travel
Outbreak
Drug use
40
30
20
10
0
1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993
Concentration of HAV in Various
Body Fluids
Source,Viral Hepatitis and Liver Disease 1984;9-22
J Infect Dis 1989;160:887-890
Feces
Serum
Saliva
Urine
100 102 104 106 108 1010
Infectious Doses per ml
Age-specific Incidence of
Hepatitis A 1983-93
Source,CDC,National Notifiable Diseases Surveillance System
Year
Rep
or
ted
C
ase
s (p
er
100
,000
)
19831984198519861987198819891990199119921993
0
5
1
0
1
5
2
0
2
5
5-14 years
15-24 years
25-39 years
0-4 years
40+ years
Endemicity
Disease
Rate
Peak Age
of Infection Transmission Patterns
High Low to
High
Early
childhood
Person to person;
outbreaks uncommon
Moderate High Late
childhood/
young adults
Person to person;
food and waterborne
outbreaks
Low Low Young adults Person to person;
food and waterborne
outbreaks
Very low Very low Adults Travelers; outbreaks
uncommon
Global Patterns of Hepatitis A Virus Transmission
诊断（ Laboratory Diagnosis）
Acute infection is diagnosed by the
detection of HAV-IgM in serum by EIA.
Past Infection i.e,immunity is determined
by the detection of HAV-IgG by EIA.
防治原则
加强食品卫生管理，水源保护。但 HAV感染以隐性感染和无黄疸型病毒例占多数，故对传染源较难控制
我国已批准将减毒疫苗株 H2株和 L1株投放市场试用
应急预防可用丙种球蛋白
基因工程疫苗也正在研究之中
Many cases occur in community-wide outbreaks
no risk factor identified for most cases
highest attack rates in 5-14 year olds
children serve as reservoir of infection
Persons at increased risk of infection
travelers
homosexual men
injecting drug users
Hepatitis A Vaccination Strategies
Epidemiologic Considerations
Pre-exposure
travelers to intermediate and high HAV-endemic regions
Post-exposure (within 14 days)
Routine
household and other intimate contacts
Selected situations
institutions (e.g.,day care centers)
common source exposure (e.g.,food prepared by infected food
handler)
Hepatitis A Prevention
- Immune Globulin
Group Age
No.
Doses EL.U.* (ml)
Schedule
(months)
Children and
adolescents 2-18 years 3 360 (0.5) 0,1,6-12
Adults >18 years 2 1,440 (1.0) 0,6-12
Doses
HAVRIX?
*ELISA units
Recommended Doses & Schedules
of HAV Vaccination
Hapatitis B Virus
1963年 Blumberg在多次输血的血友病患者中发现澳抗,1968年确与血清型肝炎高度相关,1970年 Dane在电镜下看到具有传染性的 42nm病毒颗粒
HBV在亚洲广泛流行，在中国约 10%人口携带该病毒，全球约 3.5亿
1983年将 HBV及与其分子结构、生物学特性相似的土拨鼠肝炎病毒 (woodchuck hepatitis virus,WHV)、地松鼠肝炎病毒
(ground squirrel hepatitis virus,GSHV)及鸭肝炎病毒 (duck hepatits
virus,DHV)归纳起来独立命名为 嗜肝病毒科（ Hepadnaviridae
）
HBsAg Prevalence
38% - High
2-7% - Intermediate
<2% - Low
Geographic Distribution of Chronic
