Thyroidhormonestateandqualityoflifeatlong-termfollow-up afterrandomizedtreatmentofGraves’disease
MirnaAbraham-Nordling,Go¨ranWallin,Go¨ranLundell1 andOveTo¨rring2
DepartmentofSurgery,InstitutionofMolecularMedicineandSurgery,KarolinskaInstitutet,KarolinskaUniversityHospital,Solna,Stockholm, Sweden, 1DepartmentofOncology,InstitutionofOncology-Pathology,KarolinskaInstitutet,KarolinskaUniversityHospital,Solna,Stockholm,Swedenand 2DivisionofEndocrinology,DepartmentofMedicine,InstitutionofClinicalResearchandEducation,Sodersjukhuset,Stockholm,Sweden
(CorrespondenceshouldbeaddressedtoMAbraham-NordlingwhoisnowatDepartmentofSurgery,DepartmentofMolecularInstitutionofSurgery, KarolinskaUniversityHospital,17176Stockholm,Sweden;Email:mirna.nordling@ds.se)
Abstract
Objective:Ina14–21yearfollow-upofhealth-relatedqualityoflife(HRQL)outcomeof179patients afterrandomizedtreatmentofGraves’disease(GD)withsurgical,medicalorradioiodine,wefoundno differences.TheHRQLforGraves’patients,however,waslowercomparedwithalargeage-andsexmatchedSwedishreferencepopulation.WehavenowstudiedwhetherthereportedHRQL-scoresby MedicalOutcomeStudy36-itemShort-FormHealthStatusSurvey(SF36)andqualityoflife2004 (QoL2004)answerswererelatedtothethyroidhormonestateofthepatient.
Methods:Thisreportcomprises91oftheoriginalpatientsinwhichboththeresultsofSF36and QoL2004questionnaireaswellasserumthyroidhormonesandcurrentuseof L-thyroxinetreatment wereavailable.
Results:AlargenumberofthepatientshadloworundetectableserumTSHconcentrations.SF36 scoresandanswerstoQoL2004questionnaireswerenotcorrelatedtoTSHlevelsorassociatedwith suppressedTSH.AlowfreetriiodothyroninewasweaklyassociatedwithalowGHscore(P!0.02)and elevatedthyrotropinreceptorantibodywithalowphysicalcomponentsummary(P!0.02).
Conclusion:HRQLdonotseemtobeinfluencedbythethyroidhormonestateofthepatientincluding subclinicalthyrotoxicosis.ItispossiblethatthepersonalityofGDpatientsassuchmayhaveresulted bothinthedevelopmentofGDandlowerHQRLscoreslateroninlife.Alternatively,thegenericSF36 maynotbeaproperinstrumenttodetectrelevantdifferencesinHRQLrelatedtothethyroidstate.
EuropeanJournalofEndocrinology 156 173–179
Introduction
SeveralstudieshaveshownthatpatientswithGraves’ disease(GD)andGraves’ophthalmopathyhavediminishedhealth-relatedqualityoflife(HRQL)duringand aftertreatment (1–6).
Wehavepreviouslycomparedtheoutcomeof treatmentwithsurgery,antithyroiddrugs(ATD)or 131Iinaprospective,randomizedstudy (7).Increased riskforthedevelopmentorworseningofGraves’ ophthalmopathyafterradioiodinewasobserved (7) Notreatment-relateddifferencesinsick-leaveorsatisfactionwiththetreatmentwereobserved (8) .No significantdifferencesinHRQLwerefoundbetween thethreetreatmentsasestimatedwithaspecific questionnairedevelopedforthepurpose(‘QoL1996’), 3yearsafterinitialtreatment (9).Evenafter14–21 years,therewerenosignificantdifferencesinHRQLby thefirstvalidatedcomparisonpublished,whichwas relatedtothetreatmentmodalityforGraves’hyperthyroidism(surgical,medicalor 131I) (10).Asinstruments
forHRQLinthelong-termfollow-up,thevalidated MedicalOutcomeStudy36-itemShort-FormHealth StatusSurvey(SF36)questionnairecombinedwithan updatedversionofQoL1996:‘QoL2004’wasused (10)
ThehistoryofGD,however,didhaveanegative influenceonHRQLonlong-termcomparedwitha healthy,age-matchedreferencepopulation,especially withregardtomentalperformanceand‘vitality’ (10). Slightchangesinthethyroidhormonestatesuchasin subclinicalthyrotoxicosisorhypothyroidismmaylead todiminishedHRQL (11)
Inthisreport,wehavethereforestudiedwhether thereportedQoLscoresinSF36andQoL2004answers mayhavebeeninfluencedbythecurrentthyroid hormonalstatusorthelevelofthyroxine(T4) substitution.Ourhypotheseswerethatsurrogate markersforthethyroidstateofthepatientsuchas serumthyroid-stimulatinghormone(TSH),freeT4 (fT4),freetriiodothyronine(fT3),totalT3orofthyroid immunity(TRaborTPOab)wereassociatedwithor couldpredicttheHRQLscores.
