Reviews GSGilbertsyndrome Figure1Hememetabolism Vol3August2001GilbertSyndrome fromglucoseItconjugateswithvariousendogenousandexogenoussubstancesincludingdrugstoformagroupofcompoundscollectivelyte ID: 958706
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Gilbert'sSyndrome±ClinicalandPharmacologicalImplicationsPaullRaduMDandJacobAtsmonMDSimbec-TASMCCRCandClinicalPharmacologyUnit,TelAvivSouraskyMedicalCenterandSacklerFacultyofMedicine,TelAvivUniversity,Israel Reviews GS=Gilbertsyndrome Figure1.Hememetabolism Vol3August2001GilbertSyndrome fromglucose.Itconjugateswithvariousendogenousandexogenoussubstances,includingdrugs,toformagroupofcompoundscollectivelytermedglucoronides.Conjugationofacompoundwithglucuronicacidproducesanacidic,morewater-solublemoleculewithdifferentmetabolic,transportandexcretionproperties.TheavailabilityofUDP-GlucAmaydecreasefollowingenhancedglucuronidationrequirements(e.g.,highsubstrateload)orduetoglycogendepletion(e.g.,fasting).Theconjugationreactionismediatedbyalargegroupofenzymesknownasglucuronosyltransferases[6].Inmostspecies,includinghumans,themajortransferaseactivityisdetectedintheliver.Glucuronosyltransferasesaremembrane-boundenzymes,locatedmainlyinthesmoothendoplasmicreticulumbutalsofoundincellularandnuclearmembranes.Bilirubinconjugationismediatedbyonespecificisoform:bilirubinuridinediphosphoglucuronate-glucuronosyl-transferase,alsolabeledUGT1A1accordingtotheUGTsuperfamilynomenclatureproposedbyMackenzieetal.[7].InindividualsdiagnosedashavingGS,thehepaticbilirubinglucuronidationactivitywasfoundtobeapproximately30%lowerthannormal.Thegeneticandmolecularbasisofthesyndromehasnotyetbeencompletelyelucidated.AproposedanimalmodelforexploringGSistheBoliviansquirrelmonkey(BoSM)[8],whichmanifestsfastingunconjugatedhyperbilir-ubinemiasimilartothatinhumanswithGS.Ageneticdefectinbilirubin-UDPGTwasalsofoundintheGunnrat,inwhichasingleguanosine(G)withintheUGT1A1geneismissing.Thedefectresultsinaframeshiftandaprematurestopcodon±theabsenceofenzymeactivity±resultinginhyperbilirubinemia.Thisanimalservesasamodelforyetanothercongenitalfamilialnon-hemolyticjaundice±Crigler-Najjarsyndrome[9].Infact,itisarguedbysomethatGSshouldbeconsideredasavariantoftheCNsyndrome[10].Bilirubin-UDPGToriginatesfromthesamelargegeneasthephenolUDPGTsandisencodedbyasinglegene,UGT1,locatedonchromosome2atlocus2q.37[11].TheUGT1geneconsistsoffiveexons.Thereareseveralisoformsoftheenzymegene.Exonsnumber2to5arecommontoallisoformswhereasexonnumber1containsoneofatleast13uniquevariants.Apromoterregion(5)precedesexon1,andencodesauniqueUGTisoform[Figure4].ThemRNAencodingeachUGTisoformisformedbyfusionofonetypeofexon1tothecommonexons2±5region[12].Bosmaetal.[5]foundthatindividualswithGShadanormalcodingregionoftheUGT1A1gene,butwerehomozygousfortwoextrabases(TA)intheTATAAelementofthe5promoterregionofthegene(i.e.,A(TA)TAAinsteadofthenormalTAAconfiguration).ThepresenceofthelongerTATAAelementresultedinreducedexpressionofareportergene.Thefrequencyoftheabnormalallelewas40%amongnormalsubjects.ThesubjectsinthecontrolgroupwhowerehomozygousforthelongerTATAAelementhadsignificantlyhigherserumbilirubinlevelsthantheothernormalsubjects.Although(TA)7wastheonlymutantalleleassociatedwithGSintheCaucasianpopulation,anadditionaltwomutations,(TA)5and(TA)8,wereidentifiedinblackpeoplemanifestingthissyndrome[13].Akabaetal.