肝性腦病英文課件

Hepatic

FailureTaoWang,PH.D.,AssociatedprofessorPathophysiologydepartmentAnhuiMedicalUniversity肝性腦病英文IntroductionandConceptionEtiologyHepaticinsufficiencyHepaticfailure

Hepaticencephalopathy(focalpoint)

HepatorenalsyndromeHepatic

Failure2肝性腦病英文PARTIIntroductionandConceptionLiverThelargestandmostmetabolicallycomplexorgan1.Theliver3肝性腦病英文2.TheliveranatomyTheliverisdividedinto2mainlobes,eachconsistingofmanylobules.Theselobulesaresurroundedbybranchesofthehepaticartery,whichsuppliestheliverwithoxygenatedblood.Theportalveinsuppliesnutrient-richblood.Deoxygenatedbloodfromtheliverdrainsintothehepaticveins.

Anetworkofductscarriesbilefromthelivertothegallbladderandthesmallintestine4肝性腦病英文3.Thefunctionsoftheliver☆Substancemetabolism☆immunefunction☆Hemostasisregulation☆productionandsecretionofbile☆Bio-transformation(detoxification)

5肝性腦病英文4.HepaticinsufficiencySeveredamageinlivercellswillresultinseriouscondition,manifestingasjaundice,bleeding,infection,renaldysfunctionorencephalopathy,termedalltogetherthesesyndromesofhepaticinsufficiency.AcuteHepaticinsufficiencyChronicHepaticinsufficiency6肝性腦病英文5.HepaticfailureTerminalstageofhepaticinsufficiencyHepaticencephalopathy(focalpoint)HepatorenalsyndromePrimaryclinicalmanifestations7肝性腦病英文PARTIIEtiology1.Biological2.Physicalandchemical3.Inheritedconditions4.Immune5.NutritionalcausesHepatitisvirus(suchasHBV),bacteria,parasites,etc.Industrialtoxins,somedrugs,alcohol,etc.Idiopathichemochromatosis,Wilson’sdisease,etc.Extentofinflammationandnecrosis8肝性腦病英文PARTIIIHepaticinsufficiencyLiverVariousetiologycauseshepatocytesNon-parenchymalcellsdamagedamageKupffercells,hepaticsatellitecells,lipocytes,liverassociatedlymphocytes,hepaticsinusoidendothelialcellsHepaticinsufficiency9肝性腦病英文SyndromesofHepaticinsufficiency1.Metabolicdisorders2.Waterandelectrolytesimbalance3.Disordersinproductionofbilesaltsandeliminationofbilirubin4.ImpairedkupffercellsfunctionCarbohydrateMetabolicDisordersLipidMetabolicDisordersProteinMetabolicDisordersHepaticAscitesElectrolyticMetabolicDisorders10肝性腦病英文1.Metabolicdisorders1)CarbohydrateMetabolicDisordersCarbohydrateMetabolismofliverTomaintainconcentrations

ofglucoseinbloodwithinanarrow,normalrange.

insulinAhormoneproducedbythepancreasthatregulatesglucoselevelsintheblood.Itisnormallyproducedinresponsetoraisedglucoselevelsfollowingamealandpromotesglucoseabsorptionintotheliver

andmusclecells(whereitisconvertedintoenergy).Excessglucoseenteringthebloodafteramealisrapidlytakenupbytheliverandsequesteredasthelargepolymer,glycogenglycogenesis11肝性腦病英文glyconeogenesisglycogenolysiswhenbloodconcentrationsofglucosebegintodecline,theliveractivatesotherpathwayswhichleadtodepolymerizationofglycogenWhenhepaticglycogenreservesbecomeexhaused,asoccurswhenananimalhasnoteatenforseveralhours,thehepatocytes,recognizetheproblemandactivateadditionalgroupsofenzymesthatbeginsynthesizingglucoseoutofsuchthingsasaminoacidsandnon-hexosecarbohydrates.12肝性腦病英文SevereliverdiseaseHypoglycemiaHyperglycemiaCausedbyadecreaseinfunctionalhepatocytemass.Whenglucogenreservesaredepleted:gluconeogenensisimpared;

