上海交通大学医学院内科学livercirrhosis

ARCHITECTURALLIVERDISRUPTIONISTHEMAINMECHANISMTHATLEADSTOANINCREASEDINTRAHEPATICRESISTANCEHepaticcirrhosisMaXiong,M.D.,AssociateProfessorShanghaiInstituteofDigestiveDisease,RenjiHospitalShanghaiJiaoTongUniversitySchoolofMedicineHepaticCirrhosisEndstageofanychronicliverdiseaseCharacterizedhistologicallybyregenerativenodulessurroundedbyfibroustissueClinicallytherearetwotypesofcirrhosis:CompensatedDecompensatedDEFINITIONOFCIRRHOSISCirrhosisNormalNodulesIrregularsurfaceGROSSIMAGEOFANORMALANDACIRRHOTICLIVERCirrhoticliverNodular,irregularsurfaceNodulesGROSSIMAGEOFACIRRHOTICLIVERCirrhosisNormalNodulessurroundedbyfibroustissueHISTOLOGICALIMAGEOFANORMALANDACIRRHOTICLIVERHISTOLOGICALIMAGEOFCIRRHOSISFibrosisRegenerativenodulePATHOGENESISOFLIVERFIBROSISHepatocytesSpaceofDisseSinusoidalendothelialcellHepaticstellatecellFenestraeNormalHepaticSInusoidRetinoiddropletsPATHOGENESISOFLIVERFIBROSISAlterationsinMicrovasculatureinCirrhosisActivationofstellatecellsCollagendepositioninspaceofDisseConstrictionofsinusoidsDefenestrationofsinusoidsCompensatedcirrhosisDecompensatedcirrhosisDeathChronicliverdiseaseNaturalHistoryofChronicLiverDiseaseDevelopmentofcomplications:

VaricealhemorrhageAscitesEncephalopathyJaundiceNATURALHISTORYOFCHRONICLIVERDISEASE604080100120140160040608020200100MonthsProbabilityofsurvivalAllpatientswithcirrhosisDecompensatedcirrhosis180DecompensationShortensSurvivalGineset.al.,Hepatology1987;7:122Mediansurvival~9yearsMediansurvival~1.6yearsSURVIVALTIMESINCIRRHOSIS10LiverinsufficiencyVaricealhemorrhageComplicationsofCirrhosisResultfromPortalHypertensionorLiverInsufficiencyCirrhosisAscitesEncephalopathyJaundicePortalhypertensionSpontaneousbacterialperitonitisHepatorenalsyndromeCOMPLICATIONSOFCIRRHOSISCirrhosis-DiagnosisCirrhosisisahistologicaldiagnosisHowever,inpatientswithchronicliverdiseasethepresenceofvariousclinicalfeaturessuggestscirrhosisThepresenceoftheseclinicalfeaturescanbefollowedbynon-invasivetesting,priortoliverbiopsyDIAGNOSISOFCIRRHOSISInWhomShouldWeSuspectCirrhosis?AnypatientwithchronicliverdiseaseChronicabnormalaminotransferasesand/oralkalinephosphatasePhysicalexamfindingsStigmataofchronicliverdisease(musclewasting,vascularspiders,palmarerythema)PalpableleftlobeoftheliverSmallliverspanSplenomegalySignsofdecompensation(jaundice,ascites,asterixis)DIAGNOSISOFCIRRHOSIS–CLINICALFINDINGSLaboratoryLiverinsufficiencyLowalbumin(<3.8g/dL)Prolongedprothrombintime(INR>1.3)Highbilirubin(>1.5mg/dL)PortalhypertensionLowplateletcount(<175x1000/ml)AST/ALTratio>1InWhomShouldWeSuspectCirrhosis?DIAGNOSISOFCIRRHOSIS–LABORATORYSTUDIESCTScaninCirrhosisLiverwithanirregularsurfaceSplenomegalyCollateralsDIAGNOSISOFCIRRHOSIS–CATSCANNoYesDiagnosticAlgorithmPatientwithchronicliverdiseaseandanyofthefollowing:VaricealhemorrhageAscitesHepaticencephalopathyLiverbiopsynotnecessaryforthediagnosisofcirrhosisPhysicalfindings:EnlargedlefthepaticlobeSplenomegalyStigmataofchronicliverdiseaseLaboratoryfindings:ThrombocytopeniaImpairedhepaticsyntheticfunctionRadiologicalfindings:SmallnodularliverIntra-abdominalcollateralsAscitesSplenomegalyColloidshifttospleenand/orbonemarrowYesNoYesNoLiverbiopsyDIAGNOSTICALGORITHMMechanismsofPortalHypertensionPressure(P)resultsfromtheinteractionofresistance(R)andflow(F):P=RxFPortalhypertensioncanresultfrom:increaseinresistancetoportalflowand/orincreaseinportalvenousinflowMECHANISMSOFPORTALHYPERTENSIONNormalLiverHepaticveinSinusoidPortalveinLiverSplenicveinCoronaryveinTHENORMALLIVEROFFERSALMOSTNORESISTANCETOFLOWPortalsystemiccollateralsDistortedsinusoidalarchitectureleadstoincreasedresistancePortalveinCirrhoticLiverSplenomegalyARCHITECTURALLIVERDISRUPTIONISTHEMAINMECHANISMTHATLEADSTOANINCREASEDINTRAHEPATICRESISTANCEANINCREASEINPORTALVENOUSINFLOWSUSTAINSPORTALHYPERTENSIONMesentericveins

FlowSplanchnicvasodilatationDistortedsinusoidalarchitechurePortalveinAnIncreaseinPortalVenousInflowSustainsPortalHypertension20SmallvaricesLargevaricesNovarices7-8%/year7-8%/yearVaricesIncreaseinDiameterProgressivelyMerlietal.JHepatol2003;38:266VARICESINCREASEINDIAMETERPROGRESSIVELYAThresholdPortalPressureof~12mmHgisNecessaryforVaricestoFormP<0.01510121525303520HepaticVenousPressureGradient(mmHg)Garcia-Tsaoet.al.,Hepatology1985;5:419VaricesPresent(n=72)VaricesAbsent(n=15)ATHRESHOLDPORTALPRESSUREOF~12mmHgISNECESSARYFORVARICESTOFORMVaricealGrowthVaricealrupturePortalpressureResistancetoportalflowCirrhosisSplanchnicarteriolarresistancePortalbloodinflowVaricesPROGRESSIONOFPORTALHYPERTENSIONLEADSTOVARICEALGROWTHANDVARICEALRUPTUREPredictorsofhemorrhage:VaricealsizeRedsignsChildB/CNIEC.NEnglJMed1988;319:983VaricealhemorrhageVarixwithredsignsPROGNOSTICINDICATORSOFFIRSTVARICEALHEMORRHAGETension(T)Wallthickness(w)Groszmann,Gastroenterology1984;80:1611T=tpxrwVaricealWallTension(T)isaMajorDeterminantofVaricealRuptureTransmuralpressure(tp)Radius(r)EsophagusVarixVARICEALWALLTENSIONISAMAJORDETERMINANTOFVARICEALRUPTUREProphylaxisofVaricealHemorrhageDiagnosisofCirrhosisEndoscopyNoVaricesFollow-upEGDin2-3years*SmallVaricesFollow-upEGDin1-2years*Medium/LargeVaricesStepwiseincreaseuntilmaximallytolerateddoseContinuebeta-blocker(life-long)NoContraindicationsContraindicationsorBeta-blockerintoleranceBeta-blockertherapyEndoscopicVaricealBandLigation*EGDeveryyearindecompensatedcirrhosisMANAGEMENTALGORITHMFORTHEPROPHYLAXISOFVARICEALHEMORRHAGE-SUMMARYTreatmentofAcuteVaricealHemorrhageGeneralManagement:IVaccessandfluidresuscitationDonotovertransfuse(hemoglobin~8g/dL)AntibioticprophylaxisSpecifictherapy:Pharmacologicaltherapy:terlipressin,somatostatinandanalogues,vasopressin+nitroglycerinEndoscopictherapy:ligation,sclerotherapyShunttherapy:TIPS,surgicalshuntTREATMENTOFACUTEVARICEALHEMORRHAGEEndoscopicVaricealBandLigationBleedingcontrolledin90%Rebleedingrate30%Comparedwithsclerotherapy:LessrebleedingLowermortalityFewercomplicationsFewertreatmentsessionsENDOSCOPICVARICEALBANDLIGATIONTransjugularIntrahepaticPortosystemicShuntHepaticveinPortalveinSplenicveinSuperiormesentericveinTIPSTHETRANSJUGULARINTRAHEPATICPORTOSYSTEMICSHUNTManagementofAcuteVaricealHemorrhageVaricealHemorrhageSuspectedInitialManagementNORescueTIPS/ShuntsurgeryBalloonTamponadeYESEarlyrebleeding?AcuteHemorrhageControlled?YES2ndEndoscopyFurtherbleedingNOProphylaxisagainstrecurrenthemorrhageMANAGEMENTALGORITHMINACUTEESOPHAGEALVARICEALHEMORRHAGE30EvolutionofVaricesLevelofInterventionManagementRecommendationsCirrhosiswithnovaricesSmallvaricesNohemorrhageMedium/largevaricesNohemorrhageVaricealhemorrhageRecurrentvaricealhemorrhagePre-primaryprophylaxisPrimaryprophylaxisSecondaryprophylaxisRepeatendoscopyin2-3yearsNospecifictherapySmallvaricesRepeatendoscopyin1-2yearsNospecifictherapy?beta-blockertopreventenlargementMedium/LargevaricesNon-selectivebeta-blockersEVLinthoseintoleranttodrugsEndoscopic/pharmacologictherapyAntibioticsinallpatientsTIPSorshuntsurgeryasrescuetherapyBeta-blockers+nitratesorEVLBeta-blockers+EVL?TIPSorshuntsurgeryasrescuetherapySUMMARYOFMANAGEMENTOFVARICESANDVARICEALHEMORRHAGEAscitesandHepatorenalSyndromeASCITESANDHEPATORENALSYNDROMECirrhosisActivationofneurohumoralsystems(renin,angiotensin,aldosterone)EffectivearterialbloodvolumeHepaticvenousoutflowblockAscitesSinusoidalpressure(HVPG10-12mmHg)SodiumandwaterretentionArteriolarresistance(vasodilation)PATHOGENESISOFASCITESUltrasoundistheMostSensitiveMethodtoDetectAscitesLiverAscitesULTRASOUNDISTHEMOSTSENSITIVEMETHODTODETECTASCITESInitialWorkupofAscites

DiagnosticParacentesisGlucose,LDHCytologyPMNcountCultureProtein/AlbuminAmylaseRoutineOptional?secondaryinfection?cirrhoticascites?pancreaticascites?malignantascites?SBPINITIALWORKUPOFASCITES:DIAGNOSISPARACENTESISDiagnosticParacentesisIndicationsContraindicationsNew-onsetascitesAdmissiontohospitalSymptoms/signsofSBPRenaldysfunctionUnexplainedencephalopathyNoneDIAGNOSTICPARACENTESISCirrhoticascitesCardiacascitesPeritonealmalignancy1.14.03.02.01.00Serum–ascitesalbumingradient(g/dL)Serum-AscitesAlbuminGradientisHighinPortalHypertensiveCausesofAscitesRunyon,AnnInternMed1992;117:215SERUM-ASCITESALBUMINGRADIENT(SAAG)ISHIGHINPORTALHYPERTENSIVECAUSESOFASCITESActivationofneurohumoralsystemsSiteofActionofDifferentTherapiesforAscitesCirrhosisIntrahepaticresistanceArteriolarresistance(vasodilation)SinusoidalpressureAscitesSodiumandwaterretentionTIPSTIPSDiureticsPVSPVSAlbuminLVPEffectivearterialbloodvolumeMECHANISMOFACTIONOFTHEDIFFERENTTHERAPIESFORASCITESManagementofUncomplicatedAscitesDefinition: Ascitesresponsivetodiureticsin theabsenceofinfectionand