CLINICALSTUDY
Thyroid-associatedophthalmopathy;qualityoflifefollow-up
orradioiodine
MirnaAbraham-Nordling,Go¨ranWallin1,2,FrankTra¨isk3,GertrudBerg4,JanCalissendorff5,BengtHallengren6, PavoHedner7,MikaelLantz6,ErnstNystro¨m8,PeterA ˚ sman9,Go¨ranLundell10,OveTo¨rring11,12 andTheThyroid
StudyGroupofTT96†
DepartmentofClinicalSciences,DivisionofSurgery,DanderydHospital,KarolinskaInstitute,S-18288Stockholm,Sweden, 1DepartmentofMolecular MedicineandSurgery,KarolinskaInstitute,SE-14186Stockholm,Sweden, 2DepartmentofSurgery,OrebroUniversityHospital,SE-70185Orebro, Sweden, 3DepartmentofClinicalNeurosciences,KarolinskaInstitute,StErikEyeHospital,SE-11282Stockholm,Sweden, 4DepartmentofOncology, SahlgrenskaUniversityHospital,SE-41345Gothenburg,Sweden, 5DepartmentofEndocrinology,Radiumhemmet,KarolinskaInstitute,Karolinska UniversityHospital,SE-14186Stockholm,Sweden, 6DepartmentofEndocrinology,MalmoeUniversityHospital,SE-20502Malmoe,Sweden, 7DepartmentofEndocrinology,LundUniversityHospital,SE-22185Lund,Sweden, 8DepartmentofEndocrinology,SahlgrenskaUniversityHospital, SE-41345Gothenburg,Sweden, 9DepartmentofOphthalmology,MalmoeUniversityHospital,SE-20502Malmoe,Sweden, 10DepartmentofOncology, Radiumhemmet,KarolinskaInstitute,KarolinskaUniversityHospital,SE-14186Stockholm,Sweden, 11DepartmentofClinicalResearchandEducation, KarolinskaInstituteand 12DivisionofEndocrinology,DepartmentofInternalMedicine,So¨dersjukhuset,SE-1188377Stockholm,Sweden (CorrespondenceshouldbeaddressedtoMAbraham-Nordling;Email:mirna.abraham.nordling@ki.se)
†(PleaseseeAcknowledgements)
Abstract
Objective:Theobjectiveofthisstudywastoinvestigatequalityoflife(QoL)inpatientswithGraves’ diseasetreatedwithradioiodineorantithyroiddrugs.
Designandmethods:Thedesignofthestudyconsistsofanopen,prospective,randomizedmulticenter trialbetweenradioiodineandmedicaltreatment.Atotalof308patientswereincludedinthestudy group:145patientsinthemedicalgroupand163patientsintheradioiodinegroup.QoLwas measuredwitha36-itemShortFormHealthStatusSurveyquestionnaire(SF-36)atsixtimepoints duringthe48-monthstudyperiod.
Results:Patientwhodevelopedorgotworseofthyroid-associatedophthalmopathy(TAO)atanytime pointduringthe4-yearstudyperiod(TAOgroup)hadlowerQoLwhennorespectwaspaidtothemode oftreatment.
TAOoccurredin75patientswhohadradioiodinetreatmentatsometimepointduringthestudy periodascomparedwithTAOin40medicallytreatedpatients(P!0.0009).
ComparisonsbetweenthegroupofpatientswhohavehadTAOversusthegroupwithoutTAO,in relationtotreatmentsandtime,showedsignificantlydecreasedQoLscoresfortheTAOgroupsat severaltimepointsduringthestudy.
InpatientswithoutTAO,therewerenodifferencesinQoLrelatedtomodeoftreatment.
Conclusions:TheQoLinpatientswithGraves’ophthalmopathywassimilarinradioiodineand medicallytreatedpatients,butpatientswhodevelopedorhadworseningofTAOhaddecreasedQoL independentofmodeoftreatment.Furthermore,patientswithTAOrecoveredphysicallywithin1year butittooktwiceaslongforthemtorecovermentally.