[14]evaluatedtherelationshipbetweenbilirubin-UGTgenotypeandthepresenceandseverityofjaundicein159Japanesefull-termneonates.Theyconcluded bilirubin-UDPGT=bilirubinuridinediphosphoglucuronate-glucuronosyltrans- CN=Crigler-Najjar Figure2.Conjugationofbilirubin ConjugatedbulirubinGucronosy1transferase Figure3.ImpairedbilirubinconjugationinGilbertsyndrome Glucuronosyltransferase Conjugatedbulirubin Reviews P.RaduandJ.AtsmonVol3August2001 thataGly71Arg(G71A)mutationinthecoding1oftheUGT1genecorrelateswiththeincidenceandseverityofneonatalhyperbilirubinemiaintheJapanese,KoreanandChinesepopulation.Itisnoteworthy,however,thatotherauthorsassociatethesameG71AmutationwithCrigler-Najjarsyndrome(typeII)[15].DespitearelativelyhighfrequencyoftheelongatedTATAAelementamonghealthysubjects(40%),theincidenceofaclinicalorlaboratoryestablishedGSissurprisinglylow(3±10%).AlthoughabnormalityinthepromoterregionisalwaysaccompaniedbyreducedexpressionoftheUGT1A1gene,thepenetranceofthismutationisincomplete,since``overt''Gilbertsyndromeisnotalwaysevident.Thismayimplythatother±acquiredorinherited±
factorsmayalsocontributetotheactualhyperbilirubinemiaofGS:hepatictransportabnormalities,occulthemolysis,andstress-relatedinductionofhemeoxygenase[5].Someobservationsmayindirectlysupportthisassumption.Approximatelyone-thirdofindividualswithGShaveminorabnormalitiesinplasmaclearanceofbromsulfophthaleinandindocyaninegreen.Thesetwodyeswereformerlyusedasindicatorsforhepaticclearance.NeithercompoundisconjugatedintheliverbyUDPGT,implyingthatanundefineddefectinhepaticuptake,intracellulartransportorexcretionofbilirubinmayalsoexist,atleastinsomecases[16,17].ItwasalsonotedthatalthoughoverthemolysisisnotatypicalfeatureofGS,thelifespanoferythrocytesisshorterthannormalinabout50%oftheaffectedindividuals.Thismaysuggestthatacertaindegreeofamild,compensatedhemolyticstatemaybepresentandcanfurtherincreasethebilirubinloadwithwhichUDPGThasto``cope''[18,19].ClinicalfeaturesanddiagnosisSchmid[20]pointedoutthatGilbertsyndromeisanentirelybenignandclinicallyinconsequentialentitythatrequiresneithertreatmentnorlong-termmedicalattention.Itsclinicalimpor-tanceliesinthefactthatthemildhyperbilirubinemiamaybemistakenforasignofoccult,chronic,orprogressiveliverdisease.Sincethediagnosisislargelyoneofexclusion,clinicianssometimesfinditdifficulttodispellingeringfearsofseriousliverdisease,causingpatientsunwarrantedanxiety.GSisusuallydiagnosedbetweentheagesof15and30years.Typicallymild,asymptomaticjaundiceisfirstnoticedinadolescence.Upperabdominalpain,fatintolerance,andfatiguehavebeenreportedinfrequentlyinfrequentlyTheprincipaldiagnosticcriterionforGSisanincreasedlevelofserumunconjugated(``indirect'')bilirubin,sometimesfoundaccidentallyinrou-tinelaboratorytests.Ifaccompaniedbyjaundice,serumbilirubinlevelsusuallyexceed34±43mol/L(2.0±2.5mg/dl),orabouttwicetheupperlimitofthenormalrange.Serumbilirubinconcentrationscharacteristicallyfluctuatedaily.Meanvaluesarelowerinwomenthaninmen.Sincethefluctuatingbilirubinlevelsoftenfallwithinacceptednormallimits,itisarguedbysomethatindividualswithGSactuallyrepresentadistinctnormalsubpopulationofbilirubinvalueswithintheupperendofthenormaldistributioncurve[22].Bilirubinconcentrationsmayrisesignificantlyduringfasting,physicalexercise,stress,intercurrentillnessormenstruation.Elevationofbilirubinlevelsduringfastingisused,infact,asthemostcommondiagnostictoolforGS.Followingreducedcalorieintakeof400kcal/dayfor24±48hours,asignificantincreaseinbilirubinbloodlevelsisusuallyobserved,andtotalbilirubinbloodlevelstendtobehigherthantheacceptablenormalranges[21].Routineliverfunctiontestsarecharacter-isticallynormal,andthereisnoevidenceofbiliarytractobstructionorstructuralabnormalitiesinliverscansorhepatichistology[23].AnicotinicacidprovocationtesthasalsobeensuggestedforthediagnosisofGS.Followingintravenousadministrationofnicotinicacidthereisasignificantriseinunconjugatedbilirubin.However,thistestisnon-specificandmaybepositiveinunconjugatedhyperbilirubinemiaregardlessofthecauseand,therefore,isprobablyofnovalueindifferentiatingGSfromotherentitiesincludingchronicliverdiseases[24].AlthoughthegeneticpolymorphisminthepromoterregionofUGT1A1genemaybeidentified,itisnotdoneroutinelyforclinicalpurposes.Thismethodcouldhelpinestablishingthecontributionofthispolymorphisminindividualswithjaundiceduetomultiplecauses[25].Animmunohistochemicalassay,usingpolyclonalantibodiesraisedtoUDP-glucuronosyltransferase,hasalsobeendevel-oped,primarilyasaninvestigationalratherthanadiagnostictool.InthenormalhumanliverthereisadiffusepatternofspecificstainingforUGTnotedinallhepatocytes,andparticularlyaccentuatedinzone3ofthehepatictissue.Thiszoneisconsideredtoplayaroleintheexcretionofbileacidsratherthanbeinginvolvedinbiliaryexcretionoforganicanions.InGS,stainingissignificantlyreducedthroughoutthe G6PD=glucose-6-phosphatedehydrogenase Figure4.StructureofUGT1A1gene.Exon1differsfromisoformvariants.Commonexon2±5region.Exonsareseparatedandflankedbynon-codinggenomicsequences.5±promoterregion Vol3August2001GilbertSyndrome Reviews hepaticlobule.Onlyfaintresidualstaininghasbeendetectedinzone3[26].ThedifferentialdiagnosisofGSfromotherunconjugatedhyperbilirubinemicstatesisimportantwhenconsideringfurthermanagementofapatient.Theseconditi
onsmaybeinheritedoracquired.ThehereditaryunconjugatedhyperbilirubinemiasincludeGilbertsyndrome,Crigler-NajjarsyndrometypeI(CN-I)andCrigler-NajjarsyndrometypeII(CN-II).ThelattermaybeclinicallyidenticaltoGilbertsyndrome.Table1outlinessomecausesforhyperbilirubinemiaduetoUDPGTgenedefect,andtheirdistinctfeatures.Itisnoteworthythatsomeknownsyndromes,e.g.,Dubin-Johnsonsyndrome,Rotorsyndrome,andseveralformsofintrahepaticcholestasisarecharacterizedbyapredominantlyconjugatedratherthanunconjugatedhyperbilirubinemia.Acquiredunconjugatedhyperbilirubine-miashavealsobeendescribedinnewborns.TheseincludetheLucey-DriscollsyndromeinwhichaninhibitoroftheUGTenzymeactivityisacquiredfromthemother'sserum,andbreastmilkjaundiceinwhichtheinhibitoroftheenzymeactivityistransmittedthroughthemother'smilk.ClinicalsignificanceTheclinicalsignificanceofmoderatelyhighindirectserumbilirubinlevelsorasymptomaticjaundicewithnormalliverfunctiontestsremainsunclear.CurrentlyGSisregardedasabenign,non-progressivecondition,requiringneithertreatmentnorlong-termmedicalattention.Ithasbeenshownthatsmalldosesofphenobarbital(0.05±0.15gdaily)reducebilirubinlevelstonormal,thiseffectlastingonlyfortheperiodofthedrugNevertheless,thepresenceofGSasacontributoryfactortootherprevailingdiseasesorconditionsshouldbeconsidered:Newbornjaundice:Ageneticpredispositiontodevelopprolongedneonatalhyperbilirubinemiainbreast-fedinfantsisassociatedwithTATAboxpolymorphismofthesameUGT1A1generelatedtoGSinadulthood[27].GSactuallyacceleratesthedevelopmentofneonataljaundice.Althoughpeakjaundicelevelsdidnotdifferamonggroups,jaundiceprogressedmorerapidlyduringthefirst2daysoflifeinneonatescarryingthemolecularmarkersforGS[28].Hyperbilirubinemiainheterozygousbeta-tha-lassemiaseemstoberelatedtoco-inheritedGS.Infact,homozygosityforthepromoter(TA)7motif,whichconsti-tutesthetypicalgeneticconfigurationofGS,isoneofthepredisposingfactorsofhyperbilirubinemiainheterozygousbeta-thalassemiaindividuals[29,30].Alpha-thalassemiacouldalsobeaccompaniedbyGS.Apparentlythehyper-bilirubinemiainthiscaseresultsfromimpairedbilirubinclearanceratherthanincreasederythrocytedestruction[31].Glucose-6-phosphatedehydrogenasedeficiency:Theassocia-tionbetweenG6PDdeficiencyandGSinnewbornsisunclear.ThirtypercentofnewbornswithG6PDdeficiencyencounterjaundice,sometimessevereorfatal.Thepatho-genesisofthehyperbilirubinemiaisuncertaininthesecases.Hemolysisdoesnotseemtobethemajorcauseofhyperbilirubinemia,andGSisnotnecessarilypresentinallindividuals.Kaplanandco-workers[19]concludedthatneitherG6PDdeficiencynorthevariantUDPGT1promoterincreasestheincidenceofhyperbilirubinemiaontheirown,butthatthecombinationofbothmayhavesomeeffect.IthasbeenreportedthatGScontributestotheseverityofhyperbilirubinemiainG6PD-deficientadultsubjectsduringanepisodeofacutehemolyticanemia(fabiccrisis)[32].SomeauthorshavereportedGScoexistingwithhereditaryspherocytosis.Acommoncomplicationofhereditaryspherocytosisistheprecociousformationofbilirubinategallstonesthatmaywarrantpreventivesplenect-omy.Itwasobservedthatco-inheritanceofGSincreasestheriskfordevelopinggallstonesinpatientswithhereditaryspherocytosis[33].ThepresenceofGSshouldthereforebetakenintoaccountwhenconsideringpreventivesplenectomyinthesepatients.GSandlivertransplant:ThereisnocontraindicationforusinglivertransplantsfromdonorswithGilbertsyndrome[34].Persistentunconjugatedhyperbilirubinemiahasocca-sionallybeenobservedinlivertransplantrecipientswithotherwisenormalliverfunctiontests.WhentheUGT1A-geneTATAA-boxwasinvestigatedintheDNAoftheorgandonors,itwasshownthatsomerecipientswithpersistentunconjugatedhyperbilirubinemiahadreceivedaliverfromadonorwithanabnormalTATAA-boxinthebilirubin-UGT1A-genepromotorregion[35].Crigler-Najjarsyndrome:OnecasereportnotedthatanadultwhowasheterozygousforCrigler-NajjarsyndromeandhomozygousfortheGilbert-typegeneticdefectdevelopedseverehyperbilirubinemia.Thiscasedemonstrateshow