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By

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 diagnostic methods used


It can be found in up to 50 to 70%

of cirrhotic patients if psychometric defects are included in the diagnostic definition of HE

The occurrence of hepatic encephalopathy is only possible under the following conditions:
1- Serious acute or chronic liver disease

in which the detoxification function is restricted


2- Functional or anatomic portosystemic collateral circulation must exist through which the non-toxified portal blood bypasses the liver, so that toxic substances reach the brain

Classification
The World Congress of Gastroenterology in 2002 classified hepatic encephalopathy: Type A: Associated with acute liver faliure

Type B:
Type C:

Portal-systemic bypass without intrinsic hepato-cellular disease.


Cirrhosis and portal hypertension with portal-systemic shunts.

Type C can further divided into:


1-Episodic HE. Precipitated

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

multiple-hit hypothesis that appears


most important.

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:

-Liver: (synthesis of urea, glutamine)


-Skeletal muscle: alternative target for ammonia detoxification

Ammonia and urea metabolism

Role of skeletal muscle in ammonia metabolism in patients with liver failure

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

Ammonia and glutamateglutamine cycle


Ammonia affects a number of neurotransmitter through its products of metabolism (e.g. glutamate & glutamine). In the brain, ammonia is normally detoxified within the astrocytes and eliminated by the amidation of glutamate. Glutamate is an excitatory neurotransmitter; after reacting with post-synaptic receptors, it is converted within astrocytes to glutamine

Glutamine is neuronally inactive, it modifies astrocyte signaling and action of glutamate.


In hepatic encephalopathy:
1- cerebral glutamine are increased 2- cerebral glutamate decreased 3- glutamate re-uptake mechanisms are abnormal 4- glutamate-binding sites on post-synaptic neurones are down-regulated.

Increased glutamine in astrocytes osmotic stress cellular swelling and cellular change, termed Alzheimer type 2 astrocytosis

Astrocyte , nerve cells, synapses

Ammonia & glutamateglutamine cycle

Mechanism proposed for ammonia in HE:


1- Alter blood brain barrier.

2- cerebral conc. of excitatory aa glutamine


3- Alter brain energy metabolism. 4- Direct effects on neuronal membranes with change in neurotransmitter receptors (hypothesis of primary gliopathy)

Sources and potential role of ammonia


Intestinal protein /bacteria Reduced hepstic removal Reduced muscle mass

NH3

Alter BBB

Astrocyte damage

glutamine

Direct effects Exicitatory pathways

2)Other possible Toxins:


1- Mercaptans & methionine derivatives

(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

2-False Neurotransmitter Hypothesis:


The liver plays an essential part in metabolism

of amino acids
In chronic liver disease:

12-

Aromatic amino acids (AAA)


tyrosine, phenylalanine, tryptophane Branches chain amino acids (BCAA) valine, leucine

cerebral tryptophan increase synthesis of serotonin (depressant of conciousness).


inhibit tyrosine 3hydroxylase, ( key enzyme for synthesis of catecholaminergic neurotransmtter

phenylalanine in brain

Tyrosine

increase synthesize of tyramine, octapamine which complete with catecholamine neurotransmitters for the same receptor site.

brain dopamine and displacement of dopamine

by false neurotransmitter impairment of dopamingeric neurotransmission.

Colon: protein
Tyrosine
L-dopa Intestinal bacterial decarboxylase Tyrosine Phenylalanine

Dopamine

Tyramine

Noradrenaline

Octopamine

True

False

B phenylethanolamine

Sympathetic transmitter

Disturbed brain metabolism

III) Alteration of Bl. Brain Barrier (BBB)


BBB is a complex physiologic processes by which the brain is protected from metabolic changes in the body. BBB is located at endoth cells of cerebral capill Transport depends on: 1- Lipid solubility.

2- Mediation by specific carriers

In hepatic encephalopathy, there is:


1) Increase in the permeability leading to:

a- Brain edema.
b- Brain is exposed to circulating neurotoxin. c- Loss of neurotransmitter

2) Alterations of specific carrier systems


a- Increase transport of neutral amino acid b- Decrease glucose and basic amino acids

IV) Altered Brain Energy Metabolism:


Gloucose is the most important cerebral energy fuel In cases of cirrhosis with HE, the glucose metabolism is disturbed Hypoglycemia in terminal stages of liver failure may be a consequence of impaired hepatic gluconeogenesis

V-Deficiency of essential substances


Cirrhosis lead to deficiency of certain vitamins minerals and micronutrient

Zinc:
Zinc is a cofactor in urea cycle

Found in vesicles of glutaminergic presynaptic terminals effecting neurotransmission


Replacement should be considered if the patient is deficient

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.

Probiotics are thought to exert an effect in HE

Multifactorial mechanism of H.E


Tryptophan NH3 False neurotransmitter

NH3

Arousal ( serotonin)

Direct neural toxin

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)

1) Disturbed conciousness -Hypersomnia. -Confusion, drowsiness. -Stuper and coma.