EuropeanJournalofEndocrinology 163 651–657
Introduction
Hyperthyroidismisacommondiseasewhichaffects 32.7–41.6cases/100000peryearinSweden (1,2) Inthemajorityofpatients,Graves’diseaseisthecause, andthyroid-associatedophthalmopathy(TAO)isoneof themaincomplications (3,4).
SeveralstudieshaveshownthatTAOisthemainreason fordiscomfortanddecreasedqualityoflife(QoL) (5–8).
WehavepreviouslyobservedanincreasedriskofTAO associatedwithradioiodinetreatmentofGraves’ hyperthyroidismincomparisontomedicalorsurgical treatmentinarandomizedstudy,‘Thyrotoxicosis1983 (TT83)’ (9).Inthatstudy,patientsintheradioiodine groupreceived L-thyroxine(T4)onlywhenbiochemical hypothyroidismoccurred,whichmayhaveaffected theoutcome (10–13).Therefore,wedesignedanew randomizedstudy‘Thyrotoxicosis1996(TT96)’
ofpatientsrandomizedtotreatmentwithantithyroiddrugs
betweenradioiodineandmedicaltreatmentofGraves’ hyperthyroidism,inwhichbothstudygroupsreceived L-T4 earlyafteradministrationofradioactiveiodine (131I)andafterantithyroiddrugs(ATDs)toprevent hypothyroidism.TheincreasedriskofTAOassociated with 131Itreatmentwasreconfirmed (14).Whenthe TT96studywasplannedin1994–1996,wedesigned thestudytoalsoaddressQoLaspectsandaddedthe 36-itemShortFormHealthStatusSurvey(SF-36) questionnairetothefollow-upparameters.Thereason forthatwasinouroriginalstudy (9),wehadobserveda decreasedmentalscoreandvitalityforallthree treatmentmodalitiesonafollow-up2yearslater (15).
Wehavealsoshownthatallthreetreatmentgroups hadalowerQoLcomparedtoanage-matchedSwedish referencepopulationgroupatlong-termfollow-upat17 years (16).However,apossibleimpactofTAOonthe QoLscoreswasnottakenintoaccount.Inthepresent study,wereporttheQoLresultsfromourlarge randomizedstudy,TT96,inGraves’patientstreated withradioiodineorATD (14).
Materialsandmethods Studydesign
Thestudywasdesignedasanopen,randomized, prospectivemulticentertrial.Patientswererandomized toradioiodine(groupI)ormedicaltreatment(groupM) withineachcenter(stratifiedrandomization).Randomizationwasmadeinblocksovertimeandwasperformed bytheOncologicalCentreattheKarolinskaUniversity HospitalinStockholm.(Formoredetails,seeTraisk etal.2009.)
Thestudywasapprovedbytheethicscommitteeof theKarolinskaInstitute(Ref.:KI96-096).
