Hepatolenticular Degeneration

AshutoshAshutosh Barve,Barve, M.D.,M.D., Ph.D.Ph.D. Gastroenterology/HepatologyGastroenterology/Hepatology FellowFellow UniversityUniversity ofof LouisvilleLouisville Case Presentation

„ 1717 yearyear oldold caucasiancaucasian womanwoman withwith nono previousprevious medicalmedical historyhistory „ PresentsPresents withwith aa 22--33 dayday historyhistory ofof rightright andand leftleft upperupper quadrantquadrant pain,pain, abdominalabdominal distensiondistension andand bilateralbilateral LELE edemaedema „ SheShe alsoalso c/oc/o fatiguefatigue forfor aboutabout 66 weeksweeks alongalong withwith subjectivesubjective feversfevers andand occasionaloccasional headacheheadache Case Presentation

„ PHYSICALPHYSICAL EXAM:EXAM:

¾ RightRight upperupper quadrantquadrant tendernesstenderness

¾ SlightSlight abdominalabdominal distensiondistension

¾ SoftSoft abdomenabdomen withwith nono hepatospleenomeg.hepatospleenomeg.

¾ 2+2+ bilateralbilateral lowerlower extremityextremity edemaedema

¾ NormalNormal cardiocardio--respiratoryrespiratory examexam

¾ NormalNormal neurologicalneurological examexam Case Presentation

„ INITIALINITIAL LABORATORYLABORATORY DATA:DATA:

¾ Na=134,Na=134, K=K= 3.4,3.4, Cl=107,Cl=107, CO2=23,CO2=23,

¾ BUN=11,BUN=11, Cr=1.0Cr=1.0

¾ Hgb=11.4,Hgb=11.4, Hct=33.4,Hct=33.4, Ptt=144,Ptt=144, WBC=7.6WBC=7.6

¾ AST=148,AST=148, ALT=83ALT=83,, AlkP=73,AlkP=73, TBil=1.6TBil=1.6

¾ Alb=2.5Alb=2.5,, TProt=6.1TProt=6.1

¾ PT=20.7PT=20.7,, PTT=45.5PTT=45.5 Case Presentation

„ RADIOLOGY:RADIOLOGY: ¾ ChestChest XX--rayray –– normalnormal ¾ AbdominalAbdominal USUS –– moderatemoderate ascites,ascites, mildmild diffusediffuse thicknessthickness ofof thethe gallgall bladderbladder wallwall consistentconsistent withwith hepatitis,hepatitis, otherwiseotherwise normalnormal

„ SheShe waswas admittedadmitted withwith aa provisionalprovisional diagnosisdiagnosis ofof hepatitishepatitis vs.vs. mononucleosismononucleosis withwith hepatichepatic involvementinvolvement Case Presentation

„ FURTHERFURTHER WORKWORK UP:UP:

¾ Ferritin=231Ferritin=231

¾ ANA=neg,ANA=neg, AMA=neg,AMA=neg, ASMA=negASMA=neg

¾ HepatitisHepatitis profile=negprofile=neg

¾ MonospotMonospot test=negtest=neg

¾ Ceruloplasmin=13Ceruloplasmin=13 mg/dLmg/dL (normal(normal 2020-- 45)45) Case Presentation

„ FURTHERFURTHER WORKWORK UP:UP:

¾ SlitSlit lamplamp examexam byby OphthalmologyOphthalmology revealedrevealed KayserKayser--FleischerFleischer ringsrings

¾ 2424 hrhr urineurine coppercopper == 32003200 mcg/Lmcg/L (normal(normal 55--3030 mcg/L)mcg/L)

¾ LiverLiver BiopsyBiopsy waswas donedone andand samplessamples sentsent forfor lightlight andand electronelectron microscopymicroscopy Case Presentation

„ LiverLiver Biopsy:Biopsy:

¾ LightLight Microscopy:Microscopy: ““ChronicChronic activeactive hepatitishepatitis withwith earlyearly cirrhosis.cirrhosis. AA smallsmall amountamount ofof stainablestainable coppercopper isis demonstrateddemonstrated……..”” Case Presentation „ LiverLiver biopsy:biopsy: ¾ ElectronElectron Microscopy:Microscopy: “…“….In.In somesome ofof thethe nucleinuclei areare foundfound accumulationsaccumulations ofof glycogenglycogen particlesparticles…….Many.Many mitochondriamitochondria areare ofof giantgiant sizesize andand bizarrebizarre shapesshapes……InIn additionaddition thethe membranesmembranes ofof thethe cristaecristae areare widenedwidened formingforming smallsmall andand largelarge electronelectron--lucentlucent roundround swellingsswellings borderedbordered byby aa singlesingle membranemembrane.. AlsoAlso notednoted inin thethe mitochondriamitochondria areare variousvarious electronelectron--densedense granulesgranules……....”” Impression:Impression: ElectronElectron microscopymicroscopy ofof thisthis adequateadequate liverliver biopsybiopsy isis consistentconsistent withwith WilsonWilson’’ss diseasedisease Samuel Alexander Kinnier Wilson

