肝性脑病英文课件

肝性脑病英文课件第1页/共62页Hepatic

FailureTaoWang,PH.D.,AssociatedprofessorPathophysiologydepartmentAnhuiMedicalUniversity第2页/共62页3IntroductionandConceptionEtiologyHepaticinsufficiencyHepaticfailure

Hepaticencephalopathy(focalpoint)

HepatorenalsyndromeHepatic

Failure第3页/共62页4PARTIIntroductionandConceptionLiverThelargestandmostmetabolicallycomplexorgan1.Theliver第4页/共62页52.TheliveranatomyTheliverisdividedinto2mainlobes,eachconsistingofmanylobules.Theselobulesaresurroundedbybranchesofthehepaticartery,whichsuppliestheliverwithoxygenatedblood.Theportalveinsuppliesnutrient-richblood.Deoxygenatedbloodfromtheliverdrainsintothehepaticveins.

Anetworkofductscarriesbilefromthelivertothegallbladderandthesmallintestine第5页/共62页63.Thefunctionsoftheliver☆Substancemetabolism☆immunefunction☆Hemostasisregulation☆productionandsecretionofbile☆Bio-transformation(detoxification)

第6页/共62页74.HepaticinsufficiencySeveredamageinlivercellswillresultinseriouscondition,manifestingasjaundice,bleeding,infection,renaldysfunctionorencephalopathy,termedalltogetherthesesyndromesofhepaticinsufficiency.AcuteHepaticinsufficiencyChronicHepaticinsufficiency第7页/共62页85.HepaticfailureTerminalstageofhepaticinsufficiencyHepaticencephalopathy(focalpoint)HepatorenalsyndromePrimaryclinicalmanifestations第8页/共62页9PARTIIEtiology1.Biological2.Physicalandchemical3.Inheritedconditions4.Immune5.NutritionalcausesHepatitisvirus(suchasHBV),bacteria,parasites,etc.Industrialtoxins,somedrugs,alcohol,etc.Idiopathichemochromatosis,Wilson’sdisease,etc.Extentofinflammationandnecrosis第9页/共62页10PARTIIIHepaticinsufficiencyLiverVariousetiologycauseshepatocytesNon-parenchymalcellsdamagedamageKupffercells,hepaticsatellitecells,lipocytes,liverassociatedlymphocytes,hepaticsinusoidendothelialcellsHepaticinsufficiency第10页/共62页11SyndromesofHepaticinsufficiency1.Metabolicdisorders2.Waterandelectrolytesimbalance3.Disordersinproductionofbilesaltsandeliminationofbilirubin4.ImpairedkupffercellsfunctionCarbohydrateMetabolicDisordersLipidMetabolicDisordersProteinMetabolicDisordersHepaticAscitesElectrolyticMetabolicDisorders第11页/共62页121.Metabolicdisorders1)CarbohydrateMetabolicDisordersCarbohydrateMetabolismofliverTomaintainconcentrations

ofglucoseinbloodwithinanarrow,normalrange.

insulinAhormoneproducedbythepancreasthatregulatesglucoselevelsintheblood.Itisnormallyproducedinresponsetoraisedglucoselevelsfollowingamealandpromotesglucoseabsorptionintotheliver

andmusclecells(whereitisconvertedintoenergy).Excessglucoseenteringthebloodafteramealisrapidlytakenupbytheliverandsequesteredasthelargepolymer,glycogenglycogenesis第12页/共62页13glyconeogenesisglycogenolysiswhenbloodconcentrationsofglucosebegintodecline,theliveractivatesotherpathwayswhichleadtodepolymerizationofglycogenWhenhepaticglycogenreservesbecomeexhaused,asoccurswhenananimalhasnoteatenforseveralhours,thehepatocytes,recognizetheproblemandactivateadditionalgroupsofenzymesthatbeginsynthesizingglucoseoutofsuchthingsasaminoacidsandnon-hexosecarbohydrates.第13页/共62页14SevereliverdiseaseHypoglycemiaHyperglycemiaCausedbyadecreaseinfunctionalhepatocytemass.Whenglucogenreservesaredepleted:gluconeogenensisimpared;