Table1.Differentialdiagnosisofhyperbilrubinemicstatesduetoglucoronyltransferasegenedefect(predominantlyunconjugatedEntityTransmissionGenedefectTypeofhyperbirubinemiaKernicterusBilePhenobarbitalC-NIAutosomal-recessiveStructural(exon2±5):P387R(73m)(57m)Severe+Colorless
NoinfluenceC-NIIAutosomal-recessiveStructural(exon2±5):Y486D(49m)Mild-SevereVariablePartialinfluenceGSAutosomal-dominantControllergene(TATApromoterMild±PigmentedPrompt P.RaduandJ.AtsmonVol3August2001 Reviews seeminglybenigngeneticdefects,whencombined,mayresultinaseriousclinicalcondition[36].InkindredwithahistoryofCNsyndrometypeII,onlytheheterozygouscarriers,whohadalongerTATAAelementonthestructurallynormalallele,hadmildhyperbilirubinemiacharacteristicofGS.PharmacologicalimplicationsSincetheUDP-GTsystemplaysanimportantroleintheeliminationnotonlyofendogenousmetabolitesbutalsoofxenobioticssuchasdrugsthatundergoglucuronidation,theirmetabolismcouldbeimpairedinpatientswithgenetichyperbilirubinemias.ManydrugsaredirectsubstratesofthevariousisoformsofUDPGT:paracetamol(UGT1A6,UGT1A9),morphine,oxazepam,temazepam,(UGT2B7),amitryptiline(UGT1A4),ritodrine,diflunisal,zidovudineandothers.Mostofthesedrugsalsocontainphenolacceptorgroupsandcould,therefore,undergosulfationratherthanglucuroni-dation.Otheragentssuchasibuprofenandprobenecidcontaincarboxylicacidresidues,whichexclusivelybindtoglucuronicacid.Somecompoundssuchasdiflunisaland6-hydroxybileacidshavebothphenolicandcarboxylicacceptorgroups.Inadditiontothesedirectlybindingsubstrates,manyotherdrugsundergobiotransformationbyphase-Ireactionstogenerateacceptorgroupsforglucuronicacid.SinceGSoccursquitefrequentlyamongthegeneralpopulation,itwouldseemconceivablethatdrugsthatundergoglucuronidationwilldisplayadifferentpharmacokineticprofileinaffectedindividuals.Moreover,thesepatientsareatapotentiallyhigherriskforcertaindrugtoxicities.Itisdifficult,however,todirectlycorrelatedrugmetabolismtoUGTexpressionandactivityduetomarkedinter-individualandintra-individual(age-related)variability.Contributingfactorsaregeneticandenvironmentalandhaveavariableontogeneticactivity.Halletal.[37]showedagreatvariabilityintheTArepeatsoftheUGT1A1genepromoterTATAboxpresentacrossethnicgroups.PopulationsofAfricanorigindisplayfourdifferentalleleswhilenon-Africanpopulationsappeartohaveonlytwoalleles.Moreover,thesameauthorsnotedthattherealsoseemstobeaphylogeneticvariabilitythroughouttheprimateevolutation.Inninesequentialprimatespecies,thenumberofTArepeatshasincreasedduringtheevolution,achievingthelargestnumberinhumans[37].Thefactthatotherorgansarecapableofglucuronidationwithorgan-specificactivityand/ororgan-specificontogeny,andtheavailabilityofalternativemetabolicpathways,furthercomplicatethepicture.ItisthereforenotsurprisingthatonlyasmallamountofconclusivedataareavailableonthepharmacologicalimplicationsofGS.ThebestknownexampleofdrugtoxicityrelatedtoGSisthatofCPT-11(irinotecan).CPT-11,asemi-syntheticanalogofthecytotoxicalkaloidcamptotecin,isusedforthetreatmentofmetastaticcolorectalcancer.Itisbiotransformedbytissueandserumcarboxylesteraseintoahighlyactivemetabolite,SN-38(7-ethyl-10-hydroxycamtothecin),whichisglucuronidatedbyhepaticuridinediphosphateglucuronosyltransferases(UGTs).Themajordose-limitingtoxicityofirinotecantherapyisdiarrhea,believedtobesecondarytothebiliaryexcretionofSN-38,theextentofwhichisdeterminedbySN-38glucu-ronidation[38].AwideintersubjectvariabilityinSN-38glucuronideformationrateswasfoundinhumans.PatientswithlowUGT1A1activity,suchasthosewithGS,areatincreasedriskforirinotecantoxicity.Thereisnoclearsuggestioninthedatathattherapeuticdosesofparacetamol(acetaminophen)areassociatedwithincreasedriskforhepaticorsystemictoxicityinsubjectswithGS.ThismaybeexplainedbythefactthatUGT1A6(andtoalesserextentUGT1A9)aretheisoenzymesthatareprimarilyinvolvedinparacetamolmetabolism,ratherthanUGT1A1[39].InindividualswhoarepoormetabolizersofpropafenonethroughcytochromeP4502D6,glucuronidationisthemajormetabolicpathwayforelimination.ThepossibilityofincreasedtoxicityofthisdruginpatientswhoarepoormetabolizersandalsodisplayconcomitantGShasbeeninvestigated.Thishypothesiswasnotsubstantiatedbythestudy,anditseemsthatpatientswithGSwhoarealsoslowmetabolizersofpropafenonarenotatahigherriskfortoxicity.Alternatively,propafenonemaybeasubstrateforotherUGTisoformsandnotnecessarilyUGT1A1[40].IthasbeenknownformanyyearsthatmildtoseveredeficiencyofbilirubinUDP-glucuronosyltransferaseintheliverist
hecauseoftwotypesoffamilialunconjugatedhyperbilirubine-mias:Crigler-NajjarsyndromestypesIandII,andGilbertsyndrome.SincethegeneencodingforbilirubinUDP-glucu-ronosyltransferasewaselucidated,anumberofmutationsaffectingtheexpressionofthisgenehasbeenidentified.Thesemutationscanbeclassifiedintothreegroups:mutationsthatresultinareducedproductionofthenormalenzyme,mutationsthatgiverisetothesynthesisofastructurallyabnormalanddysfunctionalenzyme,andmutationsthatcompletelyabolishtheexpressionoftheaffectedallele.Thecombinationofmutationsaffectingthecodingregionofthegeneandofpromotermutationsthatreducetheexpressionofthegeneaccountsforthewideclinicalspectrumoffamilialunconjugatedhyperbilirubinemias,rangingfromtheclinicallynegligibleGilbertsyndrometothesevereandoftenfatalCrigler-NajjartypeIsyndrome.Abetterunderstandingofthegeneticsoftheseconditionsandtheavailabilityofmoleculardiagnosiswillimprovethediagnosticefficiencyandaffordbetterinformedgeneticcounseling,notonlyforCrigler-NajjarandGilbertsyndromes,butalsoforseveralacquiredconditionscharacterizedbyunconjugatedhyperbilirubinemia.Surprisingly,onlyasmallamountofdataareavailableonthepharmacologicalimplicationsofGS.ThefactthatatleastonedrugtoxicityisalmostdefinitelyrelatedtoGilbertsyndromewarrantsfurtherinvestigationofotherdrugs. Vol3August2001GilbertSyndrome