1. Pathophysiology Department of Pathophysiology Shanghai Jiao-Tong University School of Medicine

2. Chapter ⅩⅤ Hepatic Dysfunction

3. Contents Overview Hepatic Encephalopathy, HE Definition ， Clinical features and classification Pathogenesis Precipitating factors of HE Principles of treatment for HE Hepatorenal Syndrome, HRS Concept & Pathogenesis

4. Normal function of liver Normal function of liver Etiology of liver disease and liver dysfunction Etiology of liver disease and liver dysfunction Pathogenesis of liver disease Pathogenesis of liver disease Overview

5. Overview Enviromental causes Hepatic Injury Hepatitis virusAlcohol Drugs and toxins Recovery Fulminant hepatic failure Chronic persistent hepatitis Necrosis cirrhosis Herritage/Genetic causes Hepatic Failure hepatic insufficiency Hepatorenal syndrome Hepatic Encephalopathy Triggers

6. Hepatic Encephalopathy

7. 2010 年 10 月 22 日 Definition of Hepatic Encephalopathy Hepatic encephalopathy (HE) is a complex, potentially reversible disturbance in CNS that occurs as a consequence of severe liver diseases. It is characterized by neuropsychical manifestations ranging from a slightly altered mental status to coma.

8. The West Haven criteria of altered mental state in HE (In patients with cirrhosis and overt encephalopathy) Stage 0. Lack of detectable changes in personality or behavior. Asterixis absent. Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be detected. Stage 2. Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Stage 3. Gross disorientation. Bizarre behavior. Semistupor to stupor. Asterixis generally absent. Stage 4. Coma. THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 7, 2001 Staging

9. A classification of hepatic encephalopathy was introduced at the World Congress of Gastroenterology 1998 in Vienna. According to this classification, hepatic encephalopathy is subdivided in type A, B and C depending on the underlying cause. Types Type A (=acute) describes hepatic encephalopathy associated with acute failure Type B (=bypass) is caused by portal-systemic shunting without associated intrinsic liver disease Type C (=cirrhosis) occurs in patients with cirrhosis this type is subdivided in episodic, persistent and minimal ncephalopathy

10. Pathogenesis of HE HE may be due to primarily to a failure of the liver to remove adequately vertain substances in plasma that have the ability,directly or indirectly to modulate the function of the central nervous systerm. Several hypotheses have been proposed:

11. Ammonia intoxincation hypothesis False neurotransmitters hypothesis Amono acid imbalance hypothesis The Gamma-aminobutyric acid hypothesis Synergistic actions of multiple toxins Pathogenesis

12.  Causes of elevated ammonia in hepatic inssufficiency 1 ） Decreased clearance of ammonia 2 ） Increase production of ammonia in gstrointestinal tract  Intoxicaton of ammonia on the brain 1 ） Impairment of energy metabolism in brain 2 ） Alteration of neurotransmitters 3 ） Inhibiting action of nerve cells membrane Ammonia intoxincation

13. False neurotransmisson hypothesis False neurotransmisson hypothesis In hepatic dysfunction or formation of portal-systemic shunt, some kind of amine elevated due to failure of hepatic deamination, and then filter into central nervous system interferes with physiologic functions by competitively inhibiting normal neurotransmitters (dopamine, norepinephrine) and favoring formation of false neurotransmitters (octopamine, phenylethanolamine),which have similar structure but much weaker activity than true neurotransmitters. The net physiologic result of such changes is reduced neural excitation an hence increased neural inhibition.

14. The aromatic amino acids (AAA), tyrosine,phenylalanine and tryptophan are increased in liver disease whiletge branched amino acids (BCAA), valine,leucine and isoleucine are decreased. The AAA are the precursors of false neurotransmitters. The aromatic amino acids (AAA), tyrosine,phenylalanine and tryptophan are increased in liver disease whiletge branched amino acids (BCAA), valine,leucine and isoleucine are decreased. The AAA are the precursors of false neurotransmitters. Amino acid imbalance hypothesis Amino acid imbalance hypothesis

15.  Plasma level of GABA In liver failure, a major resource of the increased plama GABA is considered to be the intestinal bacteria and the intestinal wall. The permeability of the blood-brain to GABA is increased in liver failure,if some of the GABAis not catabolized or taken up by neurons,it may reach GABA receptors and augment GABA-ergic neurotransmission. Activation of the GABA receptor increase neuronal membrane permeability to Cl- BY OPENING Cl- ionophore, and Cl- enters the neuron causing membrane hyperpolarization. Benzodizepines(BZ) recepter agonists increase the frequency of GABA-gate Cl- channel openings.  GABA and/or BZ receptor density increased  Ammonia can augment the activity of GABA-ergic neurons. Gamma-amino butyric acid hypothesis Gamma-amino butyric acid hypothesis