inactivationof

insulinweakenCausedbyportal-to-systemicshuntingDecreasethepostprandialextractionofglucosefromprotalbloodSomepatientsmaysufferabnormalglucosetolerance第14页/共62页151.Metabolicdisorders2)LipidMetabolicDisordersLiveristhecenteroflipidmetabolismManufacturing80%ofthecholesterolSynthesizing,storingandexportingtriglyceridesAssembling,secretingandtakinguplipoproteinparticle,suchasVLDL,LDL,andHDL.第15页/共62页SevereliverdiseaseDisturbanceoflipidmetabolismSyndromesoffataccumulation(fattyliver)IncertainchronicliverdiseasePrimarybiliarycirrhosisDestructionofbileductsBileflowdecreaseDecreaselipidclearanceviabilehyperlipidemiaThesepatientsoftendevelop

xanthomas——accumulationofcholesterol

第16页/共62页171.Metabolicdisorders3)ProteinMetabolicDisordersThelivermanufacturesandsecretesmanyoftheproteinfoundinplasmaalbuminSomeclottingfactorsSomebindingproteinsSomehormoneprecursorsTomaintainplasmaoncoticpressureToregulatehemostasisSteroidandthyroidhormone-bindingproteintoregulatemetabolismangiotensinogen——toregulatebloodpressureInsulinlikegrowthfactor-1——toregulategrowth第17页/共62页18OtherrolesoftheliverinproteinmetabolismProcessesofoxidativedeaminationandtransaminationTheureacycleallowsnitrogentobeexcretedintheformofurea第18页/共62页SevereliverdiseaseDisturbanceofproteinmetabolismDecreasedconversionofammoniatoureaPlasmaproteinsdecreaseElevatedammonialevelalbuminClottingfactorsHepaticencephalopathyEdemaandascitesBleedingtendancy第19页/共62页202.Waterandelectrolytesimbalance1)HepaticAscitesAsctiesisthepresenceoftheexcessfluidintheperitonealcavityItisalate-stagedmanifestationoftheliverdisease.第20页/共62页21MechanismsofHepaticAscites1)AnincreaseincapillarypressureCauses:portalhypertension;obstructionofvenousandlymphflow2)DecreaseincolloidalosmoticpressureCause:impairedsynthesisofalbumin3)SaltandwaterretentionbythekidneyCause:

effectivebloodvolumeisreducedbecauseoffluidshiftandvasodilation

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

portal-to-systemicshunting

vasodilatoryproductsaredilveredtothesystemiccirculation

第21页/共62页222.Waterandelectrolytesimbalance2)ElectrolyticMetabolicDisorders1)Hypokalemia2)Hyponatremia第22页/共62页233.DisordersinproductionofbilesaltsandEliminationofbilirubinSevereliverdiseaseAfailuretosecretebileAFailuretosolubilizesubstancesMalabsorptionanddeficiencystatesDecreasedeliminationofbilirubinElevationofserumbilirubinandjaundiceJaundice:Yellowingoftheskinandthewhitesoftheeyes,causedbyanaccumulationofbilirubinintheblood.第23页/共62页244.ImpairedkupffercellsfunctionKupffercellsfunction1)Removingandphagocytizingoldanddefectivebloodcells,bacteria,etc.2)Producingavarietyofbioactivesubstancesandcytokines,suchasIL-1,IL-6etc.第24页/共62页25dysfunctionofKupffercellsLossofclearancefunctiontobacteriaPortal-systemicshuntingEnterictoxinsenterthesystemiccirculationEntericendotoxemia第25页/共62页26BriefSymptomsofhepaticfailureWaterandelectrolytesimbalanceHypoorhyper-glycemiaHyperlipidemiaandxanthomasPlasmaproteinsdecreaseedema,bleedingMetabolicdisordersHepaticAscitesHypokalemiaandHyponatremiaDisordersinproductionofbilesaltsandEliminationofbilirubinMalabsorptionanddeficiencystatesElevationofserumbilirubinandjaundiceImpairedkupffercellsfunctionEntericendotoxemia第26页/共62页27Hepaticencephalopathy(HE)isaprimaryclinicalmanifestationofhepaticfailure.PARTIVHepaticencephalopathyIntroductionandConceptionEtiologyandclassificationPathogenesisPrecipitatingfactorsofHEPrinciplesoftreatment第27页/共62页281.IntroductionandConceptionConceptionofhepaticencephalopathyHEisacomplex,potentiallyreversibledisturbanceincentralnervoussystemthatoccursasaconsequenceofsevereliverdiseases.FourstagesofhepaticencephalopathySlightlyalteredmoodorbehaviourSomnipathyandinappropriatebehaviorsDrowsyandpsychopathyDeepcoma第28页/共62页292.EtiologyandclassificationEtiologyChronicliverdiseasesFulminanthepaticfailure(FHF)ViralinfectionDrugreactionPoisoningwithcarbontetrachlorideorphosphorusCirrhosisofanyorigin第29页/共62页30ClassificationEndogenousHEHavenoapparentprecipitatingfactorsOftencausedbyextensivelivercelldestructionExogenousHEPrecipitatedbysomeknownagentsorabnormalities