HBV Infection
形态与结构
电镜检查血清标本可见小球形颗粒（ 22nm）、管形颗粒（ 22nmx50—700nm）、大球形颗粒（ 42nm）
完整的 HBV颗粒亦称 Dane颗粒，颗粒直径为
42nm
具有双层衣壳结构。外壳相当于包膜，由脂质双层和乙肝表面抗原（ HBsAg）、多聚人血清白蛋白受体（ PHSA-r）和前 S抗原（
Pre-S）组成。内部有 28nm的核心，表面相当于内衣壳，含有乙型肝炎核心抗原（
HBcAg）和乙型肝炎 e抗原（ HBeAg）。内部有 HBV的 DNA和 DNA多聚酶
HBV 基因组
DNA是由 3.2KB的长链 L（ -）和短链 S（ +）
（约为 L链的 50%至 85%长）组成的不完全双链环状 DNA，长链载有病毒蛋白质的全部密码，有 4个开放读码框架 (ORF)，分别称为 S
,C,P和 X区
HBV,Replication
HBV 2.4 KB3.5 KB
Provirus
RT Replicate
Nuclear
2.1 KB
抗原组成
HBV表面抗原（ HBsAg），是机体受 HBV感染的标志。 226AA，由 S基因编码。 HBsAg有一个共同抗原决定簇 a和二组互相排斥的亚型抗原决定簇 d/y和 w/r。因此,HBsAg可分为 adr,adw,ayr和 ayw4种亚型。我国内地和沿海各省汉族主要为 adr型，欧美为 adw
HBsAg刺激机体产生的抗 HBs，能与 HBV表面结合,使其失去感染性，具有防御 HBV感染的作用
HBV核心抗原（ HBcAg），在肝细胞核中才能检出。分子量 22KD，由 C基因编码，是病毒的内衣壳蛋白。通常被 HBsAg或与抗 HBc
抗体结合成免疫复合物，一般方法在血中检测不到，只能在肝细胞内检出。是致敏
CTL作用的靶抗原
抗 HBc无中和作用，检出高效价抗 HBc，特别是抗 HBc IgM表示 HBV再肝内处于增殖状态
HBVe抗原（ HBeAg），由 PreC和 C基因共同编码,15KD，是 HBcAg在细胞经蛋白酶降解形成。是 HBV复制及血清有传染性的标志
抗 HBe对 HBV感染有一定保护作用
前 S抗原（ Pre-S Ag），目前认为,HBsAg由三种蛋白组成。病毒小球颗粒只有主要蛋白，而大球形颗粒和管形颗粒里则有 300—
400分子的主要蛋白和 40—80分子的中等蛋白和大分子蛋白
主要蛋白,S基因编码,226AA
中等蛋白,S + PreS2编码,226 + 55=281AA，称前 S2蛋白或抗原
大分子蛋白,S + PreS2 + PreS1编码,226 + 55 +
119 = 400AA，称前 S1蛋白或抗原
Pre-S2抗原和人肝细胞表面都具有 PHSA受体，通过 PHSAr搭桥,HBV病毒易吸附于肝细胞表面，这也可以部分解释为什么 HBV具有嗜肝细胞性
Pre-S抗原的出现与 HBsAg,HBV DNA的检出意义相同，都说明病毒在复制
抗前 S1和抗前 S2抗体具有中和血循环内的
HBV作用，故具有阻止 HBV侵入肝细胞的免疫防御作用
易感动物和细胞培养：只有黑猩猩对 HBV易感，体外细胞培养尚未成功
抵抗力：认为抵抗力相当强
对低温、干燥,UV、醚、氯仿、酚等均有抵抗性
高压蒸汽灭菌,0.5%过氧乙酸,5%次氯酸钠,3%漂白粉液,0.2%新洁尔灭均可灭活病毒，但处理时间要稍长
Incubation period,Average 60-90 days
Range 45-180 days
Clinical illness (jaundice),<5 yrs,<10%
5 yrs,30%-50%
Acute case-fatality rate,0.5%-1%
Chronic infection,<5 yrs,30%-90%
5 yrs,2%-10%
Premature mortality from
chronic liver disease,15%-25%
Hepatitis B - Clinical Features
Spectrum of Chronic Hepatitis B Diseases
Chronic Persistent Hepatitis - asymptomatic
Chronic Active Hepatitis - symptomatic
exacerbations of hepatitis
Cirrhosis of Liver
Hepatocellular Carcinoma
High (>8%),45% of global population
lifetime risk of infection >60%
early childhood infections common
Intermediate (2%-7%),43% of global population
lifetime risk of infection 20%-60%
infections occur in all age groups
Low (<2%),12% of global population
lifetime risk of infection <20%
most infections occur in adult risk groups
Global Patterns of Chronic HBV Infection
High Moderate Low/NT
blood semen urine
serum vaginal fluid feces
wound exudates saliva sweat
tears
breastmilk
Concentration of Hepatitis B Virus
in Various Body Fluids
Sexual
sexual and homosexuals are particular at risk.