„ Neurologist and Pathologist „ Born in New Jersey, USA „ Lived and worked in England „ Professor of Neurology at King’s College Hospital „ Great clinician and teacher, proficient linguist, keen gardener and avid golfer PROGRESSIVEPROGRESSIVE LENTICULARLENTICULAR DEGENERATION:DEGENERATION: AA FAMILIALFAMILIAL NERVOUSNERVOUS DISEASEDISEASE ASSOCIATEDASSOCIATED WITHWITH CIRRHOSISCIRRHOSIS OFOF THETHE LIVER.LIVER. WILSONWILSON SAK,SAK, Brain.Brain.1912;1912; 34:34: 295295-- 507.507. Wilson Disease

„ AutosomalAutosomal recessiverecessive „ PrevalencePrevalence ofof approximatelyapproximately 11 casecase inin 30,00030,000 livelive birthsbirths inin mostmost populationspopulations „ DefectDefect inin hepatichepatic coppercopper transporttransport leadingleading toto accumulationaccumulation ofof coppercopper inin thethe liverliver „ ExcessExcess coppercopper actsacts asas aa propro--oxidantoxidant andand promotespromotes thethe generationgeneration ofof freefree radicalsradicals leadingleading toto hepatocytehepatocyte injury.injury. Synonyms of Wilson Disease

„„HepatolenticularHepatolenticular DegenerationDegeneration „„ProgressiveProgressive LenticularLenticular DegenerationDegeneration „„KinnierKinnier WilsonWilson’’ss DiseaseDisease „„WestphalWestphal--StrumpellStrumpell’’ss pseudosclerosispseudosclerosis Historical Perspective

„ 18601860 –– FrerichsFrerichs describesdescribes aa casecase similarsimilar toto thosethose describeddescribed byby WilsonWilson „ 19121912 –– WilsonWilson publishespublishes hishis casecase seriesseries „ 19121912 –– EyeEye findingsfindings associatedassociated withwith WDWD describeddescribed byby KayserKayser andand FleischerFleischer „ 19291929 –– VogtVogt andand HaurowitzHaurowitz && GlazebrookGlazebrook reportreport excessexcess coppercopper inin thethe brainbrain andand liverliver ofof WDWD patientspatients Historical Perspective

„ 19361936 –– PolicardPolicard etet alal demonstratedemonstrate excessexcess coppercopper inin thethe cornealcorneal KFKF ringring „ 19561956 –– BennettsBennetts andand ChapmanChapman establishestablish relationshiprelationship betweenbetween abnormalabnormal coppercopper metabolismmetabolism andand WDWD „ 19521952 –– SternliebSternlieb andand GitlinGitlin describedescribe anan almostalmost universaluniversal lowlow ceruloplasminceruloplasmin inin WDWD „ 19931993 –– TheThe genegene thatthat isis abnormalabnormal inin WDWD isis identifiedidentified (Nature(Nature Genetics)Genetics) Copper Physiology

(60% absorbed)

Feldman: Sleisenger & Fordtran Gastrointestinal and Liver Diseases, 7th Ed Diseases of Copper Transport

„ Menkes'Menkes' Disease:Disease: ¾ XX--linkedlinked geneticgenetic disorderdisorder ¾ DefectDefect inin thethe transporttransport ofof coppercopper fromfrom thethe intestine,intestine, leadingleading toto coppercopper deficiencydeficiency ¾ ResultsResults inin deathdeath fromfrom severesevere progressiveprogressive neurodegenerationneurodegeneration „ WilsonWilson DiseaseDisease ¾ DecreasedDecreased transporttransport ofof coppercopper fromfrom thethe liverliver intointo bile,bile, leadingleading toto coppercopper excessexcess Diseases of Copper Transport

„ MenkeMenke’’ss Disease:Disease: ¾ XX--linkedlinked disorderdisorder ¾ GeneGene productproduct isis ATP7AATP7A „ WilsonWilson’’ss DiseaseDisease ¾ GeneticGenetic defectdefect localizedlocalized toto ChromosomeChromosome 1313 ¾ GeneGene productproduct isis ATP7BATP7B –– highhigh degreedegree ofof homologyhomology withwith ATP7AATP7A ATP7B Gene Product

P-Type ATPase 1443 amino acids, 6 copper-binding motifs, 1 ATP binding region Feldman: Sleisenger & Fordtran Gastrointestinal and Liver Diseases, 7th Ed Hepatocyte Copper Transport