suchas:gastrointestinalbleedingingestionmanyproteinsOftencausedbyportal-systemicshuntsAccordingtoorigin第30页/共62页31AccordingtoclinicalcharacteristicAcuteorsubacuteencephalopathyAcuteorsubacuterecurrentencephalopathyChronicrecurrentencephalopathyChronicpermanentencephalopathy第31页/共62页323.Pathogenesis◎AmmoniaIntoxication◎FalseNeurotransmitters◎

AminoAcidimbalance◎

TheGamma-AminobutyricAcidhypothesisSeveralhypotheses第32页/共62页33◎AmmoniaIntoxicationBasis1.HealthydogCreatingaportal-systemicshuntingFedbymeatcomatose2.80%patientswithHEBloodammonialevels3.CirrhosispatientsingestionofalargeamountsofproteinHepaticcoma4.HEpatientswithcirrhosisTherapiestoreduceammoniaabsorptionAmeliorationsofHE第33页/共62页34CauseforelevatedammoniaInnormalconditionsUreaAmmoniaKidneyAmmoniaProteins,aminesUrea,purinesAmmoniaismainlyproducedingastrointestinaltractAmmoniaisdetoxifiedinliverbyconversiontoureathroughKrebs-Henseleitureacycle.第34页/共62页35InHepaticfailureKrebs-HenseleitureacyclefunctionisimpairedBloodammonialevelincreased(endogenous)OrnithineCitrullineargininearginase

NH3NH3Urea

Inhepaticfailure：

substrates

enzymeATPPortal-systemicshuntingalsoreducestheureaproduction(exogenous)第35页/共62页36AmmoniaproductionincreasedBloodammonialevelincreased1)Productionofammoniainintestinelumenincreased2)ProductionofammoniainkidneyincreasedProtein,urea,purinedegradedEnzymeofbacteriaammoniaglutamineglutaminaseammonia3)Productionofammoniainskeletalmuscleincreased第36页/共62页EndogenousHEKidneyBloodNH3NH3Urea×NH3NH3proteinureaAmmoniaproductionUreaCyclefunctionimpairedLivercellmassdamagedHyperammonemiaIntoxicationofammoniaonbrain第37页/共62页38ExogenousHEAmmoniaproductionPortal-systemicshuntingHepaticcirrhosisHyperammonemiaIntoxicationofammoniaonbrain第38页/共62页39IntoxicationofammoniaonbrainAmmoniaproductionPortal-systemicshunting(exogenous)UreaCyclefunctionimpaired(endogenous)Hyper-ammonemiaHE?Intoxicationofammoniaonbrain1)Impairmentofenergymetabolisminbrain2)Alternationoftheneurotransmitters3)InhibitingactiononnervecellsmembraneMitochondrialpermeabilitytransitioninducedbyOxidativestress第39页/共62页401)ImpairmentofenergymetabolisminbrainGlucoseisthemostimportantfuelforcerebralenergy.HyperammonemiaDepressionincerebralglucosemetabolismATPoutputreductiontricarboxylicacidcycle第40页/共62页412)AlternationoftheneurotransmittersHyperammonemiaDominantneurochemicallesions第41页/共62页423)InhibitingactiononnervecellsmembraneHyperammonemiaInhibitingbrainNa+-K+ATPaseIncreaseofintracellularsodiumImpairmentofNeurotransmission第42页/共62页43Mitochondrialpermeabilitytransition(MPT)inducedbyOxidativestressHyperammonemiaDysfunctionofastrocytes1)Inculturedastrocytes,ammoniainducesMPT,frequentlycausedbyoxidativestressIncreasedfreeradicalproductioninculturedastrocytesexposedtoammonia3)AntioxidantscaninhibittheMPTinammonia-treatedculturedastrocytes第43页/共62页TherearesomeargumentagainstAmmoniaintoxicationhypothesis•10%ofHEpatientshavenormalserumammonialevels•somepatientswithhyperammonemiahavenoHEsignsSotherearesynergisticactionofmultipletoxinsontheCNS.第44页/共62页45◎FalseNeurotransmittersBasisHEpatientswithfulminanthepatitisL-dopatreatmentRecoverquicklyL-dopaisaprecursorofnormalneurotransmittersnormalneurotransmitters,suchasdopamineandnorepinephrine,areendogenoussingnalingmoleculessecretedbyneuronsthatcanalterthebehaviorofneuronsoreffectorcells.第45页/共62页46ConceptionFalseNeurotransmitters(FNT)isakindofchemicalsubstance,whichhavesimilarstructuresoftrueneurotransmitters(NNT),butmuchweakeractivitythantrueneurotransmitters.第46页/共62页HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2NorepinephinedopamineCHOHCH2NH2phenolethanolamineoctopamineNormalNeurotransmittersFalseNeurotransmitters第47页/共62页48◎

