病毒性肝炎-課件

Viralhepatitis（病毒性肝炎）

outlineOverviewEtiologyEpidemiologyPathogenesisandpathologyClinicalmanifestationTreatmentandpreventionOverview

Viralhepatitisisinfectiousdiseasecausedbyhepato-virusesMainpathologicalcharicteristicsaretheinflammationandnecrosisinliverHAVHBVHCVHEVHDV,Nocrossimmunologicreaction.Overview

Commonsymptomsandsigns:arorexia,

nausea,

vomiting,

dislikegreasiness,

abodominaldistention,

diarrheafatigue,

hepatomegalysplenomegaly,jaundice,

liverpalm,spidernevus.HBVandHCVinfectionisthemaincauseofhepatitis--livercirrhosis--hepatocellularcarcinomaOverview

HepatitisAVirusHAVHepatitisBVirusHBVHepatitisCVirusHCVHepatitisDVirusHDVHepatitisEVirusHEV

EtiologyFeaturesofdifferentkindshepato-virusVirusPhylogeneticDiameterGenomeHAVMicrovirusRNA

27nmLinearpositivestrandRNA7.8KbHBVHepatovirusDNA42nmCircularitydoublestrandsDNA3.2KbHCVFlaviviridaeRNA30~60nmLinearpositivestrandRNA7.4KbHDVSatellitevirusRNA36nmCircularitydoublestrandsRNA1.7KbHEVCaliciviridaeRNA32nmLinearpositivestrandRNA7.6KbPhotoofHAVbyEMHistoryofHBVIn1965,Dr.BaruchS.BlumbergfoundtheAustraliaAntigen(HBsAg)inserumofAustralianAborigines.Thefirstserumoriginedvaccinewasdeveloped.TogetNobelPrizeinmedicineof1976PhotoforHBVParticlesbyEMFilaments20-22nmwideVariablelengthHBsAgGlycoproteins

LipidsImmunogenicSphericalparticles22nmdiameter42nmVirionsEnvelopeInner:nucleocapsidHBcAgGenomeGolymeraseMolecularstructureofHBV

HBVgenomeorganizationnegativestrand（L）positivestrand（S）S區(qū)

preS1preS2HBsAgC區(qū)

HBeAgHBcAgP區(qū)

DNApolymeraseX區(qū)

HBxAgG1896A/BCPIn1974,Golafieldfirstlydescribednon-Anon-Bhepatitis.In1989,Choodiscoveredthevirusgenomebycloningtechnology,andnameditHCV.Molecularstructureof

HCVHBsAgRNAdAgPhotoandmolecularstructureforHDVSourceofinfectionRouteoftransmissionSusceptiblepopulationEpidemiccharactersEpidemiologyEpidemiologyofdifferenthepatitis

SourceofinfectionRouteoftransmissionSusceptiblepopulationHAVPatients,subclinicalinfectionFecal-oralPreschoolersHEViso-HAVFecal-oralGravida/AgedHBVAcute/chronicpatients,ASCBloodproducts,injections,bodyfluids,VerticalAllHCVAcute/chronicpatients,ASCBloodproductsmainlyBloodrecipient,drugaddictHDVAcute/chronicpatients,ASCSourceandRoute/HBPresentinblood,saliva,vaginalsecretions,menstrualbloodHBVsurvivesforatleastoneweekatroomtemperatureonenvironmentalsurfacesandisstillinfectiousPercutaneousneedlestick,druguse(iv),tattooMucousmembranesPerinatalSexualtransmissionNon-sexualperson-to-personcontactHCV---“Silence”KillerAccrodingtoWHOstatistics,170millionpeoplewereinfectedwithHCV.

80%ofthemarechronicinfectedwithoutclinicalsymptom.Theseso-called“silence”infectedpeopleareathighriskofprogressingtolivercirrhosis,hepatocellularcarcinomaandendstageliverdiseasesin20-30years.Epidemiologyandpublichealthburden

2billionpeople(1/3)hasbeeninfectedwithHBV6billionpeopleworldwide350-400peoplewithchronicHBVinfection2/3wereAsian1/3wereChinese15%~25%dieofHBVrelatedliverdiseases750thousand-1milliondeathsyearlyAccountingforthe7thdeathcauseLavanchyD.JViralHepatitis.2004;11:97-107HBVinfectioninChina7.18%in20069.74%in1992In2008-2012,viralhepatitiswasstillthemostimportantinfectiousdiseaseinChina.Incidenceof1.407millionannually.Nearly300,000deathsyearlywasattributedtoHBVrelatedliverdiseases.Pathogenesis