ATP7B

Copper

Apoceruloplasmin

ceruloplasmin Hepatocyte Copper Transport Genetic Basis of Wilson’s Disease

„ MoreMore thanthan 100100 mutationsmutations inin thethe genegene havehave alreadyalready beenbeen identifiedidentified inin patientspatients withwith Wilson'sWilson's diseasedisease „ MostMost patientspatients areare compoundcompound heterozygotesheterozygotes „ Histidine1069GlutamineHistidine1069Glutamine mutationmutation isis oneone ofof thethe mostmost frequentfrequent mutationmutation withwith anan allelicallelic frequencyfrequency ofof 1010 toto 4040 percentpercent Pathology

EarliestEarliest lesionlesion inin WilsonWilson DiseaseDisease isis fattyfatty infiltrationinfiltration withinwithin hepatocytes,hepatocytes, glycogenglycogen inclusionsinclusions withinwithin nuclei,nuclei, andand portalportal fibrosisfibrosis Pathology

„ AsAs thethe diseasedisease progressesprogresses thethe histologichistologic lesionlesion resemblesresembles thatthat ofof AutoimmuneAutoimmune ChronicChronic HepatitisHepatitis

„ ThereThere isis portalportal inflammationinflammation andand fibrosis,fibrosis, piecemealpiecemeal necrosis,necrosis, withwith markedmarked swellingswelling andand necrosisnecrosis ofof periportalperiportal hepatocyteshepatocytes Pathology

UltimatelyUltimately thethe inflammationinflammation andand fibrosisfibrosis leadsleads toto CirrhosisCirrhosis Clinical Presentation

„ MajorityMajority ofof clinicalclinical casescases presentpresent betweenbetween thethe agesages ofof 55 andand 3535 „ YoungestYoungest casecase inin thethe literatureliterature waswas aa 33 yearyear oldold patientpatient „ OldestOldest patientspatients describeddescribed werewere 22 siblingssiblings inin theirtheir seventiesseventies „ VariabilityVariability inin ageage probablyprobably reflectsreflects differencesdifferences inin mutationsmutations andand penetrancepenetrance asas wellwell asas extragenicextragenic factors.factors. Clinical Presentation

„ ThereThere areare twotwo principleprinciple presentationspresentations ofof WilsonWilson DiseaseDisease

¾ HepaticHepatic DiseaseDisease

¾ NeuropsychiatricNeuropsychiatric DiseaseDisease

„ PatientsPatients cancan alsoalso presentpresent withwith featuresfeatures ofof bothboth diseasesdiseases Clinical Presentation

Mayo Clin Proc. 2003 Sept;78(9):1126-36 Clinical Presentation - Hepatic

„ AsymptomaticAsymptomatic liverliver functionfunction testtest abnormalitiesabnormalities (AST(AST >> ALT)ALT) „ ChronicChronic hepatitishepatitis –– mildmild oror severesevere nonspecificnonspecific symptoms,symptoms, suchsuch asas fatiguability,fatiguability, lethargy,lethargy, malaise,malaise, anorexia,anorexia, nausea,nausea, abdominalabdominal pain,pain, andand itchingitching „ AcuteAcute hepatitishepatitis –– selfself--limitedlimited clinicalclinical illnessillness resemblingresembling acuteacute hepatitishepatitis Clinical Presentation - Hepatic

„ PortalPortal HypertensionHypertension –– splenomegaly,splenomegaly, thrombocytopenia,thrombocytopenia, andand leukopenialeukopenia occasionallyoccasionally predominatepredominate „ FulminantFulminant HepaticHepatic FailureFailure –– massivemassive hepatocellularhepatocellular necrosisnecrosis resultingresulting inin aa largelarge releaserelease ofof coppercopper ionsions intointo thethe circulation,circulation, associatedassociated withwith hemolytichemolytic anemia,anemia, hemoglobinuria,hemoglobinuria, darkdark urine,urine, andand renalrenal failurefailure Clinical Presentation - Hepatic „ FulminantFulminant HepaticHepatic FailureFailure ¾ CoombsCoombs--negativenegative hemolytichemolytic anemiaanemia ¾ CoagulopathyCoagulopathy unresponsiveunresponsive toto parenteralparenteral vitaminvitamin KK administrationadministration ¾ RapidRapid progressionprogression toto renalrenal failurefailure ¾ RelativelyRelatively modestmodest risesrises inin serumserum aminotransferasesaminotransferases (typically(typically <2000)<2000) ¾ NormalNormal oror markedlymarkedly subnormalsubnormal serumserum alkalinealkaline phosphatasephosphatase (typically(typically <40)<40) ¾ RatioRatio ofof Alk.Alk. Phos.Phos. toto TotalTotal Bil.Bil. ofof <2<2 ¾ FemaleFemale toto malemale ratioratio 2:12:1 Clinical Presentation – Hepatic “Mimic” Liver Diseases

