1、严重肝病引起以代谢严重肝病引起以代谢紊乱为基础神经福建紊乱为基础神经福建肝病医院肝病医院Definition(1)Definition(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严重肝病引起的以代谢紊乱为基础的神
2、经、精神综合征。主要临床表现为意识障碍、行为失常和昏迷障碍、行为失常和昏迷2020/11/142Definition(2)Definition(2)Subclinical or latent HE diagnosed only by precise mental tests or EEG,no obvious clinical and biochemical abnormalities 2020/11/143Incidence/prevalenceIncidence/prevalence 1 Universal feature of acute liver failure 1 50%70%in
3、 chronic hepatic failure1 Difficult to estimate2020/11/144Etiology Etiology 1Fulminant hepatic failure acute severe viral hepatitis,drug/toxin,acute fatty liver of pregnancy Due to acute hepatocellular necrosis 1Chronic liver disease cirrhosis of all types,surgically induced portal-systemic shunts,p
4、rimary liver cancer Due to one or more potentially reversible precipitating factors2020/11/145Common precipitating factorCommon precipitating factorDeterioration in hepatic functionDrugs Sedatives potentially hepatotoxic agentsGastrointestinal bleeding Excessive dietary proteinUremia/azotemiaInfecti
5、onConstipationAnesthesia and surgeryHypoxiaDiuretics hypokalemia,Alkalosis hypovolemiaNitrogenousEncephalopathyNon-NitrogenousEncephalopathy2020/11/1462020/11/147Pathogenesis(1)Pathogenesis(1)4 Toxic materials derived from nitrogeneous substrate in the gut and bypass the liver4 HE is caused by sever
6、al factors act synergistically4 Several putative gut-derived toxins identified2020/11/148Pathogenesis(2)Pathogenesis(2)Postulated factors/mechanisms:1 Ammonnia neurotoxicity1 Synergistic neurotoxins1 Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis1-Aminobutyric aci
7、d（GABA）/BZ hypothesis2020/11/1492020/11/1410Ammonia neurotoxicityAmmonia neurotoxicity+Over production and/or hypoeccrisis Poor hepato-cellular function:incomplete metabolism Portal-systemic encephalopathy:bypass+Ammonia intoxication Interfere with cerebral metabolism:Depletion of glutamic acid,aspa
8、rtic acid and ATP Depression cerebral blood flow and oxygen consumption 2020/11/1411Ammonia neurotoxicityAmmonia neurotoxicityv Elevation of ammonia:detected in 60%80%v Absolute concentration of ammonia,ammonia metabolites in blood or cerebrospinal fluids,correlates only roughly with the presence or
9、 severity of HEv Few cases:within normal range 2020/11/1412Synergistic neurotoxinsSynergistic neurotoxinsv Ammonia v Mercaptans(硫醇硫醇)v Short-chain fatty acids2020/11/1413Excitatory inhibitory neurotransmitter&plasma Excitatory inhibitory neurotransmitter&plasma amino acids imbalance amino acids imba
10、lance Neurotransmission:Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain concentration of the precursor amino acids2020/11/14144 Increased aromatic amino acids(AAAs)Tyrosine（酪氨酸）酪氨酸）Phenylalanine（苯丙氨酸）苯丙氨酸）Tryptophan（色氨酸色氨酸 Due to the failure of hepati
11、c deamination4 Decreased branched-chain amino acids(BCAAs)Valine（缬氨酸）缬氨酸）Leucine（亮氨酸）亮氨酸）Isoleucine（异亮氨异亮氨酸）酸）Due to increased metabolism by skeletal muscle and kidneys or increased insulinExcitatory inhibitory neurotransmitter&plasma Excitatory inhibitory neurotransmitter&plasma amino acids imbalan
12、ce amino acids imbalance 2020/11/1415Imbalance of plasma amino acid:3 More AAAs enter into blood-brain barrier and CNS 3 Decreased synthesis of normal neurotransmitters3Enhanced synthesis of false neurotransmitters Octopamine(苯乙醇胺苯乙醇胺)Tryptophan(-羟酪胺羟酪胺)Excitatory inhibitory neurotransmitter&plasma
13、Excitatory inhibitory neurotransmitter&plasma amino acids imbalance amino acids imbalance 2020/11/1416-Aminobutyric acid hypothesis-Aminobutyric acid hypothesis-Aminobutyric acid(GABA):2 Principal inhibitory neurotransmitters 2 Generated in the gut by bacteria2 Bypasses the diseased or shunted liver
14、2Increased blood-brain barrier permeability2020/11/14172020/11/1418PathohistologyPathohistology1 Brain may be normal or cerebral edema Particularly in fulminant heptic failure Cerebral edema is likely the secondly changes1 In patients with chronic liver disease Astrocytes:increase in number and enla
15、rgement1 In a very long-standing case Thin cortex,loss of neurons fibers,laminar necrosis,pyramidal tracts demyelination2020/11/14192020/11/1420Clinical manifestationClinical manifestation&Clinically,HE manifests diverse signs and symptoms.&Early forms,quite subtle changes in personality or level of
16、 performance.&As HE advances,a disturbance of consciousness,impaired intellectual function,neuromuscular abnormalities,mood changes,inversion of the sleep cycle,and slowed reaction time.&Day-night reversal is often an early manifestation.2020/11/1421Clinical manifestationClinical manifestationCriter