DirectactionofHepato-virusImmunologicreactioninducedybyvirusesOutcomeofHBVinfection

acuteinfectionchronicHBVinfection

adult

5%-10%

livercirrhosisliverfailureHCC

chronichepatitis12%-25%in5y5%-15%in5y20%-23%in5ylivertransplantinfancy85%-95%HBeAganti-HBeHBVDNA

ALT

toleranceclerancenoactivecarrierreactive

LokASF.NEnglJMed2002;346(22):1682NaturalhistoryofCHBPathologyHepatocytedegenerationBallooningdegenerationAcidophilicdegenerationHepatocytenecrosisSpottynecrosisFocalnecrosisPiecemealnecrosisBridgingnecrosisConfluentnecrosis.3.Infiltrationoflymphocyte4.InterstitialcellhyperplasiaKupffercell,fibroblastsExtracellularMatrixincreasedLiverfibrosis5.HepatocyteregenerationStructuralchangeofhepaticlobulePathologyCholestatichepatitis:Acutemildhepatocyteedemanecrosis,bilethrombusincholangioles.PathologyearlierstageofcirrhosislivercirrhosisPathophysiologyWhataretheliver’sfunctions?Immuno-organWatchdog,HousekeeperFilter,SanitationengineerGrocer,Energyplantsupervisor,Bodybuilder,ChemicalplantPathophysiology-JaundiceIncreasedhepatocytemembranepermeability,disordeofbilirubinmetabolism.Pathophysiology

-HepaticencephalopathyAmmonia

Disbalanceofbranched-chainaminoacid/aromaticaminoacidDecreasedbloodcoagulationfactorsThrombocytopeniawhencomplicatedwithhypersplenismPathophysiology--BleedingPathophysiology

–hepatorenalsyndromEndotoxemia，kidneyvasoconstrictionanddecreasedcapacityofcirculationandsubsequentdecreased

glomerularfiltrationrate.

ClinicalmanifestationClinicalmanifestationsIncubationperiod:

HAV：2～6WHBV：6W～6MHCV：15～150dHEV：15～75dClinicaltyping:acutehepatitis（icteric,non-icteric）chronichepatitis（mild,moderate,severe）severehepatitis（acute,subacute,chronic）Cholestatichepatitis（acute,chronic）livercirrhosis（inactivity,reactiveness）Clinicalmanifestations---clinicalstageAcuteicterichepatitis:Preictericphase(5～7d):

digestivesymptom,feverIcterusphase(2～6w):

ictericsclera,yellowsclera,darkurine,hepatomegalyandtendernessRecoveryphase(2～4W):symptomandsignsfadeaway,liverfunctionnormalityChronichepatitis

(

course≥6m)

Mild:

Withoutorwithmildsymptomandsigns≤2itemofliverfunctionmildlyabnormalityModerate:

Severe:

symptoms:

Obvioussignsofchronichepatitis

Laboratorytests:repeatedlyorpersistentlyALT/ASTelevationplusoneofthefollowingconditions:

ALB≤32g/LSB>5ULN

PTA60%～40%CHE<2500U/LClinicalmanifestations---clinicalstageClinicalmanifestation

DysfunctionofhepatocytesWeaknessFatigabilityAnorexiaNauseaOccasionalvomitingClinicalmanifestation

DysfunctionofhepatocytesJaundiceCoagulopathy：epistaxisClinicalmanifestation

DysfunctionofhepatocytesEndocrinedisturbance

SevereHepatitis(FulminateHepatitis)Acute(<2w)Subacute(2w—6m)Chronic

Clinicalmanifestation

FulminateHepatitisExtremefatigue,prominentgastrointestinalsymptomsProgressivejaundiceinshort-termProgressivelivernarrowingMorethantwodegreesofhepaticencephalopathyBleedingBileenzymeseparationPTA<40%Clinicalmanifestation

---bleedingCTofACLF(liverweight700g)M19yPTA:11%20060929

livercirrhosisClinicalmanifestation

Clinicalmanifestation

PortalhypertensionLargecollateralveinsAscitesEnlargementofspleenClinicalmanifestation