Patients
Inclusioncriteriawereasfollows:age,35–69years; symptomaticGraves’hyperthyroidism;confirmationof thediagnosisbyserumTSH(%0.1mIU/l)andelevated tri-iodothyronine(T3)and/orfreeT4;thyroiduptakeof 131I;andradionuclidescanscompatiblewithGraves’ disease,i.e.anevendistributionofradionuclide. Furthermore,theactivityofanorallyadministered doseof 131I(ascalculatedtogivethepatientan absorbedradiationdoseof120Gytothethyroidgland) shouldnotexceed600MBq,enablingthetherapytobe givenonanoutpatientbasis(seeformulain 131I section).Thisimpliedthatpatientswithlargegoiters wereexcluded.Patientswithaprevioushistoryof treatmentwithATDs, 131I,orthyroidsurgerywere excludedaswellaspatientswithsevereTAOrequiring treatmentwithcorticosteroidsatthetimeofinclusion. Thiswasdonebecauseconcomitantsteroidtreatment wouldlimitthepossibilitytoevaluatetheeffectofthe
treatmentforGraves’diseaseonworseningordevelopmentofTAO.Additionalexclusioncriteriawere incipienttoxiccrisis,coronaryheartdisease,pregnancy, breast-feeding,orpregnancyplannedwithinthe following2years.Thetotalnumberofpatientsthat mettheinclusioncriteriaisnotknown,butthereported caseswere482.Atotalof333patientsgavetheir informedconsenttoparticipateandwereenrolledinthe study.Forethicalreasons,clinicaldatawerenot documentedforthepatientswhodidnotwishto participateordidnotmeettheinclusioncriteria.Ofthe 333patientsenrolledinthestudy,20patientswere excluded,1patienthadanincorrectdiagnosis(Hashimotothyroiditis),17hadnoophthalmologicalassessmentatrandomization,and2hadnofollow-upvisits. Theseexcludedpatientshadanaverageageof50.1 years,themale/femaleratiowas5/15;of18patients,5 weresmokers,and2weremissingdata.Thenumberof patientsbelongingtoeachcenterwasasfollows: Gothenburg,58;Lund,40;Malmoe,73;andStockholm,142patientsrespectively.
Altogether,313patientswereincludedinthestudy group:150patientsinthemedicaltherapygroup (groupM)and163patientsintheradioiodinegroup (groupI).Twenty-twopatientsintheradioiodine-treated grouphadTAOatthetimeofrandomization,and53 patientsdeveloped denovo ophthalmopathy.Theradioiodinegroupthuscomprises75patientswithTAO.Inthe medicalgroup,19patientshadTAOatentry,and23 patientsdeveloped denovo ophthalmopathy(eyeproblem developedinpatientswhichatinclusiondidnothaveeye problems),togetherthus42patients.Outofthose,two patientswereexcludedfromthepresentreportduetolack ofSF-36scoreatbaseline.Threemorepatientswithout TAOinthemedicallytreatedgroupswereexcluded duetolackofSF-36questionnaire.Takentogether, thisreportthereforecomprisesof308patients(Fig.1).
Thedifferencesbetweenthemedicalandradioiodine groupswerenon-significant(fordetails,see Table1 in Traisk etal .2009).Thecumulativedropout(last observationcarriedforward)fromtheophthalmological
Figure1 PatientsinwhichbotheyescoreandSF-36questionnaire wereavailableatbaselineaccordingtotreatment(131Iandmedical therapy)andpresenceofTAOatbaselineordeveloped denovo duringthestudy.
follow-upingroupIandgroupMrespectivelywas asfollows:at1year,3and1%;at2years,6and3%; andat3years,10and9%respectively.At4years (i.e.afterprotocolforophthalmologicalfollow-up),20% ofthepatientsinbothgroupswerestillfollowedby ophthalmologists.
TreatmentforGraves’hyperthyroidism
Medical Methimazolewasgiven15mgtwicedaily,and atday14,50 mgof L-T4 wasadded,anditwasincreased to100 mgdaily2weekslater.
At6weeks,thedoseof L-T4 wasadjustedto normalizethelevelsofserumT3 andfreeT4 andto bringTSHto !0.4mIU/l.AslightlyelevatedserumfreeT4 wasacceptedupto20%abovetheupper normallimit.Beta-blockerswereusedforsymptomatictreatment.Patientsshowingseriousadverse reactionstomethimazolereceivedalternativetreatment.Methimazolewasreplacedby150mgpropylthiouracilthreetimesdailyinpatientswithminor adversereactions.
ATDtherapywasdiscontinuedafter18monthswith anadditionalmonthof L-T4 substitutionof100 mgdaily, whichthereafterwasdiscontinued.
