EFFA PRESENTATNhepatic Encephalopathy Ppt

8/4/2019 EFFA PRESENTATNhepatic Encephalopathy Ppt

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By

DR. EFFA MUJEEB KHAN

House OfficerMedical Unit 4

Civil Hospital Karachi


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Hepatic encephalopathy (HE) is a

complex metabolic mental state

disorder with a spectrum of reversibleneuropsychiatric abnormalities seen in

patients with severe acute or chronic

liver dysfunction after exclusion ofother brain diseases


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PREVALENCE

It can be found in up to 50 to 70%

of cirrhotic patients.


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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


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Associated with acute liver failureType A:

Portal-systemic bypass without intrinsic

hepato-cellular disease.

Type B:

Cirrhosis and portal hypertension withportosystemic shunts.

Type C:

The World Congress ofGastroenterology in

2002 classified hepatic encephalopathy:


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Type C can be further divided into:1-Episodic HE.

Precipitated

Spontaneous

Recurrent encephalopathy2-Persistent HE.

Mild

Severe Treatment-dependent persistent HE

3-Minimal HE.


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Many causative factors have been

implicated in the pathogenesis of HE,

but it is the multiple-hithypothesisthat

appears to be most important.

CAUSES


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I) Neurotoxins

1-Ammonia

2) Other possible Toxins

II) Neurotransmitters

1-GABA (-Amino butyric Acid):

2-False Neurotransmitters

III) Alteration of Blood Brain Barrier (BBB)

IV) Altered Brain Energy MetabolismV-Deficiency of Essential Substances

VI) Decrease in Probiotics


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I) Neurotoxins

1-Ammonia:

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: by glutamine synthetase


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How does ammonia affect the brain in HE?1- Alters blood brain barrier

2- Brain ammonia is consumed in the conversion of glutamate to

glutamine by glutamine synthetase in astrocytes. Glutamine is an

osmolyte and increased Gln accumulation in these cells may

contribute to cytotoxic brain edema (Alzheimer type 2 astrocytosis)

which often complicates FHF.

3- Alters brain energy metabolism

4- Exerts direct effects on neuronal membranes withchange in neurotransmitter receptors

(hypothesis of primary gliopathy)


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4. Acute ammonia neurotoxicity, which may be a causeof seizures in FHF, is excitotoxic in nature, being

associated with increased synaptic release of glutamate(Glu), the major excitatory neurotransmitter of thebrain, and subsequent over-activation of the ionotropicGlu receptors, mainly theN-methyl-d-aspartate(NMDA) receptors.

5. Hepatic encephalopathy complicating chronic liverfailure seems associated with a shift in the balancebetween inhibitory and excitatory neurotransmissiontowards a increase of inhibitory neurotransmission as a

consequence of down-regulation of Glu receptorsresulting in decreased glutamatergic tone. The down-regulation follows excessive extrasynapticaccumulation of Glu resulting from its impaired re-uptake into nerve endings and astrocytes. This is alsoinduced by ammonia accumulation.


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1-Nitrogenous intestinal content

2- Change in the intestinal flora

3- Degree of liver dysfunction

4- Extent of portocaval collaterals

5- Muscle wasting (muscles contain glutamine

synthetase)

6- Enzyme defect in urea synthesis


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2) Other possible Toxins:

(i) Mercaptans & methionine derivatives

(Synergism Hypothesis)

(ii) Phenolic Compounds(iii) Short Chain Fatty Acids

- Inhibit various enzymes of urea cycle

- Displace tryptophan from its

binding to albumin tryptophan


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II) Neurotransmitters

1-GABA (-Amino butyric Acid):GABA is the principal inhibitory neurotransmitter in

brain.

Synthesis:a- In presynaptic neurons: from glutamic acid

b- In intestine: by gut bacteria (enters portal vein

and metabolized by liver)

In liver failure or portosystemic shunting, GABA in the

systemic circulation crosses BBB to interact with

supersensitive postsynaptic GABA receptors.


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GABA binds to specific GABA receptors in

post-synaptic membrane. These receptors alsobind benzodiazepines and barbiturates.

The binding of benzodiazepines to GABAreceptors intensifies the effect of GABA.


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2-False Neurotransmitters:

The liver plays an essential part in metabolism of amino

acids.

