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Prof Dr. Elsaid galal Elbadrawy Tropical Medicine Hepatogastroentrology Faculty of medicine Zagazig universiy
Hepatic
encephalopathy
(HE)
describes all the neurosychatric symptoms occurring in patients with acute or chronic liver disease in the absence of other neurologic disorders
Prevalence
The prevalence of HE depends on
The occurrence of hepatic encephalopathy is only possible under the following conditions:
1- Serious acute or chronic liver disease
Classification
The World Congress of Gastroenterology in 2002 classified hepatic encephalopathy: Type A: Associated with acute liver faliure
Type B:
Type C:
Spontaneous
Recurrent encephalopathy 2-Persistent HE. Mild Severe
Treatment-dependent persistent HE
3-Minimal HE.
Pathogenesis
Many factors have been implicated in the pathogenesis of HE, but it is the
I) Neurotoxins
1-Ammonia hypothesis:
Production: -Small intestine: catabolism of glutamine -Large intestine: microbial breakdown of protein, amino acids, urea. -In peripheral tissues (esp. skeletal muscle) Detoxification:
Extent of hyperammonemia and hepatic encephalopathy depend on: 1- Nitrogenous intestinal content 2- Change in the intestinal flora 3- Degree of liver dysfunction 4- Extent of portocaval collateral
5- Muscle wasting
6- Enzyme defect in urea synthesis
Increased glutamine in astrocytes osmotic stress cellular swelling and cellular change, termed Alzheimer type 2 astrocytosis
NH3
Alter BBB
Astrocyte damage
glutamine
(Synergism Hypothesis)
2- Phenolic Compounds 3- Short Chain Fatty Acids - Inhibit various enzymes of urea cycle - Displacement of tryptophan from its binding to albumin tryptophan
II) Neurotransmitters
1-GABA hypothesis (-Amino butyric Acid):
GABA is the principal inhibitory neurotransmitter in brain Synthesis: a- In presynaptic neurones: from glutamic acid b- In intestine: by gut bacteria, enter portal vein and metabolized by liver. In liver failure or portal systemic shunting systemic circulation cross BBB to interact with supersensitive postsynaptic GABA receptors
GABA bind to specific GABA receptor in postsynaptic membrane. This receptors also binds benzodiazepines and barbiturates. Changes in affinity and denisity of postsynaptic receptors play important role for GABA and other neurotransmitter The binding of benzdiazipines to GABA receptors intensifies the effect of GABA
of amino acids
In chronic liver disease:
12-
phenylalanine in brain
Tyrosine
increase synthesize of tyramine, octapamine which complete with catecholamine neurotransmitters for the same receptor site.
Colon: protein
Tyrosine
L-dopa Intestinal bacterial decarboxylase Tyrosine Phenylalanine
Dopamine
Tyramine
Noradrenaline
Octopamine
True
False
B phenylethanolamine
Sympathetic transmitter
a- Brain edema.
b- Brain is exposed to circulating neurotoxin. c- Loss of neurotransmitter
Zinc:
Zinc is a cofactor in urea cycle
VI) Probiotics
Ammonia produced by the gut is from the deamination of dietary amino acids by bacteria In malnourished patient, the levels of the defensive bacteria strains (Bifidobacterium and Lactobacillus) decline.
NH3
Arousal ( serotonin)
Motor/cognitive (Dopamine)
Endogen BZ
Exitatory glutamate
Inhibitory (GABA)
Encephalopathy
Precipitating Factors
1- Increased protein load -Upper GI hemorrhage -Ingestion of large protein meal 2- Decreased excretion of ammonia -Renal failure -Constipation 3- Electrolyte disturbance (e.g. hypokalaemia) 4- Dehydration 5- Paracentesis 6- Creation of portacaval shunts 7- Infection (SBP) 8- Drugs (e.g. sedatives) 9- Superimposed acute liver injury
Clinical Manifestation
Patients with hepatic encephalopathy can presents with a variety of clinical features ranging from subclinical or minimal confusion to life-threatining coma with cerebral edema (often in fulminant hepatic faliure)
2) Personality Changes
-Childness, irritability, euphoria. -Inappropriate loughing or crying. 3) Intellectual Deterioration:
4) Emotional Abnormality -Anxiety or depression. 5) Other Features: a) Speech abnormalities: -Slow and slurred. -Monotonous voice. -Dysphasia. b) Convulsions. c) Brain stem dysfunction -Hypothermia. -Hyperventillation. -Sweating.
Examination:
1) Asterixes:
-Characteristic but not pathognmonic -Usually bilateral, but not synchronus -Unilateral asterixes (rare) (with focal lesions of the thalamus and parietal cortex). 2) Hyperreflexia. 3) Extenser planter reflexes. 4) Neck stiffness (rarely)
Fetor Hepaticus:
Sweet musty odor in the breath. Usually present in hepatic encephalopathy. Not correlate with degree or duration of HE
Clinical variants
1-Sub-clinical H. Encephalopathy
Dif: Patients with chronic liver disease who have no clinical symptoms of brain dysfunction, but perform worse on pyschometric tests It has high prevalence (30 - 70%) Psychometric tests show that they perform well in tests of intellect, language, memory but poor in tests requiring visual, motor and constructional skills.