inactivationof

insulinweakenCausedbyportal-to-systemicshuntingDecreasethepostprandialextractionofglucosefromprotalbloodSomepatientsmaysufferabnormalglucosetolerance13肝性腦病英文1.Metabolicdisorders2)LipidMetabolicDisordersLiveristhecenteroflipidmetabolismManufacturing80%ofthecholesterolSynthesizing,storingandexportingtriglyceridesAssembling,secretingandtakinguplipoproteinparticle,suchasVLDL,LDL,andHDL.14肝性腦病英文SevereliverdiseaseDisturbanceoflipidmetabolismSyndromesoffataccumulation(fattyliver)IncertainchronicliverdiseasePrimarybiliarycirrhosisDestructionofbileductsBileflowdecreaseDecreaselipidclearanceviabilehyperlipidemiaThesepatientsoftendevelop

xanthomas——accumulationofcholesterol

肝性腦病英文1.Metabolicdisorders3)ProteinMetabolicDisordersThelivermanufacturesandsecretesmanyoftheproteinfoundinplasmaalbuminSomeclottingfactorsSomebindingproteinsSomehormoneprecursorsTomaintainplasmaoncoticpressureToregulatehemostasisSteroidandthyroidhormone-bindingproteintoregulatemetabolismangiotensinogen——toregulatebloodpressureInsulinlikegrowthfactor-1——toregulategrowth16肝性腦病英文OtherrolesoftheliverinproteinmetabolismProcessesofoxidativedeaminationandtransaminationTheureacycleallowsnitrogentobeexcretedintheformofurea17肝性腦病英文SevereliverdiseaseDisturbanceofproteinmetabolismDecreasedconversionofammoniatoureaPlasmaproteinsdecreaseElevatedammonialevelalbuminClottingfactorsHepaticencephalopathyEdemaandascitesBleedingtendancy肝性腦病英文2.Waterandelectrolytesimbalance1)HepaticAscitesAsctiesisthepresenceoftheexcessfluidintheperitonealcavityItisalate-stagedmanifestationoftheliverdisease.19肝性腦病英文MechanismsofHepaticAscites1)AnincreaseincapillarypressureCauses:portalhypertension;obstructionofvenousandlymphflow2)DecreaseincolloidalosmoticpressureCause:impairedsynthesisofalbumin3)SaltandwaterretentionbythekidneyCause:

effectivebloodvolumeisreducedbecauseoffluidshiftandvasodilation

glomerularfiltrationrate(GFR)rennin-angiotension-aldosteronesystem(+)metabolismofaldosterone

portal-to-systemicshunting

vasodilatoryproductsaredilveredtothesystemiccirculation

20肝性腦病英文2.Waterandelectrolytesimbalance2)ElectrolyticMetabolicDisorders1)Hypokalemia2)Hyponatremia21肝性腦病英文3.DisordersinproductionofbilesaltsandEliminationofbilirubinSevereliverdiseaseAfailuretosecretebileAFailuretosolubilizesubstancesMalabsorptionanddeficiencystatesDecreasedeliminationofbilirubinElevationofserumbilirubinandjaundiceJaundice:Yellowingoftheskinandthewhitesoftheeyes,causedbyanaccumulationofbilirubinintheblood.22肝性腦病英文4.ImpairedkupffercellsfunctionKupffercellsfunction1)Removingandphagocytizingoldanddefectivebloodcells,bacteria,etc.2)Producingavarietyofbioactivesubstancesandcytokines,suchasIL-1,IL-6etc.23肝性腦病英文dysfunctionofKupffercellsLossofclearancefunctiontobacteriaPortal-systemicshuntingEnterictoxinsenterthesystemiccirculationEntericendotoxemia24肝性腦病英文BriefSymptomsofhepaticfailureWaterandelectrolytesimbalanceHypoorhyper-glycemiaHyperlipidemiaandxanthomasPlasmaproteinsdecreaseedema,bleedingMetabolicdisordersHepaticAscitesHypokalemiaandHyponatremiaDisordersinproductionofbilesaltsandEliminationofbilirubinMalabsorptionanddeficiencystatesElevationofserumbilirubinandjaundiceImpairedkupffercellsfunctionEntericendotoxemia25肝性腦病英文Hepaticencephalopathy(HE)isaprimaryclinicalmanifestationofhepaticfailure.PARTIVHepaticencephalopathyIntroductionandConceptionEtiologyandclassificationPathogenesisPrecipitatingfactorsofHEPrinciplesoftreatment26肝性腦病英文1.IntroductionandConceptionConceptionofhepaticencephalopathyHEisacomplex,potentiallyreversibledisturbanceincentralnervoussystemthatoccursasaconsequenceofsevereliverdiseases.FourstagesofhepaticencephalopathySlightlyalteredmoodorbehaviourSomnipathyandinappropriatebehaviorsDrowsyandpsychopathyDeepcoma27肝性腦病英文2.EtiologyandclassificationEtiologyChronicliverdiseasesFulminanthepaticfailure(FHF)ViralinfectionDrugreactionPoisoningwithcarbontetrachlorideorphosphorusCirrhosisofanyorigin28肝性腦病英文ClassificationEndogenousHEHavenoapparentprecipitatingfactorsOftencausedbyextensivelivercelldestructionExogenousHEPrecipitatedbysomeknownagentsorabnormalities

