Pathophysiology

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

2. Chapter ⅩⅤHepatic 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. Overview • Normal function of liver • Etiology of liver disease and liver dysfunction • Pathogenesis of liver disease

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

6. Hepatic Encephalopathy

7. 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. 2010年10月22日

8. Staging 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

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

12. Ammonia intoxincation • Causes of elevated ammonia in hepatic inssufficiency 1）Decreased clearanceof 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

13. 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. Amino acid imbalance hypothesis

15. Gamma-amino butyric acid hypothesis • 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. • GABAand/or BZ receptor density increased • Ammonia can augment the activity of GABA-ergic neurons.

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

20. The End

21. Spider angiomas • Palmar erythema

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