„ AutoimmuneAutoimmune hepatitishepatitis:: acuteacute oror chronicchronic presentationpresentation similarsimilar toto AIH,AIH, fatigue,fatigue, malaise,malaise, arthropathy,arthropathy, rashes,rashes, greatlygreatly increasedincreased serumserum immunoglobulin,immunoglobulin, positivepositive autoantibodiesautoantibodies likelike ANAANA andand ASMAASMA

„ NASHNASH:: severesevere hepatichepatic steatosissteatosis AASLD Practice Guideline

„ PatientsPatients inin thethe pediatricpediatric ageage bracketbracket whowho presentpresent aa clinicalclinical picturepicture ofof autoimmuneautoimmune hepatitishepatitis shouldshould bebe investigatedinvestigated forfor WD.WD. „ AdultAdult patientspatients withwith atypicalatypical autoimmuneautoimmune hepatitishepatitis oror whowho respondrespond poorlypoorly toto standardstandard corticosteroidcorticosteroid therapytherapy shouldshould alsoalso bebe investigatedinvestigated forfor WDWD „ WDWD shouldshould bebe consideredconsidered inin thethe differentialdifferential diagnosisdiagnosis ofof patientspatients presentingpresenting withwith nonalcoholicnonalcoholic fattyfatty liverliver oror whowho havehave pathologicpathologic findingsfindings ofof NASHNASH Clinical Presentation - Neuropsychiatric

„ NeuropsychiatricNeuropsychiatric disordersdisorders areare presentpresent inin upup toto 35%35% ofof patientspatients withwith Wilson'sWilson's disease.disease. „ AllAll ofof themthem usuallyusually havehave liverliver diseasedisease whichwhich maymay bebe wellwell compensatedcompensated „ NeurologicNeurologic -- tremor,tremor, rigidity,rigidity, clumsinessclumsiness ofof gait,gait, slurringslurring ofof speech,speech, inappropriateinappropriate andand uncontrollableuncontrollable grinninggrinning (risus(risus sardonicus),sardonicus), andand droolingdrooling „ 10%10% presentpresent withwith psychiatricpsychiatric problemsproblems „ PsychiatricPsychiatric -- subtlesubtle personalitypersonality changes,changes, deterioratingdeteriorating performanceperformance atat school,school, depression,depression, paranoia,paranoia, andand catatoniacatatonia Clinical Presentation - Neuropsychiatric

„ Bradykinesia,Bradykinesia, rigidity,rigidity, cognitivecognitive impairment,impairment, andand anan organicorganic moodmood syndromesyndrome areare associatedassociated withwith dilatationdilatation ofof thethe thirdthird ventricleventricle byby MRIMRI „ AtaxiaAtaxia andand tremortremor werewere associatedassociated withwith focalfocal thalamicthalamic lesionslesions „ Dyskinesia,Dyskinesia, dysarthria,dysarthria, andand anan organicorganic personalitypersonality syndromesyndrome werewere associatedassociated withwith focalfocal lesionslesions inin thethe putamenputamen andand pallidumpallidum Clinical Presentation - Other

„ RenalRenal ¾ FanconiFanconi syndromesyndrome -- glucosuria,glucosuria, aminoaciduria,aminoaciduria, hypouricemia,hypouricemia, andand proximalproximal renalrenal tubulartubular acidosisacidosis ¾ NephrolithiasisNephrolithiasis secondarysecondary toto distaldistal renalrenal tubulartubular acidosisacidosis „ RheumatologicRheumatologic ¾ ArthropathyArthropathy withwith featuresfeatures ofof prematurepremature arthritisarthritis ¾ ChondrocalcinosisChondrocalcinosis –– mostmost commonlycommonly inin thethe kneeknee ¾ VitaminVitamin DD--resistantresistant ricketsrickets duedue renalrenal dysfunctiondysfunction Clinical Presentation - Other „ HematologicHematologic ¾ RecurrentRecurrent lowlow--gradegrade hemolysishemolysis leadingleading toto transienttransient episodesepisodes ofof jaundicejaundice „ CardiacCardiac ¾ CardiomyopathyCardiomyopathy ¾ CongestiveCongestive heartheart failurefailure ¾ ConductionConduction abnormalitiesabnormalities „ EndocrineEndocrine ¾ HypoparathyroidismHypoparathyroidism ¾ AmenorrheaAmenorrhea ¾ TesticularTesticular atrophyatrophy „ MuscleMuscle ¾ RhabdomyolysisRhabdomyolysis Diagnosis