Parenteral
Intravenous drug abuse (IVDA),Health Workers
are at increased risk.
Perinatal
Mothers who are HBeAg positive are much more
likely to transmit to their offspring than those
who are not,Perinatal transmission is the main
means of transmission in high prevalence
populations.
Modes of Transmission of HBV
传染源：急、慢性乙肝患者及无症状携带者
传播途径：非胃肠道途径
血液、血制品传播：输血、丙种球蛋白
医源性传播：注射（吸毒）、手术、采血、针刺、拨牙、内窥镜检查、纹身等
母婴传播：发生在围产期，通过产道或吞入羊水等因素。宫内感染相对少（ <10%）。母亲
HBeAg阳性婴儿感染机会大（ 90%）,HBeAg阴性、抗 HBe阳性婴儿感染机率小（ 10%—15%）
接触传播：公共卫生洁具、剃刀、吸血昆虫
* Includes sexual contact with acute cases,carriers,and multiple partners.
Source,CDC Sentinel Counties Study of Viral Hepatitis
Heterosexual*
(41%)
Homosexual Activity
(9%)
Household Contact (2%)
Health Care Employment (1%)
Other (1%)Unknown (31%)
Injecting
Drug Use
(15%)
Risk factors for Acute Hepatitis B
1992-1993 USA
Source,CDC Viral Hepatitis Surveillance Program
0-14 15-19 20-29 30-39 40+
0
5
10
15
20
25
Rate of Reported Hepatitis B by Age Group
USA 1990
Age Group (years)
Rate
(/100,000)
Exposure
Infection
Death 1%
Fulminant
hepatitis
Recovery
90% - 95% Immune
Asymptomatic Carrier
Persistent Infection
Chromic hepatitis
Chronic active hepatitis
Cirrhosis
Hepatocellular carcinoma
致病机理
尚未完全明了。一般认为 HBV不直接损害肝细胞，而产通过宿主的免疫应答引起肝细胞的损伤和破坏，出现相应临床表现
细胞免疫损伤：以抗原特异 CTL为主。直接杀伤或释放淋巴因子间接杀伤肝细胞。细胞免疫强弱与临床过程轻重与转归密切相关。免疫力过强可出现重症肝炎，过低则是慢性肝炎
体液免疫损伤：并不十分重要，因为先天性无丙种球蛋白血症患者的乙肝仍表现为典型的肝炎病变。抗原抗 体复合物导致的超敏反应，造成了肝外症状表现，如关节炎、皮疹、肾小球肾炎等
自身免疫损伤,HBV感染后，肝细胞自身表面抗原 —肝特异性脂蛋白抗原（ Liver specific
protein,LSP）暴露，自身抗体加重肝细胞损伤
HBV与原发性肝细胞癌
乙肝患者原发性肝癌发生率比对照高。原发性肝癌患者血清中，有 HBV感染标志者比自然人群多。 HBV感染者比阴性者发生原发性肝癌的危险性高 217倍
与 HBV分子生物学相似的 WHV在其宿主土拨鼠中可诱导肝硬化及原发性肝癌。新生土拨鼠感染 WHV三年后 100%发生肝癌，未感染鼠则无一只发生肝癌
肝癌细胞 DNA整合有 HBV-DNA
免疫性
体液免疫：有免疫防御作用的有抗 HBs和抗
Pre-S2，是 HBV的中和抗体
细胞免疫,CTL是清除细胞内病毒的主要机制，如细胞免疫处于较低水平则易转为慢性微生物学检查法
病毒核酸的检测：斑点杂交法,PCR，极敏感的方法，临床常规。对血清病毒 DNA浓度可做动态监测
HBV抗原、抗体的检测
最敏感方法是 RIA,ELISA
检测的项目主要是 HBsAg和抗 -HBs、
HBeAg和抗 -HBe、以及抗 -HBcIgM和抗 HBc-
IgG
Symptoms
HBeAg anti-HBe
Total anti-HBc
IgM anti-HBc anti-HBsHBsAg
0 4 8 12 16 20 24 28 32 36 52 100
Typical Serologic Course
Weeks after Exposure
Titre
Acute Hepatitis B Virus Infection with
Recovery
IgM anti-HBc
Total anti-HBc
HBsAg
Acute
(6 months)
HBeAg
Chronic
(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52