PortalhypertensionLargecollateralveinsVaricesinesophagus/stomachVaricesinrectumVaricesontheabdomenClinicalmanifestation

PortalhypertensionVenousofabdominalwallClinicalmanifestation

PortalhypertensionAscitesClinicalmanifestation

PortalhypertensionEnlargementofspleenTipenlargement1-2cmModeratesplenomegaly3-7cmMassivespleomegaly7cmClinicalstageoflivercirrhosisLiverfibrosis:MainlybasedonliverhistopathologyUltrasonographyandserummarkersprovidereferenceLivercirrhosis:

Active:accompaniedwithclinicalmanifestationsofchronichepatitis(diseasesymptoms,abnormalliverfunction),portalhypertension

Inactive:ALT,ALBnormal,nojaundice,splenomegaly,portalhypertensionDiagnosisDiagnosticcontentClinicaldiagnosisEtiologicaldiagnosisHistopathologicaldiagnosisDiagnosticfoundation

Epidemiologicaldata(incidenceoftheseason,age,dietandhealth,exposureHistory,familyhistoryofinjectionandbloodproducts,applications,etc.)Clinicalmanifestations(symptomsandsigns)Laboratorydata(routinetest,biochemical,imagingandliverbiopsy,etc.)Diagnosis---LaboratorytestsLiverfounction:

Serumenzymes:ALT↑AST↑CHE↓SerumProteinG↑A↓Pre-ALB↓DBandTBincreasedaccompanyjaundiceProthrombintimedetectionSerologicalmarkersMolecularmarkersImmunohistochemicalmarkersSerumhepatitisvirusmarkeranti-HEV-IgManti-HEV-IgG,currentinfectionHAVHBVHDV

HEVanti-HAV-IgManti-HAV-IgGCurrentinfectionHistoryinfectionHBsAg,anti-HBs,HBeAg,anti-HBe,anti-HBcAnti-HBcIgM,HBVDNA,HBVDNAP.anti-HDV-IgManti-HDV-IgG,Currentinfection

ChronicinfectionHBV–Markers

HBsAganti-HBs

Antigenicity+,contagiousness-HBcAganti-HBc

anti-HBcIgMHBeAg

anti-HBeProtectiveantibody,potentialsusceptivitywhen<10IU/ml

Antigenicity+,contagiousness+(difficulttobedetectedinserum）Non-protectiveantibodyNewlyinfection/acuteexacerbationofchronicinfection.LowervirusreplicationandCommunicable

ImportantindexofvirusreplicationandCommunicable

HBV-DNAIndexofvirusreplicationandCommunicable

HBsAg

HBsAb

HBeAgHBeAbHBcAbHBVDNA

significanceinfectivity

+-+-++activeviralreplicationstrong+--++-nonreplicating

weaker+--+++mutantvirusstrong---++-resolvedHBVno-+----immunitytoHBVnoHBVmarkersLaboratoryindexofchronichpatitisIndexMildMidrangeSevereALTand/orAST(IU/L)≤3ULN＞3ULN＞3ULNTB(umol/L)≤2ULN2~5ULN＞5ULNAlbumin(g/L)≥3532-35≤32A/G≥1.41.4~1.0＜1.0γEP(%)≤2121~26≥26PTA(%)＞7070~6060~40CHE(U/L)＞54005400~4500≤4500DifferentialDiagnosisJaundice:Hemolyticobstructive,hepatocellularjaundiceLiverinjuryDrugs,alcohol,systemicinfections,otherviruses,Wilson'sdiseaseTreatmentGeneralTreatment

Confidence,understandingPsychologyRestDrinkandFoodHabitEducationTreatmentforSymptoms

RepairingheptocytesAnti-inflammationAnti-oxidationAnti-apoptosisTraditionalChineseMedicineDetoxificationmethod:capillaris,gardenia,rhubarbTiaoganstagnationlaw:Radix,whitepeonyroot,citrusaurantium,Spleendampness:Codonopsis,Atractylodes,Poria,LicoriceKidneyPeiElementMethod:Radix,Radix,wolfberry,ChineseyamBloodcirculationmethod:Salvia,peachkernel,safflower,angelicaTraditionalChineseMedicineXiaochaihutang:Bupleurum,Scutellaria,ginseng,licorice,ginger,jujube,pinellia.Xiaoyaosan:stagnationofliverblooddeficiencyfirewoodLongdanYiguanjian:liverandkidney,liverqistagnationRhubarbZhechongpill:BloodStasisGlycyrrhizin,lecithin,silymarin,pHGFAnti-viraltreatmentChronichepatitisB,acutehepatitisC(withviralreplication)nucleos(t)ideanalogue(NAs),interferon(IFN)HBeAgwasassociatedwithHCCYangHIetal.NEnglJMed.2002,347:168-174..HCCrate(%)0HBsAg+HBeAg+HBsAg+,HBeAg-HBsAg-,HBeAg-1243567810years9024681210N=11,893,TaiWan§N=3,774;pvalueforlog-ranktest,<0.001ChenCJetalJAMA2006;295:65IloejeUetalGastroenterology2006(InPress)HBVDNAwasassociatedwithLivercirrhosis(13yearscohortstudyfromTaiwan,N=3851)HBVDNAwasassociatedwithHCC

testoftrendp<0.01

ChenCJ.JHepatol2005,42:16(A35)testoftrendp<0.01(13yearscohortstudyfromTaiwan,N=3851)Long-termminimizeoreliminatethesuppressionHBVReduceinflammationandnecrosisofhepatocytesandliverfibrosisDelayandpreventdiseaseprogressionReduceandpreventtheoccurrenceofhepaticdecompensation,livercirrhosis,HCCanditscomplicationsImprovethequalityoflifeandprolongsurvivaltimeTargetofanti-HBVtreatmentAnti-HBVDrugs*CurrentlyapprovedforHIV**Phase3inSouthKoreaDrugTypeApprovedPhase3Phase2Nucleosideanalogues

Lamivudine*Entecavir

Clevudine**Emtricitabine*Telbivudine

ElvucitabineValtorcitabineAmdoxovirRacivirLB80380Nucleotideanalogues

Adefovirdipivoxil

Tenofovir*

AlamifovirPradefovirCytokines

InterferonalfaPeginterferonalfa-2aLdTLAMADVETVMeritanddemeritofeachdrugsNAsIFNOraladministrationStronginhibitionofHBVDNANoimmunomodulatoryeffectsFewersideeffectsDrugRiskLowerHBsAgseroconversionrateLong-termtreatment-reducedefficacyInjectionInhibitionofHBVDNAlessAnti-viralandimmuneregulationMoresideeffectsNoriskofresistanceHigherHBsAgseroconversionrateLimitedtreatmentAmeliorationoflivercirrhsis

（wildtypeHBVinfection）Pretreatment2yearsDienstagJetal.Gastroenterol.2003;124:105-17Ameliorationoflivercirrhsis

(YMDDmutationHBVinfection)Pretreatment2yearsDienstagJetal.Gastroenterol.2003;124:105-17Pre-treatmentLAM3yearsInversionofliverfibrosis(3years)DienstagJetal.Gastroenterol.2003;124:105-17FulminanthepatitisGeneralandSupportingTherapyComplications:Bleeding

Hepaticencephalopathy

Infection

Hepatorenalsyndrome

ElectrolyteimbalanceArtificialliver,livertransplantationLivertransplantation

ThirdHospitalofHebeiMedicalUniversityistheonlyonehasbeenapprovedforlivertransplantqualificationsHebeiProvincePreventionSourceofinfection:Managementofthepatient'sandisolatecarriers

Cutofftherouteoftransmission:HAV,HEV---personalhygiene;HBV,HCV,HDV---bloodandbodyfluids,

MTCT(Verticaltransmission)Protectionofvulnerablepopulations:

Activeimmunization:HAV,HBVvaccinePassiveimmunization:HBIG抗病毒藥物的作用環(huán)節(jié)：NA與干擾素PerriloRP.Seminarsinliverdisease2004,24(suppl1):23-94)增加組織相容抗原-1的表達3)抑制mRNA信息的傳遞2)抑制核心顆粒釋出1)抑制病毒與細胞膜結合NA:選擇性阻斷逆轉錄酶HBV感染的免疫應答和干擾素的作用活化DCCD8+CD4+cccDNAmRNA細胞核CD8+NK/NKTMHCIMHCI誘導2‘,5‘-寡聚腺苷合成酶激活核酸內切酶提高蛋白酶活性干擾素α直接抗病毒作用直接清除受感染肝細胞分泌細胞因子，降解病毒免疫調節(jié)作用M