„ AgeAge „ KayserKayser--FleischerFleischer RingRing // sunflowersunflower cataractscataracts „ SerumSerum aminotransferasesaminotransferases „ CeruloplasminCeruloplasmin „ SerumSerum coppercopper „ SerumSerum nonceruloplasminnonceruloplasmin coppercopper „ UrinaryUrinary coppercopper excretionexcretion „ LiverLiver biopsybiopsy „ HepaticHepatic parenchymalparenchymal coppercopper concentrationconcentration Age

„ AASLDAASLD PracticePractice Guideline:Guideline:

¾ WilsonWilson DiseaseDisease shouldshould bebe consideredconsidered inin anyany individualindividual betweenbetween thethe agesages ofof 33 andand 4545 yearsyears withwith liverliver abnormalitiesabnormalities ofof uncertainuncertain etiologyetiology Serum Aminotransferases

„ UsuallyUsually mildlymildly toto moderatelymoderately elevatedelevated „ ASTAST concentrationconcentration isis usuallyusually higherhigher thanthan thethe ALTALT „ DegreeDegree ofof elevationelevation correlatescorrelates poorlypoorly withwith thethe extentextent ofof histologichistologic injuryinjury Kayser-Fleischer Ring

„ FineFine pigmentedpigmented granulargranular depositsdeposits ofof coppercopper inin Descemet'sDescemet's membranemembrane ofof thethe corneacornea „ MostMost pronouncedpronounced atat thethe inferiorinferior andand superiorsuperior polespoles ofof thethe corneacornea Ocular signs

„ KayserKayser--FleischerFleischer RingRing

¾ InIn 5050--60%60% ofof patientspatients withwith isolatedisolated hepatichepatic involvementinvolvement

¾ InIn 95%95% ofof patientspatients withwith neurologicneurologic involvementinvolvement

¾ NotNot absolutelyabsolutely specificspecific forfor Wilson'sWilson's diseasedisease

¾ RarelyRarely reportedreported inin otherother chronicchronic cholestaticcholestatic diseasesdiseases (e.g.(e.g. PBC,PBC, PSC,PSC, neonatalneonatal cholestasis)cholestasis)

¾ DisappearDisappear withwith effectiveeffective medicalmedical treatmenttreatment „ SunflowerSunflower CataractsCataracts

¾ RepresentRepresent coppercopper depositsdeposits inin thethe lenslens Serum Ceruloplasmin

„ 132132--kdkd proteinprotein synthesizedsynthesized byby hepatocyteshepatocytes andand secretedsecreted intointo thethe circulationcirculation „ AccountsAccounts forfor 90%90% ofof circulatingcirculating coppercopper „ PossessesPossesses FeroxidaseFeroxidase activityactivity andand isis requiredrequired forfor normalnormal transporttransport ofof ironiron „ HenceHence patientspatients withwith aceruloplasminemiaaceruloplasminemia exhibitexhibit hemosiderosishemosiderosis Serum Ceruloplasmin

„ MostMost patientspatients withwith Wilson'sWilson's diseasedisease havehave lowlow serumserum ceruloplasminceruloplasmin levelslevels „ AA serumserum ceruloplasminceruloplasmin concentrationconcentration lessless thanthan 2020 mg/dLmg/dL inin aa patientpatient whowho alsoalso hashas KayserKayser--FleischerFleischer ringsrings isis consideredconsidered toto bebe diagnosticdiagnostic ofof WDWD „ AcuteAcute phasephase reactantreactant –– hencehence maybemaybe falselyfalsely raisedraised intointo thethe normalnormal rangerange inin WilsonWilson DiseaseDisease presentingpresenting withwith acuteacute illnessillness Serum Ceruloplasmin – Low Positive Predictive Value

„ ProspectiveProspective trialtrial withwith 28672867 patientspatients undergoingundergoing evaluationevaluation ofof liverliver diseasedisease „ 1717 hadhad lowlow serumserum ceruloplasminceruloplasmin (<(< 2020 mg/dL)mg/dL) ¾ WilsonWilson diseasedisease -- 11 ¾ HeterozygousHeterozygous carrierscarriers -- 33 ¾ AcuteAcute ViralViral HepatitisHepatitis –– 33 ¾ DrugDrug--inducedinduced LiverLiver DiseaseDisease –– 33 ¾ MalabsorptionMalabsorption -- 33 ¾ AlcoholAlcohol--inducedinduced LiverLiver DiseaseDisease –– 22 ¾ ChronicChronic HepatitisHepatitis –– 22 Differential Diagnosis of Low Ceruloplasmin

