ByProf Dr. Elsaid galal Elbadrawy

Tropical MedicineHepatogastroentrology

Faculty of medicine Zagazig universiy

Egypt

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

ClassificationClassification

Type A:Associated with acute liver faliure

Type B:Portal-systemic bypass without intrinsic hepato-cellular disease.

Type C:Cirrhosis and portal hypertension with portal-systemic shunts.

The World Congress of Gastroenterology’ in 2002 classified hepatic encephalopathy:

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.

Many factors have been implicated in

the pathogenesis of HE, but it is the

‘multiple-hit hypothesis’ that appears

most important.

PathogenesisPathogenesis

I) NeurotoxinsI) Neurotoxins

1-Ammonia hypothesis:1-Ammonia hypothesis:ProductionProduction::

-Small intestine: catabolism of glutamine-Small intestine: catabolism of glutamine

-Large intestine: microbial breakdown of protein,-Large intestine: microbial breakdown of protein,

amino acids, urea. amino acids, urea.

-In peripheral tissues (esp. skeletal muscle) -In peripheral tissues (esp. skeletal muscle)

DetoxificationDetoxification::

-Liver: (synthesis of urea, glutamine)-Liver: (synthesis of urea, glutamine)

-Skeletal muscle: alternative target for ammonia-Skeletal muscle: alternative target for ammonia

detoxificationdetoxification

Ammonia and urea metabolism

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

Extent of hyperammonemia and hepaticExtent of hyperammonemia and hepatic

encephalopathy depend on:encephalopathy depend on:

1- Nitrogenous intestinal content1- Nitrogenous intestinal content

2- Change in the intestinal flora2- Change in the intestinal flora

3- Degree of liver dysfunction3- Degree of liver dysfunction

4- Extent of portocaval collateral4- Extent of portocaval collateral

5- Muscle wasting5- Muscle wasting

6- Enzyme defect in urea synthesis6- 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, synapsesAstrocyte , nerve cells, synapses

Ammonia & glutamate–glutamine cycle

Mechanism proposed for ammonia in HE:Mechanism proposed for ammonia in HE:

1- 1- Alter blood brain barrier.Alter blood brain barrier.

2- 2- cerebral conc. of excitatory aa glutamine cerebral conc. of excitatory aa glutamine

3-3- Alter brain energy metabolism. Alter brain energy metabolism.

4-4- Direct effects on neuronal membranes with Direct effects on neuronal membranes with

change in neurotransmitter receptorschange in neurotransmitter receptors

(hypothesis of primary gliopathy)(hypothesis of primary gliopathy)

NH3

Intestinal protein/bacteria

Reduced hepstic removal

Reduced muscle mass

Alter BBB Astrocyte damage

glutamine

Direct effectsExicitatory pathways

Sources and potential role of ammonia

2)Other possible Toxins:2)Other possible Toxins: 1- Mercaptans & methionine derivatives1- Mercaptans & methionine derivatives

(Synergism Hypothesis)(Synergism Hypothesis)

2- Phenolic Compounds2- Phenolic Compounds

3- Short Chain Fatty Acids3- Short Chain Fatty Acids

- Inhibit various enzymes of urea cycle- Inhibit various enzymes of urea cycle

- Displacement of tryptophan from its binding- Displacement of tryptophan from its binding

to albumin → ↑ tryptophanto albumin → ↑ tryptophan

II) NeurotransmittersII) Neurotransmitters1-GABA hypothesis (1-GABA hypothesis (-Amino butyric Acid):-Amino butyric Acid):

GABA is the principal inhibitory neurotransmitter GABA is the principal inhibitory neurotransmitter in brainin brain

SynthesisSynthesis: :

a-a- In presynaptic neurones:In presynaptic neurones: from glutamic acid from glutamic acid

b- In intestine:b- In intestine: by gut bacteria, enter portal vein by gut bacteria, enter portal vein

and metabolized by liver. and metabolized by liver.

In liver failure or portal systemic shunting In liver failure or portal systemic shunting systemic circulation cross BBB to interact systemic circulation cross BBB to interact with supersensitive postsynaptic with supersensitive postsynaptic GABA receptorsGABA receptors

GABA bind to specific GABA receptor in post-GABA bind to specific GABA receptor in post-synaptic membrane. This receptors also binds synaptic membrane. This receptors also binds benzodiazepinesbenzodiazepines and and barbituratesbarbiturates..