131I Beta-blockerswereusedaspretreatmenttothe radioiodinetherapy.Theintentionwastogiveonedose ofradioactiveiodine,aimingforanestimatedabsorbed radiationdoseinthethyroidglandof120Gy.The administeredactivitywascalculatedusingthefollowing formula (10):Activity(MBq)Z(23.4!thyroidmass (g)!120(Gy))/(estimateduptake(0h;%)!effective half-life(days)).Thethyroidmasswasassessedby thyroidscintigraphyandbypalpation.Referencemodels ofathyroidglandwereusedtoaidtheassessment(30, 40,50,and60ml).Theeffectivehalf-lifeof 131Iandthe estimatedthyroiduptakeat0hwerecalculated fromtheinitial24hthyroidiodineuptakeandanew uptaketest4–9dayslater,i.e.thesamedaythe radioiodinetherapywasgiven. L-T4 substitutionwas administeredwiththesametypeofregimenasusedin groupM.
Follow-upbythyroidologist(endocrinologist oroncologist)
Thepatientswerefollowedupbyathyroidologist fourtimesinthefirstyearandthenonetotwotimes yearly(endocrinologistoroncologist)wherethetreatmentforhyperthyroidismwasmonitoredbyclinical assessmentandlaboratoryevaluationsAtthefirstvisit andafter3,12,24,36,and48months,theyanswered theSwedishversionofthevalidatedgenericMedical OutcomeStudy(MOS)SF-36questionnaire.Ifatany timeTAOdevelopedordeteriorated,thepatientswere referredtotheophthalmologistforadditionaleye examinations.(Fordetails,see(14)).
Follow-upbyophthalmologistandSF-36 Withinthefirst2weeksfollowingenrollment,all patientswereseenbyanophthalmologistandthereafterat3,12,24,and36monthsaspartofthe studyprotocolandadditionallyifTAOdeveloped.(For details,see(14)).
After36months,additionalassessmentswere performedattheeyeclinicuponreferralbythe thyroidologistsorifthepatientswerefollowedup becauseofestablishedTAO.Also,duringthe4-year follow-up,patientswithactiveTAOhadeyeassessments byophthalmologistsevery6weeksuntilthecondition hadmarkedlyimproved.Ateachvisitattheeye clinic,visualacuity,proptosis,eyelidretraction,eyelid swelling,chemosis,conjunctivalredness,impairment oftheeyemovements,cornealulceration,andoptic nerveinvolvementweredocumented(seesupplemental dataof(14)).Eyelidretractionalonewasnotclassifiedas TAO.Withineachcenter,themajorityofpatientswere followedbythesameophthalmologistthroughout thestudy.
Forthesetcriteria(worseningordevelopment andimprovementofTAO),twoofthefollowing fourdecisivefactorswererequired(comparedwith baselinedata):i)changeinexophthalmometryreadings of2mmormore;ii)improvementordeteriorationof thepatient’seyemovementsbetweenthefourscoring levels(noimpairment,clearlyimpaired,diplopiain theprimaryposition,andfixationoftheglobe); iii)changesofvisualacuitycausedbyopticneuropathy; andiv)changesintwoofthethreeTAOactivity measures(chemosis,eyelidedema,andconjunctival redness).Thepatientswhodidnotmeetthecriteria ofimprovementorworseningordevelopmentofTAO werereferredtoashavingnochangeofTAO.
SF-36 SF-36 QoLwasmeasuredwiththeSwedishversionof theMOSSF-36 (17–20)Thequestionnaireincludes36itemsthatcanbe classifiedintothefollowingeighthealthstatussubscales:physicalfunctioning,physicalrolelimitations, bodilypain,generalhealthperception,vitality,social functioning,emotionalrolelimitations,andmental health.Astandardizedphysicalcomponentsummary (PCS)andastandardizedmentalcomponentscorewere calculated (20).InSF-36,eightsubscalesaresummary scalestransformedtorange0–100,whilethePCSand thementalcomponentsummary(MCS)areweighted scores,constructedtomeanZ50and S.D.Z10 (17–20).