Materialandmethods
Subjects
Inthepresentfollow-up,172oftheinitial179patients betweentheagesof20and55yearswereincluded (10). Thepatientshadbeenreferredtoourunitsbetween 1983and1990duetoGraves’hyperthyroidism (7). ThroughMay2004,172ofthe179randomizedpatients werealiveandwereaskedtoparticipateinthestudy.Two patientsweretooill(psychotic nZ1,cerebrovascular stroke nZ1)tobeabletoanswerthequestionnaires.Out of179patients,147answeredthequestionnaires,of which145werepossibletoevaluate.Thebloodsamples wereavailablein113ofthe145patients.Outof113 patients,22hadthebloodsamplesanalysedatanother hospitalwithdifferentreferenceranges,hadreceived morethanonetreatmentforhyperthyroidismorthe SF36orQoL2004responsewaslacking.These22 patientsarethereforeexcludedfromtheinvestigation. Thus,intotal,thepresentreportcomprises91subjectsin whombothbloodanalysesaswellasSF36orQoL2004 (nZ89)HRQLquestionnaireswereavailable.
Thestudygroups Sincetherewerenosignificantsexandage-relateddifferencesintheresultsofHRQL questionnairesinourpreviousstudy (10),wehave groupedthepatientsbasedonthemodeofinitial treatmentonly.Thus,thepresentreportconsistsofthe surgicalgroup(nZ38),medicalgroup(nZ17)and radioiodinegroup 131I(nZ27).The‘additional 131I group’consistsofninesubjects,whoinadditiontothe initialmedicalorsurgicaltreatmenthadbeengiven 131I (nZ9; Table1).
Follow-up Theperiodfromthelastfollow-upat3years afterinitiationoftreatment (9) anduntil2003.The follow-uptimethereforeconsistsof14–21yearsafter initialtreatmentforGraves’hyperthyroidism.
Studydesign Aself-assessmentquestionnairewassent toeachpatient,whichincluded(a)theSwedishversionof
thevalidatedgenericMedicalOutcomeStudy(MOS) 36-itemSF36;(b)somedisease-specifictreatment-related questionsfrom‘QoL1996’thatwehaveusedinthe previous3yearsfollow-up (9);(c)additionaldiseasespecificitemswhichaddressedoccurrenceofother autoimmunediseases,osteoporosis,cardiacdiseasesor psychosocialeventswhicharenotcoveredbySF36;and (d)thepatientswerealsoaskedtogiveabloodsample.The questionsin(c)and(d)arecomprisedinthediseasespecific‘QoL2004’.ThegenericHRQLinstrumentMOS SF36isvalidatedandwellestablished (10,12–15).From fourphysical(PF,physicalfunctioning;RP,rolephysical; BP,bodilypain;GH,generalhealth)andfourmentalitems (VT,vitality;SF,socialfunctioning;RE,role-emotional; MH,mentalhealth),astandardizedphysicalcomponent summary(PCS)andamentalcomponentsummary (MCS)werecalculatedwhichrepresentthedeviationfrom thereferencepopulationinSweden (14,15) (forfurther detailsofthestudydesign,SF36andQoL2004,pleasesee Ref. (10) withappendix.).
Thestudywasapprovedbythelocalethicscommittee oftheKarolinskaInstitutet(KIno.03-232).
Laboratoryassessment
TSHwasdeterminedbychemiluminescentimmunoassay (BeckmanCoulter,Fullerton,CA,USA,referencerange 0.2–4.0mU/l;intraassaycoefficientofvariation(CV) value,3.1%;interassayCVvalue,3.86%).Thelower detectionlimitis0.01mU/l.fT3wasdeterminedbytimeresolvedfluoroimmunoassay(AutoDELFIATriiodothyronine,WallacOy,Turku,Finland),referencerange 4.0–7.0pmol/l;intraassayCVvalue,3.9%,interassay CVvalue,4.4%.T3wasdeterminedbytime-resolved fluoroimmunoassay(AutoDELFIATriiodothyronine, WallacOy,Finland),referencerange1.1–2.5nmol/l. fT4wasdeterminedbychemiluminescentimmunoassay (BeckmanCoulter,refere ncerange10–20pmol/l). Antibodiestothyroidperoxidase(anti-TPO)was determinedbychemiluminescentimmunoassay(Nichols Advantage,SanClemente,CA,USA,referencerange !2kU/l;intraassayCVvalue,3%,interassayCVvalue,
5%)andthyrotropinreceptorantibody(TRab)was determinedbyradioreceptorantibodyassay(BRAHMS, TRABhuman,Henningsdorf,Germany,referencerange !8U/l).