Changes in Changes in affinityaffinity and and denisitydenisity of postsynaptic of postsynaptic receptors play important role for GABA and receptors play important role for GABA and other neurotransmitterother neurotransmitter

The binding of benzdiazipines to GABA The binding of benzdiazipines to GABA receptors intensifies the effect of GABAreceptors intensifies the effect of GABA

22-False Neurotransmitter Hypothesis:-False Neurotransmitter Hypothesis:

The liver plays an essential part in metabolism The liver plays an essential part in metabolism

of amino acidsof amino acids

In chronic liver diseaseIn chronic liver disease::

1-1- Aromatic amino acids (AAA)Aromatic amino acids (AAA)

tyrosine, phenylalanine, tryptophanetyrosine, phenylalanine, tryptophane

2-2- Branches chain amino acids (BCAA)Branches chain amino acids (BCAA)

valine, leucinevaline, leucine

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

phenylalanine in brainphenylalanine in brain inhibit tyrosine 3- inhibit tyrosine 3-hydroxylase, hydroxylase, ( key enzyme for synthesis of ( key enzyme for synthesis of catecholaminergic neurotransmttercatecholaminergic neurotransmtter

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

brain dopaminebrain dopamine and displacement of dopamine and displacement of dopamine by false neurotransmitter impairment of by false neurotransmitter impairment of dopamingeric dopamingeric neurotransmission.neurotransmission.

Noradrenaline

L-dopa

Dopamine

Sympathetic transmitter

Tyrosine

Tyramine

Octopamine

Phenylalanine

B phenylethanolamine

Tyrosine

Colon: protein

Intestinal bacterial decarboxylase

Disturbed brain metabolism

True False

III) Alteration of Bl. Brain Barrier (BBB)III) Alteration of Bl. Brain Barrier (BBB)

BBB is a BBB is a complex physiologic processescomplex physiologic processes by by

which the brain is protected from metabolic which the brain is protected from metabolic

changes in the body.changes in the body.

BBB is located at BBB is located at endoth cells of cerebral capillendoth cells of cerebral capill

Transport depends on:Transport depends on:

1- Lipid solubility.1- Lipid solubility.

2- Mediation by specific carriers2- Mediation by specific carriers

In hepatic encephalopathy, there is:In hepatic encephalopathy, there is: 1) 1) Increase in the permeability leading toIncrease in the permeability leading to::

a- Brain edema.a- Brain edema.

b- Brain is exposed to circulating neurotoxin.b- Brain is exposed to circulating neurotoxin.

c- Loss of neurotransmitter c- Loss of neurotransmitter

2) 2) Alterations of specific carrier systemsAlterations of specific carrier systems

a- Increase transport of neutral amino acid a- Increase transport of neutral amino acid

b- Decrease glucose and basic amino acidsb- Decrease glucose and basic amino acids

IV) Altered Brain Energy IV) Altered Brain Energy Metabolism:Metabolism:

GloucoseGloucose is the most important cerebral is the most important cerebral

energy fuelenergy fuel

In cases of cirrhosis with HE, the glucose In cases of cirrhosis with HE, the glucose

metabolism is disturbedmetabolism is disturbed

HypoglycemiaHypoglycemia in terminal stages of liver in terminal stages of liver

failure may be a consequence of impaired failure may be a consequence of impaired

hepatic gluconeogenesis hepatic gluconeogenesis

V-Deficiency of essential substancesV-Deficiency of essential substancesCirrhosis lead to deficiency of certain vitamins Cirrhosis lead to deficiency of certain vitamins

minerals and micronutrientminerals and micronutrient

Zinc:Zinc:

Zinc is a cofactor in urea cycle Zinc is a cofactor in urea cycle

Found in vesicles of glutaminergic presynaptic Found in vesicles of glutaminergic presynaptic

terminals effecting neurotransmissionterminals effecting neurotransmission

Replacement should be considered if the patient Replacement should be considered if the patient

is deficientis deficient

VI) ProbioticsAmmonia 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.EMultifactorial mechanism of H.E

Encephalopathy

Exitatory glutamate

Arousal )serotonin(

NH3

Motor/cognitive)Dopamine(

Inhibitory)GABA(

NH3

Tryptophan

Direct neural toxin

False neurotransmitter

Endogen

BZ

Precipitating Factors1- Increased protein load -Upper GI hemorrhage -Ingestion of large protein meal2- Decreased excretion of ammonia -Renal failure -Constipation3- Electrolyte disturbance (e.g. hypokalaemia)4- Dehydration5- Paracentesis6- Creation of portacaval shunts7- Infection (SBP)8- Drugs (e.g. sedatives)9- Superimposed acute liver injury

Clinical ManifestationClinical Manifestation

Patients with hepatic encephalopathy Patients with hepatic encephalopathy

can presents with a variety of clinical can presents with a variety of clinical

features ranging from features ranging from subclinical or subclinical or

minimalminimal confusion to confusion to life-threatining life-threatining

comacoma with cerebral edema (often in with cerebral edema (often in

fulminant hepatic faliure)fulminant hepatic faliure)

1) 1) Disturbed conciousnessDisturbed conciousness

-Hypersomnia.-Hypersomnia.