suchas:gastrointestinalbleedingingestionmanyproteinsOftencausedbyportal-systemicshuntsAccordingtoorigin29肝性腦病英文AccordingtoclinicalcharacteristicAcuteorsubacuteencephalopathyAcuteorsubacuterecurrentencephalopathyChronicrecurrentencephalopathyChronicpermanentencephalopathy30肝性腦病英文3.Pathogenesis◎AmmoniaIntoxication◎FalseNeurotransmitters◎

AminoAcidimbalance◎

TheGamma-AminobutyricAcidhypothesisSeveralhypotheses31肝性腦病英文◎AmmoniaIntoxicationBasis1.HealthydogCreatingaportal-systemicshuntingFedbymeatcomatose2.80%patientswithHEBloodammonialevels3.CirrhosispatientsingestionofalargeamountsofproteinHepaticcoma4.HEpatientswithcirrhosisTherapiestoreduceammoniaabsorptionAmeliorationsofHE32肝性腦病英文CauseforelevatedammoniaInnormalconditionsUreaAmmoniaKidneyAmmoniaProteins,aminesUrea,purinesAmmoniaismainlyproducedingastrointestinaltractAmmoniaisdetoxifiedinliverbyconversiontoureathroughKrebs-Henseleitureacycle.33肝性腦病英文InHepaticfailureKrebs-HenseleitureacyclefunctionisimpairedBloodammonialevelincreased(endogenous)OrnithineCitrullineargininearginase

NH3NH3Urea

Inhepaticfailure：

substrates

enzymeATP

Portal-systemicshuntingalsoreducestheureaproduction(exogenous)34肝性腦病英文AmmoniaproductionincreasedBloodammonialevelincreased1)Productionofammoniainintestinelumenincreased2)ProductionofammoniainkidneyincreasedProtein,urea,purinedegradedEnzymeofbacteriaammoniaglutamineglutaminaseammonia3)Productionofammoniainskeletalmuscleincreased35肝性腦病英文EndogenousHEKidneyBloodNH3

NH3Urea×NH3

NH3proteinureaAmmoniaproductionUreaCyclefunctionimpairedLivercellmassdamagedHyperammonemiaIntoxicationofammoniaonbrain肝性腦病英文ExogenousHEAmmoniaproductionPortal-systemicshuntingHepaticcirrhosisHyperammonemiaIntoxicationofammoniaonbrain37肝性腦病英文IntoxicationofammoniaonbrainAmmoniaproductionPortal-systemicshunting(exogenous)UreaCyclefunctionimpaired(endogenous)Hyper-ammonemiaHE?Intoxicationofammoniaonbrain1)Impairmentofenergymetabolisminbrain2)Alternationoftheneurotransmitters3)InhibitingactiononnervecellsmembraneMitochondrialpermeabilitytransitioninducedbyOxidativestress38肝性腦病英文1)ImpairmentofenergymetabolisminbrainGlucoseisthemostimportantfuelforcerebralenergy.HyperammonemiaDepressionincerebralglucosemetabolismATPoutputreductiontricarboxylicacidcycle39肝性腦病英文2)AlternationoftheneurotransmittersHyperammonemiaDominantneurochemicallesions40肝性腦病英文3)InhibitingactiononnervecellsmembraneHyperammonemiaInhibitingbrainNa+-K+ATPaseIncreaseofintracellularsodiumImpairmentofNeurotransmission41肝性腦病英文Mitochondrialpermeabilitytransition(MPT)inducedbyOxidativestressHyperammonemiaDysfunctionofastrocytes1)Inculturedastrocytes,ammoniainducesMPT,frequentlycausedbyoxidativestressIncreasedfreeradicalproductioninculturedastrocytesexposedtoammonia3)AntioxidantscaninhibittheMPTinammonia-treatedculturedastrocytes42肝性腦病英文TherearesomeargumentagainstAmmoniaintoxicationhypothesis?10%ofHEpatientshavenormalserumammonialevels?somepatientswithhyperammonemiahavenoHEsignsSotherearesynergisticactionofmultipletoxinsontheCNS.肝性腦病英文◎FalseNeurotransmittersBasisHEpatientswithfulminanthepatitisL-dopatreatmentRecoverquicklyL-dopaisaprecursorofnormalneurotransmittersnormalneurotransmitters,suchasdopamineandnorepinephrine,areendogenoussingnalingmoleculessecretedbyneuronsthatcanalterthebehaviorofneuronsoreffectorcells.44肝性腦病英文ConceptionFalseNeurotransmitters(FNT)isakindofchemicalsubstance,whichhavesimilarstructuresoftrueneurotransmitters(NNT),butmuchweakeractivitythantrueneurotransmitters.45肝性腦病英文HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2NorepinephinedopamineCHOHCH2NH2phenolethanolamineoctopamineNormalNeurotransmittersFalseNeurotransmitters肝性腦病英文◎

