1. 1 Chapter 17 ． Hepatic Failure

2. 2 Section 1. Concept of hepatic failure

3. 3 1. Definition of hepatic failure Various harmful factors ↓ parenchymal cells and Kupffer cells damadged severely and extensively ↓ severe disturbance of liver function in metabolism, secretion, synthesis, detoxication and immunity ↓ jaundice, bleeding, infection, renal dysfunction and encephalopathy ↓ “Hepatic insufficiency” ↓ (late stage) “Hepatic failure” hepatorenal syndrome and hepatic encephalopathy

4. 4 Severe, extensive degeneration and necrosis of hepatic cells → Acute (fulminant) hepatic failure Late stage of cirrhosis or carcinoma of the liver → Chronic hepatic failure 2. Classification and causes

5. 5 (1) metabolism: (2) bile secrete and excrete: (3) coagulation: (4) bioconversion (5) immune Disturbance of metabolism: carbohydrate, protein, electrolyte Obstacle of bile secrete and excrete: hyperbilirubinemia, intrahepatic cholestasis Disorder of coagulation: generation↓ or consumption↑ → clotting factor↓→ bleeding tendency Dysfunction of bioconversion drug metabolism; detoxication of toxin; inactivation of hormone Dysfunction of immune (Kuppfer cells) bacterial infection, bacteremia, intestinal endotoxemia 3. Function of normal liver 3. Effects of hepatic failure on the body

6. 6 Section 2. Hepatic Encephalopathy

7. 7 A serial of Neuropsychical symptoms hepatic encephalopathy A. Concept and classification Acute or chronic liver disease Hepatic coma ultimate clinical manifestation of HE

8. 8 Classification : According to the Clinic course Clinical neuropsychical symptoms Etiology Acute, subacute and chronic types 1 st stage (prodromal period) 2 nd stage (pre-coma period) 3 rd stage (lethargy period) 4 th stage (coma period) Virus infection or drug intoxication → extensive hepatocyte necrosis → acute (fulminant) hepatitis → endogenous HE Portal or Schistosome hepatic cirrhosis → exogenous HE ( usually with obvious inducing factors)

9. 9 B. Pathogenesis of HE HE is a neuropsychical disturbance. The following features may imply HE is mainly caused by the metabolic and functional disturbance of the brain: l ) Reversibility of symptoms 2) Dissemination of disease region 3) No clear evidence of morphologic alteration 4) Accompanied with biochemical abnormality

10. 10 Theory of ammonia intoxication False neurotransmitter hypothesis Theory of amino acid imbalance Theory of GABA(gamma-aminobutyric acid) Several hypotheses of the pathogenesis of HE have been proposed: None of them is necessarily exclusive. A conservative and conventional view of HE is Almost certainly the etiology is multifactorial

11. 11 1. Theory of ammonia intoxication Ammonia is wildly believed to play a role in the pathogenesis of HE. However, a precise role for ammonia in the pathogens of HE has yet to be clearly defined.

12. 12 Evidences supporting ammonia intoxication ① The ammonia level in blood or CSF of patient with HE was increased by 1~3 fold. ② HE may be induced by eating nitrogen-containing food in patients with liver cirrhosis, and restricting intake may alleviate HE. ③ Ammonia-lowering treatment was effective in part of patients with HE. ④ Animal model of HE may created with ammonium chloride.

13. 13 citrulline The metabolism of ammonia 1 2 3 urea 25% ATP Enzymes

14. 14 (1) Causes of increased plasma level of ammonia l ) Decreased urea synthesis and inadequate removal of ammonia 2) Excessive generation of ammonia

15. 15 l ) Decreased urea synthesis inadequate removal of NH 3 Severe damaged of liver ↓ dysfunction of enzyme system, inadequate substrate and lack of ATP ↓ disturbance of ornithine circle ↓ diminished removal of ammonia by urea synthesis.

16. 16 2) Excessive generation of ammonia ① Liver cirrhosis and portal vein hypertension → decreased bile secretion, blood stagnancy and edema of enteric wall → dysfunction of digestion and absorption bacteria propagation → increased generation of ammonia; ② Accompanied bleeding of alimentary tract;

17. 17 ③ Accompanied renal dysfunction → urea excretion↓, urea diffusion into intestine↑ ④ jactitation, tremor → muscle motion↑ → ammonia generation by catabolism of adenosine. Besides, decreased H + in renal tubule caused by respiratory alkalosis or carbonic anhydrase inhibiter may increase NH 3 diffuse from kidney into blood. Elevation of pH in bowel lumen may increase absorption of NH 3 into blood.