-Confusion, drowsiness. -Confusion, drowsiness.

-Stuper and coma.-Stuper and coma.

2) 2) Personality ChangesPersonality Changes

-Childness, irritability, euphoria.-Childness, irritability, euphoria.

-Inappropriate loughing or crying.-Inappropriate loughing or crying.

3) 3) Intellectual Deterioration:Intellectual Deterioration:

4) 4) Emotional AbnormalityEmotional Abnormality

-Anxiety or depression.-Anxiety or depression.

5) 5) Other Features:Other Features:

a) Speech abnormalities:a) Speech abnormalities:

-Slow and slurred.-Slow and slurred.

-Monotonous voice.-Monotonous voice.

-Dysphasia.-Dysphasia.

b) Convulsions.b) Convulsions.

c) Brain stem dysfunction c) Brain stem dysfunction

-Hypothermia.-Hypothermia.

-Hyperventillation.-Hyperventillation.

-Sweating.-Sweating.

Examination:Examination:11)) Asterixes: Asterixes:

-Characteristic but not pathognmonic -Characteristic but not pathognmonic

-Usually bilateral, but not synchronus -Usually bilateral, but not synchronus

-Unilateral asterixes (rare) (with focal lesions of -Unilateral asterixes (rare) (with focal lesions of the thalamus and parietal cortex).the thalamus and parietal cortex).

2) Hyperreflexia.2) Hyperreflexia.

3) Extenser planter reflexes.3) Extenser planter reflexes.

4) Neck stiffness (rarely)4) Neck stiffness (rarely)

Fetor Hepaticus:Fetor Hepaticus:

Sweet musty odor in the breath.Sweet musty odor in the breath.

Usually present in hepatic encephalopathy.Usually present in hepatic encephalopathy.

Not correlate with degree or duration of HENot correlate with degree or duration of HE

Attributed to Attributed to mercaptansmercaptans which formed in the which formed in the

intestine by action of bacteriaintestine by action of bacteria. .

Clinical variantsClinical variants1-Sub-clinical H. Encephalopathy1-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%) It has high prevalence (30 - 70%)

Psychometric tests show that they perform Psychometric tests show that they perform

well in tests of well in tests of intellect, language, memoryintellect, language, memory

but poor in tests requiring visual, motor and but poor in tests requiring visual, motor and

constructional skills. constructional skills.

Associated with objective changes by C.TAssociated with objective changes by C.T

Diagnosed by psychomotric tests:Diagnosed by psychomotric tests:

1- Number connection test1- Number connection test

2- Digital symbol test2- Digital symbol test

3- Trail test3- Trail test

4- Block design test.4- Block design test.

Reversal of subclinical HE can occur with Reversal of subclinical HE can occur with

application of therapyapplication of therapy

2-Acute episodic (recurrent) form2-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

3-3-Fulminant liver faliure:Fulminant liver faliure:

The clinical features are essentially the same as those seen in patients with cirrhosis but

The onset is generally abruptThe onset is generally abrupt

Marked hepatic fetor is present at early stageMarked hepatic fetor is present at early stage

Neuropsychatric picture is more aggressiveNeuropsychatric picture is more aggressive

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

4-4-Chronic persistent encephalopathyChronic persistent encephalopathy::

- - Rare, irreversible encephalopathic syndromesRare, irreversible encephalopathic syndromes

- Found in patients with extended collateral - Found in patients with extended collateral

circulatory pathwayscirculatory pathways

- Neuropsychatric disorder dominate the picture- Neuropsychatric disorder dominate the picture

- Picture of liver disease may be equivocal - Picture of liver disease may be equivocal

- - The most frequent features areThe most frequent features are::

1- Progressive paraplegia1- Progressive paraplegia

2- Damage to basal ganglia & cerebellar system.2- Damage to basal ganglia & cerebellar system.