16. Synergistic actions of multiple toxins Manganese: induce pathologicalchanges of astrocyte Mercaptans: inhibit the production of urea and Na + -k + - ATPase on neuron membrane ， disturbe the electron transport on mitochondria Short-chain fatty acids: inhibit energy metabolismof the brain, disturbe the post neuron potential Phenols: inhibite the activit of many enzymes

17. precipitating factors of HE  Gastrointestinal hemorrhage  Unadvisable dietary protein  Excessive diuresis  Abuse of sedatives, tranquilizers and narcotic analgesic  Renal failure  Severe infections  Constipation  Others

18. Hepatorenal syndrome Hepatorenal syndrome is the development of a reversible and functional renal failure in patients with severe liver diseases in absence of any other identified cause of renal pathology. It is characterized by a marked decrease in GFR and renal plasma flow.

19. Pathogenesis of HRS decompensated cirrhosis Hepatic dysfunction portal hypertension hydroperitoneum Gastrointestinal hemorrhage Abdominal organs congestion effective circulating blood volume  Aympathetic nervous systerm  Renin-angiotensin aldosterone systerm  Andotoxemia Kallikrein —kinin  PGE2  TXA2  LTs  Vasoconstriction of kidney GFR  HRS

20. The End

21. Urea AA NH 3 NH 3  Ornithine CitrullineArgininosuccinate   Urea NH 3  Kidney Brain Systemic circulation Liver Intestine Protal-systemic shunts Other tissues to produce NH 3 1 ） Impairment of energy metabolism in brain 2 ） Alteration of neurotransmitters 3 ） Inhibiting action of nerve cells membrane

22. GlutamateL-glutamine  Glutatrate GABA Citric acid Oxaloacetate Succinate NH 3 ATPADP NAD NADH Pyruvic acid Acetyl-CoA Acetylcholine Choline    NADH NAD Toxicaton effect of ammonia on brain tissue  NH 3

23. Phenylalanine Tyrosine Phenylethyla mine Tyramine Phenylethylamine Tyramine MAO  Phenylethylamine  Tyramine  Phenolethanolamine Octopamine Tyramine  Phenylethylamine 

24. CH 2 CHCOOH NH 2 CH 2 CHCOOH NH 2 HO CH 2 CHCOOH NH 2 HO CH 2 NH 2 HO OH CH 2 CHCOOH NH 2 HO CH 2 NH 2 HO CH 2 NH 2 HO CH 2 NH 2 HO OH CH 2 NH 2 CH 2 NH 2 OH True neurotransmitter hydroxyl ase Hydrox ylase   Hydroxylase Decarbo xylase Hydroxy lase Octopamine Phenolethanol amine Dopamine Norepineph rine Tyrosin e Dolbar Tyramine Phenylala nine Phenyleth ylamine Tyrosin e False neurotransmitter   Hydroxylase

25. Aromatic amino acid AAA AAA  Metabolism   Insulin Glucago n BRAA  Insulin  Glucagon  AAAPhenylalanineTyrosine Tryptophan Phenolethanolamine Octopamine Serotonin BCAA AAA from other tissue BCAAAAA

26. Glutamic acidGABA Metabolism  GABA GABA  Inhibit brain function

27. Hepatic funtion Clinical manifestations Body’s metabolism 1 ． Carbohydrate metabolism 2 ． Protein metabolism 3 ． Lipid metabolism 4. Water and Electrolyte metabolism 5 ． Hormone metabolism Blood coagulation Biotransformation and detoxifcation Immunity Secretion and excretory function Metabolism dysfunction 1 ． Hypoglycemia 1 ． Hypoglycemia 2 ． Hypoalbuminemia 、 high ammonia 、 increased transaminase 3 ． Fatty liver 、 decreased plasma cholesteryl ester 4 ． Disorders Water and Electrolyte metabolism 5. High estrogen ， spider angioma 、 spider angioma spider angioma liver palms etc. liver palms etc. Bleeding tendency Intoxication Infection Jaundice

28. Conditions in which the liver functions fall below the normal ranges. The symptom include jaundice, bleeding, secondary infection, renal dysfunction and hepatic encephalopathy.Severe hepatic insufficiency may cause liver failure or death. Hepatic insufficiency Hepatic failure Hepatic failure is a terminal stage of hepatic insufficiency. Hepatic encephalopathy and hepatorenal syndrom are the primary clinical manifestations.

29. Palmar erythema Spider angiomas