18. 18 (2) Toxic role of ammonia on brain l ) Interfering cerebral energy metabolism. 2) Changing neurotransmitter in the brain 3) Direct inhibitory effect on neural cell membrane

19. 19 Krebs citric acid cycle glutamine   - aminobutyric acid  acetyl COA  NH 3  Glutamic acid  GlycoseGlucose-6-phosphate Pyruvic acid Lactic acid Oxaloacetic acid Citric acid Succinic acid  -Ketoglu- taric acid ATP Choline Acetylcholine  ① Excessive consumption of  - ketoglutaric acid → hindering tricarboxylic acid cycle ③ Inhibiting activity of pyruvic acid decarboxylase → generation of acetyl coenzyme A↓ →impairing TA cycle Krebs citric acid cycle ④ Excessive consumption of ATP by synthesis of glutamine ② Excessive consumption reduced coenzyme I → hindering delivery of H + in respiratory chain →ATP generation↓ l ) Interfering cerebral energy metabolism ATP   ATP

20. 20 2) Changing neurotransmitter in the brain ① Excitative neurotransmitter↓ Glutamic acid consumed by combination with NH3 Inhibition of pyruvic acid decarboxylase by NH3 glutamine   - aminobutyric acid  acetyl COA  NH 3  Glutamic  acid  GlycoseGlucose-6-phosphate Pyruvic acid Lactic acid Oxaloacetic acid Citric acid Succinic acid  -Ketoglu- taric acid ATP Choline Acetylcholine 

21. 21 ② Inhibitive neurotransmitter ↑ ① Excitative neurotransmitter↓ 2) Changing neurotransmitter in the brain glutamine   - aminobutyric acid  acetyl COA  NH 3  Glutamic  acid  GlycoseGlucose-6-phosphate Pyruvic acid Lactic acid Oxaloacetic acid Citric acid Succinic acid  -Ketoglu- taric acid ATP Choline Acetylcholine 

22. 22. 3) Direct inhibitory effect on neural cell membrane Interfere membrane potential and excitation of neuron by inhibiting Na + -K + -ATPase and competitively inhibit K + enter cells.

23. 23 2. False neurotransmitter hypothesis (1) Reticular activating system (RAS) and conscious state Consciousness neurotransmitter noradrenalin dopamine Nonspecific ascending project system Various impulses

24. 24 (2) True and false neurotransmitter phenylethanolamine Octopamine —CHOHCH 2 NH 2 HO — —CHOHCH 2 NH 2 True neurotransmitter False neurotransmitter noradrenalin HO — —CHOHCH 2 NH 2 HO — —CHCH 2 NH 2 dopamine

25. 25 LIVER. Phenylalanine  Phenylethylamine (bacterial decorboxylase ) Tyrosine - - -  Tyramine INTESTINE. BRAIN phenylethanolamine (  -hydroxylase) Octopamine (MAO) Catabolism CNS dysfunction → COMA obstacle in transfer of neural impulse→ → Accumulation of false neurotransmitter in reticular formation (3) Mechanisms of false neurotransmitter formation

26. 26 3. Theory of amino acid imbalance Aromatic amino acid (AAA): Phenylalanine, Tyrosine and tryptophan Branched chain amino acid (BCAA): Valine, leucine, isoleucine Normal: BCAA/AAA 3~3.5 In hepatic coma: BCAA↓, AAA↑, BCAA/AAA 0.6~1.2

27. 27 AAA (1) Cause of amino acids imbalance AAA  BCAA  MUSCLE ADIPOSE CELL LIVER DISEASED inactivate Insulin BCAA NORMAL catabolism

28. 28 Dysfunction of the liver Ratio of insulin / (HGF)   AAA generation from the catabolism of proteins of muscle and liver  Catabolism of AAA  AAA  AAA to be converted into glucose  Inactivation of insulin   hyperinsulinemia  BCAA uptake and degradation in skeletal muscle and fat  BCAA  (HGF = hyperglycemic-glycogenolytic factor, glucagon )

