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:

Associated with acute liver faliure Type A:

Portal-systemic bypass without Type B:

intrinsic hepato-cellular disease.
Cirrhosis and portal hypertension Type C:
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 glutamate–glutamine 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 & glutamate–glutamine 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 Reduced hepstic Reduced muscle
bacteria/ removal mass

NH3

Direct effects
Alter BBB Astrocyte glutamine Exicitatory
damage 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 post-
synaptic 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:
1- Aromatic amino acids (AAA)
tyrosine, phenylalanine, tryptophane
2- Branches chain amino acids (BCAA)
valine, leucine
 cerebral tryptophan increase synthesis of
serotonin (depressant of conciousness).

 phenylalanine in brain inhibit tyrosine 3-

hydroxylase, ( key enzyme for synthesis of
catecholaminergic neurotransmtter

 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 Intestinal bacterial decarboxylase

L-dopa 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

NH3
False
Tryptophan
neurotransmitter

Arousal Direct Motor/cognitive

)serotonin ( neural Endogen
NH3 )Dopamine(
toxin BZ

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

Severe confusion, incoherent language, Grade III.

semi-stupor but awakes with language.
Asterixis
Coma, initially can respond to painful Grade IV.
stimuli.
 Differential Diagnosis
-Trauma (e.g., subdural hematoma), I-Intracranial
-Bleeding, Cerebral infarction lesions
-Tumors , Abscess
-Meningitis ,Encephalitis, 2-Infections
-Subarachnoid hemorrhage
-Anoxia, Uremia ,Ketoacidosis 3-Metabolic
-Hypoglycemia, Electrolyte imbalance Encephalopathies
-Inborn error of urea cycle, Reye's synd
-Alcohol: -Acute intoxication 4-Toxic
-Withdrawal syndrome encephalopathy
- 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 consideration of liver
transplantation
 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

Intestinal Metabolic
Ammniogenic
ammonia ammonia
substrate
production fixation

Dietary -1 Ornithine aspart-1

Antibiotics -1
protein & Benzoate-2
Lactulose -2
Enema -2 Phenylacetate
 1- Decrease of Ammoniagenic
Substrates.
a) Reduce dietary protein :
Subclinical HE 40 gm/day
Grade 1 or 2 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 false-
neurotransmitter 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.