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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