YearsWeeks after
Exposure
Titre
Progression to Chronic Hepatitis B Virus
Infection Typical Serologic
Course
HBsA：表示机体感染了 HBV。阳性见于
急性乙型肝炎潜伏期和急性期（ 70%）
HBV所致的慢性肝病如慢性乙型肝炎、
肝硬化和原发性肝炎
无症状 HBsAg携带者
抗 HBs：表示机体曾感染过 HBV，并获得对 HBV的免疫力
HBcAg：常规方法难以检出，临床不做
抗 HBc
抗 HBc IgM出现于急性乙型肝炎急性期
抗 HBc IgG阳性表示过去感染过 HBV，少数也可能仍有 HBV感染
HBeAg,HBeAg阳性是体内有 HBV复制和血液传染性强的标志
急性乙肝 HBeAg呈短暂阳性，如持续阳性提示转为慢性，预后不良
孕妇 HBeAg阳性，新生儿感染率高
抗 Hbe：见于急性乙肝的恢复期，可持续较长时间，表示机体获得一定免疫力
Pre-S1,Pre-S2和 PHSA受体,HBV新感染的标志，检出表示 HBV正在复制
抗 Pre-S1、抗 Pre-S2：有中和病毒作用，
出现于急性乙肝恢复早期，消失较快
Examples of Serology Test
HBs
Ag
HBe
Ag
A nt i -
HBs
A nt i -
HBc
A nt i -
HBe
A naly s is
+ + - - - A c ut e or Ea rly
+ + - + - A c ut e or c hro nic
- - + + + re c ov ry f rom a c ut e
ph a s e
- - - + + pas t infec t ion
- - - + - had bee n Inf e c t e d
- - - - + H a d bee n inf e c t e d
or ino c ulation
预防原则
要采取切断传播途径为主的综合性措施
自动免疫,HBsAg疫苗（血源或重组）
被动免疫：乙肝免疫球蛋白 (HBIg)。接种者,
医务人员或实验室工作人员
HBsAg,HBeAg阳性母亲的新生儿
发现已误用 HBsAg阳性的血液或血制品者
与 HBsAg,HBeAg阳性者有密切性接触者
Prevent perinatal HBV transmission
Routine vaccination
all infants
children in high-risk groups
adolescents
–all unvaccinated children at 11-12 years
adults in high-risk groups
Strategy
Elimination of HBV Transmission
Vaccine
licensed
HBsAg screening
of pregnant
women
recommended
Infant
immunization
recommende
d
Adolescent
immunization
recommende
d
Decline
among
homosexual
men & HCWs
Decline
among
injecting
drug users
80
70
60
50
40
30
20
10
0
78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95
Year
Cas
es
per
100,
000
Populat
ion
Estimated Incidence of Acute Hepatitis
B,USA 1978-1995
Hepatitis C virus
1978年 WHO将非甲非乙型肝炎病毒按传播途径分为肠道传播的非甲非乙型病毒和肠道外传播的非甲非乙型肝炎病毒
1989年进一步将前者命名为戊型肝炎病毒
（ HEV），将后者命名为丙型肝炎病毒（
HCV）
目前拟将 HCV和庚型肝炎病毒（ HGV）列入黄病毒科（ Flavivurus） Hepacivirus属生物学性状
HCV属于黄病毒科，电镜照片不清晰，似球形，直径 55～ 65 nm，有脂蛋白包膜，包膜上有短突起。核酸为 +ssRNA,9.4Kb
由于不能培养，故尚不能进行血清分型。
据基因序列同源性，现分为 I — VI六个基因型。中国和亚洲流行多 Ⅱ 型，欧美为 I 型
细胞培养未成功。黑猩猩是唯一易感动物
hypervariabl
e
region
capsi
d envelop
e
protein
protease/helica
se RNA polymerase
c22
5’
cor
e
E1 E2 NS
2
NS
3
33c
NS
4
c-100
NS
5
3’
Hepatitis C Virus
Genome
Hepatitis C - Clinical Features
潜伏期 平均 6-7周（ 2-26周）
急性表现（黄疸） 轻微 (<20%)
急性期死亡率 低慢性感染率 75%-85%
慢性肝炎 70%
肝硬化 10%-20%
慢性肝脏疾病导致死亡 1%-5%
Chronic Hepatitis C Infection