3- Focal cerebral symptoms (Epilepsy, dementia)3- Focal cerebral symptoms (Epilepsy, dementia)

Grades of hepatic encephalopathy

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

Grade II. 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.

II-Intracranial -Intracranial lesionslesions

-Trauma (e.g., subdural hematoma), -Trauma (e.g., subdural hematoma),

-Bleeding, Cerebral infarction-Bleeding, Cerebral infarction

-Tumors , Abscess -Tumors , Abscess

2-Infections2-Infections -Meningitis ,Encephalitis, -Meningitis ,Encephalitis,

-Subarachnoid hemorrhage -Subarachnoid hemorrhage

33-Metabolic -Metabolic EncephalopathiesEncephalopathies

-Anoxia, Uremia-Anoxia, Uremia ,Ketoacidosis ,Ketoacidosis

-Hypoglycemia, Electrolyte imbalance-Hypoglycemia, Electrolyte imbalance

-Inborn error of urea cycle, Reye's synd-Inborn error of urea cycle, Reye's synd

4-Toxic 4-Toxic encephalopathyencephalopathy

-Alcohol: -Acute intoxication -Alcohol: -Acute intoxication

-Withdrawal syndrome -Withdrawal syndrome

- Wernicke's syndrome- Wernicke's syndrome

-Tranquilizers-Tranquilizers

5-Neuropsychatric 5-Neuropsychatric disordersdisorders

Differential Diagnosis

InvestigationInvestigation

1- 1- Clinical Tests (Psychometric testsClinical Tests (Psychometric tests):):2- 2- CSF examCSF exam: : Glutamic acid and glutamine Glutamic acid and glutamine 3- 3- Ammonia:Ammonia: Raised but Raised but not correlatenot correlate with degree of enceph. with degree of enceph.4- 4- Electroencephalography (EEGElectroencephalography (EEG):): Sensitive means of detecting hepatic encephalopathy.Sensitive means of detecting hepatic encephalopathy. Not specific to hepatic encephalopathy.Not specific to hepatic encephalopathy.5- 5- Evoked PotentialsEvoked Potentials::6- 6- C.T BrainC.T Brain::7- 7- I C P MonitoringI C P Monitoring8- 8- MyelogramMyelogram::

9-Other investigations:9-Other investigations:To define To define causecause and and precepitatingprecepitating factors factors Liver function tests.Liver function tests. Bl. Glucose.Bl. Glucose. Serum electrolyteSerum electrolyte Bl. Urea nitrogen.Bl. Urea nitrogen. S. creatinine.S. creatinine. Arterial blood gases.Arterial blood gases. Cultures: blood, urine, sputum.Cultures: blood, urine, sputum. Blood ethanol level.Blood ethanol level. S. and urine drug screenS. and urine drug screen..

PathologyPathology

1-1-Acute encephalopathyAcute encephalopathy::

Cerebral edema are found in 25-50% Cerebral edema are found in 25-50%

2-2-Chronic encephalopathyChronic encephalopathy::

-Hypertrophy and hyperplasia of astrcoytes-Hypertrophy and hyperplasia of astrcoytes

-Astrocytes are swollen -Astrocytes are swollen (Alzhemer's type II cells)(Alzhemer's type II cells)

3-3-Acquired Hepatocerebral degenerationAcquired Hepatocerebral degeneration::

-Irreversible degenerative changes in CNS-Irreversible degenerative changes in CNS

-Diffuse necrosis in cortex -Diffuse necrosis in cortex

-Demylination in spinal cord.-Demylination in spinal cord.

PrognosisPrognosis The presence of HE is a serious prognostic The presence of HE is a serious prognostic

development in liver diseasesdevelopment in liver diseases

In ALFIn ALF , it defines the disease and the , it defines the disease and the

prognosis is generally very bad . prognosis is generally very bad .

In cirrhosisIn cirrhosis , the 1 year survival rate after any , the 1 year survival rate after any

episode of encephalopathy is only 40%episode of encephalopathy is only 40%

Encephalopathy indicate liver failure , and Encephalopathy indicate liver failure , and

should prompt consideration of liver should prompt consideration of liver

transplantationtransplantation

TREATMENTTREATMENT

1-Treatment of Precipitating Factors:1-Treatment of Precipitating Factors: Constipation

Electrolyte and acid-base imbalance

Infection (SBP)

Gastrointestinal bleeding

Portal-systemic shunts.

