嚴重肝病引起的以代謝紊亂為基礎的神經福建肝病醫(yī)院

1、Hepatic Encephalopathy福州白湖亭醫(yī)院肝病科,Definition (1),Hepatic encephalopathy (HE) It represents a reversible decrease in neurological function, based upon the disorder of metabolism which is caused by severe decompens

2、ated liver disease .嚴重肝病引起的以代謝紊亂為基礎的神經、精神綜合征。主要臨床表現(xiàn)為意識障礙、行為失常和昏迷,Definition (2),Subclinical or latent HE diagnosed only by precise mental tests or EEG, no obvious clinical and biochemical abnormalities,Incidence/p

3、revalence,Universal feature of acute liver failure 50%~70% in chronic hepatic failure Difficult to estimate,Etiology,Fulminant hepatic failure acute severe viral hepatitis, drug/toxin, acute fatty li

4、ver of pregnancy Due to acute hepatocellular necrosis Chronic liver disease cirrhosis of all types , surgically induced portal-systemic shunts, primary liver cancer Due to one or more potentially reversib

5、le precipitating factors,Common precipitating factor,Deterioration in hepatic functionDrugs Sedatives potentially hepatotoxic agentsGastrointestinal bleeding Excessive dietary proteinUremia/azotemi

6、a,InfectionConstipationAnesthesia and surgeryHypoxiaDiuretics hypokalemia, Alkalosis hypovolemia,NitrogenousEncephalopathy,Non-NitrogenousEncephalopathy,,Pathogenesis (1),Toxic materials derived from nitro

7、geneous substrate in the gut and bypass the liver HE is caused by several factors act synergistically Several putative gut-derived toxins identified,Pathogenesis (2),Postulated factors/mechanisms: Ammonnia neurotoxici

8、ty Synergistic neurotoxins Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis γ-Aminobutyric acid（GABA）/BZ hypothesis,Ammonia neurotoxicity,Over production and/or hypoeccrisis Poor

9、hepato-cellular function:incomplete metabolism Portal-systemic encephalopathy: bypass Ammonia intoxication Interfere with cerebral metabolism: Depletion of glutamic acid, aspartic acid and ATP Depression

10、 cerebral blood flow and oxygen consumption,Ammonia neurotoxicity,Elevation of ammonia: detected in 60%~80% Absolute concentration of ammonia, ammonia metabolites in blood or cerebrospinal fluids, correlate

11、s only roughly with the presence or severity of HE Few cases: within normal range,Synergistic neurotoxins,Ammonia Mercaptans (硫醇) Short-chain fatty acids,Excitatory inhibitory neurotransmitter & plasma amino a

12、cids imbalance,Neurotransmission: Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain concentration of the precursor amino acids,Increased aromatic amino acids (AAAs)

13、 Tyrosine（酪氨酸）Phenylalanine（苯丙氨酸） Tryptophan（色氨酸〕 Due to the failure of hepatic deamination Decreased branched-chain amino acids (BCAAs) Valine（纈氨酸） Leucine（亮氨酸） Isoleucine（異亮氨酸） Due to increased met

14、abolism by skeletal muscle and kidneys or increased insulin,Excitatory inhibitory neurotransmitter & plasma amino acids imbalance,Imbalance of plasma amino acid: More AAAs enter into blood-brain barrier and CNS

15、Decreased synthesis of normal neurotransmittersEnhanced synthesis of false neurotransmitters Octopamine(苯乙醇胺) Tryptophan (?-羥酪胺),Excitatory inhibitory neurotransmitter & plasma amino acids imbalance,γ- Aminobuty

16、ric acid hypothesis,γ- Aminobutyric acid (GABA): Principal inhibitory neurotransmitters Generated in the gut by bacteria Bypasses the diseased or shunted liverIncreased blood-brain barrier permeability,Pathohistolog

17、y,Brain may be normal or cerebral edema Particularly in fulminant heptic failure Cerebral edema is likely the secondly changes In patients with chronic liver disease Astrocytes: increase in number and enlarg

18、ement In a very long-standing case Thin cortex, loss of neurons fibers, laminar necrosis , pyramidal tracts demyelination,Clinical manifestation,Clinically, HE manifests diverse signs and symptoms. Early forms,