Reviews 1.GilbertA,LereboulletP.Lacholemiesimplefamiliale.SemaineMedicale1901;21:241±3.2.AriasIM.Chronicunconjugatedhyperbilirubinemiawithoutovertsignsofhemolysisinadolescentsandadults.JClinInvest1962;3.SleisengerMH,KahnI,BarnivilleH,RubinW,Ben-EzzerJ,AriasIM.Nonhemolyticunconjugatedhyperbilirubinemiawithhepaticglucuronyltransferasedeficiency:ageneticstudyinfourgenerations.TransAssocAmPhys1967;80:259±66.4.SiegA,ArabL,SchlierfG,StiehlA,KommerellB.PrevalenceofGilbert'ssyndromeinGermany.DtschMedWochenschr1987;112(31±32):1206±8.5.BosmaPJ,ChowdhuryJR,BakkerC,GantlaS,deBoerA,OostraBA,LindhoutD,TytgatGN,JansenPL,OudeElferinkRP,etal.ThegeneticbasisofthereducedexpressionofbilirubinUDP-glucuronosyltransferase1inGilbert'ssyndrome.NEnglJMed1995;333(18):1171±5.6.BurcellB,CoughtrieMW.UDP-glucuronosyltransferases.PharmacolTher1989;43(2):261±89.7.MackenziePI,OwensIS,BurchellB,BockKW,BairochA,BelangerA,Fournel-GigleuxS,GreenM,HumDW,IyanagiT,LancetD,LouisotP,MagdalouJ,ChowdhuryJR,RitterJK,SchachterH,TephlyTR,TiptonKF,NebertDW.TheUDP-glycosyltransferasegenesuperfamily:recom-mendednomenclatureupdatebasedonevolutionarydivergence.1997;7(4):255±69.8.CorneliusCE.FastinghyperbilirubinemiainBoliviansquirrelmonkeyswithaGilbert's-likesyndrome.AdvVetSciCompMed1993;37:127±47.9.OwensIS,RitterJK.Thenovelbilirubin/phenolUDP-glucuronosyltransfer-aseUGT1genelocus:implicationsformultiplenonhemolyticfamilialhyperbilirubinemia.Pharmacogenetics1992;2(3):93±108.10.WatsonKJ,GollanJL.Gilbert'ssyndrome.BaillieresClinGastroenterol1989;3(2):337±55.11.MoghrabiN,ClarkeDJ,BoxerM,BurchellB.IdentificationofanA-to-Gmissensemutationinexon2oftheUGT1genecomplexthatcausesCrigler-Najjarsyndrometype2.1993;18(1):171±3.12.MeechR,MackenziePI.Structureandfunctionofuridinediphosphateglucuronosyltransferases.ClinExpPharmacolPhysiol1997;24:907±15.13.IolasconA,FaienzaMF,CentraM,StorelliS,ZelanteL,SavoiaA.(TA)8alleleintheUGT1A1genepromoterofaCaucasianwithGilbert'ssyndrome.Haematologica1999;84(2):106±9.14.AkabaK,KimuraT,SasakiA,TanabeS,WakabayashiT,HiroiM,YasumuraS,MakiK,AikawaS,HayasakaK.Neonatalhyperbilirubinemiaandacommonmutationofthebilirubinuridinediphosphate-glucuronosyl-transferasegeneinJapanese.JHumGenet1999;44(1):22±5.15.MaruoY,SatoH,YamanoT,DoidaY,ShimadaM.Gilbertsyndromecausedbyahomozygousmissensemutation(Tyr486Asp)ofbilirubinUDP-glucuronosyltransferasegene.JPediatr1998;132(6):1045±7.16.GentileS,PersicoM,TiribelliC.AbnormalhepaticuptakeoflowdosesofsulfobromophthaleininGilbert'ssyndrome:theroleofreducedaffinityoftheplasmamembranecarrieroforganicanions.Hepatology1990;12(2):213±17.17.BerkPD,BlaschkeTF,WaggonerJG.Defectivebromosulfophthaleinclearanceinpatientswithconstitutionalhepaticdysfunction(Gilbert'sGastroenterology1972;63(3):472±81.18.FiorelliG,PortaleoneD,ChiesaG,BittoT,DelNinnoE.HemolyticcomponentsinGilbert'ssyndrome.QuadSclavoD
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