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Hepatic encephalopathy

Hepatic encephalopathy. a potentially-reversible neuropsychiatric abnormality in the setting of liver failure, whether chronic (as in cirrhosis), or acute. Section 1 Hepatic insufficiency. Etiology of Hepatic failure. 1. biological 2. physical and chemical 3. inherital(congenital)

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Hepatic encephalopathy

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  1. Hepatic encephalopathy a potentially-reversible neuropsychiatric abnormality in the setting of liver failure, whether chronic (as in cirrhosis), or acute

  2. Section 1 Hepatic insufficiency

  3. Etiology of Hepatic failure 1. biological 2. physical and chemical 3. inherital(congenital) 4. immunol 5. nutritional

  4. Hepatic function & dysfunctions 1. metabolism: 2. secreting & excreting: 3. detoxication & defense 4. coagulation 5. affecting other organ hepatic encephalophcy

  5. Clinical Manifestations of Cirrhosis

  6. Impact of Hepatic Encephalopathy on survival in 1402 cirrhotic patients

  7. Section 2 hepatic encephalopathy a potentially-reversible neuropsychiatric abnormality in the setting of liver failure

  8. Part 1 Etiology and classification of HE

  9. Major types of hepatic encephalophcy ①Acute fulminant type: hepatic necrosis ②Chronic recurrent type: cirrhosis Type A (=acute) : HE associated with ALF Type B (=bypass): portal-systemic shunting without associated intrinsic liver disease Type C (=cirrhosis): cirrhosis 1998 in Vienna,

  10. Clinical presentation Coma Drowsiness Confusion Sleeping disorder Apathy Childishness Hepatic coma = HE？

  11. Chronic hepatic encephalopathy ①prodromal ~: mood & behavior ②precoma ~: drowsy, asterixis ③stuporous ~: speaking and obeying simple commands ④coma ~: no response to painful stimuli

  12. Part 2 pathogenesis of HE

  13. Pathogenesis Multifarious toxins → Dysfunction of CNS (No obvious morphological change) Several hypotheses to uncover the mystery

  14. 1. NH3 intoxication Normal: plasma NH3 < 100μg％ 80~90％ of patient: ↑2~3 folds (200~500 μg％）

  15. Blood NH3 configuration • NH3 NH4+ • 2% 98% pH  pH

  16. (1) NH3 increased in HE

  17. Clearing Generation Urea syntheses↓ Intestinal NH3↑ liver Blood NH3↑ Via collateral↑ Renal backflow NH3↑ Muscle production↑ Syntheses with NH3↓ The reasons of NH3↑

  18. UREOGENESIS AMMONIA Aspartic acid Citrulline UREA CYCLE Ornithine Arginine Ureogenesis takes place in the liver and is essential for ammonia detoxification UREA

  19. (2) NH3 toxicity on CNS NH3↑interferes with ① cerebrocellular energy: ？ ② neurotransmitter imbalance ③ neurocellular membrane ion transferring

  20. Glucose choline NADH NAD+ ⑥ AcetylCoA acetylcholine Pyruvate Lactic acid ⑥ Oxaloacetat CoA ⑦ Citrate ⑥ Succinate NADH NAD+ ① α-ketoglutatrate GABA ⑦ NADH NH3 ② ATP ADP NAD+ ③ Glutamate Glutamine ④ ⑤ NH3 Energy metabolism & Neurotransmitter in HE

  21. Balance of exiting & inhibition

  22. Mercaptan(metheonine) NH3 Indole(tryptophan) Phenol(tyrosine, tyramine) monoamine Short chain fatty acid Synergistic effect of neurotoxin neurotoxin cerebral energy cerebral cell respiration Na+ pump neural impulse delivery synapse intoxication decayed products of enteric bacteria

  23. 2. False neurotransmitter(FNT) & plasma amino acid imbalance Serious liver disease， BCAA/AAA ratio ↓ < 1( Nor > 3 ) → ? CNS disorder BCAA: branchchainamino acid AAA：aromatic amino acid leucine, isoleucine, and valine / Tryptophan, Tyrosine , phenylalanine

  24. Liver deactivation↓ uptake & utilizing BCAA↑in tissue insulin↑ glucagon ↑ Protein decomposed↑ in muscle & liver Blood NH3↑ glyconeogenesis↓ AAA↑ (1) Causes of plasma amino acid imbalance

  25. (2) FNT formation phenylalanine Tyrosine phenylalamine tyramine MAO decarboxylation  ? in liver BBB in brain Tyrosine hydrogenase β- hydrogenase dopa β -phenylethanolamine、 octpamine ↑ （FNT） NE dopamine

  26. CHOHCH2NH2 HO CHOHCH2NH2 HO phenylethanolamine noradrenaline HO CHCH2NH2 CHOHCH2NH2 HO HO octopamine dopamine Comparison between TNT and FNT

  27. NT ARAS maintains consciousness through NT

  28. AAA ↑ BCAA tryptophan ↑ (3) plasma amino acid imbalance and FNT formation glutamine antiport FNT ? tryptamine 5-HT blood BBB

  29. 3. GABA alteration and HE 1. GABA↑: Originated from gut and brain 2. Affinity of GABA to its receptor ↑ 3. Synergistic allosteric effect of other:

  30. transferaminase decarboxygenase succinic acid semialdehyde GABA Glutamatic acid － + NH3 ↑ NH3↑ early stage late stage GABA alteration

  31. 4. Comprehensive view BloodBrain Intestine GABA ↑ → GABA↑ ATP↓ NH3 ↑ → GA↓, Ach↓ ↓ Glutamine↑ Glucagon→ AAA↑ → AAA↑→FNT Insulin → BCAA↓

  32. Part 3 Precipitating factors 1. Toxins produced in intestine↑ 2. Permeability of blood – brain barrier↑ 3. Increased sensitivity of brain to toxins by hypoxia, fluid and electrolytes abnormalities, infection, hypnotics etc

  33. Part 4 Principle of prevent & treatment (1) protect hepatic cell (2) decrease NH3 : benzoate, lactulose (3) restore plasma amino acid balance (4) increase normal neurotransmitter

  34. What are they doing?

  35. Thanks!

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