Advances in Cerebral Dysfunction in Hepatic Encephalopathy
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Transcript of Advances in Cerebral Dysfunction in Hepatic Encephalopathy
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nderstandingnderstandingerebral Dysfunctionerebral Dysfunctionnn epaticepaticEncephalopathyncephalopathy
By
Dr Junaid SaleemConsultant Physician
Special Interest: Liver Disorders
Hearts International Hospital
Rawalpindi
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Presentation At A GlanceDefinition(s)Preconditions to be met for
Development of HepaticEncephalopathy (HE)
Precipitating Factors
Cerebral and Neuronal DysfunctionsBiochemical Abnormalities and
Advances in Diagnostic Imaging
Techniques
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( )efinition s)efinition s
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DefinitionHepatic Encephalopathy reflects aspectrum of neuropsychiatricabnormalities seen in patients withliver dysfunction after exclusion ofother known brain diseases.
. , . , . , Working Group of WCOG Final Report Hepatology Vol 35 No 3 2002
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DefinitionHepatic encephalopathy is apotentially reversible syndrome ofglobal cerebral dysfunction observedin patients with liver diseases(reduced liver mass) or porto-systemic shunting, characterized by:
Personality changesIntellectual impairment
Depressed level of consciousness
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reconditions toreconditions toe met fore met for evelopment ofevelopment of
epaticepaticEncephalopathyncephalopathy
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Preconditions to be metfor Development ofHepatic Encephalopathy
1.Reduced Liver Mass< 25 30 % of Functional Liver
Unable to deal with the Gut derivedNitrogen Load
Passes through, but is not Detoxified /Metabolized
2.Porto-Systemic ShuntsBypassing Liver
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Liver DiseasesAcuteAcute Liver Failure (ALF) Fulminant
Hepatic Failure (FHF)
ChronicChronic Hepatitis
Cirrhosis
Cholestatic liver DiseaseWilsons Disease
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Porto-Systemic Shunts
(PSSs)Congenital or acquired vascularabnormalities
Single or multiple vascular bypasschannels
Permit portal blood flow to bypass theliver and enter the systemic circulationdirectly.
Neurotoxic substances get a direct accessto the CNS
Hepatic Encephalopathy
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o te n tia l-o rto yste m icS h u n ts1.Under the
Diaphragm
2.LowerEsophagus
3.AbdominalWall
4.Colon andRectum
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( :// . /ttp maxshouse com portosystemic_shunts. )pathogenesis_and_pathophysiology htm
Liver
Spleenortal Vein
Shunt
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Iatrogenic ShuntsTIPS Surgical Shunts
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epaticEncephalopaty MechanismGut DerivedNitrogenousMaterialBypasses LiverVia Shunts andReaches theBrain Directly
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recipitatingrecipitatingFactorsactors
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epatic Encephalopathyxacerbating factors
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erebral anderebral andeuronaleuronalDysfunctionsysfunctions
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Pathogenesis
Multifarious toxins Dysfunction of CNS
(No obvious morphological change)
Several hypotheses touncover the mystery
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Cerebral and Neuronal
DysfunctionsAstro-glial edema and resultant:Selective alterations of blood-brain barrier
permeability
Changes in cerebral energy metabolismAlterations of gene expression. e.g.
Mono-amine oxidasePeripheral-type benzodiazepine receptor
(PTBR)Neuronal NO synthetase
Changes in neurotransmitter systems (Falseneurotransmitters)
. .Butterworth RF Complications of cirrhosis III Hepa
.encephalopathy , ; : - J Hepatol 2000 32 171 180
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Neuronal Dysfunctions
Role of AstrocytesImportant constituents of the blood-brainbarrier
Transastrocytic transport.
Communicate directly with neuronsRegulate neurotransmitter processing
Regulate ionic milieu
Provide substrates for neurons
Only cells in brain containing glutaminesynthetase
Major site of cerebral ammonia detoxification
Upon exposure to ammonia, culturedastrocytes develop Alzheimer type II.Stephan vom Dahl et L Hepatic encephalopathy as a complicati.of liver Disease , ; ( ): - World J Gastroentero 2001 7 2 152 156
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Role of AstrocytesPathophysiology of both acute or chronicliver failure is similar, but different kinetics.