2-2-Treatment of Complications of Acute Treatment of Complications of Acute

Liver failure:Liver failure:

1-Monitored cardiovascular , respiration and 1-Monitored cardiovascular , respiration and

metabolic parameters metabolic parameters

2-Prophylactic antibiotic2-Prophylactic antibiotic

3-Intracranial pressure monitoring.3-Intracranial pressure monitoring.

If above 25 mm Hg If above 25 mm Hg Mannitol, ThiopentalMannitol, Thiopental

3-3-Orthotropic liver TransplantationOrthotropic liver Transplantation

Specific TreatmentSpecific Treatment

1- Treatment based on ammonia hypothesis1- Treatment based on ammonia hypothesis

2- Treatment based on false neurotransmitter2- Treatment based on false neurotransmitter

3- Treatment based on GABA hypothesis3- Treatment based on GABA hypothesis

4- Adjuvant therapy4- Adjuvant therapy

4- Probiotics 4- Probiotics

I-Treatment based on ammonia I-Treatment based on ammonia hypothesishypothesis

Ammniogenic substrate

Intestinal ammonia

production

Metabolic ammonia fixation

1 - Dietary protein2 -Enema

1 -Antibiotics2 -Lactulose

1-Ornithine aspart2-Benzoate&

Phenylacetate

1- 1- Decrease of Ammoniagenic Decrease of Ammoniagenic

Substrates.Substrates.

a) a) Reduce dietary protein Reduce dietary protein ::

Subclinical HE 40 gm/daySubclinical HE 40 gm/day

Grade 1 or 2 30 gm/dayGrade 1 or 2 30 gm/day

Acute and severe attack (Grade 3 or 4)Acute and severe attack (Grade 3 or 4)

-Withdrowal all dietary protein -Withdrowal all dietary protein

- Calories intake is maintained at 2000 cal - Calories intake is maintained at 2000 cal

/day or above either oral or IV./day or above either oral or IV.

During Recovery:During Recovery:

Protein intake is increased by 10 gm/day every Protein intake is increased by 10 gm/day every

33rdrd day until normal intake (60-80 gm/d) day until normal intake (60-80 gm/d)

In Chronic Cases:In Chronic Cases:

Perminant protein restriction Perminant protein restriction

The limit of tolerance is 40-60 gm/day.The limit of tolerance is 40-60 gm/day.

Vegitable Protein:Vegitable Protein:

Tolerated better than animal protein.Tolerated better than animal protein.

Less ammoniagnicLess ammoniagnic

More laxative due to their high fiber content.More laxative due to their high fiber content.

Calorie intake:Calorie intake:

1,800-2,500 (cal/d) is guaranteed by the 1,800-2,500 (cal/d) is guaranteed by the

adequate adminstration of fats (70-140 g) and adequate adminstration of fats (70-140 g) and

CHO (280-325g)CHO (280-325g)

Insulin (cirrhotic patients show insulin Insulin (cirrhotic patients show insulin

resistance) resistance)

VitaminsVitamins : :

Daily intake of multivitamins , trace element , Daily intake of multivitamins , trace element ,

minerals , zinc is recommendedminerals , zinc is recommended

2) Enema:2) Enema:In acute and severe coma especially in In acute and severe coma especially in

highly constipated patients or in cases of highly constipated patients or in cases of

massive GIT bleedingmassive GIT bleeding

The volume used should be at least 1000 mlThe volume used should be at least 1000 ml

300 ml lactulose with 700 ml water are 300 ml lactulose with 700 ml water are

efficaciousefficacious

(2) Inhibition of Intestinal Ammonia Production:(2) Inhibition of Intestinal Ammonia Production:

1-1-Anhibiotics:Anhibiotics:

1-1-NeomycinNeomycin

Alter gut flora ( E-coli , urease producing org.)Alter gut flora ( E-coli , urease producing org.)

Impair absorption of ammoniaImpair absorption of ammonia

Inhibit uptake of glutamic acid by mucosal cellsInhibit uptake of glutamic acid by mucosal cells

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

Only used for short-term therapy (toxicity)Only used for short-term therapy (toxicity)

2-Metronidazole.2-Metronidazole.

Active aginst bacteroids and other anerobes Active aginst bacteroids and other anerobes

Effective as neomycin.Effective as neomycin.

