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 failure1. biological2. physical and chemical3. inherital(congenital)4. immunol 5. nutritional

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

Clinical Manifestations of Cirrhosis

Impact of Hepatic Encephalopathy on survival in 1402 cirrhotic patients

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

Part 1 Etiology and classification of HE

Major types of hepatic encephalophcyAcute fulminant type: hepatic necrosisChronic recurrent type: cirrhosis Type A (=acute) : HE associated with ALF Type B (=bypass): portal-systemic shunting without associated intrinsic liver disease Type C (=cirrhosis): cirrhosis1998 in Vienna,

Clinical presentationSleeping disorderApathyChildishnessHepatic coma = HEConfusionDrowsinessComa

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

Part 2 pathogenesis of HE

PathogenesisMultifarious toxins Dysfunction of CNS

(No obvious morphological change)Several hypotheses to uncover the mystery

1. NH3 intoxication Normal: plasma NH3 < 100g80~90 of patient: 2~3 folds (200~500 g

NH3 NH4+ 2% 98%

pH pHBlood NH3 configuration

(1) NH3 increased in HE

Renal backflow NH3 Muscle productionVia collateralGenerationClearing Syntheses with NH3 liver

Intestinal NH3Blood NH3Urea synthesesThe reasons of NH3

Ureogenesis takes place in the liver and is essential for ammonia detoxificationUREOGENESISCitrullineArginineOrnithineAspartic acidUREA CYCLEUREAAMMONIA

(2) NH3 toxicity on CNS cerebrocellular energy: neurotransmitter imbalance neurocellular membrane ion transferring NH3interferes with

Energy metabolism & Neurotransmitter in HE

Balance of exiting & inhibition

cerebral energycerebral cell respirationNa+ pumpneural impulse deliverysynapse intoxication

Mercaptan(metheonine)NH3 Indole (tryptophan)Phenol(tyrosine, tyramine)monoamineShort chain fatty acidSynergistic effect of neurotoxin

neurotoxin

decayed products of enteric bacteria

2. False neurotransmitter(FNT) & plasma amino acid imbalance

BCAA: branch chain amino acid AAAaromatic amino acidleucine, isoleucine, and valine /Tryptophan, Tyrosine , phenylalanine

Serious liver diseaseBCAA/AAA ratio < 1 ( Nor > 3 ) ?CNS disorder

(1) Causes of plasma amino acid imbalance

phenylalanineTyrosine phenylalamine tyraminedopa

- hydrogenasein brain Tyrosine hydrogenaseMAONE -phenylethanolamineoctpamine FNTdecarboxylationin liver?BBBdopamine(2) FNT formation

Comparison between TNT and FNT

ARAS maintains consciousness through NTNT

AAA BCAAtryptophan

BBBbloodFNT5-HT

?tryptamineglutamineantiport(3) plasma amino acid imbalance and FNT formation

3. GABA alteration and HE1. GABA: Originated from gut and brain2. Affinity of GABA to its receptor 3. Synergistic allosteric effect of other:

decarboxygenaseGlutamatic acidGABAtransferaminaseNH3 NH3

+early stage late stagesuccinic acidsemialdehyde GABA alteration

4. Comprehensive view Blood Brain

Intestine GABA GABA ATP NH3 GA, Ach GlutamineGlucagon AAA AAAFNT Insulin BCAA

Part 3 Precipitating factors1. Toxins produced in intestine2. Permeability of blood brain barrier3. Increased sensitivity of brain to toxins by hypoxia, fluid and electrolytes abnormalities, infection, hypnotics etc

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

What are they doing?

Thanks!

*Hepatic encephalopathy (sometimes hepatoencephalopathy or portosystemic encephalopathy) isHepatic encephalopathy is a syndrome observed in patients with cirrhosis. Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of other known brain disease. Hepatic encephalopathy is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels.1 Hepatic encephalopathyis also described in patients without cirrhosis with either spontaneous or surgically createdportosystemic shunts.The development of hepatic encephalopathy is explained, to some extent, by the effect of neurotoxic substances, which occurs in the setting of cirrhosis and portal hypertension. ***Hepatic enteric endotoxemia alopecia [.l'pii]

n. gynecomastia [gainiku'msti]

adj. =gynaecomastia()Merli M et al., Hepatology 1996***is caused by occurs in patients with *Sleeping disorder Apathy Childishness Confusion Drowsiness Coma Flapping tremor **hepatolenticular degeneration ******za-zen sitcrosslegged sitinmeditation *hepatic odor fetor hepaticus

**Except for histidine, the aromatic amino acids contain a benzene ring. phenylalanine, histidine and tryptophan are essential amino acids since they are not synthesized in the human body, they must be derived from the diet. Tyrosine is semi-essential, it can be synthesized, but only from phenylalanine. A lack of the enzyme phenylalanine hydroxylase used in Tyrosine synthesis causes phenylketonuria.Many plants and microorganisms synthesize aromatic amino acids. Many herbicides inhibit aromatic acid synthesis which is why they are ok around pets and humansThe essential branched chain amino acids (BCAA's) include leucine, isoleucine, and valine

*ascending reticular activating system *****carnitine 1905,GULEUITSCHKRIBERG, L-CARNITINE();1927,TOMITASENDJU:3 ,161.2;1948,FRAENKEL ...