„ WilsonWilson DiseaseDisease „ AsymptomaticAsymptomatic heterozygoteheterozygote carrierscarriers (10(10--20%)20%) „ RenalRenal proteinprotein lossloss (nephrotic(nephrotic syndrome)syndrome) „ ProteinProtein--losinglosing enteropathyenteropathy „ SevereSevere endend--stagestage liverliver diseasedisease ofof anyany causecause „ MenkeMenke’’ss diseasedisease (disorder(disorder ofof coppercopper transport)transport) „ AceruloplasminemiaAceruloplasminemia „ NutritionNutrition coppercopper deficiencydeficiency (eg.(eg. inadequateinadequate coppercopper inin TPN)TPN) AASLD Practice Guideline

SerumSerum ceruloplasminceruloplasmin shouldshould bebe routinelyroutinely measuredmeasured duringduring thethe evaluationevaluation ofof unexplainedunexplained hepatic,hepatic, neurologicneurologic oror psychiatricpsychiatric abnormalitiesabnormalities inin childrenchildren andand adultsadults throughthrough middlemiddle age.age. AnAn extremelyextremely lowlow serumserum ceruloplasminceruloplasmin (<5mg/dL)(<5mg/dL) shouldshould bebe takentaken asas strongstrong evidenceevidence forfor thethe diagnosisdiagnosis ofof WDWD Serum Copper

„ SerumSerum coppercopper isis decreaseddecreased inin proportionproportion toto thethe reductionreduction inin serumserum ceruloplasminceruloplasmin „ SerumSerum nonceruloplasminnonceruloplasmin--boundbound coppercopper levelslevels areare raisedraised –– greatergreater thanthan 2525 mcg/dLmcg/dL inin thethe majoritymajority ofof untreateduntreated patientspatients (normal(normal <15<15 mcg/dL)mcg/dL) „ MarkedMarked elevationelevation maymay bebe seenseen inin fulminantfulminant hepatichepatic failurefailure duedue toto Wilson'sWilson's disease,disease, wherewhere coppercopper isis releasedreleased suddenlysuddenly fromfrom tissuetissue stores.stores. Serum Nonceruloplasmin Copper or Serum Free Copper „ Sensitivity,Sensitivity, specificity,specificity, andand predictivepredictive valuesvalues ofof thethe nonceruloplasminnonceruloplasmin--boundbound coppercopper concentrationconcentration asas aa diagnosticdiagnostic testtest forfor Wilson'sWilson's diseasedisease havehave notnot beenbeen wellwell-- establishedestablished „ MayMay bebe elevatedelevated inin acuteacute liverliver failurefailure ofof anyany etiologyetiology andand inin patientspatients withwith chronicchronic cholestasischolestasis „ DecreasedDecreased valuesvalues havehave beenbeen reportedreported inin patientspatients overusingoverusing zinczinc supplementssupplements Urinary Copper Excretion

„ WilsonWilson DiseaseDisease isis typicallytypically associatedassociated withwith 2424-- hourhour urinaryurinary coppercopper excretionexcretion ofof >100>100 mcgmcg „ LowerLower valuesvalues havehave beenbeen describeddescribed inin upup toto 2525 percentpercent ofof presymptomaticpresymptomatic patientspatients withwith confirmedconfirmed WilsonWilson DiseaseDisease „ NormalNormal valuesvalues areare inin thethe rangerange ofof 3030 toto 4040 mcg/daymcg/day „ AA valuevalue >40>40 mcg/daymcg/day warrantswarrants furtherfurther investigationinvestigation (AASLD(AASLD PracticePractice Guideline)Guideline) Hepatic Parenchymal Copper Concentration „ QuantitativeQuantitative hepatichepatic coppercopper concentrationconcentration >250>250 mcgmcg ofof coppercopper perper gramgram ofof drydry weightweight (normal(normal <50<50 mcg/gmmcg/gm ofof drydry weight)weight) isis generallygenerally consideredconsidered toto bebe thethe goldgold standardstandard forfor diagnosisdiagnosis ofof WDWD „ FalseFalse negativesnegatives areare possiblepossible ¾ UnevenUneven coppercopper distributiondistribution withinwithin aa cirrhoticcirrhotic liverliver ¾ MassiveMassive releaserelease ofof coppercopper fromfrom necroticnecrotic hepatocyteshepatocytes asas inin fulminantfulminant hepatichepatic failurefailure „ FalseFalse positivepositive areare possiblepossible inin patientspatients withwith chronicchronic cholestasischolestasis Hepatic Parenchymal Copper Concentration „ AASLDAASLD PracticePractice GuidelineGuideline ¾ HepaticHepatic parenchymalparenchymal coppercopper contentcontent greatergreater thanthan 250250 mcg/gmmcg/gm drydry weightweight providesprovides criticalcritical diagnosticdiagnostic informationinformation andand shouldshould bebe obtainedobtained inin casescases wherewhere thethe diagnosisdiagnosis isis notnot straightforwardstraightforward andand inin youngeryounger patients.patients. ¾ InIn untreateduntreated patients,patients, normalnormal hepatichepatic coppercopper contentcontent (<40(<40--50)50) excludesexcludes aa diagnosisdiagnosis ofof WDWD Genetic Studies