Statisticalanalysis
TheresultfromtheSF-36scorescomprisesofeight subscales,whicharesummaryscalestransformedto range0–100,whilePCSandMCSareweightedscores, constructedtomeanZ50and S.D.Z10.
Thestatisticalanalysesthatwereusedwerethe Mann–Whitney U testandthePearson c 2 test.TheSAS Systemwasusedforanalysis.
Results
Patientswhohadexperienceddevelopmentorworseningofeyeproblemsatanytimepointduringthe4-year studyperiod(TAOgroup)hadlowerQoLestimatedby theSF-36questionnairewhennoattentionwaspaidto themodeoftreatment.TheTAOgroupatbaseline alreadyhadasomewhatlowerMCSscore,althoughnot
statisticallysignificant.Throughoutthewholestudy period,theTAOgrouphadlowerMCSandPCSforthe first3years(Fig.2aandb).
Tostudythepossibleinfluenceoftreatmentmodality ontheoccurrenceofTAO,wethusfoundthatmore patients(nZ75)whohadradioiodinetreatmenthad experiencedTAOatentryoratsometimepointsduring thestudyperiodascomparedwiththe40medically treatedpatients(P!0.0009, Table1).
TherewerenodifferencesintheresultsoftheSF-36 scoresbetweenthetwotreatmentgroups. Figure3 showstheMCSandPCSscores.Itisevidentfrom Fig.3 thatatdiagnosis(month0)ofGraves’disease,both groupshaddecreasedQoLSF-36scoreascompared withtheSwedishreferencepopulation.TheQoLscores increasedinbothtreatmentgroupsduringthestudy. Alreadyafter3months,thephysicalcomponentscore reachedtheaveragefortheSwedishreferencepopulation(score50)andremainedatthislevelthroughout thestudyperiod(48months; Fig.3a).Themental componentscoreshowedsomedelayinboththe radioiodineandmedicallytreatedgroupstoreachthe averagescoreof50notuntil12months.Thereafter, thementalcomponentscoreremainedratherconstant for3yearsoratleastuntil48months(Fig.3b).
Comparisonsbetweenthetwogroupsofpatients withoutTAOshowednosignificantdifferences inQoLregardlesswhethertheyhadbeentreatedwith radioiodineorATDs.
Comparisonsbetweenthegroupofpatientswhohave hadTAOversusthegroupwithoutTAO,inrelationto
Table2 Patientswiththyroid-associatedophthalmopathy(TAO)and36-itemshortformhealthstatussurveyinrelationtotreatment group.Thetableshows,forbothtreatmentgroups,alltimepointsduringthestudywhenpatientswithTAOasagrouphada significantlydecreasedQoLcomparedwithpatientswithoutTAO.Analysesweredoneforalltimepoints,butonlysignificantresultsare shown(Mann–Whitney U test).
treatmentsandtime,showedsignificantlydecreased QoL(SF-36)scoresfortheTAOgroupsatseveraltime pointsduringthestudy(Table2).
Inthewholestudygroup,thefrequencyof patientswithmoresevereophthalmopathywashighest at1yearafterenrollment,11.2%)comparedwith6.1% atbaseline.Severeophthalmopathywasdenotedhere asincreaseofproptosisof3mmormoreand/or deteriorationofeyemotilitycomparedtobaselinedata.
Atthe1-yeartimepoint,therewasnoclear correlationassociationbetweentheobjectiveeyescore andPCSandMCS.Neitherwerethereanysignificant differencesbetweenthosewitheyescoresabove3 orbelow3timepointswithrespecttoPCSandMCS.
Discussion
Thepatientswerethoroughlyandequallycontrolledin bothtreatmentgroupsthroughoutthefollow-upperiod. Inaddition,hypothyroidismwasavoidedbyearly additionof L-T4 inbothtreatmentgroups.
Whennoconsiderationofthemodeoftreatmentwas takenintoaccount,itwasclearthatpatientswithTAO hadasignificantlydecreasedQoLforaconsiderable amountoftimeaftertreatment(Fig.2 aandb).