renaldysfunctionSodiumrestrictionEffectivein10-20%ofcasesPredictorsofresponse:mildormoderateascites,UrineNaexcretion>50mEq/dayDiureticsShouldbespironolactone-basedAprogressiveschedule(spironolactonefurosemide)requiresfewerdoseadjustmentsthanacombinedtherapy(spironolactone+furosemide)MANAGEMENTOFUNCOMPLICATEDASCITESSodiumRestriction2g(or5.2gofdietarysalt)adayFluidrestrictionisnotnecessaryunlessthereishyponatremia(<125mmol/L)Goal:negativesodiumbalanceSideeffect:unpalatabilitymaycompromisenutritionalstatusManagementofUncomplicatedAscitesMANAGEMENTOFUNCOMPLICATEDASCITES:SODIUMRESTRICTION40DiureticTherapyDosageSpironolactone100-400mg/dayFurosemide(40-160mg/d)forinadequateweightlossorifhyperkalemiadevelopsIncreasediureticsifweightloss<1kginthefirstweekand<2kg/weekthereafterDecreasediureticsifweightloss>0.5kg/dayinpatientswithoutedemaand>1kg/dayinthosewithedemaSideeffectsRenaldysfunction,hyponatremia,hyperkalemia,encephalopathy,gynecomastiaManagementofUncomplicatedAscitesMANAGEMENTOFUNCOMPLICATEDASCITES:DIURETICTHERAPYDefinitionandTypesofRefractoryAscitesOccursin~10%ofcirrhoticpatientsDiuretic-intractableascites

Therapeuticdosesofdiureticscannotbeachieved becauseofdiuretic-inducedcomplicationsDiuretic-resistantascites

Noresponsetomaximaldiuretictherapy(400mg spironolactone+160mgfurosemide/day)20%80%Arroyoetal.Hepatology1996;23:164DEFINITIONANDTYPESOFREFRACTORYASCITESPeritoneo-VenousShunt(PVS)isUsefulintheTreatmentofRefractoryAscitesUseofjugularveinwillhinderTIPSplacementIntraabdominaladhesionsmaycomplicatelivertransplantsurgeryOne-wayvalvePERITONEO-VENOUSSHUNT(PVS)ISUSEFULINTHETREATMENTOFREFRACTORYASCITESTreatmentofAscitesHepatorenalSyndromeRefractoryAscitesUncomplicatedAscitesPortalHypertensionNoAscites1)LVP+albumin2)TIPS3)PVS(innon-TIPS,non-transplant candidates)LVP=largevolumeparacentesisTIPS=transjugularintrahepaticportosystemicshuntTREATMENTOFREFRACTORYASCITES44SpontaneousBacterialPeritonitis(SBP)ComplicatesAscitesandCanLeadtoRenalDysfunctionSBPHVPG>10mmHgExtremeVasodilationHVPG>10mmHgSevereVasodilationHVPG>10mmHgModerateVasodilationHVPG<10mmHgMildVasodilationHepatorenalSyndromeRefractoryAscitesUncomplicatedAscitesPortalHypertensionNoAscitesSPONTANEOUSBACTERIALPERITONITIS(SBP)COMPLICATESASCITESANDCANLEADTORENALDYSFUNCTIONEarlyDiagnosisofSBPDiagnosticparacentesis:Ifsymptoms/signsofSBPoccurUnexplainedencephalopathyand/orrenaldysfunctionAtanyhospitaladmissionDiagnosisbasedonasciticfluid PMNcount>250/mm3Rimolaetal.,JHepatol2000;32:142EARLYDIAGNOSISOFSPONTANEOUSBACTERIALPERITONITIS(SBP)TREATMENTINDICATEDDiagnosisandManagementofSpontaneousBacterialPeritonitisDiagnosticParacentesisPMN>250?CulturePositive?TREATMENTNOTINDICATEDNORepeatParacentesisYESPMN>250?CulturePositive?NONOYESYESYESNOMANAGEMENTALGORITHMINSPONTANEOUSBACTERIALPERITONITIS(SBP)TreatmentofSpontaneousBacterialPeritonitisRecommendedantibioticsforinitialempirictherapyi.v.cefotaxime,amoxicillin-clavulanicacidoralnofloxacin(uncomplicatedSBP)avoidaminoglycosidesMinimumduration:5daysRe-evaluationifasciticfluidPMNcounthasnotdecreasedbyatleast25%after2daysoftreatmentRimolaetal.,JHepatol2000;32:142TREATMENTOFSPONTANEOUSBACTERIALPERITONITIS(SBP)AllSBPsSBPcausedbygram-negativebacteriaProbabilityofSBPrecurrenceMonthsp=0.0063PlaceboNorfloxacinPlacebop=0.0013Norfloxacin01.0.8.4.2.6481220016048122016MonthsNorfloxacinReducesRecurrenceofSpontaneousBacterialPeritonitisGinesetal.,Hepatology1990;12:716NORFLOXACINREDUCESRECURRENCEOFSPONTANEOUSBACTERIALPERITONITIS(SBP)IndicationsforProphylacticAntibioticstoPreventSpontaneousBacterialPeritonitisCirrhoticpatientshospitalizedwithGIhemorrhage(short-term)Norfloxacin400mgp.o.BIDx7daysPatientswhohaverecoveredfromSBP(long-term)Norfloxacin400mgp.o.daily,indefinitelyWeeklyquinolonesnotrecommended(lowerefficacy,developmentofquinolone-resistance)INDICATIONSFORPROPHYLACTICANTIBIOTICSTOPREVENTSPONTANEOUSBACTERIALPERITONITIS(SBP)50CharacteristicsofHepatorenalSyndromeRenalfailureinpatientswithcirrhosis,advancedliverfailureandseveresinusoidalportalhypertensionAbsenceofsignificanthistologicalchangesinthekidney(“functional”renalfailure)Markedarteriolarvasodilationintheextra-renalcirculationMarkedrenalvasoconstrictionleadingtoreducedglomerularfiltrationrateCHARACTERISTICSOFHEPATORENALSYNDROME(HRS)TwoTypesofHepatorenalSyndromeType1Rapidlyprogressiverenalfailure(2weeks)Doublingofcreatinineto>2.5orhalvingofcreatinineclearance(CrCl)to<20ml/minType2MoreslowlyprogressiveCreatinine>1.5mg/dLorCrCl<40ml/minAssociatedwithrefractoryascitesArroyoetal.,Hepatology1996;23:164TYPESOFHEPATORENALSYNDROME(HRS)SURVIVALINTHEDIFFERENTTYPESOFHEPATORENALSYNDROME(HRS)024681210Months10.20.40.60.8Survivalprobability0Type2p=0.001SurvivalinDifferentTypesofHepatorenalSyndrome(HRS)Ginesetal.,Lancet2003;362:1819Type1CirrhosisIntrahepaticresistanceSinusoidalpressureArteriolarresistance(vasodilation)EffectivearterialbloodvolumeAscitesSodiumandwaterretentionActivationofneurohumoralsystemsRenalvasoconstrictionRenaldysfunctionNSAIDsDiureticsDiarrheaHemorrhageVasodilatorsLVPw/oalbuminInfectionTHEREAREMANYCONDITIONSOTHERTHANHEPATORENALSYNDROMETHATCANLEADTORENALFAILUREINPATIENTSWITHCIRRHOSISCirrhosisIntrahepaticresistanceSinusoidalpressureArteriolarresistance(vasodilation)EffectivearterialbloodvolumeAscitesSodiumandwaterretentionActivationofneurohumoralsystemsRenalvasoconstrictionRenaldysfunctionNSAIDsDiureticsDiarrheaHemorrhageVasodilatorsLVPw/oalbuminInfectionHepatorenalSyndromeHEPATORENALSYNDROME(HRS)ISADIAGNOSISOFEXCLUSIONNaturalHistoryofHepatorenalSyndrome(HRS)Arroyoetal.,Gastroenterology2002;122:16585310MonthsCreatinine(mg/dL)60-401342-6-22WeeksType2HRSType1HRSSBPCefotaximeTherapeuticparacentesesNATURALHISTORYOFHEPATORENALSYNDROME(HRS)AdvancedhepaticfailureandportalhypertensionCreatinine>1.5mg/dLorcreatinineclearance<40ml/minAbsenceofshock,bacterialinfection