Advances in Cerebral Dysfunction in Hepatic Encephalopathy

8/9/2019 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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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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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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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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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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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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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

Documents

Advances in Cerebral Dysfunction in Hepatic Encephalopathy