The spectrum of chronic hepatitis C infection is
essentially the same as chronic hepatitis B
infection.
All the manifestations of chronic hepatitis B
infection may be seen,albeit with a lower
frequency i.e,chronic persistent hepatitis,chronic
active hepatitis,cirrhosis,and hepatocellular
carcinoma.
病理
HCV不直接杀伤细胞，故其致病机理被认是病理免疫和细胞凋亡是造成伤害的原因
Transmission of HCV
Percutaneous
Intravenous drug abuse
Transfusion,transplant
Therapeutic (contaminated equipment,
unsafe injection practices)
Permucosal
Perinatal
Sexual
Sources of Infection for
Persons with Hepatitis C
Sexual 15%
Other* 5%
Unknown 10%
Injecting drug use 60%
Transfusion 10%
(before screening)
*Nosocomial; Health-care work; Perinatal
Source,Centers for Disease Control and Prevention
HCV Prevalence by Selected
Groups,USA
0 10 20 30 40 50 60 70 80 90
Hemophilia
Injecting drug users
Surgeons,PSWs
Hemodialysis
Average Percent Anti-HCV Positive
Gen population adults
Military personnel
STD clients
Pregnant women
Prevalence of HCV Infection by
Age & Gender,1988-1994 USA0
1
2
3
4
5
6
6-1 1 12- 19 20- 29 30- 39 40- 49 50- 59 60- 69 70+
A g e i n Y ea rs
P
e
r
c
e
n
t A
n
ti
-H
C
V
P
os
i
ti
v
e
Males
Females
Source,CDC,NHANES III
Total
Perinatal Transmission of HCV
Transmission only from women HCV-RNA
positive at delivery
Average rate of infection 6%
Higher (17%) if woman co-infected with HIV
No association with
Delivery method
Breastfeeding
Infected infants do well
Severe hepatitis is rare
*Reported in U.S.
Household Transmission of HCV
Rare but not absent
Could occur through percutaneous/mucosal
exposures to blood
Theoretically through sharing of contaminated
personal articles (razors,toothbrushes)
Contaminated equipment used for home therapies
Injections*
Folk remedies
Serologic Pattern of Acute HCV Infection
with Recovery
Symptoms +/-
Time after Exposure
Tit
er
anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
Serologic Pattern of Chronic HCV
Infection with Progression Infection
Symptoms +/-
Time after Exposure
Tit
er
anti-
HCV
ALT
Normal
0 1 2 3 4 5 6 1 2 3 4
YearsMonths
HCV RNA
Laboratory Diagnosis
HCV antibody - generally used to diagnose hepatitis C
infection,Not useful in the acute phase as it takes at least 4
weeks after infection before antibody appears.