AminoAcidimbalanceSynthesisofneurotransmitterisdependentontherateofprecursoraminoacidsBranchchainaminoacids(BCAA)Aromaticaminoacids(AAA)Valine,leucineandisoleucinePrecursorsofNNTTyrosine,phenylalanineandtryptophanPrecursorsofFNTNormally,plasmaBCAAtoAAArateis3-3.5InHEpatients,plasmaBCAAtoAAArateis0.6-1.2第48页/共62页49DecreasedplasmaBCAAlevelsMechanisms1)AmmoniaInHEpatients,BCAAmightbeutilizedfordetoxificationofammonia.2)hyperinsulinismmetabolismofinsulinhyperinsulinismPortal-systemicshuntingUptakeofBCAAintomuscle3)InflammationcytokineTumornecrosisfactor-αDecreasedplasmaBCAAlevels第49页/共62页50IncreasedplasmaAAAlevelsMechanisms1)Dysfunctionofhepaticdeamination2)ReleaseofAAAfromthenecrotichepatocytes第50页/共62页phenethylaminephenolethanolaminetyrosameinoctopamineAAA↑BCAA↓Blood-brainbarrier5-hydroxytryptophanserotoninDopa×phenylalaninetyrosinetryptophanvector多巴胺NE××dopamineNE↓InhibitoryFNTFNTNNTDysfunctionofsynthesisofneurotransmittersinbrain第51页/共62页52DecreasedplasmaBCAAlevelsIncreasedplasmaAAAlevelsInHEpatients,plasmaBCAAtoAAAratedecreasedNeuronalcontentsofNNT

FNTReducedneuralexitationIncreasedneuralinhibitonBRIEFFNTandaminoacidimbalance第52页/共62页53◎

TheGamma-AminobutyricAcidhypothesisBasisTheGamma-AminobutyricAcid(GABA)isainhibitoryneurotransmitterinCNS,asacauseofHE.2)IncreasedGABA-ergictoneisobservedinpatientswithcirrhosis3)Flumazenil,abenzodiazepineantagonist,cantransientlyreverseHEinpatientswithcirrhosis第53页/共62页54IncreasedplasmaGABAlevelsHepaticfailureDecreasedhepaticmetabolismofGABAGutabsorption(intestinalbacteriaandtheintestinalwall)BloodGABAlevelsThepermeabilityoftheblood-brainbarriertoGABASomeGABAreachesGABAreceptorsandaugmentGABA-ergicneurotransmission第54页/共62页55Mechanism1.Increaseddensityand/oraffinityofreceptorsforGABAonthesupramolecularcomplex.GABA/BZreceptor/chlorideionophorecomplexAGABAreceptoraBZreceptorachlorideionophore(thatcontainsreceptorforbarbiturates)Notes:AdministrationofbenzodiazepinesandbarbituratestopatientswithcirrhosisincreasesGABA-ergictoneandpredisposesde