,ornephrotoxicdrugsAbsenceofexcessivegastrointestinalorrenalfluidlossNoimprovementinrenalfunctionafterplasmavolumeexpansionwith1.5LofisotonicsalineUrinaryprotein<500mg/dLandnormalrenalultrasoundMajorCriteriaintheDiagnosisofHepatorenalSyndromeArroyoetal.,Hepatology1996;23:164MAJORCRITERIAINDIAGNOSINGHEPATORENALSYNDROMEUrineSodiumandUrineVolumeareMinorCriteriaintheDiagnosisofHRSMinorcriteriaUrinesodium<10mEq/LUrineosmolality>plasmaosmolalitySerumsodium<130mEq/LUrinevolume<500ml/dayUrineRBCs<50/HPFArroyoetal.,Hepatology1996;23:164URINESODIUMANDURINEVOLUMEAREMINORCRITERIAINTHEDIAGNOSISOFHEPATORENALSYNDROME(HRS)ActivationofneurohumoralsystemsSiteofActionofDifferentTherapiesforHRSAdvancedCirrhosisIntrahepaticresistanceArteriolarresistance(vasodilation)SinusoidalpressureHepatorenalsyndromeRenalvasoconstrictionTIPSTIPSTransplantEffectivearterialbloodvolumeVaso-constrictorsAlbuminMECHANISMOFACTIONOFTHEDIFFERENTTHERAPIESFORHEPATORENALSYNDROME(HRS)ManagementofHepatorenalSyndromeProvenefficacyLivertransplantationUnderinvestigationVasoconstrictor+albuminTransjugularintrahepaticportosystemicshunt(TIPS)Vasoconstrictor+TIPSExtracorporealalbumindialysis(ECAD)IneffectiveRenalvasodilators(prostaglandin,dopamine)HemodialysisMANAGEMENTOFHEPATORENALSYNDROMEHEPATICENCEPHALOPATHYHepaticEncephalopathy60HepaticEncephalopathy

NomenclatureTypeA AssociatedwithAcuteliverfailureTypeB Associatedwithporto-systemicBypasswithoutintrinsichepatocellulardiseaseTypeC AssociatedwithCirrhosisandporto-systemicshuntingFerencietal.,Hepatology2002;35:716HEPATICENCEPHALOPATHY–NOMENCLATURETreatment:rarelyeffective shortoflivertransplantCharacteristicsofTypeAvs.TypeC

HepaticEncephalopathyGradualonsetRarelyfatalMaincause: shunting/toxinPrecipitantTreatment:usually effectiveRapidonsetFrequentlyfatalMaincause: cerebraledemaTypeATypeCCHARACTERISTICSOFTYPEAVS.TYPECENCEPHALOPATHYTypeCHepaticEncephalopathyistheEncephalopathyofCirrhosisNeuropsychiatriccomplicationofcirrhosisResultsfromspontaneousorsurgical/radiologicalportal-systemicshunt+chronicliverfailureFailuretometabolizeneurotoxicsubstancesAlterationsofastrocytemorphologyandfunction(AlzheimertypeIIastrocytosis)TYPECHEPATICENCEPHALOPATHYISTHEENCEPHALOPATHYOFCIRRHOSISHepaticEncephalopathyPathogenesisBacterialactionProteinloadFailuretometabolizeNH3NH3ShuntingGABA-BDreceptorsToxinsPATHOPHYSIOLOGYOFHEPATICENCEPHALOPATHYHepaticEncephalopathyIsAClinicalDiagnosisClinicalfindingsandhistoryimportantAmmonialevelsareunreliableAmmoniahaspoorcorrelationwithdiagnosisMeasurementofammonianotnecessaryNumberconnectiontestSlowdominantrhythmonEEGHEPATICENCEPHALOPATHYISACLINICALDIAGNOSISStage Mentalstate Neurologicsigns

1 Mildconfusion:limitedattention Incoordination,tremor, span,irritability,invertedsleep impairedhandwriting pattern 2 Drowsiness,personalitychanges, Asterixis,ataxia,dysarthria intermittentdisorient