17、ia for clinical stagesv Personality and mental changesv Asterixisv Abnormal EEG patterns2020/11/14222020/11/1423Clinical Grading of HEClinical Grading of HE2020/11/1424Clinical Grading of HEClinical Grading of HE2020/11/1425Laboratory and other testsLaboratory and other testsv Serum ammonia Elevatio
18、n of serum ammonia:60%80%particularly in chronic HE (with portosystemic shunting)v Electroencephalogram(EEG)Severe slowing with frequencies in the theta and deltav Evoked potentials Variation,lack of specificity and sensitivity 2020/11/1426 Reitan trail-making testPsychometric tests-Number connectio
19、n test2020/11/1427Writing chartPsychometric tests-Digit symbol test2020/11/1428Diagnosis and Diagnosis and differential diagnosisdifferential diagnosis2020/11/1429DiagnosisDiagnosis4 Patients with severe liver disease and/or portal hypertension,portosystemic shunting 4 Mental changes:confusion,somno
20、lence,coma4 Factors precipitating or aggravating HE exist4 Severely impaired liver function and/or hyperammonemia4 Flapping tremor and typical EEG changes2020/11/1430DiagnosisDiagnosis+Recognition of the latent and/or subclinical HE Important for view of the prevalence of cirrhosis+In the absence of
21、 characteristic features Abnormal neuropsychiatric function:Number connection test Digit symbol tests Block design Visual reaction times2020/11/1431Differential diagnosisDifferential 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 hyperosmolar syndrome
22、（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）2020/11/1432TreatmentTreatment2020/11/1433The goals of therapy The goals of therapy vTo treat the underlying liver disease and improve mental.vThe most important initial aspects of care are to diagnose the condi
23、tion properly,exclude other causes of encephalopathy,and search for precipitating factors 2020/11/1434一、一、Identification and treatment of precipitating Identification and treatment of precipitating factorsfactorsvThese precipitating events may be readily apparent or subtle.Therefore,detailed discuss
24、ions and a careful assessment of changes in laboratory values are necessary.vSupportive care Correction of fluid,electrolyte,glucose,acid-alkaline abnormalities Management of cerebral edema,bacteremia 2020/11/1435二、二、Decreasing nitrogen load and ammonia Decreasing nitrogen load and ammonia productio
25、ns and absorption of enteric toxinsproductions and absorption of enteric toxins4Decreasing ammonia productions3 Dietary protein restriction3 Bowel cleaning(clysis 灌肠,catharsis 导泻)3 Nonabsorbable disaccharides3 Antibiotics3 eradication of Hp4Increasing ammonia metabolisms 2020/11/1436Dietary protein
26、restrictionDietary protein restrictionRestriction of dietary protein at the time of acute HE with subsequent increments to assess clinical tolerance is a classic cornerstone of therapy Protein restriction:0.8 1.0g/kg.d Vegetable and dairy sources are preferable to animal proteinA positive nitrogen b
27、alance positive efects2020/11/1437Bowel cleaningBowel cleaning Clysis Laxative(e.g.magnesium citrate 硫酸镁硫酸镁)Notes:all enemas must be neutral or acidic to reduce ammonia absorption2020/11/1438Nonabsorbable disaccharidesNonabsorbable disaccharidesLactulose（乳果糖）（乳果糖）Synthetic disaccharide First-line ph
28、armacological treatment Release lactic and acetic acids by colonic bacteria Decreasing stool pH to about 5.5 Reduce portion of ammonia and its absorption Effective in 80%of patients Cause 23 soft stool/d 2020/11/1439AntibioticsAntibioticsNeomycin（新霉素）新霉素）:24g/D Litter is absorbed Impaired hearing or
29、 deafness(long term use)Long term use(1 month)is not advisable Metronidozol（甲硝唑）甲硝唑）:0.2g qid as effective as neomycin Rifaximin（利福昔明）利福昔明）2020/11/1440Increasing ammonia Increasing ammonia metabolismsmetabolismsL-Ornithine-L-asparagic acid（L-鸟氨酸-L-天冬氨酸）Benzoate（苯甲酸盐），Phenylacetic acid（苯乙酸）Zinc(锌)Pot
30、assium glutamate(谷氨酸钾)，sodium glutamate(谷氨酸钠)Arginine(精氨酸)2020/11/1441三、三、Drugs that affect neurotransmissionDrugs that affect neurotransmission Administration of BCAAs Oral or parenteral administration L-dopa（左旋多巴）左旋多巴）Precursor of the neurotransmitter norepinephrine dopamine penetrate blood-brain
31、barrier Increase the normal neurotransmitter2020/11/1442四、四、GABA/BZ receptor antagonistsGABA/BZ receptor antagonists Flumazenil（氟马西尼）氟马西尼）and others:may have a therapwutic role in selected patients A formal recommendation on the use of these drugs cannot be made on the basis of evidence-based data20
32、20/11/1443Liver transplantationLiver transplantationUltimate answer to the problem of chronic HE2020/11/1444Summary Summary Key issues of the HE topicKey issues of the HE topicClinical manifestations-Clinical stages of HE Diagnosis and differential diagnosis Factors precipitating and/or aggravating HE2020/11/1445
