Hepatic insufficiency

1. Hepatic insufficiency

2. Two type of cells in liver Hepatocyte Kupffer

3. Normal function of liver Metabolism (synthesis & catabolism) Secretion and Excretion Detoxication Hepatocyte Kupffer Phagocytic and Endocytic

4. 1. Metabolic dysfunction ﹡ Hypoglycemia Hypoproteinemia half time fibrinogen (4 d) thrombinogen (12d) albumin (20d) Hypokalemia, hyponatremia Energy crisis

5. 2. Disturbed secretion and excretion Hyperbilirubinemia ------Jaundice Unconjugated: fat soluble Conjugated: low affinity to albumin Intrahepatic cholestasis Bile salt → inflammation liver cirrhosis HR↓, Bp ↓ Pruritus

6. 3. Decreased detoxication and clearance poisons, drugs, hormones 4. Decreased phagocytic and endocytic Dysfunction of Kupffer cells → Intestinal endotoxemia

7. Hepatic insufficiency Jaundice Bleeding Hepatic encephalopathy Hepatorenal syndrome

8. Hepatic Encephalopathy

9. General Concept Liver disease neuropsychiatric syndrome

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

11. Etiology Endogenous HE 25% Fulminant hepatic failure Exogenous HE 75% Portal-systemic encephalopathy Plasma level of ammonia↑

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

13. Ammonia intoxication hypothesis Supporting evidence 80% of HE show increased plasmaammonia level patients with hepatocirrhosis have elevated level of ammonia, symptom of HE and alteration in electroencephalogram after high protein diet

14. 1. Ammonia intoxication hypothesis NH3 clearance （ urea cycle） NH3 production Under normal condition, the production and the clearance of NH3isin balance

15. Causes NH3 clearance dysfunction of urea cycle （substrate ATP , enzymeinactivation） NH3 production Upper alimentary tract bleeding Gastrointestinal dysfunction Renal dysfunction Muscle contraction Portal-systemic shunt Severe hepatic dysfunction

16. Effect of ammonia on CNS (1) Decreasing energy production (2) Changing neurotransmitters increasing glutamine and GABA decreasing glutamic acid and acetyl choline (3) Disturb membrane function

17. 高血氨的毒性作用 葡萄糖 6-磷酸葡萄糖 磷酸果糖激酶 NADH NAD 乙酰辅酶A 丙酮酸 乳酸 + 草酰乙酸 胆碱 乙酰胆碱 琥珀酸 柠檬酸 ATP NAD NADH α-酮戊二酸 γ-氨基丁酸 NADH +NH3 NAD +NH3 谷氨酰胺 谷氨酸 ATP

18. Summary of ammonia intoxication Severe hepatic dysfunction Urea synthesis hyperammonemia Brain dysfunction Elevated level of brain ammonia

19. 2. False neurotransmitter hypothesis

20. Positive evidence No correlation in ammonia lever and clinical symptom in 20% HE patients Treatment of coma patients with L-dopa recover the consciousness

21. Neurotransmitter Truth neurotransmitter (Phenylalanine, Tyrosine, Tryptophan) False neurotransmitter (Phenylethanolamine, Octopamine, Serotonin) Excitatory neurotransmitter (Ach, aspartic acid, etc) Inhibitory neurotransmitter (GABA, glutamine)

22. Brain stem reticular structure maintains consciousness through NT Cerebral cortex Secondary Neuron Interbrain NT Brain stem reticular structure Ascending nerve impulse

23. Excitation of secondary neuron Excitation of secondary neuron synapse FNT compete receptor True NT Normal Hepatic failure Mode shown replacement of true NTs FNT in HF

24. Phe Try Tyr Plasma BBB Brain NAA decarboxylase Phe Tyr Try decarboxylase hydroxylase FNT, Phe, Try hydroxylase Dopa FNT, NAA,5-HT tyramine phenylethyamine Hydroxylase Dopamine 5-HTA Hydroxylas FNT PEA NA HPEA 5-HT Pathway for production of FNT in the brain

25. Central dogma for AA imbalance & FNT hypothesis AAA FNT Phenylalanine Phenylethanolanine Tyrosine → Octopamine Tryptophan Serotonin Ascending reticular activating system (-) Coma

26. 3. Amino acid imbalance hypothesis

27. Supporting evidence BCAA / AAA normal: 3 - 3.5 /1 patient: 0.6 –1.2 /1 To correct the imbalance by administration of neutral AA improves the situation of the patients

28. Curses for the imbalance BCAA↓--- Insulin↑→ uptake in skeletal muscle and fat tissue ↑ AAA↑ --- Glucagon↑→ catabolism↑, production in muscle and liver ↑

29. Hormone regulation of AA imbalance and NT production Insulin BCAA Hepatic dysfunction BCAA/AAA Portal systemic circulation Insulin / glucagon AAA Dysfunction in excitation NT FNT AAA enter to brain Coma

30. Negative evidence for FNT and AA imbalance hypothesis （1）significant decrease in DA or NE, or ventricle administration of octopamine in normal animals do not induce coma （2） The decrease in BCAA/AAA ratio is not correlated with encephalopathy in patients with liver disease （3）No obvious amelioration by correcting imbalance in BCAA/AAA in some patients

31. 4. GABA hypothesis

32. Supporting evidence Blood GABA level significantly increased in experimental rabbits with hepartic encephalopathy Over-expressed GABA receptor was seen in brain of hepatic encephalopathy

33. Glutamic acid (intestinal bacteria) ↓ (decarboxylase) GABA ↓ Activation of GABA receptor ↓ Opening of Cl- channel ↓ Membrane hyperpolarization of neuron GABA hypothesis

34. Comprehensive view Blood Brain Intestine GABA ↑ → GABA↑ ATP↓ NH3 ↑ → GA↓, Ach↓ ↓ Glutamine↑ Glucagon→ AAA↑ → AAA↑→FNT Insulin → BCAA↓

35. 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

36. Treatment of hepatic coma Acute administration of lactulose Antibiotics and BCAAs in patients who do not respond to lactulose Limitation of protein in the diet Future research will likely focus on the correction of alterations in neurotransmission Abeu – Assi S. 2001

37. Hepatorenal syndrome Portal hypertension Ascites → Effective circulatory FNT blood volume↓ ↓ ↑ TxA2 → Renal vasoconstriction Endotoxin →LTs ↓ ↓ Endothelin Renal perfusion↓ GFR↓ ATN ↓ Functional renal failure