嚴(yán)重肝病引起的以代謝紊亂為基礎(chǔ)的神經(jīng)_福建肝病醫(yī)院

1、Heptic EcephlopahyHeptic Ecephlopahy福州白湖亭醫(yī)院肝病科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 .嚴(yán)重肝病引起的以代謝紊亂為基礎(chǔ)的神經(jīng)、精神綜合征。主要臨床表現(xiàn)為意識(shí)障礙、行為失常和

2、昏迷Definition (2)Definition (2)Subclinical or latent HE diagnosed only by precise mental tests or EEG, no obvious clinical and biochemical abnormalities Incidence/prevalenceIncidence/prevalence 1 Universal feature of acute liver failure 1 50%70% in chronic hepatic failure1 Difficult to estimateEtiolo

3、gy 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, primary liver cancer Due to one or more potentially reversib

4、le precipitating factorsCommon precipitating Common precipitating factorfactorDeterioration in hepatic functionDrugs Sedatives potentially hepatotoxic agentsGastrointestinal bleeding Excessive dietary proteinUremia/azotemiaInfectionConstipationAnesthesia and surgeryHypoxiaDiuretics hypokalemia, Alka

5、losis hypovolemiaNitrogenousEncephalopathyNon-NitrogenousEncephalopathyPathogenesis (1)Pathogenesis (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 identifiedPathogenesi

6、s (2)Pathogenesis (2)Postulated factors/mechanisms:1 Ammonnia neurotoxicity1 Synergistic neurotoxins1 Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis1 -Aminobutyric acid（GABA）/BZ hypothesisAmmonia neurotoxicityAmmonia neurotoxicity+ Over production and/or hypoeccri

7、sis Poor hepato-cellular function:incomplete metabolism Portal-systemic encephalopathy: bypass + Ammonia intoxication Interfere with cerebral metabolism: Depletion of glutamic acid, aspartic acid and ATP Depression cerebral blood flow and oxygen consumption Ammonia neurotoxicityAmmonia neurotoxicity

8、v 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 severity of HEv Few cases: within normal range Synergistic neurotoxinsSynergistic neurotoxinsv Ammonia v Mercaptans (硫醇)v

9、Short-chain fatty acidsExcitatory inhibitory Excitatory inhibitory neurotransmitter & plasma amino neurotransmitter & plasma amino acids imbalance acids imbalance Neurotransmission: Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain concentration

10、 of the precursor amino acids4 Increased aromatic amino acids (AAAs) Tyrosine（酪氨酸）Phenylalanine（苯丙氨酸） Tryptophan（色氨酸 Due to the failure of hepatic deamination4 Decreased branched-chain amino acids (BCAAs) Valine（纈氨酸） Leucine（亮氨酸） Isoleucine（異亮氨酸） Due to increased metabolism by skeletal muscle and ki

11、dneys or increased insulinExcitatory inhibitory Excitatory inhibitory neurotransmitter & plasma amino neurotransmitter & plasma amino acids imbalance acids imbalance Imbalance of plasma amino acid:3 More AAAs enter into blood-brain barrier and CNS 3 Decreased synthesis of normal neurotransmi

12、tters3Enhanced synthesis of false neurotransmitters Octopamine(苯乙醇胺) Tryptophan ( -羥酪胺) Excitatory inhibitory Excitatory inhibitory neurotransmitter & plasma amino neurotransmitter & plasma amino acids imbalance acids imbalance - Aminobutyric acid - Aminobutyric acid hypothesishypothesis- Am

13、inobutyric acid (GABA):2 Principal inhibitory neurotransmitters 2 Generated in the gut by bacteria2 Bypasses the diseased or shunted liver2Increased blood-brain barrier permeabilityPathohistologyPathohistology1 Brain may be normal or cerebral edema Particularly in fulminant heptic failure Cerebral e

14、dema is likely the secondly changes1 In patients with chronic liver disease Astrocytes: increase in number and enlargement1 In a very long-standing case Thin cortex, loss of neurons fibers, laminar necrosis , pyramidal tracts demyelinationClinical manifestationClinical manifestation& Clinically,

