hepatic encephalopathy ppt

8/15/2019 hepatic Encephalopathy Ppt

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ByProf Dr. Elsaid galal Elbadrawy

Tropical MedicineHepatogastroentrology

Faculty of medicine

Zagazig universiy


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Hepatic encephalopathy (HE)

describes all the neurosychatric

symptoms occurring in patients

with acute or chronic liver disease

in the absence of other neurologic

disorders


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PrevalenceThe 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 includedin the diagnostic definition of HE


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The occurrence of hepatic encephalopathy is onlypossible 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 whichthe non-toxified portal blood bypasses the liver,so that toxic substances reach the brain


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Classification

Associated with acute liver faliureType A:

Portal-systemic bypass withoutintrinsic hepato-cellular disease.

Type B:

Cirrhosis and portal hypertensionwith portal-systemic shunts.

Type C:

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


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Type C can fur ther divided into:1-Episodic HE.

Precipitated

Spontaneous

Recurrent encephalopathy

2-Persistent HE.

Mild

SevereTreatment-dependent persistent HE

3-Minimal HE.


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Many factors have been implicated in

the pathogenesis of HE, but it is the‘multiple -hi t hypothesis’ that appears

most important.

Pathogenes is


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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


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Ammonia and urea metabolism


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Role of skeletal muscle in ammonia metabolism inpatients with liver failure


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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 wasting6- Enzyme defect in urea synthesis


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Ammonia and glutamate – glutamine cycle

Ammonia affects a number of neurotransmitterthrough its products of metabolism (e.g.glutamate & glutamine ).

In the brain, ammonia is normally detoxified

within the astrocytes and eliminated by theamidation of glutamate.

Glutamate is an excitatory neurotransmitter ;

after reacting with post-synaptic receptors, it isconverted within astrocytes to glutamine


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

In hepatic encephalopathy:1- cerebral glutamine are increased2- cerebral glutamate decreased3- glutamate re-uptake mechanisms are abnormal4- glutamate-binding sites on post-synaptic

neurones are down-regulated.

Increased glutamine in astrocytes → osmoticstress → cellular swelling and cellular change,termed Alzheimer type 2 astrocytosis


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Astrocyte , nerve cells, synapses


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Ammonia & glutamate – glutamine cycle


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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

(hyp o thes i s o f p r im ary g l iop athy)


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NH3

Intestinal protein/bacteria

Reduced hepsticremoval

Reduced muscle mass

Alter BBB Astrocytedamage

glutamineDirect effects

Exicitatory pathways

Sources and potential role of ammonia


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

(Synergism Hypoth es is )

2- Phenolic Compounds

3- Short Chain Fatty Acids

- Inhibit various enzymes of urea cycle

- Displacement of tryptophan from its bindingto albumin → ↑ tryptophan


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II) Neurotransmitters

1-GABA hypothesis ( -Amino butyric Acid):GABA is the principal inhibitory neurotransmitterin brainSynthesis:a- In presynaptic neurones: from glutamic acidb- In intestine: by gut bacteria, enter portal vein

and metabolized by liver.In liver failure or portal systemic shuntingsystemic circulation cross BBB to interactwith supersensitive postsynaptic GABA receptors


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GABA bind to specific GABA receptor in post-

synaptic membrane. This receptors also bindsbenzodiazepines and barbiturates .

Changes in affinity and denisity of postsynapticreceptors play important role for GABA andother neurotransmitter

The binding of benzdiazipines to GABAreceptors intensifies the effect of GABA


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2-False Neurotransmitter Hypothesis:

The liver plays an essential part in metabolismof amino acids

In chronic liver disease:1- Aromatic amino acids (AAA)

tyrosine, phenylalanine, tryptophane

2- Branches chain amino acids (BCAA) valine, leucine


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cerebral tryptophan increase synthesis ofserotonin (depressant of conciousness).

phenylalanine in brain inhibit tyrosine 3-hydroxylase, ( key enzyme for synthesis ofcatecholaminergic neurotransmtter

Tyrosine increase synthesize of tyramine, octapamine which complete with catecholamineneurotransmitters for the same receptor site.

brain dopamine and displacement of dopamineby false neurotransmitter impairment ofdopamingeric neurotransmission.


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Noradrenaline

L-dopa

Dopamine

Sympathetic transmitter

Tyrosine

Tyramine

Octopamine

Phenylalanine

B phenylethanolamine

Tyrosine

Colon: protein

Intestinal bacterial decarboxylase

Disturbed brain metabolism

True False


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III) Alteration of Bl. Brain Barrier (BBB)

BBB is a complex physiologic processes bywhich the brain is protected from metabolicchanges in the body.