- Found in patients with extended collateral circulatory pathways - Neuropsychatric disorder dominate the picture - Picture of liver disease may be equivocal - The most frequent features are:
1- Progressive paraplegia 2- Damage to basal ganglia & cerebellar system. 3- Focal cerebral symptoms (Epilepsy, dementia)
Differential Diagnosis
I-Intracranial lesions
2-Infections
-Trauma (e.g., subdural hematoma), -Bleeding, Cerebral infarction -Tumors , Abscess
-Meningitis ,Encephalitis, -Subarachnoid hemorrhage
3-Metabolic Encephalopathies
4-Toxic encephalopathy
-Anoxia, Uremia ,Ketoacidosis -Hypoglycemia, Electrolyte imbalance -Inborn error of urea cycle, Reye's synd
-Alcohol: -Acute intoxication -Withdrawal syndrome - Wernicke's syndrome -Tranquilizers
5-Neuropsychatric disorders
Investigation
1- Clinical Tests (Psychometric tests): 2- CSF exam: Glutamic acid and glutamine 3- Ammonia: Raised but not correlate with degree of enceph. 4- Electroencephalography (EEG): Sensitive means of detecting hepatic encephalopathy. Not specific to hepatic encephalopathy. 5- Evoked Potentials: 6- C.T Brain: 7- I C P Monitoring 8- Myelogram:
9-Other investigations:
To define cause and precepitating factors Liver function tests. Bl. Glucose. Serum electrolyte Bl. Urea nitrogen. S. creatinine. Arterial blood gases. Cultures: blood, urine, sputum. Blood ethanol level.
S. and urine drug screen.
Pathology
1-Acute encephalopathy:
Prognosis
The presence of HE is a serious prognostic
consideration
of
liver
TREATMENT
1-Treatment of Precipitating Factors:
Constipation Electrolyte and acid-base imbalance
Infection (SBP)
Gastrointestinal bleeding Portal-systemic shunts.
Specific Treatment
1- Treatment based on ammonia hypothesis
2- Treatment based on false neurotransmitter 3- Treatment based on GABA hypothesis 4- Adjuvant therapy 4- Probiotics
Ammniogenic substrate
1-
1- Antibiotics 2- Lactulose
Acute and severe attack (Grade 3 or 4) -Withdrowal all dietary protein - Calories intake is maintained at 2000 cal
During Recovery: Protein intake is increased by 10 gm/day every 3rd day until normal intake (60-80 gm/d)
In Chronic Cases:
Perminant protein restriction The limit of tolerance is 40-60 gm/day. Vegitable Protein: Tolerated better than animal protein.
Less ammoniagnic
More laxative due to their high fiber content.
Calorie intake:
1,800-2,500 (cal/d) is guaranteed by the adequate adminstration of fats (70-140 g) and CHO (280-325g) Insulin (cirrhotic patients show insulin resistance) Vitamins : Daily intake of multivitamins , trace element , minerals , zinc is recommended
2) Enema:
In acute and severe coma especially in highly constipated patients or in cases of massive GIT bleeding
The volume used should be at least 1000 ml 300 ml lactulose with 700 ml water are efficacious
1-Anhibiotics:
1-Neomycin Alter gut flora ( E-coli , urease producing org.) Impair absorption of ammonia Inhibit uptake of glutamic acid by mucosal cells
2-Metronidazole. Active aginst bacteroids and other anerobes Effective as neomycin. Dose: 200 mg 4 times daily. should not be used long-term (CNS toxicity) 3-Vancomycin Reduces bacteroids Successively used in patients with lactulose therapy faliure Dose: 4 X 0.5 gm/day
2-Lactulose
-Non absorbable, synthetic disaccharide. Mode of action: 1-Osmotic laxative. 2-Promotes lactobacilli growth increased lactic, acetic, and formic acids decreased colonic PH inhibits growth of urease-producing bacteria especially E-coli. 3-Traps luminal ammonia and its absorption. 4-Increase diffusion of ammonia from the mucosal blood into the gut.
Lactitol:
Similar to lactulose in action. More palatable (Less sweet ) Causes less diarrhea and flatulence.
Lactose:
Effective substitute for lactulose in patients who are known to be lactase deficient.
a) Levo-dopa:
A precursor of the neurotransmetters norepinephrine and dopamine b) Bromocreptine : -Specific dopamine receptor agonist
IV-Adjuvant therapy
1-Piracetam
Nootropic substance improve typical electrical brain activities
2-L-carnitine
Markedly reduce hyperammonaemia Improve the clinical symptoms of HE in cirrhotic patients
V- Probiotics
They have multiple beneficial effects in treatment of minimal HE by: 1- Decrease total ammonia in portal blood by: a) bacterial urease activity b) ammonia absorption by decreasing pH c) intestinal permeability d) improving nutritional status of gut epithelium. 2- Decrease inflammation and oxidative stress in hepatocyte hepatic clearance of ammonia 3- Decreasing uptake of other toxins.