„ AbundanceAbundance ofof diseasedisease--specificspecific mutationsmutations andand theirtheir locationlocation atat multiplemultiple sitessites acrossacross thethe genomegenome havehave limitedlimited thethe utilityutility ofof molecularmolecular diagnosisdiagnosis „ MostMost patientspatients areare compoundcompound heterozygotesheterozygotes „ DirectDirect mutationmutation analysisanalysis oror haplotypehaplotype analysisanalysis cancan bebe usedused toto testtest firstfirst degreedegree relativerelative ofof aa confirmedconfirmed patientpatient toto determinedetermine whetherwhether theythey areare unaffected,unaffected, heterozygousheterozygous oror patientspatients ofof WDWD Neurologic Evaluation

„ AASLDAASLD PracticePractice Guideline:Guideline:

¾ NeurologicNeurologic evaluationevaluation andand radiologicradiologic imagingimaging ofof thethe brain,brain, preferablypreferably byby MR,MR, shouldshould bebe consideredconsidered priorprior toto treatmenttreatment inin allall patientspatients withwith neurologicneurologic WDWD andand shouldshould bebe partpart ofof thethe evaluationevaluation ofof anyany patientpatient presentingpresenting withwith neurologicneurologic symptomssymptoms consistentconsistent withwith WDWD AASLD Practice Guidelines Hepatology 2003; 37:1475 Treatment

„ ChelatingChelating agentsagents –– DD--Penicillamine,Penicillamine, Trientine,Trientine, TetrathiomolybdateTetrathiomolybdate „ ZincZinc „ LiverLiver TransplantationTransplantation „ DietDiet „ AntioxidantsAntioxidants D-Penicillamine

„ ChelatesChelates coppercopper andand causescauses cupriuresiscupriuresis „ 1010--50%50% ofof patientspatients treatedtreated couldcould havehave worseningworsening ofof neurologicneurologic symptomssymptoms „ SevereSevere sideside--effectseffects requiringrequiring discontinuationdiscontinuation occuroccur inin 2020--30%30% ofof patientspatients „ SESE –– cutaneouscutaneous eruptions,eruptions, lymphadenopathy,lymphadenopathy, neutropenia,neutropenia, thrombocytopenia,thrombocytopenia, aplasia,aplasia, proteinuria,proteinuria, nephrotoxicity,nephrotoxicity, lupuslupus--likelike syndrome,syndrome, GoodpastureGoodpasture syndrome,syndrome, serousserous retinitis,retinitis, hepatotoxicityhepatotoxicity andand hepatichepatic siderosissiderosis fromfrom overover suppressionsuppression ofof coppercopper Trientene

„ ChelatesChelates coppercopper andand causescauses cupriuresiscupriuresis „ IndicatedIndicated inin patientspatients whowho areare intolerentintolerent ofof penicillaminepenicillamine asas wellwell asas aa firstfirst lineline agentagent „ BetterBetter toleratedtolerated thanthan DD--penicillaminepenicillamine „ SESE –– gastritis,gastritis, aplasticaplastic anemia/pancytopeniaanemia/pancytopenia (rare),(rare), sideroblasticsideroblastic anemiaanemia fromfrom overover suppressionsuppression ofof copper,copper, formsforms aa toxictoxic complexcomplex withwith ironiron andand hencehence coadministrationcoadministration withwith ironiron shouldshould bebe avoidedavoided Zinc

„ InducesInduces enterocyteenterocyte metallothioneinmetallothionein „ MetallothioneinMetallothionein hashas greatergreater affinityaffinity forfor coppercopper thanthan forfor zinc,zinc, thusthus preferentiallypreferentially bindsbinds toto coppercopper inin thethe enterocyteenterocyte andand inhibitsinhibits itsits entryentry intointo thethe portalportal circulationcirculation „ MayMay alsoalso actact byby inducinginducing hepatocellularhepatocellular metallothioneinmetallothionein „ WellWell toleratedtolerated „ SESE –– gastricgastric irritation,irritation, biochemicalbiochemical pancreatitispancreatitis Tetrathiomolybdate

„ ChelatingChelating agentagent „ DoesDoes notnot worsenworsen neurologicneurologic symptomssymptoms likelike DD--penicillaminepenicillamine andand TrienteneTrientene toto aa lesserlesser extentextent „ UsefulUseful inin neurologicneurologic diseasedisease „ HasHas beenbeen inin clinicalclinical trialstrials „ NotNot yetyet commerciallycommercially availableavailable Diet