BBB is located at endoth cells of cerebral capill

Transport depends on:

1- Lipid solubility.2- Mediation by specific carriers


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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 neurotransmitter2) Alterations of specific carrier systems

a- Increase transport of neutral amino acid

b- Decrease glucose and basic amino acids


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IV) Altered Brain Energy Metabolism:

Gloucose is the most important cerebralenergy fuel

In cases of cirrhosis with HE, the glucosemetabolism is disturbed

Hypoglycemia in terminal stages of liverfailure may be a consequence of impairedhepatic gluconeogenesis


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

minerals and micronutrient

Zinc:

Zinc is a cofactor in urea cycleFound in vesicles of glutaminergic presynapticterminals effecting neurotransmission

Replacement should be considered if the patientis deficient


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VI) Probiotics Ammonia produced by the gut is from thedeamination of dietary amino acids bybacteria

In malnourished patient, the levels of thedefensive bacteria strains (Bifidobacteriumand Lactobacillus) decline.

Probiotics are thought to exert an effect inHE


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Mult i fac to r ial m ech anis m of H.E

Encephalopathy

Exitatoryglutamate

Arousal( serotonin)

NH3

Motor/cognitive(Dopamine)

Inhibitory

(GABA)

NH3

Tryptophan

Directneuraltoxin

Falseneurotransmitter

EndogenBZ


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Precipitating F actors

1- Increased protein load

-Upper GI hemorrhage-Ingestion of large protein meal

2- 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


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Clinical Manifestation

Patients with hepatic encephalopathycan presents with a variety of clinical

features ranging from subc l in ica l o rmin ima l confusion to l i fe-threat iningc o m a with cerebral edema (often infulminant hepatic faliure)


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1) Disturbed conciousness

-Hypersomnia.

-Confusion, drowsiness.

-Stuper and coma.

2) Personality Changes-Childness, irritability, euphoria.

-Inappropriate loughing or crying.

3) Intellectual Deterioration:


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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.


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Examination:

1 ) Asterixes:-Characteristic but not pathognmonic

-Usually bilateral, but not synchronus

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

2) Hyperreflexia.

3) Extenser planter reflexes.4) Neck stiffness (rarely)


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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 .


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Clinical variants1-Sub-clinical H. Encephalopathy

Dif: Patients with chronic liver disease whohave no clinical symptoms of braindysfunction, but perform worse onpyschometric tests

It has high prevalence (30 - 70%)

Psychometric tests show that they performwell in tests of intellect, language, memory but poor in tests requiring visual, motor andconstructional skills.


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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 withapplication of therapy


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2-A cu te episo d ic (recu rrent) for m Dif: An acute confusional syndrome with

impaired mental state, neuromuscularabnormalities, fetor hepaticus, hyperventilation.

The symptoms appear abruptly and developover a period of hours to days, with oscillationof severity over time

Asterixis is very characteristic

Relapses are common.

Respond well to treatment


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3-Fulm in an t liv er fal iure:

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

The onset is generally abrupt

Marked hepatic fetor is present at early stageNeuropsychatric picture is more aggressive

Signs of increased intracranial pressure

(bradycardia, hypertension, dilated pupils,decerebrate posturing) may also be seen.


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4-Chro nic pers is tent enc eph alop athy:

- 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 paraplegia2- Damage to basal ganglia & cerebellar system.3- Focal cerebral symptoms (Epilepsy, dementia)


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Grades of hepatic encephalopathy

Euphoria or depression, mild confusion,monotonous voice and/or sleep cycledisorders. Asterixis +

Grade I.

Lethargy and/or confusion.Asterixis,

Grade II.

Severe confusion, incoherent language,semi-stupor but awakes with language.

Asterixis

Grade III.

Coma, initially can respond to painfulstimuli.

Grade IV.


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

-Bleeding, Cerebral infarction-Tumors , Abscess

I-Intracranialles ions

-Meningitis ,Encephalitis,-Subarachnoid hemorrhage

2-Infections

-Anoxia, Uremia ,Ketoacidosis-Hypoglycemia, Electrolyte imbalance-Inborn error of urea cycle, Reye's synd

3 -MetabolicEnceph alopathies

-Alcohol: -Acute intoxication-Withdrawal syndrome- Wernicke's syndrome

-Tranquilizers

4-Toxic

encephalopa thy

5-Neuropsychatr icd isorders

Differential Diagnosis


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Investigation

1- Clinical Tests (Psychometric tests):2- CSF exam: Glutamic acid and glutamine3- 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 Monitoring8- Myelogram:


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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 .


