醫(yī)學(xué)免疫學(xué)：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組織/細胞Hepatitisvirus2011年7月28日，世界衛(wèi)生組織確定的首個世界肝炎日?

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病理變化：以肝細胞變性、壞死為主，同時伴有不同程度的炎細胞浸潤、肝細胞再生和纖維組織增生1肝細胞變性、壞死(1)點狀壞死(spottynecrosis)－－單個或數(shù)個肝細胞的壞死，常見于急性普通型肝炎(2)碎片狀壞死(piecemealnecrosis)－－肝小葉周邊部界板肝細胞的灶性壞死，常見于慢性肝炎(3)橋接壞死(bridgingnecrosis)－－中央靜脈與匯管區(qū)之間，兩個匯管區(qū)之間，或兩個中央靜脈之間出現(xiàn)的互相連接的壞死帶，常見于中度和重度慢性肝炎1肝細胞變性、壞死(1)炎細胞浸潤：淋巴細胞和單核細胞浸潤，散在或局灶性浸潤于肝小葉或匯管區(qū)(2)肝細胞再生：周圍肝細胞分裂再生，肝小葉網(wǎng)狀支架塌陷，呈結(jié)節(jié)性再生(3)間質(zhì)反應(yīng)性增生和小膽管增生：Kupffer細胞增生，成纖維細胞增生，小膽管增生2其他IntroductionSectionⅠoverviewSectionⅡpathologySectionⅢclinicalfeatureSectionⅣtransmissionwaySectionⅤpathogenesis&immunitySectionⅥanti-HBVinfectionSectionⅦModelsforstudyingHBVSectionⅧHepatitisDeltavirus1CourseandclassificationHBVinfection(1)HBsAg與抗-HBs

HBsAg（乙肝病毒表面抗原）為已經(jīng)感染病毒的標志，并不反映病毒有無復(fù)制、復(fù)制程度、傳染性強弱?？?HBs為中和性抗體標志，是否康復(fù)或是否有抵抗力的主要標志。乙肝疫苗接種者，若僅此項陽性，應(yīng)視為乙肝疫苗接種后正?，F(xiàn)象。(2)

抗-HBcHBcAb（乙肝病毒核心抗體）為曾經(jīng)感染過或正在感染者都會出現(xiàn)的標志。核心抗體IgM是新近感染或病毒復(fù)制標志。(3)

HBeAg及抗-HBeHBeAg（乙肝病毒e抗原）為病毒復(fù)制標志。持續(xù)陽性3個月以上則有慢性化傾向。HBeAb（乙肝病毒e抗體）為病毒復(fù)制停止標志。病毒復(fù)制減少，傳染性較弱，但并非完全沒有傳染性。(4)

HBV-DNA及DNA-pHBV-DNA是HBV感染最直接、特異性強和靈敏性高的指標，HBV-DNA陽性，提示HBV復(fù)制和有傳染性。HBV-DNA越高表示病毒復(fù)制越厲害，傳染性強。2SerologicalDiagnosisofHBVinfection3.1急性黃疸型乙型肝炎(1)黃疸前期：發(fā)熱、不典型全身癥狀、消化道癥狀明顯、血液化驗血清丙氨酸轉(zhuǎn)氨酶（簡稱ALT）明顯升高。黃疸前期一般持續(xù)時間為1-21天，多數(shù)為5-7天。(2)黃疸期：

黃疸黃疸出現(xiàn)最早見于鞏膜，由淡貢色漸加深至深黃色，甚至棕黃色。皮膚黃色則由淺到深，小便也由淺黃至深棕色。黃疸出現(xiàn)后1-2周內(nèi)達最高峰。部分患者可有皮膚瘙癢、脈搏緩慢，大便短期內(nèi)（數(shù)日）顏色較淺，甚至可呈白陶土色。