In chronic liver disease:

1- Aromatic amino acids (AAA) like

tyrosine, phenylalanine and tryptophan

(Due to the failure of hepatic deamination)

2- Branched-chain amino acids (BCAA) like

valine and leucine

(Due to increased metabolism by skeletal muscle and

kidneys)


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cerebral tryptophan increases synthesis ofserotonin (depressant of consciousness)

Phenylalanine in brain inhibits tyrosine 3-hydroxylase ( key enzyme for synthesis ofcatecholaminergic neurotransmitter)

Tyrosine increases synthesis of tyramine,octapamine which competes with catecholamineneurotransmitters for the same receptor site

Brain dopamine due to displacement ofdopamine by false neurotransmitterimpairment of dopaminergic neurotransmission


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III) Alteration of Blood Brain Barrier(BBB)

BBB is a complex physiologic barrier by which

the brain is protected from metabolic changes in

the body.BBB is located at endothelial cells of cerebral

capillaries.

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 causing:a- Brain edema

b- Exposure of brain to circulating

neurotoxins

c- Loss of neurotransmitter

2) Alterations of specific carrier systems causing:

a- Increased transport of neutral amino acids

b- Decreased transport of glucose and basic

amino acids


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IV) Altered Brain Energy

Metabolism:

Glucose 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.


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V-Deficiency of essential substances

Cirrhosis leads to deficiency of certain vitamins,minerals and micronutrients

Zinc:

Zinc is a cofactor in urea cycle

Found in vesicles of glutaminergic presynaptic

terminals affecting neurotransmissionReplacement should be considered if the

patient is deficient


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VI) Decrease in Probiotics

Probiotics are live micro-organisms beneficialto the host organism. In a malnourished

patient like one who has a cirrhotic liver, the

levels of these defensive bacteria strains

(Bifidobacterium and Lactobacillus) decline.

Their decline results deprives the patient oftheir several benefits (discussed later).


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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- Paracentesis6- Creation of portacaval shunts

7- Infection (SBP)

8- Drugs (e.g. sedatives)

9- Superimposed acute liver injury


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CLINICALMANIFESTATIONS

CLINICALGRADE

CLINICAL SIGNS

Grade 1 Poor concentration, slurred speech, disordered sleeprhythm (day night reversal)

Grade 2 Drowsy but easily rousable, occasional aggressivebehaviour, lethargic (flapping tremors on examination)

Grade 3 Marked confusion, sleepy but responds to pain andvoice, gross disorientation ( Increased tone onexamination)

Grade 4 Unresponsive to voice, may or may not respond topainful stimuli, unconscious


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FINDINGS ONEXAMINATION1) Asterixes:

-Characteristic but not pathgnomonic-Usually bilateral, but not synchronous

-Unilateral asterixis - rare (with focal lesionsof the thalamus and parietal cortex).

2) Hyperreflexia

3) Extensor plantar reflexes


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4) Neck stiffnessrare

5) Fetor hepaticus: Sweet musty odor in the breath

usually present in hepatic encephalopathy. It does not

correlate with the degree or duration of HE and is

attributed tomercaptans which are formed in theintestine by action of bacteria and are normally

degraded by the liver


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FOUR CLINICAL VARIANTS1-Sub-clinical H. Encephalopathy It can be defined as a state of chronic liver disease

with no clinical symptoms of brain dysfunction,

but unsatisfactory performance on pyschometric

tests.

It has high prevalence (30 - 70%).

Psychometric testing show that such patients

perform well in tests of intellect, language,

memory but poor in tests requiring visual, motorand constructional skills. These tests include

Number Connection Test, Trail Test and Block

Design Test.


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2-Acute episodic (recurrent) form

It is an acute confusional syndrome with impairedmental state, neuromuscular abnormalities, fetor

hepaticus, hyperventilation.

The symptoms appear abruptly and develop over aperiod of hours to days, with oscillation of severity

over time.

Asterixis is very characteristic

Relapses are common.

Responds well to treatment.


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3-Fulminant liver failure:

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

The onset is generally abrupt.

Marked hepatic fetor is present at an early stage.

Neuropsychatric picture is more aggressive.

Signs of increased intracranial pressure

(bradycardia, hypertension, dilated pupils,

decerebrate posturing) may also be seen.


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4-Chronic persistent

encephalopathy:

Arare, irreversible encephalopathic syndrome Found in patients with extended collateral

circulatory pathways Neuropsychiatric disorder dominates 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)

MANAGEMENT


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MANAGEMENTINVESTIGATIONS

Preliminary:Liver function tests

Bl. Glucose

Serum electrolyteBlood Urea nitrogen

Serum Creatinine

Arterial blood gasesCultures: Blood, urine, sputum

Blood ethanol level

Serum and urine drug screen


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Clinical Tests (Psychometric tests)

CSF exam: Raised glutamineArterial Ammonia:

-Raised but does not correlate with degree ofencephalopathy

Electroencephalography (EEG):-Slowing of the normal alpha waves with

eventual development of delta waves-Sensitive means of detecting hepatic

encephalopathy but not specific for hepaticencephalopathy.