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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.


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PrognosisThe presence of HE is a serious prognosticdevelopment in liver diseases

In ALF , it defines the disease and theprognosis is generally very bad .

In cirrhosis , the 1 year survival rate after anyepisode of encephalopathy is only 40%

Encephalopathy indicate liver failure , andshould prompt consideration of livertransplantation


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TREATMENT

1-Tr eatment of Precipitating F actors: Constipation

Electrolyte and acid-base imbalance Infection (SBP)

Gastrointestinal bleeding

Portal-systemic shunts .


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2-Tr eatment of Complications of Acute

L iver failure: 1-Monitored cardiovascular , respiration and

metabolic parameters

2-Prophylactic antibiotic3-Intracranial pressure monitoring.

If above 25 mm Hg Mannitol, Thiopental

3-Orthotropic liver Transplantation


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Specif ic Treatment

1- Treatment based on ammonia hypothesis

2- Treatment based on false neurotransmitter

3- Treatment based on GABA hypothesis

4- Adjuvant therapy

4- Probiotics


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I-Treatm en t b ased o n am m o niahypo thes i s

Ammniogenic

substrate

Intestinalammonia

production

Metabolicammonia

fixation

1- Dietary protein

2- Enema

1- Antibiotics2- Lactulose

1-Ornithine aspart2-Benzoate &

Phenylacetate


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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.


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Dur ing Reco very :

Protein intake is increased by 10 gm/day

every 3 rd day until normal intake (60-80 gm/d)In Chr on ic Cases:

Perminant protein restriction

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

Vegitable Pro te in:

Tolerated better than animal protein.

Less ammoniagnic

More laxative due to their high fiber content.


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Calor ie intake:

1,800-2,500 (cal/d) is guaranteed by theadequate adminstration of fats (70-140 g) andCHO (280-325g)

Insulin (cirrhotic patients show insulinresistance)

Vitam ins :

Daily intake of multivitamins , trace element ,minerals , zinc is recommended


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2) Enema:In acute and severe coma especially inhighly constipated patients or in cases ofmassive GIT bleeding

The volume used should be at least 1000 ml

300 ml lactulose with 700 ml water areefficacious


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(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)


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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-VancomycinReduces bacteroidsSuccessively used in patients with lactulose

therapy faliureDose: 4 X 0.5 gm/day


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2-Lactulose-Non absorbable, synthetic disaccharide. Mode of action: 1-Osmotic laxative.2-Promotes lactobacilli growth increased lactic,

acetic, and formic acids decreased colonicPH inhibits growth of urease-producingbacteria especially E-coli.

3-Traps luminal ammonia and its absorption.4- Increase diffusion of ammonia from themucosal blood into the gut.


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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.


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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 congenitalenzymatic defect of urea synthesis


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II-Treatm ent b ased o n th e false-

neuro t rans m i t ter Hypo thes i s

1-Branched-Chain Amino Acids:

May be of value for long term treatment of HE.

Provides safe and well-tolerated source ofnutrition in patients with cirrhosis

BCAAs treatment leads to:-

1- Improvement in nitrogen balance.

2- Less protein catabolism.

3- Enhanced protein synthesis.


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2-L-Dopa and Bromocryptine:

Decreased dopaminergic neurotransmission is

a component of false neurotransmitter theory.a) Levo -do pa:

A precursor of the neurotransmettersnorepinephrine and dopamine

b) Bromocreptine :

-Specific dopamine receptor agonist

-Give improvement in chronic portosystemicencephalopathy


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III- Treatmen t B ased o n th e GAB A

Hypo thes i s " Flum azeni l

Benzodiazepine-receptor antagonist.

induce transient improvement in 70% ofpatients with HE

Dose: 0.2- 0.3 mg IV bolus, followed by5mg/h as IV infusion


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IV-A d juv an t therap y

1-PiracetamNootropic substance

improve typical electrical brain activities

2-L-carnitineMarkedly reduce hyperammonaemia

Improve the clinical symptoms of HE in cirrhoticpatients


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V- Prob iot ics 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 pHc) ↓ intestinal permeabilityd) improving nutritional status of gut epithelium.

2- Decrease inflammation and oxidative stress inhepatocyte → ↑ hepatic clearance of ammonia

3- Decreasing uptake of other toxins.


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hepatic encephalopathy ppt

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