Wilson's Disease

brief description of Wilson's Disease

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

2. WILSON’S DISEASE
INTRODUCTION1
2
3
PATHOPHYSIOLOGY
4 PROGNOSIS
MANAGEMENT

3. INTRODUCTION
•WDwasfirstdescribedin1912,byKinnearWilson,asafamilial
diseasecharacterizedbyprogressive,lethalneurologicdysfunction
withLCandacornealabnormality,theKayser-Fleischer(“KF”)ring.
•WD(hepatolenticulardegeneration)isduetoagenetic
abnormalityinheritedinanARmannerthatleadstoimpairmentof
cellularcoppertransport.
•Itisfoundworldwide,withaprevalenceofapprox.1casein30,000
livebirths.
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4. NORMAL COPPER FLUXES AND POOLS
•Thedailyrequirementforcopperisapproximately0.9mg.
•Dietarycopperintakeisapprox.2-5mgperday.
•Thebodycontains50-150mgofCu,predominantlyinthemuscles,bones,and
connectivetissues.
•TheCupoolinthemusculoskeletalsystemisinconstantexchangewithplasma.
•Plasmacontainsapproximately1mcg/mL,ofwhich60–95%boundtoceruloplasmin.
•CeruloplasminisasourceofCuforperipheralorgans,whereCuisanessentialcofactor
formanyenzymes.
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5. COPPER FLUXES AND POOLS
•Dietarycopperintakeisapprox.2-5mg
perday.
•Excesscopper(60%)ispredominantly
excretedintothebile,whereitendsup
asfecalcopper.Renallossesaccountfor
only5-15%ofthedailyexcretionof
copper.
•Copper(40%)isabsorbedinthe
duodenumandproximalsmallintestine.
,bindsmainlytocirculatingalbumin,and
istakenupbyvarioustissues.
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6. COPPER FLUXES AND POOLS
•Fromthisintestinalpool,75%flows
throughtheportalsystemwithalbumin
ortranscupreinandistakenupbythe
liver.
•Theremaining25%isboundtoalbumin
inthecirculation.
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7. COPPER FLUXES AND POOLS: liver
•Intheliver,20%ofCuisre-excretedback
intotheGITthroughbileand80%is
transportedtotheperiphery,boundto
ceruloplasmin.
•Thebiliaryexcretionisapprox2.5mg/d.Near-similar
amountsareexcretedfromothersecretions(saliva,
gastric,pancreatic,andintestinalfluid).
•ThesearetheendogenousCuexcretions,andalarge
proportion(approx80%)isagainreabsorbedbythe
intestinalmucosa.
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Whencopperisdeficientinthediet,thereisenhancedaffinityofmetallothioneinsinenterocytesforcopper,thus
increasingitsabsorptionandviceversa.

8. COPPER FLUXES AND POOLS: fecal/urine
•Thedailyfecallossesareacombination
ofunabsorbeddietaryCuandsmall
proportionofexcretedendogenousCu
amountingtoapprox1.5–4mg/d.
•UrinaryCuexcretionislow(10–
100μg/d).
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Excesscopper(60%)ispredominantlyexcretedintothebile,whereitendsupasfecalcopper.Renallossesaccount
foronly5-15%ofthedailyexcretionofcopper.

9. COPPER FLUXES : Summary
•Ingestedcopperisabsorbedbyenterocytes
mainlyintheduodenumandproximalsmall
intestine.
•Absorbedcopperistransportedintheportal
circulationinassociationwithalbuminandthe
aminoacidhistidineandisavidlyremovedfrom
thecirculationbytheliver.
•Hepatocytesutilizecopperformetabolicneeds,
incorporatecopperintonascentceruloplasmin,
andtransportexcesscopperintobile.
•Mostexcesscopperisexcretedviathisbiliary
pathwayintofeces;onlyaminoramountis
excretedviathekidneys.
•Impairedbiliarycopperexcretioncanleadto
hepaticcopperretention.
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10. PATHOGENESIS
•Thegene,ATPasecoppertransportingbeta(ATP7B),isexpressedmainlyin
hepatocytes.
•ThegeneproductATP7Bfacilitatestransmembranetransportofcopperwithin
hepatocytes.
•AbsentorimpairedATP7Bfunctiondecreasesbiliaryexcretionofcopper,resultingin
toxichepatocellularcopperaccumulation.
•Eventuallyexceedingstoragecapacity,hepaticcopperreleasedintothebloodstream
depositsinotherorgans,notablythebrain,kidneys,andcornea.
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LossoffunctionalATP7Bdiminisheshepatocellularincorporationofcopperintoceruloplasmin.
ThisexplainsthedecreasedbloodlevelofceruloplasmininmostpatientswithWDbecauseapoceruloplasminhasa
shortercirculatinghalf-lifethanceruloplasmin

