医学免疫学：乙型病毒性肝炎

乙型病毒性肝炎

(hepatitisB)IntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus1concept肝炎：Hepatitis=inflammationoftheliverSiximportantvirusesarecommonlydescribedas“hepatitisviruses”:HAV,HBV,HCV,HDV,HEV,HGV甲肝,乙肝,丙肝,丁肝,戊肝,庚肝注：其他病毒也可以引起肝炎,但也可感染其他器官或组织/细胞Hepatitisvirus2011年7月28日，世界卫生组织确定的首个世界肝炎日•

Family:

Hepadnaviridae肝DNA病毒科•

Genus:

正嗜肝DNA病毒•

Species:

Hepatitis

B

virusVirion,

42nmDane

particle

Subviral

Particles

spheres

&filaments

forms2HepatitisBvirusIntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus病理变化：以肝细胞变性、坏死为主，同时伴有不同程度的炎细胞浸润、肝细胞再生和纤维组织增生1肝细胞变性、坏死(1)点状坏死(spottynecrosis)－－单个或数个肝细胞的坏死，常见于急性普通型肝炎(2)碎片状坏死(piecemealnecrosis)－－肝小叶周边部界板肝细胞的灶性坏死，常见于慢性肝炎(3)桥接坏死(bridgingnecrosis)－－中央静脉与汇管区之间，两个汇管区之间，或两个中央静脉之间出现的互相连接的坏死带，常见于中度和重度慢性肝炎1肝细胞变性、坏死(1)炎细胞浸润：淋巴细胞和单核细胞浸润，散在或局灶性浸润于肝小叶或汇管区(2)肝细胞再生：周围肝细胞分裂再生，肝小叶网状支架塌陷，呈结节性再生(3)间质反应性增生和小胆管增生：Kupffer细胞增生，成纤维细胞增生，小胆管增生2其他IntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus1CourseandclassificationHBVinfection(1)HBsAg与抗-HBs

HBsAg（乙肝病毒表面抗原）为已经感染病毒的标志，并不反映病毒有无复制、复制程度、传染性强弱。抗-HBs为中和性抗体标志，是否康复或是否有抵抗力的主要标志。乙肝疫苗接种者，若仅此项阳性，应视为乙肝疫苗接种后正常现象。(2)

抗-HBcHBcAb（乙肝病毒核心抗体）为曾经感染过或正在感染者都会出现的标志。核心抗体IgM是新近感染或病毒复制标志。(3)

HBeAg及抗-HBeHBeAg（乙肝病毒e抗原）为病毒复制标志。持续阳性3个月以上则有慢性化倾向。HBeAb（乙肝病毒e抗体）为病毒复制停止标志。病毒复制减少，传染性较弱，但并非完全没有传染性。(4)

HBV-DNA及DNA-pHBV-DNA是HBV感染最直接、特异性强和灵敏性高的指标，HBV-DNA阳性，提示HBV复制和有传染性。HBV-DNA越高表示病毒复制越厉害，传染性强。2SerologicalDiagnosisofHBVinfection3.1急性黄疸型乙型肝炎(1)黄疸前期：发热、不典型全身症状、消化道症状明显、血液化验血清丙氨酸转氨酶（简称ALT）明显升高。黄疸前期一般持续时间为1-21天，多数为5-7天。(2)黄疸期：

黄疸黄疸出现最早见于巩膜，由淡贡色渐加深至深黄色，甚至棕黄色。皮肤黄色则由浅到深，小便也由浅黄至深棕色。黄疸出现后1-2周内达最高峰。部分患者可有皮肤瘙痒、脉搏缓慢，大便短期内（数日）颜色较浅，甚至可呈白陶土色。

肝脏肿大

黄疽期可见肝脏肿大，尤其是儿童和青少年。肝脏肿大常达右肋缘下1～3厘米，质地中等（不硬、不软），有压痛及叩击痛，肝功能有损害。儿童常见有脾肿大。(3)恢复期：此期黄疸消退，临床症状减轻甚至消失。恢复期持续时间2-16周一般在1个月左右。3signsandsymptoms3.2急性无黄疸型乙型肝炎(1)黄疸：整个病程中无黄疸出现，血清总胆红素应在17.0微摩尔／升以下。如果大于17.1微摩尔／升，而皮肤、巩膜等未见黄疸者，称之为“隐性黄疸”。(2)症状与体征：临床症状、体征比黄疸型者轻。(3)肝功能：肝功能损害较黄疸型患者轻。(4)病程：病程迁延较长。3signsandsymptoms3.3慢性乙型肝炎(1)轻度

病情较轻，症状不明显或虽有症状、体征，但指标仅1-2项轻区异常。(2)中度

慢性乙型肝炎的症状、体征、实验室检查居于轻度和重度之间。(3)重度

慢性乙型肝炎的症状明显，可伴有肝病面容、肝掌、蜘蛛痣或肝、脾肿大。但是，无门静脉高压征。实验室检查凡白蛋白小于32克／升、胆红素大于85.5微摩尔／升、凝血酶原活动度60%-40%，三项指标中有一项达到标准的患者即可诊断为慢性乙型肝炎重度。3signsandsymptoms3.4暴发型乙型肝炎发病多有诱因，如起病后没有适当休息，营养不良、嗜酒或服用损害肝脏的药物、妊娠合并感染等。其临床特点有：(1)起病