Evoked PotentialsOther Monitoring: C.T. Brain

I C P Monitoring

Suggestive of PSE:


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Our treatment objectivesshould be1. Normalization of neurological functions2. Elimination of precipitating factors

3. Suppressing production of neurotoxins by

bacteria in the bowel

4. Monitoring and stabilization of

cardiovascular, respiratory and metabolic

parameters


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I- Treatment based on ammonia hypothesis

II- Treatment based on false neurotransmitterhypothesis

III- Treatment based on GABA hypothesis

IV- Adjuvant therapy

V- Probiotics


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Ammoniogenic

substrate

Intestinalammoniaproduction

Metabolicammonia

fixation

1- Dietaryprotein

2- Enema

1- Antibiotics2- Lactulose

1-Ornithine aspart2-Benzoate &

Phenylacetate


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(i) Decrease Ammoniogenic 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)

-Withdraw all dietary protein

- Calories intake is maintained at 2000 cal

/day or above either oral or IV


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During Recovery:

Protein intake is increased by 10 gm/day every 3rd

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

In Chronic Cases:

Permanent protein restriction to 40-60 gm/day

Vegetable Protein:

Tolerated better than animal protein

Less ammoniogenic

More laxative due to its high fiber content


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b) 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


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(ii) Inhibition of Intestinal Ammonia

Productiona) Antibiotics:

NeomycinAlters gut flora (Decreases E-coli , a urease producing

organism)

Impairs absorption of ammonia

Inhibits uptake of glutamic acid by mucosal cells

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

Only used for short-term therapy (oto- and nephrotoxicity)


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MetronidazoleActive against bacteroides and other anerobes

As effective as neomycin

Dose: 200 mg/6hrs daily orally

Should not be used long-term (CNS toxicity)

Vancomycin

Reduces bacteroides

Successfully used in patients with lactulose therapy

failureDose: 0.5 gm/6hrs daily orally


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b) Lactulose

-Non absorbable, synthetic disaccharide.

Mode of action:

1-Exerts osmotic laxative effect

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-Increases diffusion of ammonia from the mucosal

blood into the gut

-Dose: 30-50ml/8hrs orally


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(iii) Stimulation of Metabolic AmmoniaFixation

a) Ornithine -keto glutarate or ornithine aspartate

-Ornithine is a substrate of urea synthesis

-Ornithine aspartate reinforces glutamine synthesis

which serves to detoxify ammonia

-They improves HE in cirrhotic patients

b) Benzoate and Phenylacetate:

-Successfully used in treatment of congenital

enzymatic defect of urea synthesis


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II-Treatment based on the False

Neurotransmitter Hypothesis(i) Branched-Chain Amino Acids:

May be of value for long term treatment of HE

Provide 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


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(ii) L-Dopa and Bromocriptine:

Decreased dopaminergic neurotransmission is a

component of false neurotransmitter theory.

a) Levo-dopa:

A precursor of the neurotransmitters norepinephrine

and dopamine

b) Bromocriptine :

-Specific dopamine receptor agonist-Provides improvement in chronic portosystemic

encephalopathy


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III- Treatment Based on the GABA

Hypothesis: Flumazenil

Benzodiazepine-receptor antagonist

Induces transient improvement in 70% of patients

with HE

Dose: 0.2- 0.3 mg IV bolus, followed by 5mg/h asIV infusion


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IV-Adjuvant therapy

(i) PiracetamNootropic substance

Improves typical electrical brain activities

(ii) L-Carnitine

Markedly reduces hyperammonaemia

Improve the clinical symptoms of HE in cirrhotic

patients

(iii) Zinc


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V-ProbioticsThey have multiple beneficial effects in treatment of

minimal HE by:

1- Decreasing 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- Decreasing inflammation and oxidative stress inhepatocyte hepatic clearance of ammonia

3- Decreasing uptake of other toxins


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PROGNOSISThe 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%.

Chronic or refractory hepatic encephalopathy is

one of the main indications for liver transplantation.


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Documents

EFFA PRESENTATNhepatic Encephalopathy Ppt