Dose: 200 mg 4 times daily.Dose: 200 mg 4 times daily.

should not be used long-term (should not be used long-term (CNS toxicity) CNS toxicity)

3-Vancomycin3-Vancomycin

Reduces bacteroidsReduces bacteroids

Successively used in patients with lactulose Successively used in patients with lactulose therapy faliuretherapy faliure

Dose: 4 X 0.5 gm/dayDose: 4 X 0.5 gm/day

2-Lactulose2-Lactulose-Non absorbable, synthetic disaccharide.-Non absorbable, synthetic disaccharide.

Mode of action:Mode of action:

1-1-Osmotic laxative.Osmotic laxative.

2-2-Promotes lactobacilli growth Promotes lactobacilli growth increased lactic, increased lactic, acetic, and formic acids acetic, and formic acids decreased colonic decreased colonic PH PH inhibits growth of urease-producing inhibits growth of urease-producing bacteria especially E-coli.bacteria especially E-coli.

3-3-Traps luminal ammonia and its absorption.Traps luminal ammonia and its absorption.

4-4-Increase diffusion of ammonia from the Increase diffusion of ammonia from the mucosal blood into the gut.mucosal blood into the gut.

Lactitol:Lactitol:Similar to lactulose in action.Similar to lactulose in action.

More palatable (Less sweet )More palatable (Less sweet )

Causes less diarrhea and flatulenceCauses less diarrhea and flatulence..

Lactose:Lactose:Effective substitute for lactulose in patients Effective substitute for lactulose in patients

who are known to be lactase deficient.who are known to be lactase deficient.

3-3-Stimulation of Metabolic Ammonia FixationStimulation of Metabolic Ammonia Fixation::

a)a)Ornithine Ornithine -keto glutarate or ornithine -keto glutarate or ornithine

aspartateaspartate

-Ornithine is a substrate of urea synthesis-Ornithine is a substrate of urea synthesis

-Aspartate, ornithine reinforce glutamine -Aspartate, ornithine reinforce glutamine

synthesis which serve to detoxify ammoniasynthesis which serve to detoxify ammonia

-They improves HE in cirrhotic patients-They improves HE in cirrhotic patients

b)b)Benzoate and Phenylacetate:Benzoate and Phenylacetate:

-Successfully used in treatment of congenital -Successfully used in treatment of congenital

enzymatic defect of urea synthesisenzymatic defect of urea synthesis

II-Treatment based on the false-II-Treatment based on the false-

neurotransmitter Hypothesisneurotransmitter Hypothesis

1-Branched-Chain Amino Acids:1-Branched-Chain Amino Acids:

May be of value for long term treatment of HE.May be of value for long term treatment of HE.

Provides safe and well-tolerated source of Provides safe and well-tolerated source of nutrition in patients with cirrhosis nutrition in patients with cirrhosis

BCAAs treatment leads toBCAAs treatment leads to:-:-

1- Improvement in nitrogen balance.1- Improvement in nitrogen balance.

2- Less protein catabolism.2- Less protein catabolism.

3- Enhanced protein synthesis.3- Enhanced protein synthesis.

2-L-Dopa and Bromocryptine:2-L-Dopa and Bromocryptine:

Decreased dopaminergic neurotransmission is Decreased dopaminergic neurotransmission is

a component of false neurotransmitter theory.a component of false neurotransmitter theory.

a) a) Levo-dopaLevo-dopa: :

A precursor of the neurotransmetters A precursor of the neurotransmetters

norepinephrine and dopamine norepinephrine and dopamine

b) b) BromocreptineBromocreptine : :

-Specific dopamine receptor agonist-Specific dopamine receptor agonist

-Give improvement in chronic portosystemic -Give improvement in chronic portosystemic

encephalopathyencephalopathy

III- Treatment Based on the GABA III- Treatment Based on the GABA

Hypothesis "Flumazenil Hypothesis "Flumazenil

Benzodiazepine-receptor antagonist.Benzodiazepine-receptor antagonist.

induce transient improvement in 70% of induce transient improvement in 70% of

patients with HEpatients with HE

Dose:Dose: 0.2- 0.3 mg IV bolus, followed by 0.2- 0.3 mg IV bolus, followed by

5mg/h as IV infusion5mg/h as IV infusion

IV-Adjuvant therapyIV-Adjuvant therapy

1-1-PiracetamPiracetam

Nootropic substanceNootropic substance

improve typical electrical brain activitiesimprove typical electrical brain activities

2-2-L-carnitineL-carnitine

Markedly reduce hyperammonaemia Markedly reduce hyperammonaemia

Improve the clinical symptoms of HE in cirrhotic Improve the clinical symptoms of HE in cirrhotic

patientspatients

V- ProbioticsThey 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.