Hepatic Encephalopathy

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

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

Incidence/prevalence
Universal feature of acute liver failure 50%~70% in chronic hepatic failure

Difficult to estimate

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

HE---common precipitating factors

Nitrogenous Encephalopathy Non-Nitrogenous Encephalopathy

Uremia/azotemia Gastrointestinal bleeding Dehydration Metabolic alkalosis Hypokalemia Constipation Excessive dietary protein Infection

Sedative Benzodiazepines Hypoxia Hypoglycemia Hypothyroidism Anemia

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

Pathogenesis (2)
Postulated factors/mechanisms:

Ammonnia neurotoxicity Synergistic neurotoxins Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypothesis -Aminobutyric acid hypothesis

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:

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)

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

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

Synergistic neurotoxins
Ammonia

Mercaptans ()
Short-chain fatty acids Phenols

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

Synergistic neurotoxins
Short-chain fatty acids

Butyrate, valerate, octanote

Marked increased in the blood flow and cerebrospinol fluids

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

Excitatory inhibitory neurotransmitter

Neurotransmission: Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain concentration of the precursor amino acids

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

Excitatory inhibitory neurotransmitter

Imbalance of plasma amino acid: More AAAs enter into blood-brain barrier and CNS Decreased synthesis of normal neurotransmitters
L-Dopa Octopamine Dopamine Tryptophan Noradrenoline Serotonin

Enhanced synthesis of false neurotransmitters

- Aminobutyric acid hypothesis

- Aminobutyric acid (GABA):

Principle inhibitory neurotransmitters

Generated in the gut by bacteria Bypasses the diseased or shunted liver

- 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

- 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

Summary for the hypothesis

HE may represent the synergistic effects of a number of toxins on an unusually susceptible nervous system

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

Pathohistology
CT/MRI : Cerebral atrophy related to the severity of the liver dysfunction Marked in chronic persistent encephalopathy

Clinical manifestation
In acute liver failure Spontaneously appearing Severe fatal hepatic dysfunction + abrupt mental deterioration + coma/death high fever tachycardia tachypnea hyperventilation

Clinical manifestation
In chronic liver disease
Insidious onset Characterized by subtle and/or intermittent changes in consciousness personality intelligence speech

Clinical manifestation
In chronic liver disease

Disturbed consciousness: slowness, somnolence, disorientation, confusion deep coma

Personality changes: childishness irritability

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

Clinical manifestation
Criteria for clinical stages

Personality and mental changes

Abnormal EEG patterns Asterixis

Clinical stages of HE

Clinical stages of HE

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

Diagnosis and differential diagnosis

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

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

Differential diagnosis
Hypoglycemia Uremia Diabetic ketoacidosis Nonketotic hyperosmolar syndrome Subdural hematoma Cerebrospinal infection

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

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

Identification and treatment of precipitating factors

Supportive care Correction of fluid, electrolyte, glucose, acidalkaline abnormalities Management of cerebral edema, bacteremia

Initiate ammonia-lowing therapy

Decreasing nitrogen load Decreasing ammonia production

Decreasing absorption of enteric toxins

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

Initiate ammonia-lowing therapy

Dietary protein restriction: Vegetable protein in priority
lower rate of ammonia production

contain small amounts of methionine and AAAs

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

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

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

Initiate ammonia-lowing therapy

Lactulose Given by retention enema 30ml lactulose + 70ml water
Side-effects: abdominal cramping diarrhea flatulence

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

Dopaminergic neurotransmitters
L-Dopa: Precursor of the neurotransmitter norepinephrine and dopamine penetrate blood-brain barrier Increase the normal neurotransmitter

Liver transplantation

Ultimate answer to the problem of chronic HE

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

Summary

Key issues of HE topic

Key issues of the HE topic

Clinical manifestations------ Clinical stages of HE

Diagnosis and differential diagnosis

Factors precipitating and/or aggravating HE