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

Attributed to mercaptans which formed in the


intestine by action of bacteria.

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.

Associated with objective changes by C.T

Diagnosed by psychomotric tests:


1- Number connection test 2- Digital symbol test 3- Trail test 4- Block design test.

Reversal of subclinical HE can occur with application of therapy

2-Acute episodic (recurrent) form


Dif: An acute confusional syndrome with impaired mental state, neuromuscular abnormalities, fetor hepaticus, hyperventilation. The symptoms appear abruptly and develop over a period of hours to days, with oscillation of severity over time Asterixis is very characteristic

Relapses are common.


Respond well to treatment

3-Fulminant liver faliure:


The clinical features are essentially the same as those seen in patients with cirrhosis but The onset is generally abrupt Marked hepatic fetor is present at early stage

Neuropsychatric picture is more aggressive


Signs of increased intracranial pressure (bradycardia, hypertension, dilated pupils, decerebrate posturing) may also be seen.

4-Chronic persistent encephalopathy:


- Rare, irreversible encephalopathic syndromes

- 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)

Grades of hepatic encephalopathy


Grade I. Grade II.
Euphoria or depression, mild confusion, monotonous voice and/or sleep cycle disorders. Asterixis + Lethargy and/or confusion. Asterixis,

Grade III. Severe confusion, incoherent language,


semi-stupor but awakes with language. Asterixis

Grade IV. Coma, initially can respond to painful


stimuli.

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:

Cerebral edema are found in 25-50%


2-Chronic encephalopathy: -Hypertrophy and hyperplasia of astrcoytes -Astrocytes are swollen (Alzhemer's type II cells) 3-Acquired Hepatocerebral degeneration: -Irreversible degenerative changes in CNS -Diffuse necrosis in cortex -Demylination in spinal cord.

Prognosis
The presence of HE is a serious prognostic

development in liver diseases


In ALF , it defines the disease and the

prognosis is generally very bad .


In cirrhosis , the 1 year survival rate after any

episode of encephalopathy is only 40%


Encephalopathy indicate liver failure , and

should prompt transplantation

consideration

of

liver

TREATMENT
1-Treatment of Precipitating Factors:
Constipation Electrolyte and acid-base imbalance

Infection (SBP)
Gastrointestinal bleeding Portal-systemic shunts.

2-Treatment of Complications of Acute Liver failure:


1-Monitored cardiovascular , respiration and metabolic parameters 2-Prophylactic antibiotic

3-Intracranial pressure monitoring.


If above 25 mm Hg Mannitol, Thiopental

3-Orthotropic liver Transplantation

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

I-Treatment based on ammonia hypothesis

Ammniogenic substrate

Intestinal ammonia production

Metabolic ammonia fixation

1-

Dietary protein 2- Enema

1- Antibiotics 2- Lactulose

1-Ornithine aspart 2-Benzoate & Phenylacetate

1- Decrease of Ammoniagenic Substrates.


a) Reduce dietary protein :
Subclinical HE Grade 1 or 2 40 gm/day 30 gm/day

Acute and severe attack (Grade 3 or 4) -Withdrowal all dietary protein - Calories intake is maintained at 2000 cal

/day or above either oral or IV.

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

(2) Inhibition of Intestinal Ammonia Production:

1-Anhibiotics:
1-Neomycin Alter gut flora ( E-coli , urease producing org.) Impair absorption of ammonia Inhibit uptake of glutamic acid by mucosal cells

Dose: 1-2 gm / 6h oral or rectally


Only used for short-term therapy (toxicity)

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.

3-Stimulation of Metabolic Ammonia Fixation:


a)Ornithine -keto glutarate or ornithine aspartate

-Ornithine is a substrate of urea synthesis


-Aspartate, ornithine reinforce glutamine synthesis which serve to detoxify ammonia -They improves HE in cirrhotic patients b)Benzoate and Phenylacetate: -Successfully used in treatment of congenital enzymatic defect of urea synthesis

II-Treatment based on the falseneurotransmitter Hypothesis


1-Branched-Chain Amino Acids: May be of value for long term treatment of HE. Provides safe and well-tolerated source of nutrition in patients with cirrhosis BCAAs treatment leads to:1- Improvement in nitrogen balance.

2- Less protein catabolism.


3- Enhanced protein synthesis.

2-L-Dopa and Bromocryptine:


Decreased dopaminergic neurotransmission is a component of false neurotransmitter theory.

a) Levo-dopa:
A precursor of the neurotransmetters norepinephrine and dopamine b) Bromocreptine : -Specific dopamine receptor agonist

-Give improvement in chronic portosystemic encephalopathy

III- Treatment Based on the GABA Hypothesis "Flumazenil


Benzodiazepine-receptor antagonist. induce transient improvement in 70% of patients with HE Dose: 0.2- 0.3 mg IV bolus, followed by 5mg/h as IV infusion

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.

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