Statistics
ThedatawereanalysedusingthesoftwareStatisticaTM (Statsoft,Tulsa,OK,USA).Non-parametricalstatistics wereused(Kruskal-WallisANOVAbyranks,Spearman’srankcorrelations,Mann–Whitney U-testand c 2test)(forfurtherdetailscf.Ref. (10)).Theassociation betweenthesubscalesSF36andthevariables;thefour treatmentgroups,doseof L-T4,TRab,antibodiesto thyroidperoxidase(TPOab),TSH,T4,fT4,T3,fT3were performedusingstepwiselogisticregressionanalysesfor ordinalresponsevariables,aproportionaloddsmodel. ThesubscalesinSF36werecategorizedintofour categories,accordingtopercentiles0–25,25–50, 50–75and75–100%.Theassociationbetweenthe QoL2004‘Doyoufeelwell’andtheindependent variablesabovewasanalysedbyastepwiselogistic regressionforbinaryresponse.SoftwareusedwasSAS System9.1(SASInstituteInc.,Cary,NC,USA).
Results
PCSandMCSinrelationtoserumTSH
IntheSurgicalATD-and 131 I-treatedgroups,a substantialnumberofpatientshadaPCSorMCS
scorebelowthereferencemean50,independentoftheir serumTSHvalue(Fig.1).However,itisapparentthat mostofthelowerscoresbothforPCSandMCSareseen withsuppressedorlow-normalTSHvaluesinthe surgicaland 131I-treatedgroups,whichbothhad alargeproportionofpatientswithsuppressed(! 0.2mU/l)orundetectable(!0.01mU/l)serumTSH values.However,manysubjectwithsuppressedTSH alsohadPCSandMCSscoresabovetheaverage,which wereunrelatedtotheserumTSHconcentrations (Fig.1).ThedissociationbetweenTSHandPCSor MCSwasseeninallfourgroups.Therewasno significantdifferencebetweenthefourgroupsinPCS (PZ0.97, nZ91,n.s.)orinMCS(PZ0.76, nZ91,n.s.) (ANOVA).Thefollowinganalysesarethereforeperformedonthewholestudygroup.
Forty-fourpatients(48%)hadTSHwithinthe referencerange(0.2–4.0mU/l)andPCSof45.7 G 11.5(mean GS D.);range18.7–57.6andMCSof47.1 G 12.2;range15.9–60.9.Forty-threepatients(47%)had suppressedTSH(!0.2mU/l)andPCSof46.3 G10.7; range23.5–62.4andMCSof47.2 G 10.6;range 14.4–60.9.Therewasnostatisticaldifferencebetween thenormalversusthesuppressedTSHgroupinmedian PCSormedianMCS(Mann–Whitney U-test).The remainingfourpatientshadelevatedTSHwithno consistentpatterninPCSorMCS.
SixteenpatientshadnoT4substitution.Twoofthose hadTSH ! 0.2mU/landonehadTSH O 4mU/l. Figure2 showsthePCSandMCSresultsforthe16 l ll
l
Figure1 PCSandMCSinrelationtologserumTSHinthetreatmentgroups.TheshadedareaindicatesthereferencerangeforTSH (0.2–4.0mU/l,logreferencerange 0.69to0.6).Pleasenotethedifferentscalesonthe X-axis.
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70 –2–1.5–1–0.500.51 logTSH(mU/l)
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Figure2 PCSandMCSinrelationtologserumTSHin16subjectswithoutsubstitutionwith L-thyroxine.Theshadedareaindicatesthe referencerangeforTSH(0.2–4.0mU/l,logreferencerange 0.69to0.6).
subjectswithoutT4substitution.Therewereno significantdifferencesinthedistributionofPCS (PZ0.91,n.s. c2)orMCS(PZ0.15;n.s.)aboveor belowthereferenceaverageof50forthepopulationin relationtosuppressedornormalTSH.
PCSandMCSinthyroxine-substitutedpatients
Seventy-fivepatientshadT4asthyroidhormone replacementtherapy.TherelationbetweenserumTSH andPCSorMCSthereforehasbeenanalysed.In31 cases(41%),theresultofsubstitutionwaseuthyroidism withnormalserumTSHandinothercases(nZ41, 55%)suppressedTSHwithsubclinicalexogenous thyrotoxicosis(Fig.3aandb).
