Hepatic insufficiency

Hepatocyte Kupffer Two type of cells in liver

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

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

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

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

Jaundice Bleeding Hepatic encephalopathy Hepatorenal syndrome Hepatic insufficiency

Hepatic Encephalopathy

Liver disease neuropsychiatric syndrome General Concept

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

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

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

Supporting evidence 80% of HE show increased plasma ammonia level patients with hepatocirrhosis have elevated level of ammonia, symptom of HE and alteration in electroencephalogram after high protein diet 1.Ammonia intoxication hypothesis

NH 3 production NH 3 clearance （ urea cycle ） 1. Ammonia intoxication hypothesis Under normal condition, the production and the clearance of NH 3 is in balance

Upper alimentary tract bleeding Gastrointestinal dysfunction Renal dysfunction Muscle contraction Portal-systemic shunt Severe hepatic dysfunction dysfunction of urea cycle （ substrate ATP, enzyme inactivation ） NH 3 production NH 3 clearance Causes

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

高血氨的毒性作用 葡萄糖 6- 磷酸葡萄糖 磷酸果糖激酶 乳酸 丙酮酸 乙酰胆碱 乙酰辅酶 A 胆碱 草酰乙酸 琥珀酸柠檬酸 α- 酮戊二酸 γ- 氨基丁酸 谷氨酸 谷氨酰胺 NADHNAD + + NH 3 NADH NAD NADH ATP

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

2. False neurotransmitter hypothesis

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

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

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

Mode shown replacement of true NTs FNT in HF Excitation of secondary neuron True NT synapse Excitation of secondary neuron FNT compete receptor NormalHepatic failure

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

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

3. Amino acid imbalance hypothesis

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

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

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

（ 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 Negative evidence for FNT and AA imbalance hypothesis

4. GABA hypothesis

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

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

Comprehensive view Blood Brain Intestine GABA ↑ → GABA↑ ATP↓ NH 3 ↑ → GA↓, Ach↓ ↓ Glutamine↑ Glucagon→ AAA↑ → AAA↑→FNT Insulin → BCAA↓

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

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 Treatment of hepatic coma

Portal hypertension Ascites → Effective circulatory FNT blood volume↓ ↓ ↑ TxA 2 → Renal vasoconstriction Endotoxin → LTs ↓ ↓ Endothelin Renal perfusion↓ GFR↓ ATN ↓ Functional renal failure Hepatorenal syndrome