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