HCV-RNA - various techniques are available e.g,PCR and
branched DNA,May be used to diagnose HCV infection in
the acute phase,However,its main use is in monitoring the
response to antiviral therapy.
HCV-antigen - an EIA for HCV antigen is available,It is
used in the same capacity as HCV-RNA tests but is much
easier to carry out.
HCV Infection Testing Algorithm
for Diagnosis of Asymptomatic Persons
EIA for Anti-HCV
Negative
(non-reactive)
STOP
Positive (repeat reactive)
OR
RIBA for Anti-HCV RT-PCR for HCV RNANegative
STOP Additional Laboratory Evaluation (e.g,PCR,ALT)
Negative PositiveIndeterminate
Medical
Evaluation
Positive
Negative PCR,
Normal ALT
Positive PCR,
Abnormal ALT
Source,MMWR 1998;47 (No,RR 19)
Routine HCV Testing Not Recommended
(Unless Risk Factor Identified)
Health-care,emergency medical,and public safety workers
Pregnant women
Household (non-sexual) contacts of HCV-positive persons
Screening of blood,organ,tissue donors
High-risk behavior modification
Blood and body fluid precautions
Prevention of Hepatitis C
Estimated Incidence of Acute
HCV Infection,1960-1999 USA0
20
40
60
80
100
120
140
1960 1965 1970 1975 1980 1985 1989 1995 1999
Y ea r
N
ew
I
nfec
ti
o
ns
/
1
0
0
,
0
0
0
Decline in
transfusion recipients
Decline in injection
drug users
Source,Hepatology 2000;31:777-82
Hepatology 1997;26:62S-65S
Posttransfusion Hepatitis C0
5
10
15
20
25
30
1965 1970 1975 1980 1985 1990 1995 2000
Y e ar
%
of
R
e
c
i
p
i
e
n
ts
I
n
f
e
c
te
d
All volunteer donors
HBsAg
Donor Screening for HIV Risk Factors
Anti-HIV
ALT/Anti-HBc
Anti-HCV
Improved
HCV Tests
Adapted from HJ Alter and Tobler and Busch,Clin Chem 1997
Treatment
Interferon - may be considered for patients
with chronic active hepatitis,The response
rate is around 50% but 50% of responders
will relapse upon withdrawal of treatment.
Ribavirin - there is less experience with
ribavirin than interferon,However,recent
studies suggest that a combination of
interferon and ribavirin is more effective
than interferon alone.
Hepatitis D virus
又称 δ肝炎病毒（ Hepatitis δ virus）
从 HBV感染者中发现的
HDV Prevalence
High
Intermediate
Low
Very Low
No Data
Taiwan
Pacific Islands
Geographic Distribution of HDV Infection
生物学性状
HDV为直径 35～ 37nm的球形颗粒，核心含有环状单股负链 RNA和 HDAg（即 δ抗原），表面为 HBV包膜蛋白（ HBsAg）包裹。 HDV
RNA全长为 1.7Kb
HBsAg
RNA
d antigen
HDV为缺陷病毒，不能独立进行复制，
必须在 HBV或其它嗜肝 DNA病毒辅助才能增殖
敏感动物黑猩猩，土拨鼠和北京鸭等
Coinfection
– severe acute disease.
– low risk of chronic infection.
Superinfection
– usually develop chronic HDV infection.
– high risk of severe chronic liver disease.
– may present as an acute hepatitis.