以急性黄疸型乙型肝炎起病，在10日以内症状、体征明显加重，黄疸迅速加深。(2)合并出现肝性脑病症状

患者开始表现为嗜睡，对外界反应迟钝等。继之呈现烦躁不安、狂妄、狂躁、随后即进入半昏迷或完全昏迷状态，少数病例出现抽搐。(3)有出血倾向：可发生于不同部位，如皮下出血点及瘀斑、呕血、咯血、柏油样大便，其中以皮下出血与呕血最多见，黑色柏油样大便次之。一般发生于黄疸高峰期。(4)腹水

35%-68%的重症乙型肝炎病例有腹水，多与中毒性腹胀同时出现。(5)肝缩小

肝脏迅速缩小。(6)肝肾综合征

自发性少尿或无尿、氮质血症、稀释性低钠血症和低尿钠等3.5无症状HBsAg携带者持续HBsAg阳性的人，无临床症状、肝功能正常(或基本正常)。诊断标准：

（1）HBsAg阳性＞6个月；（2）HBeAg阴性，抗－HBe阳性；（3）血清HBVDNA＜105拷贝／毫升；（4）转氨酶（ALT及AST）水平持续正常；（5）肝脏活体组织检查没有明显炎症（坏死炎症评分≤4）。3signsandsymptoms4HBVinfectionandHCCModelDirectIndirect

Possible

causesIntegration

of

HBV

genomic

sequence

inhost

cell

chromosome

(insertionalmutagenesis,

gene

stimulation

orsuppression

by

HBV

cis-elements);Tumorigenesis

by

HBV

protein

in

transFaster

hepatocyte

turn-over

due

tochronic

liver

inflammationIntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus1MajorTransmissionway•

HBV

infected

mother

to

baby•

Contact

with

blood•

Needle

sticks

or

sharp

instrumentsexposures•

Oral,

anal,

and

vaginal

sex

with

a

infectedperson•

Injection

drug

usage:

sharing

needlesCo-infection

with

HIVModerateSemenVaginal

fluidSaliva

High

Blood

SerumWound

exudates

Detectable

urine

feces

sweat

tearsbreast

milk2DetectionofHepatitisBVirusinVariousBodyFluids

Low/NotIntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus•

HBV

is

not

cytolytic•

Immune

response

(cytotoxic

T

cell)

to

viral

antigens

expressed

on

hepatocyte

cell

surface

responsible

for

clinical

syndrome•

Hepatitis

B

surface

antibody

likely

confers

lifelongimmunity

(IgG

anti-HBs)1mechanismofinjuryc2innateimmuneresponsetoHBV3cellularimmuneresponsestoHBVIntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus1TreatmentofchronichepatitisB拉米夫定阿德福韦酯恩替卡韦替比夫定LifecycleofHBVanddrugtargetsNTCP：钠离子-牛磺胆酸共转运蛋白2Controlandprevention

•HepatitisBisavaccine-preventabledisease•

Wash

hands

thoroughly

after

any

potential

exposure•

Practice

safe

sex

with

all

partners•

Avoid

direct

contact

with

blood

and

bodily

fluids•

Avoid

sharing

needle

or

syringesHepatitis

B

vaccineHBsAgsubunit2.1vaccineandHBIG•

Vaccination

-

highly

effective

recombinantsubunit

vaccines•

Hepatitis

B

Immunoglobulin

(HBIG)

-exposed

within

48

hours

of

the

incident-neonates

whose

mothers

are

HBsAg

and

HBeAgpositive.•

Other

measures-

Screening

of

blood

donors-

Blood

and

body

fluid

precautionsRECOMBIVAXHB2.2Vaccination•

Vaccine

recommended

in–

All

those

aged

0-18–

People

at

high

risk•

Infants:

several

options

that

depend

on

status

of

themother–

If

mother

HBsAg

negative:

birth,

1-2m,6-18m–

If

mother

HBsAg

positive:

vaccine

and

HBIG

within

12hours

of

birth,

1-2m,

<6m•

Adults*

0,1,

6

monthsIntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirusPro:

develop

a

cellular

immuneresponse

similar

to

that

observed

inhumans

acutely

infected

with

HBV;

orasymptomatic

carriers;

model

forevaluation

of

HBV

vaccines.Con:

ethical

constraints,

high

cost,usually

do

not

develop

chronic

liverdiseases

1AnimalssusceptibletoHBVInfectionChimpanzeeTupaia树鼩Pro:

susceptible

to

HBV

infection

andreplication,

relatively

low-cost;cultivable.Con:

inoculation

of

HBV

causes

onlytransient

infectionÿ

lowreproducibilityDuck

北京鸭Pro:

infected

by

DHBV,

elucidating

thereplication

cycle

of

hepadnaviruses;suitable

for

laboratory

use.Con:

DHBV

has

no

X

protein;usually

not

develop

chronic

liverdiseases;

more

tolerable

to

toxic

effectsof

antiviralsÿ

immune

system

differfrom

mammals2AnimalsmodelsofotherHepadnavirusesWoodchuck

土拨鼠Pro:

chronically

infected

by

WHV;

highrate

of

developing

HCC;

useful

instudying

the

pathogenesis

of

CLD

andHCC;

standard

model

for

preclinicalevaluation

of

anti-HBV

nucleosideanalogsCon:

not

develop

cirrhosis;

outbred;immune

systems

are

not

clearlycharacterized;

hibernationIntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus1HepatitisDeltaVirion(HDV)From

Murray

et.

al.,

MedicalMicrobiology

5th

edition,

2005,Chapter

66,

published

by

MosbyPhiladelphia,,2HepatitisDeltaVirus•Single

stranded,

self

complem