Thisobservationcorroboratedearlierfindingbyothers whenaneye-specificquestionnairehadbeenused (6–8). Hypothyroidismafterradioiodinetreatmenthasbeen consideredtoincreasetheriskofTAO.However,nosuch
associationcouldberevealedina posthoc analysisofa randomizedprospectivestudy (21).Furthermore,inthe presentstudywherehypothyroidismwasavoided,an increasedriskofTAOassociatedwithradioiodinewas stillobserved.Thestudythussupportedtheconceptof radioiodineasanindependentriskfactorfordevelopmentorworseningofTAOaswehadproposedearlier (9,22).ThestudyalsoshowedthatQoLwasrather equalinbothtreatmentgroupswhennoattentionwas paidtothepossibleinfluenceofTAO(Fig.3aandb). Interestingly,theimprovementinmentalQoLwas somewhatslowertonormalizeascomparedwiththe physicalperformancecapacity.Inpreviousstudies,we haveobservedthatpatientswithGraves’hyperthyroidismhadlowermentalQoLscoresatfollow-upafter treatment (16).Mostlikely,thenegativeinfluenceon normalbrainfunctionsbythehyperthyroidphase beforetreatmentmayhavetakenaconsiderable amountoftimetoresolveafterstartoftreatment.
Accordingto Fig.3 b,ittook3monthsforthe radioiodinegroupandalmostayearforthemedically treatedgrouptoreachtheaverageof50pointsforthe Swedishreferencepopulation.Thepatientswere substitutedtohaveaTSHvalue !0.4mIU/l,and whetherthiswasofimportancefortheratherslow improvementinmentalQoLisopentospeculation.
TheobservationthattheQoLscoreswererather equalinbothtreatmentgroupswasapositiveoutcome oftreatmentofsuchacommonandseriousdisease.The findingalsocorroboratesourpreviousresultsfrom TT83thatthemodeoftreatmentdidnotsignificantly affecttheQoLasestimatedbythegenericquestionnaire SF-36 (16,23).However,inthisanalysis,noattention waspaidtowheninthestudyperiodeyeproblems occurredortheclinicalcourseofTAO.Thiscould potentiallyhaveequaledoutpossibleinfluencesofTAO onSF-36scoring.Wethereforeperformedasubsequent analysisofwhenduringthefollow-upperiodtheTAO occurredineachtreatmentgroup(Table2).Patients withTAOgenerallyhadsignificantlylowerQoLscores ascomparedwithpatientswithoutTAOatseveraltime points,butnoconsistenttreatment-ortime-related patterncouldbefound.However,patientswithoutTAO neverhadlowerQoLcomparedwithTAOpatients. PatientswithTAO,ontheotherhand,hadlowerSF-36 scoresindependentofthemodeoftreatment.
Itisimportanttokeepinmindthatthematerialwas analyzedinthewaythatonceapatientexperienced TAOthatparticularpatientwasincludedintheTAO groupwithoutregardtothetimepointduringthestudy theeventoccurred.Therefore,wehaveanalyzedthe relationbetweentheSF-36scoreandTAOatthe1-year follow-upwheretheTAOpatientshadthehighesteye scores (14).Thiswasdoneinanattempttoexplore whethertheSF-36questionnaireatalltimepoints reflectedtheinfluenceofeyeproblemsonQoL,sinceitis possiblethatthepatients’responsetothequestionsin SF-36mayhavereflectednotonlytheprobableeye
problemsbutalsotheGraves’disease(GD)initself.The 1-yearfollow-upwasselectedsincepreviousstudies haveshownthatthemajorityofpatientsfeltrather wellat1year.