19、 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

20、 slowed reaction time. Day-night reversal is often an early manifestation.,Clinical manifestation,Criteria for clinical stages Personality and mental changes Asterixis Abnormal EEG patterns,Clinical Grading of HE

21、,Clinical Grading of HE,Laboratory and other tests,Serum ammonia Elevation of serum ammonia: 60%~80% particularly in chronic HE (with portosystemic shunting) Electroencephalogram (EEG) Severe slowing with freq

22、uencies in the theta and delta Evoked potentials Variation, lack of specificity and sensitivity,Reitan trail-making test,Psychometric tests ----Number connection test,Writing chart,Psychometric tests ----Digit symb

23、ol test,Diagnosis and differential diagnosis,Diagnosis,Patients with severe liver disease and/or portal hypertension, portosystemic shunting Mental changes: confusion, somnolence, coma Factors precipitating or ag

24、gravating HE exist Severely impaired liver function and/or hyperammonemia Flapping tremor and typical EEG changes,Diagnosis,Recognition of the latent and/or subclinical HE Important for view of the

25、 prevalence of cirrhosis In the absence of characteristic features Abnormal neuropsychiatric function: Number connection test Digit symbol tests Block design Visual reaction times,Differential diagno

26、sis,Hypoglycemia（低血糖） Uremia Diabetic ketoacidosis（糖尿病酮癥酸中毒） Nonketotic hyperosmolar syndrome（非酮癥高滲綜合癥） Subdural hematoma（硬膜下血腫） Cerebrospinal infection （腦脊髓感染）,Treatment,The goals of therapy,To treat the underlying

27、 liver disease and improve mental. The most important initial aspects of care are to diagnose the condition properly, exclude other causes of encephalopathy, and search for precipitating factors,一、Identification and tre

28、atment of precipitating factors,These precipitating events may be readily apparent or subtle. Therefore, detailed discussions and a careful assessment of changes in laboratory values are necessary.Supportive care Cor

29、rection of fluid, electrolyte, glucose, acid-alkaline abnormalities Management of cerebral edema, bacteremia,二、Decreasing nitrogen load and ammonia productions and absorption of enteric toxins,Decreasing ammonia prod

30、uctionsDietary protein restrictionBowel cleaning(clysis 灌腸, catharsis 導瀉)Nonabsorbable disaccharides Antibioticseradication of HpIncreasing ammonia metabolisms,Dietary protein restriction,Restriction of dietary pro

31、tein 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

32、 positive nitrogen balance ?positive efects,Bowel cleaning,Clysis Laxative (e.g. magnesium citrate 硫酸鎂) Notes: all enemas must be neutral or acidic to reduce ammonia absorption,Nonabsorbable disaccharides,Lactulos

33、e （乳果糖） Synthetic disaccharide First-line pharmacological 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%

34、 of patients Cause 2~3 soft stool/d,Antibiotics,Neomycin（新霉素）: 2~4g/D Litter is absorbed Impaired hearing or deafness ( long term use) Long term use (>1 month) is not advisable Metronidozol（甲硝唑）: 0.2g

35、qid as effective as neomycin Rifaximin（利福昔明）,Increasing ammonia metabolisms,L-Ornithine-L-asparagic acid（L-鳥氨酸-L-天冬氨酸）Benzoate（苯甲酸鹽），Phenylacetic acid（苯乙酸）Zinc (鋅)Potassium glutamate(谷氨酸鉀)，sodium glutamate (谷氨酸鈉)

36、Arginine(精氨酸),三、Drugs that affect neurotransmission,Administration of BCAAs Oral or parenteral administration L-dopa（左旋多巴）Precursor of the neurotransmitter norepinephrine dopamine penetrate blood-brain barrier I

37、ncrease the normal neurotransmitter,四、GABA/BZ receptor antagonists,Flumazenil（氟馬西尼） and others: may have a therapwutic role in selected patients A formal recommendation on the use of these drugs cannot be made on the ba

38、sis of evidence-based data,Liver transplantation,Ultimate answer to the problem of chronic HE,Summary Key issues of the HE topic,Clinical manifestations------ Clinical stages of HE Diagnosis and different