Hepatitis D - Clinical Features
Percutanous exposures
– injecting drug use
Permucosal exposures
– sex contact
HDV Transmission
免疫性
抗 HDV 不能清除病毒，为诊断指标
抗 HDV IgM感染 2周后产生。如 HDV IgM和
IgG持续存在，提示为 HDV慢性感染
Time after
Exposure
Ti
te
r anti-
HBs
Symptoms
ALT
Elevated
Total anti-
HDV
IgM anti-HDV
HDV RNA
HBsAg
Serological Course of Acute HDV infection
Time after
Exposure
Ti
te
r
Jaundice
Symptoms
ALT Total anti-HDV
IgM anti-HDV
HDV RNA
HBsAg
Serological Course of HDV superinfection
微生物学检查法
血清学方法,ELISA检查 HDAg或抗 HDV。
HDAg在急性期可阳性，检出率低。慢性感染检不到
核酸分子杂交法
HBV-HDV Coinfection
Pre or postexposure prophylaxis to prevent
HBV infection.
HBV-HDV Superinfection
Education to reduce risk behaviors among
persons with chronic HBV infection.
Hepatitis D -
Prevention
Hepatitis E virus
戊型肝炎病毒（ Hepatitis E virus,HEV），所致的疾病称为戊型肝炎。是经肠道传播的非甲非乙型肝炎病毒
Geographic Distribution of Hepatitis E
生物学性状
HEV呈球形，直径 27～ 38nm，核酸为线形（
-） ssRNA，无包膜，表面呈现锯齿状,20面体立体对称。现分类于杯状病毒
只有一个血清型。但基因序列有差异
易感动物是非洲绿猴、恒河猴、黑猩猩致病性
主要通过粪－口途径传播，主要因水源污染造成流行，极小生活接触导致感染
多感染 20—40岁成人，潜伏期 2—9周，临床表现为急性肝炎,6周即恢复。少数重症死亡。无慢性感染病例
致病机理不明，免疫损伤是主要机制。病后有一定免疫力
Weeks after
Exposure
Ti
te
r
Symptoms
ALT
IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 1
0
1
1
1
2
1
3
Serological Course of HEV infection
微生物学检查法
免疫电镜
血清学方法，检测抗 -HEV
HEV核酸检测
Avoid drinking water (and beverages with ice) of
unknown purity,uncooked shellfish,and uncooked
fruit/vegetables not peeled or prepared by traveler.
IG prepared from donors in Western countries
does not prevent infection.
Unknown efficacy of IG prepared from donors in
endemic areas.
Vaccine?
Prevention and Control Measures
for Travelers to HEV-Endemic
Regions
庚型肝炎病毒
近年来新发现的一些肝炎病毒，研究较多的是庚型肝炎病毒（ HGV）
HGV是 1995年发现，属黄病毒科，核酸为
+ssRNA,9.4KB，编码一个 ORF。黑猩猩易感
HGV感染世界分布，主要经血或肠道外传播、垂直传播和性传播。受血者、接触血源的医务工作者和静脉注射吸毒者是高危人群
临床感染可表现为急性和慢性过程。 HGV
常与 HCV重叠感染。病后抗 HGV E2具有一定保护作用
诊断主要是血清学方法或 PCR。 HGV是否嗜肝仍不清楚，因为与疾病关系必须将 HBV、
HDV,HCV感染排除后才可确认
Source of
virus
feces blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
Route of
transmission
fecal-oral percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
Chronic
infection
no yes yes yes no
Prevention pre/post-
exposure
immunization
pre/post-
exposure
immunization
blood donor
screening;
risk behavior
modification
pre/post-
exposure
immunization;
risk behavior
modification
ensure safe
drinking
water
Summary,Type of Hepatitis
A B C D E
Question Examples
Compare HAV and HBV according to the
following criteria,classification,genome,
presence of envelope,clinical features,and
transmissions.
What are the three important antigens in the
HBV particle?
Why is the delta agent found only in persons
infected with HBV?
