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1、Hepatic EncephalopathyDefinition(1)Hepatic encephalopathy(HE)It represents a reversible decrease in neurological function,based upon the disorder of metabolism which is caused by severe decompensated liver disease.严重肝病引起的以代谢紊乱为基础的神经、精神综合征。主要临床表现为意识障碍、严重肝病引起的以代谢紊乱为基础的神经、精神综合征。主要临床表现为意识障碍、行为失常和昏迷行为失常和
2、昏迷Definition(2)Subclinical or latent HE diagnosed only by precise mental tests or EEG,no obvious clinical and biochemical abnormalities Incidence/prevalence 1 Universal feature of acute liver failure 1 50%70%in chronic hepatic failure1 Difficult to estimateEtiology 1.Fulminant hepatic failure 2.acut
3、e severe viral hepatitis,drug/toxin,3.acute fatty liver of pregnancy4.Due to acute hepatocellular necrosis 5.Chronic liver disease6.cirrhosis of all types,surgically induced portal-systemic shunts,primary liver cancer 7.Due to one or more potentially reversible precipitating factorsCommon precipitat
4、ing factorDeterioration in hepatic functionDrugs Sedatives potentially hepatotoxic agentsGastrointestinal bleeding Excessive dietary proteinUremia/azotemiaInfectionConstipationAnesthesia and surgeryHypoxiaDiuretics hypokalemia,Alkalosis hypovolemiaNitrogenousEncephalopathyNon-NitrogenousEncephalopat
5、hyPathogenesis(1)4 Toxic materials derived from nitrogeneous substrate in the gut and bypass the liver4 HE is caused by several factors act synergistically4 Several putative gut-derived toxins identifiedPathogenesis(2)Postulated factors/mechanisms:1 Ammonnia neurotoxicity1 Synergistic neurotoxins1 E
6、xcitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis1-Aminobutyric acid（GABA）/BZ hypothesisAmmonia neurotoxicity1.Over production and/or hypoeccrisis2.Poor hepato-cellular function:incomplete metabolism3.Portal-systemic encephalopathy:bypass 4.Ammonia intoxication5.Inter
7、fere with cerebral metabolism:6.Depletion of glutamic acid,aspartic acid and ATP7.Depression cerebral blood flow and oxygen8.consumption Ammonia neurotoxicityv Elevation of ammonia:detected in 60%80%v Absolute concentration of ammonia,ammonia metabolites in blood or cerebrospinal fluids,correlates o
8、nly roughly with the presence or severity of HEv Few cases:within normal range Synergistic neurotoxinsv Ammonia v Mercaptans(硫醇硫醇)v Short-chain fatty acidsExcitatory inhibitory neurotransmitter&plasma amino acids imbalance Neurotransmission:Mediated by both excitatory and inhibitory neurotransmitter
9、s Their synthesis controlled by brain concentration of the precursor amino acids1.Increased aromatic amino acids(AAAs)2.Tyrosine（酪氨酸）酪氨酸）Phenylalanine（苯丙氨酸）苯丙氨酸）Tryptophan（色氨酸色氨酸3.Due to the failure of hepatic deamination4.Decreased branched-chain amino acids(BCAAs)5.Valine（缬氨酸）缬氨酸）Leucine（亮氨酸）亮氨酸）I
10、soleucine（异异亮氨酸）亮氨酸）6.Due to increased metabolism by skeletal muscle and kidneys or increased insulinExcitatory inhibitory neurotransmitter&plasma amino acids imbalance Imbalance of plasma amino acid:3 More AAAs enter into blood-brain barrier and CNS 3 Decreased synthesis of normal neurotransmitters
11、3Enhanced synthesis of false neurotransmitters Octopamine(苯乙醇胺苯乙醇胺)Tryptophan(-羟酪胺羟酪胺)Excitatory inhibitory neurotransmitter&plasma amino acids imbalance-Aminobutyric acid hypothesis-Aminobutyric acid(GABA):2 Principal inhibitory neurotransmitters 2 Generated in the gut by bacteria2 Bypasses the dis
12、eased or shunted liver2Increased blood-brain barrier permeabilityPathohistology1.Brain may be normal or cerebral edema2.Particularly in fulminant heptic failure3.Cerebral edema is likely the secondly changes4.In patients with chronic liver disease5.Astrocytes:increase in number and enlargement6.In a
13、 very long-standing case7.Thin cortex,loss of neurons fibers,laminar8.necrosis,pyramidal tracts demyelinationClinical manifestation&Clinically,HE manifests diverse signs and symptoms.&Early forms,quite subtle changes in personality or level of performance.&As HE advances,a disturbance of consciousne
14、ss,impaired intellectual function,neuromuscular abnormalities,mood changes,inversion of the sleep cycle,and slowed reaction time.&Day-night reversal is often an early manifestation.Clinical manifestationCriteria for clinical stagesv Personality and mental changesv Asterixisv Abnormal EEG patternsCli
15、nical Grading of HEGradeSymptomsSignEEG AbnormalitiesI-ProdromeAltered sleep patternsFluctuating mood-euphoria,depressionInappropriate behaviorApathyLoss of affectWriting difficultConstructional apraxiaAsterixis may be presentMay be presentII-Mild HEMild confusionDisorientation Drowsiness（嗜睡）嗜睡）Aste
16、rixis(easily elicitated)Ataxia（共济失调）共济失调）Fetor hepaticus肝臭肝臭AbnormalSlower rhythmsClinical Grading of HEGradeSymptomsSignEEG AbnormalitiesIII-Moderate HEMarked confusionArousable from sleepResponsiveAsterixisRigidity of limbsHyperflexiaClonusGrasping and sucking reflexesBabinskiModerateIV-ComaUncons
17、ciousnessUnresponsive to stimuliFlaccid limbsDiminished reflexesNo muscle tonesignificantLaboratory and other tests1.Serum ammonia Elevation of serum ammonia:60%80%2.particularly in chronic HE 3.(with portosystemic shunting)4.Electroencephalogram(EEG)5.Severe slowing with frequencies in the theta 6.