11. CLINICAL MANIFESTATIONS
•ThereiswidevariabilityinthereportedratesofthediffCMsseenatthetimeof
presentation:
1.Liverdisease:18to84%ofpts
2.Neurologicsymptoms:18to73%ofpts
3.Psychiatricsymptoms:10to100%ofpts
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12. MANIFESTATIONS IN WILSON DISEASE
➢Asymptomatic
➢AcuteHepatitis
➢ALF/ACLF
➢ChronicHepatitis
➢Cirrhosis
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•CopperdepositionbeginsatbirthinptswithWDandgraduallyproducesclinicaldisease.
ThemajorityofptsareDXbetweentheagesof5-45years,thoughithasbeenDXin
youngerptsandinptsintheir70s.
•ChildrenmaybeDXthroughscreeningbecauseofanaffectedsibling.

13. MANIFESTATIONS IN WILSON DISEASE
➢Asymptomatic
•AcuteHepatitis
•ALF/ACLF
•ChronicHepatitis
•Cirrhosis
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•AsymptomaticWDhasbeendocumentedin3–40%ptsinvarious
studies.
•Theseptshaveincidentallydetectedhepatomegaly,raised
transaminases,oraresiblingsoftheindexWDptsdetectedon
screening.
•Amajorityofthesecasesareidentifiedinfirstdecadeoflifeorin
adolescence.

14. MANIFESTATIONS IN WILSON DISEASE
•Asymptomatic
➢AcuteHepatitis
•ALF/ACLF
•ChronicHepatitis
•Cirrhosis
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•Acutehepatitis(10–25%)mimicsacuteviralhepatitis,
autoimmunehepatitis,anddrug-inducedliverinjury.
•Jaundice,anorexia,nausea,malaise,fever,palestools,andpain
intheabdomenareoftenthepredominantsymptoms.
•Thebiochemicalinvestigationsshowunconjugated
hyperbilirubinemia,raisedtransaminases.

15. MANIFESTATIONS IN WILSON DISEASE
•Asymptomatic
•AcuteHepatitis
➢ALF/ACLF
•ChronicHepatitis
•Cirrhosis
15
•ALF(8–20%)ispredominantlyseeninchildhoodandadolescents.
•Itisusuallya/withCoombs-negativenonimmuneintravascular
hemolysis.
•Thepresentationmimicsacutehepatitis,butthecondition
deterioratesrapidlyoverdaystoweeksandisoftenfatal.
•Itresultsindeepjaundice,hemolysis,coagulopathy,ascites,
encephalopathy,andrenalfailure.

16. MANIFESTATIONS IN WILSON DISEASE
•Asymptomatic
•AcuteHepatitis
•ALF/ACLF
➢ChronicHepatitis
•Cirrhosis
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•Chronichepatitis(10–30%)isseenespeciallyinadolescentsand
youngadults.
•Nonspecificandconstitutionalsymptomssuchasfatigue,
anorexia,nausea,andmalaisemaypresentbeforeonsetof
jaundiceandhepaticdysfunction.
•Associateddelayedpuberty,amenorrhea,polyarthralgia,maybe
present.

17. MANIFESTATIONS IN WILSON DISEASE
•Asymptomatic
•AcuteHepatitis
•ALF/ACLF
•ChronicHepatitis
➢Cirrhosis
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•Ptsmaypresentwithcomplicationsofcirrhosis(35%–
60%),includingascites(SBP),HE,andAKI(includingHRS)orPHTN
(varicealbleeding).

18. CLINICAL MANIFESTATIONS
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19. KAYSER–FLEISCHER RINGS
•Theseconstitutethemostimportantsingleclinicalclueto
thediagnosisandcanbeseenin60%ofadultswith
Wilson’sdisease(lessofteninchildrenbutalmostalways
inneurologicalWilson’sdisease),albeitsometimesonly
byslit-lampexamination.
•Kayser–Fleischerringsarecharacterisedbygreenish-
browndiscolorationofthecornealmarginappearingfirst
attheupperperiphery.
•Theydisappearwithtreatment.

