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Add as Friendhepatic encephalopathy

by: samith

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1 : Hepatic Encephalopathy
2 : Definition (1) Hepatic encephalopathy (HE) It represents a reversible decrease in neurologic function, based upon the disorder of metabolism which are caused by severe decompensated liver disease
3 : Definition (2) “Portal-systemic encephalopathy” patients with portal hypertension abnormal shunting of blood “Subclinical or latent HE” diagnosed only by using precise mental tests or EEG no obvious clinical and biochemical abnomalities
4 : Incidence/prevalence Universal feature of acute liver failure 50%~70% in chronic hepatic failure Difficult to estimate
5 : Etiology Fulminant hepatic failure acute severe viral hepatitis, drug/toxin acute fatty liver of pregnancy Due to acute hepatocellular necrosis Chronic liver disease cirrhosis of all types (70%), primary liver cancer surgically induced portal-cava shunts Due to one or more potentially reversible precipitating factors
6 : HE---common precipitating factors Uremia/azotemia Gastrointestinal bleeding Dehydration Metabolic alkalosis Hypokalemia Constipation Excessive dietary protein Infection Sedative Benzodiazepines Hypoxia Hypoglycemia Hypothyroidism Anemia Nitrogenous Encephalopathy Non-Nitrogenous Encephalopathy
7 : Pathogenesis (1) Toxic materials derived from nitrogeneous substrate in the gut and bypass the liver Caused by several factors act synergistically Several putative gut-derived toxins identified
8 : Pathogenesis (2) Postulated factors/mechanisms: Ammonnia neurotoxicity Synergistic neurotoxins Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis ?-Aminobutyric acid hypothesis
9 : Ammonia neurotoxicity Ammonia production resulting from the degradation of urea or protein primary site: gut other site: kidney and skeletal muscles Gut-generating ammonia: 4g/day Equilibrium of ammonia and ammonium:
10 : Ammonia neurotoxicity Ammonia elimination Transfer to the liver Metabolized by series of urea cycle enzymes Comsumpted by brain, liver, kidney: to synthesize glutamic acid and glutamine Excreted into the urine Eliminated by lung (trace amounts)
11 : Ammonia neurotoxicity Over production and/or hypoeccrisis Poor hepato-cellular function: incomplete metabolism Portal-systemic encephalopathy: bypass Ammonia intoxication Interfere with cerebral metabolism: Depletion of glutamic acid, aspartic acid and ATP Depression cerebral blood flow and oxigen consumption
12 : Ammonia neurotoxicity Elevation of ammonia: detected in 60%~80% Absolute concentration of ammonia, ammonia metabolites in blood or cerebrospinal fluids, correlates only roughly with the presence or severity of HE Few cases: within normal range
13 : Synergistic neurotoxins Ammonia Mercaptans (??) Short-chain fatty acids Phenols
14 : Synergistic neurotoxins Mercaptans Generated from the degradation of methionine in the gut The cause of fetor hepaticus ( ??) Inducing changes of mental state in animal model
15 : Synergistic neurotoxins Short-chain fatty acids Butyrate, valerate, octanote Marked increased in the blood flow and cerebrospinol fluids
16 : Synergistic neurotoxins In animal models: Both mercaptains and short-chain fatty acids have direct neuron cytotoxicity Individually, their failed to induce HE Synergism was noted
17 : Excitatory inhibitory neurotransmitter Neurotransmission: Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain concentration of the precursor amino acids
18 : Excitatory inhibitory neurotransmitter Increased aromatic amino acids (AAAs) Tyrosine Phenylalanine Tryptophan Due to the failure of hepatic deamination Decreased branched-chain amino acids (BCAAs) Valine Leucine Isoleucine Due to increased metabolism by skeletal muscle and kidneys or increased insulin
19 : Excitatory inhibitory neurotransmitter Imbalance of plasma amino acid: More AAAs enter into blood-brain barrier and CNS Decreased synthesis of normal neurotransmitters L-Dopa Dopamine Noradrenoline Enhanced synthesis of false neurotransmitters Octopamine Tryptophan Serotonin
20 : ?- Aminobutyric acid hypothesis ?- Aminobutyric acid (GABA): Principle inhibitory neurotransmitters Generated in the gut by bacteria Bypasses the diseased or shunted liver
21 : ?- Aminobutyric acid hypothesis GABA-receptor complex: Localized to postsynaptic membranes Key contributor to neuronal inhibition in HE GABA-ergic: 25% ~ 65% of nerve endings Increased blood-brain barrier permeability Increased number of binding sites
22 : ?- Aminobutyric acid hypothesis Endogenous ligands for the BZ receptor: unknown VEP = induced by BZ or barbiturate Substances in the brain: bind to BZ receptor GABA/BZs receptors antagonists: improve HE symptoms
23 : Summary for the hypothesis HE may represent the synergistic effects of a number of toxins on an unusually susceptible nervous system
24 : Pathohistology Brain may be normal or cerebral edema Particularly in fulminant heptic failure Cerebral edema is likely the secondly changes In patients with chronic liver disease Astrocytes: increase in number and enlargement In a very long-standing case Thin cortex, loss of neurons fibers, laminar necrosis , pyramidal tracts demyelination