TheresultofthisanalysisshowedthattheSF-36due toitsgenericpropertiesisnotanoptimalinstrument formeasuringQoL-relatedissuesinthispopulation. Acaveatofthisstudythereforeisthepossibilitythatthe SF-36questionnairedoesnotcapturealltheappropriatequality-of-lifeissuesthatarerelevantforpatients whohavehadGD.AlthoughtheSF-36isused extensively,ithasnotbeenspecificallyevaluatedina populationofGDpatients,butneitherhaveother disease-specificinstruments.However,theHyperthyroidismComplaintQuestionnairedevelopedby Fahrenfort etal (4) hasapproachedthisissuewith respecttolong-termcomplaints.Wehowever,decidedto usetheSF-36,forthefollowingimportantreasons. TheSF-36questionnairehasbeenextensivelyevaluated inalargeage-matchedSwedishreferencepopulation, allowingustomakeanappropriatecomparisonwith ourstudygroup.Anothercaveatofthestudyisthat itdidnotcoverthewholespectrumofeyeproblems associatedwithGraves’ophthalmopathysincepatients withthemostsevereTAO,whoatinclusionrequired steroidtreatment,werenotincluded.
Conclusions
TheQoLinpatientswithGraves’ophthalmopathywas similarinradioiodineandmedicallytreatedpatients, butpatientswhodevelopedorhadworseningofTAO haddecreasedQoLindependentofmodeoftreatment. Furthermore,patientswithTAOrecoveredphysically within1year,butittooktwiceaslongforthemto recovermentally.TheQoLinpatientswithoutTAO seemedtobeindependentofmodeoftreatment.
Declarationofinterest
Theauthorsdeclarethatthereisnoconflictofinterestthatcouldbe perceivedasprejudicingtheimpartialityoftheresearchreported.
Funding
Thisresearchdidnotreceiveanyspecificgrantfromanyfunding agencyinthepublic,commercialornot-for-profitsector.
Acknowledgements
WethankElisabethBjurstedtattheDepartmentofOncology, Radiumhemmet,forsecretarialhelp.
TheThyroidStudyGroupoftheTT96trialisrepresentedbythe authorslistedaboveandthefollowingcollaborators:LTallstedtfrom DepartmentofClinicalNeurosciences,StErikEyeHospital;VPonjavic fromDepartmentsofEndocrinologyandOphthalmology,Lund UniversityHospital;ATaubefromDepartmentofInformationScience, UniversityofUppsala;TAnderssonfromDepartmentofOphthalmology,SahlgrenskaUniversity;GLindstedtfromtheDepartmentof ClinicalChemistry,SahlgrenskaUniversityHospital,Gothenburg;
AMichanekfromtheDepartmentofOncology,SahlgrenskaUniversity Hospital,Gothenburg;KNorrsellfromtheDepartmentofOphthalmology,SahlgrenskaUniversityHospital,Gothenburg;SValdemarssonfromtheDepartmentofEndocrinology,LundUniversityHospital; MGarkavij,JTennvall,andHWidmarkfromtheDepartmentof Oncology,LundUniversityHospital;GStigmarfromtheDepartment ofOphthalmology,Lund UniversityHospital;A ˚ Arwidiand GBjelkengrenfromtheDepartmentofOncology,MalmoeUniversity Hospital;BHemdahlandHJo¨nssonfromtheDepartmentof Radiophysics,MalmoeUniversityHospital;CBeckerfromthe DepartmentofClinicalChemistry,MalmoeUniversityHospital;B Freyschuss,JHoffstedt,OTullgren,HWahrenberg,andAWennlund fromtheDepartmentofEndocrinology,KarolinskaUniversityHospital (Huddinge),Stockholm;SRo¨jdmark,MSa¨a¨f,andMThorenfromthe DepartmentofEndocrinology,KarolinskaUniversityHospital(Solna), Stockholm;BHambergerfromtheDepartmentofSurgery,Karolinska UniversityHospital,Stockholm;andHBlomgren,CHilding,and A-LHjelmSkogfromtheDepartmentofOncology,Karolinska UniversityHospital,Stockholm.
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Received21June2010
Accepted21July2010