20. INVESTIGATION: SERUM CERULOPLASMIN
•SerumCeruloplasmin:Approx85-90%ofptswithWDhavelowserumceruloplasmin
levels(<20mg/dLor200mg/L).
•Averylowserumceruloplasminconcentration(<5mg/dLor<50mg/L)providesstrong
evidencefortheDXofWD.
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21. CAUSES OF LOW SERUM CERULOPLASMIN
Approx10-20%ofasymptomaticheterozygouscarriershaveserumceruloplasmin
<20mg/dL(200mg/L).Othercausesoflowserumceruloplasmininclude:
•Disordersthatcausemarkedrenalorentericproteinloss,suchasnephroticsyndromeor
protein-losinggastroenteropathy.
•End-stageliverdiseaseofanycausewithassociatedpoorsyntheticfunctionfor
productionofallhepaticproteins.
•RarediseasessuchasMenkesdisease(anX-linkeddisorderofcoppertransportleadingto
decreasedintestinalcopperabsorption)andaceruloplasminemia(araredisorderleading
totheabsenceofceruloplasminandproblemsinironmetabolism).
•Copperdeficiency(eg,duetoinadequatecopperinclusioninparenteralnutrition,
malabsorptionfollowinggastricbypasssurgery,excessivezincadministration.
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Ceruloplasminisanacutephasereactant,solevelsmaybeelevatedinthesettingofinflammationandtissueinjury.

22. TOTAL SERUM COPPER
•Serumcoppermeasuresthetotalserumcopper(ceruloplasmin-bound
copper+nonceruloplasmincopperor“freecopper”).Ninetypercentoftheserum
copperisboundtoceruloplasmin.
•Totalserumcopperdoesnotreflecttissuelevelsandthereforeunreliablein
diagnosis.

23. 24–HOUR URINARY COPPER ASSAY
•UrinarycopperexcretionisusefulfortheDXsofWDandformonitoringtherapy.
•Values>40mcg/24-hours(0.64micromol/24-hours)aresuggestiveofWD,andindividuals
withthisfindingshouldundergofurtherevaluation.
•NOTE:Elevatedurinarycopperexcretionmayalsobeseeninptswithotherformsof
chronicactiveliverdiseaseandinheterozygotesforWD,butmostoftenlevelsarebelow
100mcgper24hours.Thetestshouldnotbeusedinptswithrenalfailure.
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Measuring24-hoururinarycopperexcretionwhilegivingD-penicillamineisausefulconfirmatorytest;morethan25
μmol/24hrsisconsidereddiagnosticofWilson’sdisease.

24. MANAGEMENT OF WD
•LifetimetherapyaimedprimarilyattreatingcopperoverloadisrequiredinptswithWD,
andtreatmentshouldbeconsideredinthesephases:
1.Removingordetoxifyingthetissuecopperthathasaccumulated.
2.Preventingreaccumulation.
3.TreatmentofcomplicationsofPHTN.
4.Additionaltreatmentofneurologicsymptoms.
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25. TREATMANT
Thecopper-bindingagent:D-penicillamine,Trientine,Trientine
•D-penicillamine:1.5μg/day(range1–4μg).Thedosecanbereducedoncethedisease
isinremissionbuttreatmentmustcontinueforlife,eventhroughpregnancy.Toxic
effectsoccurinone-thirdofpatientsandincluderashes,protein-losingnephropathy,
lupus-likesyndromeandbonemarrowdepression.
•Ifthesedoarise,trientinedihydrochloride(1.2–2.4μg/day)andzinc(50mg3times
daily)arepotentialalternatives.

26. SURVIVAL
•DataarelackingregardinglifeexpectancyamonguntreatedptswithWD.
•Onestudyfoundthatthemediansurvivalfollowingthedevelopmentofneurologic
symptomswasapproximatelyfiveyears.
•PtswhodevelopALFduetoWDhaveanacutemortalityrateofatleast95%inthe
absenceofaLT,withdeathoccurringindaystoweeks.
•TheprognosisforptswhoreceiveandareadherenttotreatmentforWDisexcellent,
providedadvancedliverdiseaseisnotalreadypresent.Insuchpatients,lifeexpectancy
isnormal,thoughtreatmentmayleadtoworseningofneurologicsymptoms.
•Livertransplantationisindicatedforfulminantliverfailureorforadvancedcirrhosis
withliverfailure.ThevalueoflivertransplantationinsevereneurologicalWilson’s
diseaseisunclear.
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27. END OF SLIDES