25 : Pathohistology CT/MRI : Cerebral atrophy related to the severity of the liver dysfunction Marked in chronic persistent encephalopathy
26 : Clinical manifestation In acute liver failure Spontaneously appearing Severe fatal hepatic dysfunction + abrupt mental deterioration + coma/death high fever tachycardia tachypnea hyperventilation
27 : Clinical manifestation In chronic liver disease Insidious onset Characterized by subtle and/or intermittent changes in consciousness personality intelligence speech
28 : Clinical manifestation In chronic liver disease Disturbed consciousness: slowness, somnolence, disorientation, confusion deep coma Personality changes: childishness irritability
29 : Clinical manifestation Intellectual deterioration: inability to produce simple designs with blocks or matches Reitan trail-making test Daily writing chart Speech: slow slurred monotonous voice Flapping tremor (asterixis) Fetor hepaticus
30 : Clinical manifestation Criteria for clinical stages Personality and mental changes Abnormal EEG patterns Asterixis
31 : Clinical stages of HE
32 : Clinical stages of HE
33 : Laboratory and other tests Serum ammonia Elevation of serum ammonia: 60%~80% particularly in chronic HE (with portosystemic shunting) Electroencephalogram (EEG) Severe slowing with frequencies in the theta and delta Evoked potentials Variation, lack of specificity and sensitivity
34 : Diagnosis and differential diagnosis
35 : Diagnosis Patients with severe liver disease and/or portal hypertension, portosystemic shunting Mental changes: confusion, somnolence, coma Factors precipitating or aggravating HE exist Severely impaired liver function and/or hyperammonemia Flapping tremor and typical EEG changes
36 : Diagnosis Recognition of the latent and/or subclinical HE Important for view of the prevalence of cirrhosis In the absence of characteristic features Abnormal neuropsychiatric function: Reitan trial test Digit symbol tests Block design Visual reaction times
37 : Differential diagnosis Hypoglycemia Uremia Diabetic ketoacidosis Nonketotic hyperosmolar syndrome Subdural hematoma Cerebrospinal infection
38 : Treatment Strategy for the management of HE Identify and correct the precipitating cause(s) Initiate ammonia-lowering therapy Minimize the potential medical complications of cirrhosis and depressed consciousness
39 : Identification and treatment of precipitating factors Essential management Bleeeding: it must be controlled Azotemia: rehydration attention to other prerenal factors Eliminate sedative/tranquilizers/similar drugs
40 : Identification and treatment of precipitating factors Supportive care Correction of fluid, electrolyte, glucose, acid- alkaline abnormalities Management of cerebral edema, bacteremia
41 : Initiate ammonia-lowing therapy Decreasing nitrogen load Decreasing ammonia production Decreasing absorption of enteric toxins
42 : Initiate ammonia-lowing therapy Dietary protein restriction: In patients with chronic HE permanent protein restriction: 40~60g/D In patients with acute HE more restricted protein intake: < 40, 20, 10 or 0 g/D Relapse return to the former regime
43 : Initiate ammonia-lowing therapy Dietary protein restriction: Vegetable protein in priority lower rate of ammonia production contain small amounts of methionine and AAAs
44 : Initiate ammonia-lowing therapy Bowel cleaning Laxative (e.g., magnesium citrate) Cleaning enema Notes: all enemas must be neutral or acidic to reduce ammonia absorption
45 : Initiate ammonia-lowing therapy Antibiotics Neomycin: 2~4g/D (4~6g/D) Litter is absorbed Impaired hearing or deafness (in long term use) Long term use (>1 month) is not advisable Metronidozol: 0.2g qid as effective as neomycin
46 : Initiate ammonia-lowing therapy Lactulose Synthetic disaccharide Drug of choice Release lactic and acetic acids by bacteria Decreasing stool pH to about 5.5 Reduce portion of ammonia and its absorption Effective in 80% of patients Cause 2~4 soft stool/d
47 : Initiate ammonia-lowing therapy Lactulose Given by retention enema 30ml lactulose + 70ml water Side-effects: abdominal cramping diarrhea flatulence
48 : Detoxification of toxic substances Blood ammonia lowering agents glutamate and arginine infusion failed to demonstrate their efficiency Administration of BCAAs Oral or parenteral administration no clear evidence of efficacy GABA/BZ receptor antagonists Flumazenil and others: may be beneficial adjunctive treatment
49 : Dopaminergic neurotransmitters L-Dopa: Precursor of the neurotransmitter norepinephrine and dopamine penetrate blood-brain barrier Increase the normal neurotransmitter
50 : Liver transplantation Ultimate answer to the problem of chronic HE
51 : Prognosis HE results from fulminant hepatic failure (FHF): Poor 20% survival rates HE results from chronic liver disease Short-term: better than FHF Long-term: guarded
52 : Summary Key issues of HE topic
53 : Key issues of the HE topic Clinical manifestations------ Clinical stages of HE Diagnosis and differential diagnosis Factors precipitating and/or aggravating HE

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