肝臟腫大

黃疽期可見肝臟腫大，尤其是兒童和青少年。肝臟腫大常達右肋緣下1～3厘米，質(zhì)地中等（不硬、不軟），有壓痛及叩擊痛，肝功能有損害。兒童常見有脾腫大。(3)恢復(fù)期：此期黃疸消退，臨床癥狀減輕甚至消失?；謴?fù)期持續(xù)時間2-16周一般在1個月左右。3signsandsymptoms3.2急性無黃疸型乙型肝炎(1)黃疸：整個病程中無黃疸出現(xiàn)，血清總膽紅素應(yīng)在17.0微摩爾／升以下。如果大于17.1微摩爾／升，而皮膚、鞏膜等未見黃疸者，稱之為“隱性黃疸”。(2)癥狀與體征：臨床癥狀、體征比黃疸型者輕。(3)肝功能：肝功能損害較黃疸型患者輕。(4)病程：病程遷延較長。3signsandsymptoms3.3慢性乙型肝炎(1)輕度

病情較輕，癥狀不明顯或雖有癥狀、體征，但指標僅1-2項輕區(qū)異常。(2)中度

慢性乙型肝炎的癥狀、體征、實驗室檢查居于輕度和重度之間。(3)重度

慢性乙型肝炎的癥狀明顯，可伴有肝病面容、肝掌、蜘蛛痣或肝、脾腫大。但是，無門靜脈高壓征。實驗室檢查凡白蛋白小于32克／升、膽紅素大于85.5微摩爾／升、凝血酶原活動度60%-40%，三項指標中有一項達到標準的患者即可診斷為慢性乙型肝炎重度。3signsandsymptoms3.4暴發(fā)型乙型肝炎發(fā)病多有誘因，如起病后沒有適當休息，營養(yǎng)不良、嗜酒或服用損害肝臟的藥物、妊娠合并感染等。其臨床特點有：(1)起病

以急性黃疸型乙型肝炎起病，在10日以內(nèi)癥狀、體征明顯加重，黃疸迅速加深。(2)合并出現(xiàn)肝性腦病癥狀

患者開始表現(xiàn)為嗜睡，對外界反應(yīng)遲鈍等。繼之呈現(xiàn)煩躁不安、狂妄、狂躁、隨后即進入半昏迷或完全昏迷狀態(tài)，少數(shù)病例出現(xiàn)抽搐。(3)有出血傾向：可發(fā)生于不同部位，如皮下出血點及瘀斑、嘔血、咯血、柏油樣大便，其中以皮下出血與嘔血最多見，黑色柏油樣大便次之。一般發(fā)生于黃疸高峰期。(4)腹水

35%-68%的重癥乙型肝炎病例有腹水，多與中毒性腹脹同時出現(xiàn)。(5)肝縮小

肝臟迅速縮小。(6)肝腎綜合征

自發(fā)性少尿或無尿、氮質(zhì)血癥、稀釋性低鈉血癥和低尿鈉等3.5無癥狀HBsAg攜帶者持續(xù)HBsAg陽性的人，無臨床癥狀、肝功能正常(或基本正常)。診斷標準：

（1）HBsAg陽性＞6個月；（2）HBeAg陰性，抗－HBe陽性；（3）血清HBVDNA＜105拷貝／毫升；（4）轉(zhuǎn)氨酶（ALT及AST）水平持續(xù)正常；（5）肝臟活體組織檢查沒有明顯炎癥（壞死炎癥評分≤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拉米夫定阿德福韋酯恩替卡韋替比夫定LifecycleofHBVanddrugtargetsNTCP：鈉離子-牛磺膽酸共轉(zhuǎn)運蛋白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樹鼩Pro:

susceptible

to

HBV

infection

andreplication,

relatively

low-cost;cultivable.Con:

inoculation

of

HBV

causes

onlytransient

infection?

lowreproducibilityDuck

北京鴨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

antivirals?

immune

system

differfrom

mammals2AnimalsmodelsofotherHepadnavirusesWoodchuck

土撥鼠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