hepatic-encephalopathy-2015-5

HepaticEncephalopathyDepartmentofPathophysiologyTangLi•Introductionandconcept•Classification•Pathogenesis•PrecipitatingfactorsofHE•PrinciplesoftreatmentLiveristhelargestandmostmetabolicallycomplexorganTheliverisdividedinto2mainlobes,eachconsistingofmanylobules.Theselobulesaresurroundedbybranchesofthehepaticartery,whichsuppliestheliverwithoxygenatedblood.Theportalveinsuppliesnutrient-richblood.Deoxygenatedbloodfromtheliverdrainsintothehepaticveins.metabolism,secretion,synthesis,detoxicationandimmunityVariousharmfulfactors↓ParenchymalcellsandKupffercellsdamadgedseverelyandextensively↓Severedisturbanceofliverfunctionin↓“Hepaticinsufficiency”↓(latestage)“Hepaticfailure”hepaticencephalopathyConceptHepaticeencephalopathy(HE)isaserialofneuropsychicalsymptomsthatoccursasaconsequenceofsevereliverdiseases.HepaticcomaUltimateclinicalmanifestationofHEEndogenousHEOftencausedbyextensivelivercelldestructionsuchas:virusinfectionordrugintoxicationHavenoapparentprecipitatingfactorsExogenousHEOftencausedbyportal-systemicshuntssuchas:PortalorschistosomehepaticcirrhosisPrecipitatedbysomeknownagentsorabnormalitiessuchas:gastrointestinalbleeding;ingestionmanyproteinsClassificationStagesStage1：Slightlyalteredmoodorbehavior；Stage2：Somnipathy,inappropriatebehavior,lightflappingtremor；Stage3：Drowsyandpsychopathy；Stage4：Deepcoma,noresponsetopainfulstimuli,noflappingtremor.PathogenesisofHEHEisaneuropsychicaldisturbance.l)Reversibilityofsymptoms2)Disseminationofdiseaseregion3)Noclearevidenceofmorphologicalteration4)AccompaniedwithbiochemicalabnormalityHEismainlycausedbythemetabolicandfunctionaldisturbanceofthebrain.SeveralhypothesesofthepathogenesisofHEhavebeenproposed:•Theoryofammoniaintoxication•Falseneurotransmitterhypothesis•Theoryofaminoacidimbalance•TheoryofGABA(gamma-aminobutyricacid)Noneofthemisnecessarilyexclusive.AconservativeandconventionalviewofHEisalmostcertainlytheetiologyismultifactorial.1.TheoryofammoniaintoxicationEvidencessupportingammoniaintoxication1.Healthydog→Creatingaportal-systemicshunting→Fedbymeat→coma2.80%patientswithHE→Bloodammonialevels↑3.Cirrhosispatients→Ingestionofalargeamountsofprotein→Hepaticcoma4.HEpatientswithcirrhosis→Therapiestoreduceammoniaabsorption→AmeliorationsofHEThemetabolismofammoniaUrea（尿素）Aminoacids（氨基酸）Purines(嘌呤)Amines(胺)NH3NH3NH3ornithinecircleureaKidneyLiverIntestines75%25%argininecitrullineornithineureaNH3ATPEnzymesOrnithinecircle(1)Causesofincreasedplasmalevelofammonial)DecreasedureasynthesisandinadequateremovalofNH3Severedamagedliver↓dysfunctionofenzymesystem,inadequatesubstrateandlackofATP↓disturbanceofornithinecircle↓diminishedremovalofammoniabyureasynthesis.argininecitrullineornithineureaNH3ATPEnzymesOrnithinecircleNH3NH4+excrementH+OH-NH3NH3ornithinecircleureaKidneyLiverintestinesaa①bacteria2)Excessivegenerationofammonia①bacteriapropagationNH3NH4+excrementH+OH-NH3NH3ornithinecircleureaKidneyLiverintestines②Accompaniedbleedingofalimentarytract②AANH3NH4+excrementH+OH-NH3NH3ornithinecircleureaKidneyLiverintestines③Accompaniedrenaldysfunction→ureaexcretion↓,ureadiffusionintointestine↑③ureaNH3NH3ornithinecircleureaKidneyLiverintestines④Jactitation,tremor→musclemotion↑→ammoniagenerationbycatabolismofadenosine↑④adenosinepH↓RenaltubularepithelialcellTubularlumenBloodOH-NH3AlkalosisBloodRenaltubularepithelialcellTubularlumenNH3H+NH4+DecreasedH+inrenaltubulecausedbyrespiratoryalkalosisorcarbonicanhydraseinhibitermayincreaseNH3diffusefromkidneyintoblood.IntestinaltractBloodpHNH3NH3H+＋NH4+ElevationofpHinintestinaltractmayincreaseabsorptionofNH3intoblood.(2)Toxicroleofammoniaonbrainl)Interferingcerebralenergymetabolism2)Changingneurotransmitterinthebrain3)Directinhibitoryeffectonneuralcellmembranel)InterferingcerebralenergymetabolismTricarboxylicacidcycleATP①Inhibitactivityofpyruvicaciddecarboxylase→generationofacetylcoenzymeA↓→impairTAcyclel)InterferingcerebralenergymetabolismTricarboxylicacidcycleATP②Excessiveconsumptionofa-ketoglutaricacidandcoenzymeI→ATPgeneration↓l)InterferingcerebralenergymetabolismTricarboxylicacidcycleATP③ExcessiveconsumptionofATPbysynthesisofglutamineTricarboxylicacidcycleATP2)Changingneurotransmitterinthebrain①Excitativeneurotransmitter↓Acetylcholine,Glutamate②Inhibitiveneurotransmitter↑γ-aminobutyricacid,Glutamine.3)Directinhibitoryeffectonneuralcellmembrane①InhibitNa+-K+-ATPase②CompetitivelyinhibitK+entercells.Na+-K+-ATPaseNa+K+NH3•Nocorrelationinammonialevelandclinicalsymptomin20%HEpatients•TreatmentofcomapatientswithL-doparecovertheconsciousnessPositiveevidence:2.FalseneurotransmitterhypothesisNormalneurotransmitters,suchasdopamineandnorepinephrine,areendogenoussingnalingmoleculessecretedbyneuronsthatcanalterthebehaviorofneuronsoreffectorcells.FalseNeurotransmittersisakindofchemicalsubstance,whichhavesimilarstructuresoftrueneurotransmitters,butmuchweakeractivitythantrueneurotransmitters,suchasoctopamineandphenylethanolamine.HOHOCHOHCH2NH2HOCHOHCH2NH2HOHOCH2CH2NH2NorepinephinedopamineCHOHCH2NH2PhenolethanolamineOctopamineTrueNeurotransmittersFalseNeurotransmi