In ALF/ FHF and High Grade HE associate withCLD astrocytes swell cerebral edema
In Low Grade HE (0-I) no clinical signs of
cerebral edema, but evidence of increasedcell hydration
A disturbance of astrocyte hydration is
apparently a major pathophysiologic event
in both forms. .Stephan vom Dahl et L Hepatic encephalopathy as acomplication-
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Increase Permeability of
Blood-Brain BarrierAstrocyte (glialcell) volume iscontrolled byintracellular
organic osmolyte-glutamine.
Glutamine levels
in the brain resultin volume offluid withinastrocytes
cerebral edema
Neurological =Normal Astrocytes
=lz Alzheimer type IIstrocytes ale enlarged nuclei
rominent nucleoli argination of chromatin
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ffects of Increased AstrocyticHydration
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iochemicaliochemicalAbnormalitiesbnormalities
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Pathogenesis TheoriesEndogenous Neurotoxins
AmmoniaMercaptansPhenolsShort-medium fatty acids
Change in Neurotransmitters andReceptors
An increased GABA-ergic toneAltered BCAA/AAA ratio
False NeurotransmittersOther
Zinc deficiencyManganese deposits
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Pathogenesis Theories:
Ammonia HypothesisAmmonia enters the bloodstream as aresult of its absorption from the GI tractand its liberation from kidney andmuscle cells.
Ammonia accumulates because damaged
liver cells fail to detoxify and convert tourea the ammonia that is constantly
entering the bloodstream.The increased ammonia concentration in
the blood causes brain dysfunction anddamage, resulting in hepatic
encephalopathy.
N t i A ti f
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Neurotoxic Action ofAmmoniaReadily crosses blood-brain barrier
Increased NH3 increased glutamate
-ketoglutarate + NH3 + NADH glutamate + NAD
glutamate + NH3 + ATP glutamine +ADP + Pi
As -ketoglutarate is depleted TCA cycleactivity halted decreased cellular energy
productionIncreased glutamine formation depletes
glutamate stores which are needed byneural tissue
Irrepairable cell damage and neural cell
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Pathogenesis Theories:
Ammonia HypothesisThe largest source of ammonia isthe enzymatic and bacterialdigestion of dietary and bloodproteins in the GI tract as aresult of:GI bleeding
High-protein dietBacterial infectionsUremia
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Pathogenesis Theories:
Ammonia HypothesisThe ingestion of ammonium salts
also increases the bloodammonia level.
Increased ammonia absorption
from the GI tract and from the
renal tubular fluid in:AlkalosisHypokalemia
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Pathogenesis Theories:
Ammonia HypothesisConversely, serum ammonia is decreasedby:elimination of protein from the diet
administration of antibiotic agents thatreduce the number of intestinalbacteria capable of converting urea toammonia, such as:
Neomycin sulfate Metronidazole
Rifaximin
, . .Nathan M et al Rifaximin Treatment in Hepatic Encephalopathy N Engl J Med 36
Ne roto ic Action of
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Neurotoxic Action ofAmmoniaReadily crosses blood-brain barrierIncreased NH3 increased glutamate
-ketoglutarate + NH3 + NADH glutamate + NAD
glutamate + NH3 + ATP glutamine +ADP + Pi
As -ketoglutarate is depleted TCA cycleactivity halted decreased cellular energy
productionIncreased glutamine formation depletes
glutamate stores which are needed byneural tissue
Irrepairable cell damage and neural cell
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Pathogenesis Theories:Change In Neurotransmitters and Receptors
BCAA-Ammonia Connection
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Pathogenesis Theories:False Neurotransmitter
HypothesisLiver cirrhosis characterized by altered
amino acid metabolismIncreased Aromatic Amino Acids
(AAA) in plasma and influx in brain
Decrease in plasma Branched ChainAmino Acids (BCAA)
Share a common carrier at blood-brain barrier
BCAAs in blood may result in AAAtransport to brain
P th i Th i
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Pathogenesis Theories:False Neurotransmitter HypothesisAAA are precursors to neurotransmitters andelevated levels result in shunting tosecondary pathways
Normal Transmitter /Modulator
Amino Acid Precursor False Neurotransmitter /Modulator
Dopamine Tyrosine Tyramine
Norepinephrine Tyrosine Octopamine
? Phenylalanine Phenethyamine
? Phenylalanine Phenylthanolamnine
Serotonin (5-
Hydroxytrptamine)
Tryptophan ? Tryptamine
Histamine Histidine ?
