6. HEPATIC ENCEPHALOPATHY

This is a lecture note for 5th semester MBBS students. Lecture notes on hepatology, liver disease, alcoholic liver disease, alcohol-related liver disease, portal hypertension, and hepatic encephalopathy. Introduction to hepatic encephalopathy, causes, differentials, approach, and management of hepatic encephalopathy .

1. Hepatology lectures for
5
th
Sem;MBBS
Pratap Sagar Tiwari
MBBS,MD (Medicine),DM (Hepatology)

2. HEPATIC ENCEPHALOPATHY
DEFINITION1
2
3
PATHOPHYSIOLOGY
4 DIFFERENTIALS
MANAGEMENT

3. INTRODUCTION
•HEisabraindysfunctioncausedbyliverinsufficiencyand/orPSS;itmanifestsasawide
spectrumofneurologicalorpsychiatricabnormalitiesrangingfromsubclinical
alterationstocoma.EASL
•TheprevalenceofOHEatthetimeofDXofLCis15%ingeneral,20%inthosewith
decompensatedLC,and50%inptswithTIPS.
•Itsoccurrenceisapoorprognosticindicator,withprojected1-yearsurvivalratesof
42%,withoutlivertransplantation.
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DEFINITION
PREVALENCE
PROGNOSIS

4. CLASSIFICATION: ACC TO UNDERLYING DISEASE
•Thereare3majortypesofHE:
1.TypeA,a/withacuteliverfailure;
2.TypeB,a/withportosystemicshuntsintheabsenceofliverdisease;
3.TypeC,a/withCLDandportalhypertension.
4
GRADING
TypeCHEistheMCtypeandhashistoricallybeengradedfrom0to4basedontheWest
Havencriteria.

5. WEST HAVEN CRITERIA

6. POSSIBLE MECHANISMS IN DEVELOPMENT OF HE
A. NEUROTOXINS Ammonia
Oxidative stress
Oxindole
B. IMPAIRMENT OF NEUROTRANSMISSION GABA-benzodiazepine neurotransmitter system
Glutamine
Catecholamines
Serotonin
Histamine
Melatonin
C. ALTERATION OF THE BLOOD-BRAIN BARRIER
D. SYSTEMIC RESPONSE TO INFECTIONS AND NEUROINFLAMMATION
E. BACTERIAL OVERGROWTH
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7. Ammonia: Ammonia Production
•BacterialproductionofAmmonia
•EndogenousproductionofAmmonia
•RenalAmmoniaflux
•Ammoniafluxinmuscles
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Production Ammoniaflux
endogenous
bacterial
muscles
renal

8. Creation of state of hyperammonia
Gut production of Ammonia
•Thebacterialureasecanbreakdownureaderivedfromthebloodstream
intoammoniaandCO2.
•Enterocyteswithinthesmallbowel(toalesserextent,inthecolon)also
generatealargeamountofammoniaviaintestinalglutaminaseasthey
metabolizetheirmainenergysource,glutamineintoglutamate&ammonia.
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Glutamine glutamate + ammonia

9. Creation of state of hyperammonia
Renal Ammonia Flux
•Kidneyareinvolvedinbothproductionandexcretionofammonia,thatis
largelydrivenbyacid-basestatus.
•Intermsofexcretion,thekidneyscanremoveasignificantamountof
ammoniaintheurine,eitherasammoniumion(NH
4
+
)orintheformofurea.
•Excretionisimpairedinstateof↓renalperfusionorAKI.
•Dehydration,overdiuresis,diarrhea,GIBleedingcanleadtoprerenal
azotemiathatfurtherleadtoreducedperfusionanda↓GFR.
Gut production of Ammonia
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10. Creation of state of hyperammonia
Renal Ammonia Flux
•Generationofammonia:Glutamineismetabolizedtoammonia,bicarbonate,
andglutamate.Thisammonia-genesisprimarilyservesaroleinacid-base
homeostasis,sincebicarbonateisalsoproducedduringthereaction;thus
servestobuffersystemicacidosis.
•However,duringperiodsofacidosis,thekidneyscan↑theamountofNH
4
+
releasedintotheurineseveralfold.
Gut production of Ammonia
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Glutamine glutamate + ammonia +HCo3

11. Creation of state of hyperammonia
•Ammoniaincorporatedintoglutamineviaglutaminesynthetasein
skeletalmyocyte.
•InSarcopenia:impairedincorporationofammonia,soammonia↑.
•CatabolismstateinLC:excessiveglutamine(andotheraminoacids)from
muscleintothecirculation.
Hypokalemia
Ammonia flux in muscle
•Aslesspotassiumreachesthecollectingtubules,morehydrogenionsare
movedintothecells,leadingtoastateofrelativeintracellularacidosis.
Thekidneysthengeneratemoreammoniaandbicarbonatefrom
glutamineinanefforttobalancetheacid-basestatusofthept.
Renal Ammonia Flux
Gut production of Ammonia
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Glutamate + Ammonia ----> Glutamine

12. Fate of hyperammonia in brain
Furthermore,glutamineentersthemitochondriaandiscleavedbyglutaminasetoammoniaandglutamate,which
subsequentlyincreasestheintracellularammoniaconcentration.This↑inintracellularammoniaconcentrationcausesa
“feedforwardloop,”alsoknownastheTrojanhorsehypothesis,wherebyintracellularammonialeadstoproductionof
reactiveoxygenandnitrogenspecies,causingfurtheredema.
Glutamineisosmoticallyactive,andthusan↑inglutamineleadstoastrocyteswellingandedema.
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13. CEREBRAL OEDEMA
•Cerebraloedemamayoccurduetoincreasedintracranialpressure,causing
➢unequalorabnormallyreactingpupils,fixedpupils,
➢hypertensiveepisodes,bradycardia,
➢hyperventilation,profusesweating,
➢localorgeneralmyoclonus,focalfitsordecerebrateposturing.
•Papilloedemaoccursrarelyandisalatesign.
•Moregeneralsymptomsincludeweakness,nauseaandvomiting

14. FACTORS
Controlling precipitating factors in the MX of overt HE is of paramount importance, as
nearly 90% of pts can be treated with just correction of the precipitating factor .