18、and delta7.Evoked potentials8.Variation,lack of specificity and sensitivity Reitan trail-making testPsychometric tests-Number connection testWriting chartPsychometric tests-Digit symbol testDiagnosis and differential diagnosisDiagnosis1.Patients with severe liver disease and/or2.portal hypertension,
19、portosystemic shunting 3.Mental changes:confusion,somnolence,coma4.Factors precipitating or aggravating HE exist5.Severely impaired liver function and/or 6.hyperammonemia7.Flapping tremor and typical EEG changesDiagnosis1.Recognition of the latent and/or subclinical HE2.Important for view of the pre
20、valence of cirrhosis3.In the absence of characteristic features4.Abnormal neuropsychiatric function:5.Number connection test6.Digit symbol tests7.Block design8.Visual reaction timesDifferential diagnosis 4 Hypoglycemia（低血糖）低血糖）4 Uremia4 Diabetic ketoacidosis（糖尿病酮症酸中毒）糖尿病酮症酸中毒）4 Nonketotic hyperosmol
21、ar syndrome（非酮症高渗综合症）非酮症高渗综合症）4 Subdural hematoma（硬膜下血肿）硬膜下血肿）4 Cerebrospinal infection（脑脊髓感染）脑脊髓感染）TreatmentThe goals of therapy vTo treat the underlying liver disease and improve mental.vThe most important initial aspects of care are to diagnose the condition properly,exclude other causes of encep
22、halopathy,and search for precipitating factors 一、一、Identification and treatment of precipitating factors1.These precipitating events may be readily apparent or subtle.Therefore,detailed discussions and a careful assessment of changes in laboratory values are necessary.2.Supportive care3.Correction o
23、f fluid,electrolyte,glucose,acid-alkaline abnormalities4.Management of cerebral edema,bacteremia 二、二、Decreasing nitrogen load and ammonia productions and absorption of enteric toxins4Decreasing ammonia productions3Dietary protein restriction3Bowel cleaning(clysis 灌肠灌肠,catharsis 导泻导泻)3Nonabsorbable d
24、isaccharides3 Antibiotics3eradication of Hp4Increasing ammonia metabolisms Dietary protein restrictionlRestriction of dietary protein at the time of acute HE with subsequent increments to assess clinical tolerance is a classic cornerstone of therapy lProtein restriction:0.8 1.0g/kg.dl Vegetable and
25、dairy sources are preferable to animal proteinlA positive nitrogen balance positive efectsBowel cleaningl Clysisl Laxative(e.g.magnesium citrate 硫酸镁硫酸镁)Notes:all enemas must be neutral or acidic to reduce ammonia absorptionNonabsorbable disaccharidesLactulose（乳果糖）乳果糖）l Synthetic disaccharidel First-
26、line pharmacological treatmentl Release lactic and acetic acids by colonic bacterial Decreasing stool pH to about 5.5l Reduce portion of ammonia and its absorptionl Effective in 80%of patientsl Cause 23 soft stool/d AntibioticslNeomycin（新霉素）新霉素）:24g/D Litter is absorbed Impaired hearing or deafness(
27、long term use)Long term use(1 month)is not advisablel Metronidozol（甲硝唑）甲硝唑）:0.2g qid as effective as neomycinl Rifaximin（利福昔明）利福昔明）Increasing ammonia metabolismslL-Ornithine-L-asparagic acid（L-鸟氨酸鸟氨酸-L-天冬氨酸）天冬氨酸）lBenzoate（苯甲酸盐），苯甲酸盐），Phenylacetic acid（苯乙酸）苯乙酸）lZinc(锌锌)lPotassium glutamate(谷氨酸钾谷氨酸钾)，
28、sodium glutamate(谷氨酸钠谷氨酸钠)lArginine(精氨酸精氨酸)三、三、Drugs that affect neurotransmission l Administration of BCAAs Oral or parenteral administration l L-dopa（左旋多巴）左旋多巴）Precursor of the neurotransmitter norepinephrine dopamine penetrate blood-brain barrier Increase the normal neurotransmitter四、四、GABA/BZ re
29、ceptor antagonistsl Flumazenil（氟马西尼）氟马西尼）and others:may have a therapwutic role in selected patientsl A formal recommendation on the use of these drugs cannot be made on the basis of evidence-based dataLiver transplantationUltimate answer to the problem of chronic HESummary Key issues of the HE topiclClinical manifestations-Clinical stages of HEl Diagnosis and differential diagnosisl Factors precipitating and/or aggravating HE