„ AvoidAvoid foodsfoods containingcontaining highhigh concentrationconcentration ofof coppercopper –– shellfish,shellfish, nuts,nuts, choclatechoclate,, mushroomsmushrooms andand organorgan meatsmeats –– atat leastleast inin thethe firstfirst yearyear ofof medicalmedical therapytherapy „ EvaluateEvaluate coppercopper contentcontent inin domesticdomestic waterwater supplysupply ifif beingbeing pipedpiped throughthrough coppercopper pipespipes oror comingcoming fromfrom aa wellwell Treatment

Brewer GJ, Askari FK, Journal of Hepatology 2005; 42 Suppl(1):S13-S21 Classification of hepatic failure based upon the prognostic index of Nazer et al. Laboratory Normal Score (in points) measurement value 01234 Serum 0.2 – 11.7– <5.8 5.8–8.8 8.8–11.7 >17.5 bilirubin 1.2 mg/dl 17.5 Serum aspartate 10–35 IU/L <100 100–150 151–200 201–300 >300 transferase (AST) Prolongation of prothrombin – <4 4–8 9–12 13–20 >20 time in seconds (PT)

Brewer GJ, Askari FK, Journal of Hepatology 2005; 42 Suppl(1):S13-S21 AASLD Practice Guidelines

„ InitialInitial treatmenttreatment forfor symptomaticsymptomatic patientspatients shouldshould includeinclude aa chelatingchelating agentagent „ TreatmentTreatment ofof presymptomaticpresymptomatic patientspatients oror maintenancemaintenance therapytherapy ofof successfullysuccessfully treatedtreated symptomaticsymptomatic patientspatients cancan bebe accomplishedaccomplished withwith thethe chelatingchelating agentagent oror withwith zinczinc „ TreatmentTreatment shouldshould notnot bebe discontinueddiscontinued unlessunless aa liverliver transplanttransplant hashas beenbeen performedperformed „ TreatmentTreatment shouldshould bebe continuedcontinued duringduring pregnancypregnancy (dose(dose reductionreduction advisableadvisable forfor DD--penicillaminepenicillamine andand trientene)trientene) Cancer risk in Wilson Disease

„ WhetherWhether patientspatients withwith Wilson'sWilson's diseasedisease areare atat increasedincreased riskrisk forfor hepatocellularhepatocellular carcinomacarcinoma oror otherother malignanciesmalignancies isis unclearunclear „ OccasionalOccasional reportsreports havehave describeddescribed hepatocellularhepatocellular carcinomacarcinoma andand cholangiocarcinomacholangiocarcinoma „ ScreeningScreening forfor hepatocellularhepatocellular carcinomacarcinoma hashas notnot beenbeen recommendedrecommended inin thethe AASLDAASLD PracticePractice GuidelinesGuidelines Case Presentation

„ OurOur patientpatient waswas treatedtreated initiallyinitially withwith DD-- penicillaminepenicillamine andand isis maintainedmaintained onon trientinetrientine atat presentpresent „ SheShe initiallyinitially presentedpresented inin 19881988 andand herher diseasedisease hashas beenbeen successfullysuccessfully controlledcontrolled withwith medicalmedical therapytherapy toto datedate „ HerHer cirrhosiscirrhosis resolvedresolved Case Presentation

„ LatestLatest LiverLiver BiopsyBiopsy report:report:

¾ ModerateModerate steatosissteatosis withwith slightslight distortiondistortion ofof thethe hepatichepatic architecturearchitecture andand mildmild periportalperiportal chronicchronic inflammationinflammation

¾ StageStage 11 FibrosisFibrosis Take Home Points

„ WDWD shouldshould bebe consideredconsidered inin anyany individualindividual betweenbetween thethe agesages ofof 33 andand 4545 withwith liverliver functionfunction abnormalitiesabnormalities „ WDWD shouldshould bebe suspectedsuspected inin anyany patientpatient withwith fulminentfulminent liverliver failurefailure associatedassociated withwith CoombsCoombs negativenegative hemolytichemolytic anemia,anemia, unresponsiveunresponsive coagulopathy,coagulopathy, renalrenal failurefailure andand modestmodest AST/ALTAST/ALT elevationselevations –– liverliver transplantationtransplantation cancan bebe lifesavinglifesaving „ MedicalMedical treatmenttreatment ofof WDWD isis lifelonglifelong –– andand withdrawalwithdrawal ofof treatmenttreatment couldcould resultresult inin rapidrapid deteriorationdeterioration ofof liverliver functionfunction requiringrequiring transplanttransplant

Acknowledgements

„ DrDr RichardRichard WrightWright „ DrDr LuisLuis MarsanoMarsano „ SteveSteve MahanesMahanes