15. DIFFERENTIAL DIAGNOSIS
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16. Diagnosis
•NospecificlaboratoryfindingsindicatethepresenceofHEdefinitively.
•Bloodammonialevelsarecommonlymeasuredinptswithcirrhosisand
PHTNbutarenotsensitiveorspecificforthepresenceofHE.
BloodammonialevelsmaybeausefulindicatorofHEintheabsenceofcirrhosisandPHTN,asinptswithmetabolic
disordersthatinfluenceammoniagenerationormetabolism,suchasureacycledisorders
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17. MANAGEMENT OF OHE:
•OHE therapy follows a four-pronged approach
(i) Excludingother causes of altered mental status
(ii) Caring for the unconscious patient
(iii) Determining and treating precipitating factors
(iv) Initiating empiric therapy.
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18. THERAPIES
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LUMINAL THERAPY
EXTRA LUMINAL THERAPY
•LACTULOSE
•RIFAXIMIN
•L-ORNITHINE L-ASPARTATE
•ALBUMIN
•PROBIOTICS / PREBIOTICS
•BCAA
•ZINC
•NUTRITION
•OTHERS:FMT, SHUNT EMBOLIZATION

19. NONABSORBABLE DISACCHARIDES
•Lactulose(β-galactosidofructose)andlactitol(β-galactosidosorbitol)aretwovery
commonnonabsorbablesyntheticdisaccharides.
•TheMOAoftheseagentsaremultifactorial.
➢Whenadministered,theseagentsaredegradedbythenaturalflorainthelarge
intestinetoshort-chainorganicacids,creatingbothanacidicenvironmentandan
osmoticgradientintheintestinallumen.
➢Theacidicenvironmentcreatedcausesdestructionofurease-producingbacteriaand
alsofacilitatestheconversionofammoniatononabsorbableammonium.
➢Inaddition,theincreasedosmolalityalsocausesintestinalcleansingviaremovalof
excessfecalnitrogenthroughalaxativeeffect.
➢Alloftheseeffectsdecreaseammonialevelsinthecolonandportalcirculation.
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20. NONABSORBABLE DISACCHARIDES
•Itisusuallyadministeredasanoralsyrupwithdosagesbeingbasedon
clinicalresponseforagoalof2-3softbowelmovementsaday.
•Lactulosecanalsobegivenrectally,whichispreferredinthoseinwhom
oraladministrationisCI.
•Commonsideeffects:flatulence,abdominaldiscomfort,anddiarrhea.
•Lactitol:bettertoleratedthanandasefficaciousaslactulose.
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21. RIFAXIMIN
•Rifaximinisanonabsorbableantibioticbelongingtotherifamycinclass.
•ItsantibioticactionisduetotheinhibitionofchainformationinRNA
synthesis.Ithasabroadspectrumofactionagainstseveralaerobicand
anaerobicgram-positiveandgram-negativebacteriaanddoesnothave
anyinteractionswiththecytochromeP450substrates.
•Themostcommonsideeffectsreportedincludeflatulence,abdominal
pain,headaches,andconstipation.
•Dosing:550mgtwiceperday
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22. PROBIOTICS AND PREBIOTICS
•Probioticsarelivemicrobiologicdietarysupplementsthatareintendedto
havehealthbenefitswhenconsumed.
•Prebioticsarenondigestablefoodingredientsthatselectivelystimulate
thegrowthofbacteriainthecolon.
•Thecombinationofprebioticsandprobioticsiscalledsynbiotics.
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23. ALBUMIN
•AlbumininfusionhasbeenusedforthetreatmentofOHE,specifically
diuretic-inducedOHE.
•Inadditiontovolumeexpansion,albuminhasantiinflammatory,
detoxifying,andimmunemodulatingproperties.
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24. NUTRITION
•ThecurrentrecommendationspertheInternationalSocietyforHepatic
EncephalopathyandNitrogenMetabolism-tohaveproteinintakeof1.2
g/kgto1.5g/kgidealbodyweight.
•Inaddition,itisalsorecommendedforHEptstoconsume35-40kcal/kgby
eatingsmallsmealsthatareevenlydistributedthroughoutthedayaswell
astohavealate-nightsnackofcomplexcarbohydratetohelpminimize
proteinutilization.
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25. REASONS FOR HE RESISTANT TO RX
1.End-stage liver disease .
2.Excessive purgation leading to dehydration/free water loss
3.Failure to identify and treat sepsis
4.Ileus, especially in association with azotemia
5.Long-acting sedative drug intake
6.Undiagnosed concomitant CNS problem
7.Too-effective portosystemic shunt procedure
8.Profound zinc deficiency
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26. LIVER TRANSPLANTATION
•AlthoughitisnotcommonlytheprimaryindicationforLT,HEisgenerally
relievedbyasuccessfulgraft.
•Atpresent,recurrentorpersistentHEdoesnotgiveptspriorityforliver
transplantation.
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ISSUES OF LIVER TRANSPLANTATION AND HE
•HEisnotincludedintheMELDscore
•NopriorityisgiventoptswithsevererecurrentorresistantHE
•HowmuchHEistoomuchHEbeforetransplant?

27. END OF SLIDES