Hepatic insufficiency Severe damage in liver cells will result in serious dysfunction in metabolism, secretion, synthesis, detoxification and immune system, manifesting as jaundice, bleeding, infection, renal dysfunction and encephalopathy. The syndrome is called hepatic insufficiency. Acute and chronic Hepatic failure is the terminal stage of hepatic insufficiency.

Hepatic dysfunction Injury of hepatocytes and hepatic dysfunction metabolic dysfunction carbohydrate, protein and electrolyte dysfunction of bile secretion and excretion coagulation system dysfunction biological transforming dysfunction drug and hormone metabolism, detoxification Injury of stromal cells and hepatic dysfunction immune dysfunction hepatic fibrosis microcirculation dysfunction

Etiology Biological factors HBV, bacteria, parasites Chemical factors industrial toxins, drugs, alcohol Nutritional factors Inherited factors Wilson’s disease Immune factors AIH

Hepatic encephalopathy Hepatic encephalopathy is a complex, potentially reversible disturbance in central nervous system that occurs as a consequence of severe liver diseases. It is generally divided into four stages, manifestating from slightly altered mood or behavior, through to somnipathy, and inappropriate behavior, to drowsy and psychopathy, and even finally to deep coma.

Pathogenesis Ammonia intoxication hypothesis False neurotransmitter hypothesis Amino acid imbalance hypothesis The gamma-aminobutyric acid hypothesis

Ammonia intoxication hypothesis Causes for elevated ammonia Decreased ammonia clearance impaired Krebs-Henseleit urea cycle Increased ammonia production urea in the blood is emitted into intestinal lumen and degraded by urease in bacteria to produce ammonia ammonia is produced in the kidneys and muscles gastrointestinal hemorrhage and absorption dysfunction

Intoxication of ammonia on the brain Impairment of energy metabolism in brain ammonia reacts with α-ketoglutatrate to produce glutamate and glutamine consumption of α-ketoglutatrate, NADH and ATP, inhibition of pyruvate decarboxylase leading to the reduction of acetyl CoA and acetylcholine Alteration of neurotransmitters decreased excitatory neurotransmitters glutamate and acetylcholine increased inhibitory neurotransmitters glutamine and gamma-aminobutyric acid Inhibiting action on nerve cell membrane

False neurotransmitter hypothesis phenylalanine → phenylethanolamine tyrosine → octopamine Dopamine and norepinephrine

Amino acid imbalance hypothesis BCAA/AAA↓ Insulin↑, glucagon ↑ ↑, insulin/glucagon ↓ Increased production of aromatic AA and increased uptake and utilization of branch chain AA Inhibiting the production of normal neurotransmitters Promoting the production of false neurotransmitters Increased production of 5-hydroxytryptophan(5-HT)

The gamma-aminobutyric acid hypothesis GABA Inhibitory neurotransmitters Glutamate →GABA Decarboxylase ↓

Precipitating factors Overload of Nitrogen digestive tract hemorrhage Increased permeability of blood brain barrier endotoxin Increased sensibility of brain narcotics and sedatives

Prevention and treatment Eliminating or correcting precipitating factors Reducing plasma ammonia Correcting plasma amino acid imbalance and supplying normal neurotransmitters Liver transplantation

Hepatorenal syndrome Hepatorenal syndrome is referred to the development to renal failure in patients with severe liver disease in absence of any other identified cause of renal pathology.

Pathogenesis Stimulated sympathetic nervous system Activated renin-angiotensin system Abnormal function of kinin system Action of PGs Endothelin-1 Endotoxin False neurotransmitters