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Val
:bnormal plasma amino acidshronic liver disease400
350
300
250
150
200
100
50Thr
Leu
Ileu
Lys
Try
Meth
Phe
Tau
Asp
Glu
Ser
Pro
Gly
Ala
Tyr
OrnHis
Arg
Essential Non-Essential
%
of
Norm
al
Cerra, et al; JPEN, 1985 J. Y. Pang
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-ncreased GABA ergicActivitystrocyteEdema eripheral Typeenzodiazepine( )eceptors PTBRs
ynthesis of- (euro steroids eg)llopregnenolone ABAActivity
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False NeurotransmitterHypothesis
Other theories exist about the causes ofencephalopathy, including excesstryptophan and its metabolites, and
endogenous benzodiazepines or opiates.
Benzodiazepine-like chemicals(compounds) have been detected in the
plasma and cerebrospinal fluid ofpatients with hepatic encephalopathydue to cirrhosis
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dvances indvances iniagnosticiagnosticTechniquesechniques
euro mag ng
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euro mag ngTechniques
CT ScanControversialInformation inpatients with
cirrhosis withoutencephalopathy.
Anatomic
abnormalitiesattributed toatrophy and edema,correlate withneuro- psychologic
test performance
euro mag ng
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euro mag ngTechniques
MR ImagingSymmetrical high-signalabnormalities in theglobus pallidus on T1-weighted images due to
accumulation ofManganese (Mn)
Generalized increase in
white matter, limbic, andother extrapyramidalareas.
These abnormalities
correlate well with liver
euro mag ng
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euro mag ngTechniques
MR SpectroscopyThis technique canproduce measures ofcommon chemicals in
the brain.
1H-Spectra have showna characteristic
pattern: an increasein the glutamine /glutamate peakcoupled with adecrease in the myo-
inositol and choline,enberger J .et al Proton magnetic resonance spectroscopy of the brain in sympto
. ; : - .asymptomatic patients with liver cirrhosis Gastroenterology 1997 112 1610 1616
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-H MNRspectra (A) From a healthy
person (B) Patients with
post hepatiticcirrhosis andlatent (subclinical)
HE (C) Manifest grade
I-II HE.
An increase in the
glutamine/glutamate signal (Glx)and a decrease ofthe inositol signal(Ino) is observed.
Furtherabbreviations:
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Parietal 1H-
MNR spectrafrom a 47-year-old patientwith alcoholic
cirrhosis 3 daysbefore and 7days afterimplantationof TIPS, showingan increased Glxsignal and a
decreased Ino
euro mag ng
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euro mag ngTechniques
PET ScanThis technique canprovide images ofthe brain that reflecta specific
biochemical orphysiologic process.The exact nature of
the image dependson the tracer used.
PET measures ofcerebral blood flow(using 15O-water)
Using 13N Ammoniametabolic ate can bedetermined
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Neuro Imaging
TechniquesPreliminary results show that hepaticretinopathy, as detected by neuro-physiological testing, very sensitively
reflects the degree of HE, and respondsto HE therapy.
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outine Labsoutine Labs
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Do Not Forget The
Good OldProthrombin Time (PT)International Normalized Ratio (INR)
Albumen
Alanine Transaminase
BilirubinConjugated
UnconjugatedUrea
Creatinine
Fibrinogen
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hank youhank you