29. 29 Phenylalanine Tyrosine (P-hydoxylase) (A-decarboxylase) (A-decarboxylase) (T-hydoxylase) Dopa (  -hydroxylase) (Tr-hydroxylase) (D-decarboxylase)  -hydroxylase) Dopamine (D-  -hydoxylase) Phenylethanolamin 5-HT NE Octopamine ( →↓normal conversion pathway; →↓abnormal conversion pathway; inhibition) (2) Effects of amino acids imbalance Tryptophan Tyramine Phenylethylamine

30. 30 BCAA , AAA  excessive AAA enter brain false neurotransmitter  true neurotransmitter  (octopamine and (noradrenalin phenylethanolamin) and dopamine) Disturbed brain function

31. 31 4. Theory of GABA(gamma-aminobutyric acid) GABA → permeability of cellular membrane to Cl － → neuron ultra-polarization or depolarization （ inhibitive neurotransmitter ） Hepatic encephlopathy has been reported to be associated with increased plasma levels of GABA. A major source of GABA is considered to be the gut (intestinal bacteria and the intestinal wall). In hepatic failure, GABA is not catabolized effectively by the liver and the permeability of the blood-brain barrier to GABA is increased, it may enter into brain and exert inhibitive effect on axons of the neuron through the GABA receptors.

32. 32 Excitation ↓ GABA synthesis GABA release from vesicle by enteric bacteria of presynaptic neurons Removal of GABA by liver ↓ Combined to GABA-R on postsynaptic neurons ↓ Inflow of extracellular Cl － into postsynaptic neurons ↓ Hyperpolarization of postsynaptic neurons Hepatic failure ↓ CNS inhibition BBB permeability↑ The mechanism of GABA in HE Normal Liver Removal of GABA↓ GABA synthesis by enteric bacteria BBB normal

33. 33 5. Other neurotoxins Mercaptan (derived fron methionine)  inhibit urea synthesis, mitochondria respiration and Na + -K + -ATPase activity Short-chain fatty acid (obstacle of fat metabolism)  inhibit Na + -K + -ATPase activity, interfere membrane ion and neural impulse transference Phenol (derived fron tyrosine)  toxic action to brain

34. 34 Inhibition GABA trnsaminase   Accumulation of GABA in brain Hepatic Encephlopathy Comprehensive hypothesis dysfunction of the liver Hyperammonemia Toxic effects on brain true neurotransmitter  AAA enter brain  5HT  false neurotransmitter  Glutamine AAA  BCAA  Insulin  HGF 

35. 35 C. Inducing factors of HE 1. Increased nitrogen load Exogenous: bleeding of alimental tract, excessive intake of protein, blood transfusion. Endogenous: azotemia caused by hepatorenal syndrome, hypokalemic alkalosis, constipation and infection 2. Increased permeability of the blood-brain barrier Infection → TNF- , IL-6↑ 3. Increased sensitivity of brain Neurotoxin, drugs, infection, hypoxia, electrolyte disturbance

36. 36 D. Pathophysiological basis of prevention and treatment l. Preventing inducing factors 2. Decreasing blood ammonia 3. Artificial liver, liver transplantation 4. Other measures: supplement of BCAA-rich amino acid mixture to correct amino acid unbalance; administration of L-dopa to regain consciousness, etc.

37. 37 Section 4. Hepatic Renal Failure

38. 38 1. Conception S evere liver disease (acute or chronic ) absence of any other identifiable cause of renal failure （ hypovolaemia, drug nephrotoxicity, sepsis or glomerulonephritis ） Renal failure Hepatic renal failure or hepatorenal syndrome (HRS).

39. 39 2. pathogenesis Liver cirrhosis Decreased effective renal blood flow Excitation of sympathetic nerve system Activation of Renin-angiotensin system Deficiency of kallikrein-kinin system Increase of ET and TXA 2 Renal vasoconstriction

40. 40 1. A serial of neuropsychical symptoms caused by acute or chronic liver disease are called hepatic encephalopathy 2. HE is mainly caused by the metabolic and functional disturbance of the brain, the etiology is multifactorial, including,, and. Summary ammonia intoxicationfalse neurotransmitter amino acid imbalanceincreased GABA formation

41. 41 disturbance of the brain, the etiology is multifactorial, including ammonia intoxication, false neurotransmitter, amino acid imbalance and increased GABA formation 3. Inducing factors of HE include increased nitrogen load increased permeability of the blood-brain barrier and increased sensitivity of brain 4. Hepatic renal failure or hepatorenal syndrome is defined as the renal failure occurred in patients with severe liver disease who absence of any other identifiable cause of renal failure Summary