AminoAcidimbalanceSynthesisofneurotransmitterisdependentontherateofprecursoraminoacidsBranchchainaminoacids(BCAA)Aromaticaminoacids(AAA)Valine,leucineandisoleucinePrecursorsofNNTTyrosine,phenylalanineandtryptophanPrecursorsofFNTNormally,plasmaBCAAtoAAArateis3-3.5InHEpatients,plasmaBCAAtoAAArateis0.6-1.247肝性腦病英文DecreasedplasmaBCAAlevelsMechanisms1)AmmoniaInHEpatients,BCAAmightbeutilizedfordetoxificationofammonia.2)hyperinsulinismmetabolismofinsulinhyperinsulinismPortal-systemicshuntingUptakeofBCAAintomuscle3)InflammationcytokineTumornecrosisfactor-αDecreasedplasmaBCAAlevels48肝性腦病英文IncreasedplasmaAAAlevelsMechanisms1)Dysfunctionofhepaticdeamination2)ReleaseofAAAfromthenecrotichepatocytes49肝性腦病英文phenethylaminephenolethanolaminetyrosameinoctopamineAAA↑BCAA↓Blood-brainbarrier5-hydroxytryptophanserotoninDopa×phenylalaninetyrosinetryptophanvector多巴胺NE××dopamineNE↓InhibitoryFNTFNTNNTDysfunctionofsynthesisofneurotransmittersinbrain肝性腦病英文DecreasedplasmaBCAAlevelsIncreasedplasmaAAAlevelsInHEpatients,plasmaBCAAtoAAAratedecreasedNeuronalcontentsofNNT

FNTReducedneuralexitationIncreasedneuralinhibitonBRIEFFNTandaminoacidimbalance51肝性腦病英文◎

TheGamma-AminobutyricAcidhypothesisBasisTheGamma-AminobutyricAcid(GABA)isainhibitoryneurotransmitterinCNS,asacauseofHE.2)IncreasedGABA-ergictoneisobservedinpatientswithcirrhosis3)Flumazenil,abenzodiazepineantagonist,cantransientlyreverseHEinpatientswithcirrhosis52肝性腦病英文IncreasedplasmaGABAlevelsHepaticfailureDecreasedhepaticmetabolismofGABAGutabsorption(intestinalbacteriaandtheintestinalwall)BloodGABAlevelsThepermeabilityoftheblood-brainbarriertoGABASomeGABAreachesGABAreceptorsandaugmentGABA-ergicneurotransmission53肝性腦病英文Mechanism1.Increaseddensityand/oraffinityofreceptorsforGABAonthesupramolecularcomplex.GABA/BZreceptor/chlorideionophorecomplexAGABAreceptoraBZreceptorachlorideionophore(thatcontainsreceptorforbarbiturates)Notes:AdministrationofbenzodiazepinesandbarbituratestopatientswithcirrhosisincreasesGABA-ergictoneandpredisposesdep