15、 HE manifests diverse signs and symptoms.& Early forms, quite subtle changes in personality or level of performance.& As HE advances, a disturbance of consciousness, impaired intellectual function, neuromuscular abnormalities, mood changes, inversion of the sleep cycle, and slowed reaction t

16、ime. & Day-night reversal is often an early manifestation.Clinical manifestationClinical manifestationCriteria for clinical stagesv Personality and mental changesv Asterixisv Abnormal EEG patternsClinical Grading of HEClinical Grading of HEClinical Grading of HEClinical Grading of HELaboratory a

17、nd other testsLaboratory and other testsv Serum ammonia Elevation 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 Rei

18、tan trail-making testPsychometric tests -Number connection testWriting chartPsychometric tests -Digit symbol testDiagnosis and Diagnosis and differential diagnosisdifferential diagnosisDiagnosisDiagnosis4 Patients with severe liver disease and/or portal hypertension, portosystemic shunting 4 Mental

19、changes: confusion, somnolence, coma4 Factors precipitating or aggravating HE exist4 Severely impaired liver function and/or hyperammonemia4 Flapping tremor and typical EEG changesDiagnosisDiagnosis+ Recognition of the latent and/or subclinical HE Important for view of the prevalence of cirrhosis+ I

20、n the absence of characteristic features Abnormal neuropsychiatric function: Number connection test Digit symbol tests Block design Visual reaction timesDifferential diagnosisDifferential diagnosis 4 Hypoglycemia（低血糖）4 Uremia4 Diabetic ketoacidosis（糖尿病酮癥酸中毒）4 Nonketotic hyperosmolar syndrome（非酮癥高滲綜合

21、癥）4 Subdural hematoma（硬膜下血腫）4 Cerebrospinal infection （腦脊髓感染）TreatmentTreatmentThe 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 condition properly, exclude other causes of encephalopat

22、hy, and search for precipitating factors 一、Identification and treatment of Identification and treatment of precipitating factorsprecipitating factorsvThese precipitating events may be readily apparent or subtle. Therefore, detailed discussions and a careful assessment of changes in laboratory values

23、 are necessary.vSupportive care Correction of fluid, electrolyte, glucose, acid-alkaline abnormalities Management of cerebral edema, bacteremia 二、Decreasing nitrogen load and Decreasing nitrogen load and ammonia productions and ammonia productions and absorption of enteric toxinsabsorption of enteri

24、c toxins4Decreasing ammonia productions3Dietary protein restriction3Bowel cleaning(clysis 灌腸, catharsis 導(dǎo)瀉)3Nonabsorbable disaccharides3 Antibiotics3eradication of Hp4Increasing ammonia metabolisms Dietary protein restrictionDietary protein restrictionmRestriction of dietary protein at the time of a

25、cute HE with subsequent increments to assess clinical tolerance is a classic cornerstone of therapy mProtein restriction: 0.8 1.0g/kg.dm Vegetable and dairy sources are preferable to animal proteinmA positive nitrogen balance positive efectsBowel cleaningBowel cleaningm Clysism Laxative (e.g. magnes

26、ium citrate 硫酸鎂) Notes: all enemas must be neutral or acidic to reduce ammonia absorptionNonabsorbable Nonabsorbable disaccharidesdisaccharidesLactulose （乳果糖）m Synthetic disaccharidem First-line pharmacological treatmentm Release lactic and acetic acids by colonic bacteriam Decreasing stool pH to ab

27、out 5.5m Reduce portion of ammonia and its absorptionm Effective in 80% of patientsm Cause 23 soft stool/d AntibioticsAntibioticsmNeomycin（新霉素）: 24g/D Litter is absorbed Impaired hearing or deafness ( long term use) Long term use (1 month) is not advisablem Metronidozol（甲硝唑）: 0.2g qid as effective as neomycinm Rifaximin（利福昔明）Increasing ammonia Increasing ammonia metabolismsmetabolismsmL-Ornithine-L-asparagic acid（L-鳥(niǎo)氨酸