PCS OfpatientswithsuppressedTSH,24(59%)hadaPCS belowaverage(50)forthereferencepopulationand17 (41%)hadaPCSaboveaverage(Fig.3a).Ofpatientswith normalserumTSH,14(45%)hadaPCSbelowthe referenceaverageand17(55%)above50.Threepatients (4%)hadelevatedserumTSH.Therewasnosignificant differencebetweenthemedianPCSinthenormalversus thesuppressedTSHgroup45.1G12.7; nZ31versus 45.9G10.7; nZ41(Mann–Whitney U-test)
ThenumberofPCSaboveorbelow50forpatients withTSH !0.2mU/lwasnotstatisticallysignificantly differentfromthedistributionofPCSaboveorbelow50 forpatientswithTSHbetween0.2and4.0mU/l(PZ 0.26, c2).
MCS SuppressedTSH(!0.2mU/l)wasseenin41of the75patients(55%)(Fig.3b).Ofthose,20patients (49%)hadMCSbelowaverageforthereference population(!50)and21(51%)hadascore O50.Of the31patientswithanormalTSH,12(39%)hadMCS
!50and19(61%)hadMCS O50.Therewasno significantdifferencebetweenthemedianMCSinthe normalversusthesuppressedTSHgroup(46.9 G13.1; nZ31vs47.4 G10.9; nZ41,Mann–Whitney U-test). ThenumberofMCSaboveorbelow50forpatients withTSH !0.2mU/lwasnotstatisticallysignificantly differentfromthedistributionofMCSaboveorbelow 50forpatientswithTSHbetween0.2and4.0mU/l (PZ0.39, c2).
FreeT4,totalT3,freeT3,TRabandTPOab,and daily
L-thyroxinedose
MCSwaspositivelycorrelatedwithserum-fT3inthe wholegroup(RZ0.26, nZ89, P!0.02,Spearman rank).NocorrelationwasfoundbetweenfT3andPCS. Inaddition,nootherstatisticalsignificantcorrelations wereseenbetweenPCSorMCSandTSH,fT4,dailydose ofT4,TRaborTPOab(Fig.4).
SF36:multivariateanalysesbystepwise logisticregression
Multivariateanalysesofpossibleassociationsbetween PCSaswellasMCSandTSH,doseof L-T4,fT4,totalT3, fT3andTPOab,TRabinthefourtreatmentgroupswere performed.Theanalysesconfirmedtheabsenceof correlationbetweenPCSorMCSscoresandserum TSH,fT4,totalT3,fT3andTPOab.
However,thereseemstobearelationbetweenTRab andPCSsincetheoddsratio(OR)forlowerPCSscorewere 4.4higherthanforthepatientswhohadTRabR8U/l (95%confidenceinterval1.2–15.4)comparedwiththe oneswhohadnormalTRab(!8U/l)(P!0.02).
Multivariateanalyseswerealsoperformedforthe eightsubdomainsinSF36.Onlyaweakrelation betweenfT3andGHwasobservedbutnotforPCS.
(a) (b)
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QoL2004
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AlowfT3wasassociatedwithalowscoreintheGH subdomain(P!0.02).
FromtheQoL2004HRQLquestionnaire,therealso seemedtobenorelationbetweenthelevelofserumTSH
andtheresponsetothewell-beingquestions‘Doyoufeel wellnow’ (11).Of89patients,69(78%)amongthe combinedtreatmentgroupanswered‘yes’tothe question(Table2).Ofthose,32/69(46%)hada suppressedTSH(!0.2mU/l),ofwhich27(39%)had TSHbelow0.1mU/land35(51%)hadnormalTSH. Amongthosewhoanswered‘no’tothequestion
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Figure3 PCS(a)andMCS(b)inthepatientswith L-thyroxinesubstitution(nZ75)inrelationtologserumTSH.Theshadedareaindicates thereferencerangeforTSH(0.2–4.0mU/l,logreferencerange 0.69to0.6). 0
70 90100110120130140150160170180190200210220230240 Thyroxinedose/day(mg)
PCS MCS
Figure4 PCSandMCSinthepatientswithTSHlevelsbelow0.1mU/l(nZ34)andthyroxinesubstitutionversusthe L-thyroxinesubstitution dose/day.Thescoresatdose150 mg/dayareshiftedtoeasetheinterpretationofthefigure.
Table2 Self-reportedanswerstotheQoL2004questionnaireamongthesubjectswherebloodsamplewasalsoavailable(TSH: nZ89; freeT4(fT4): nZ84).
TSH
(mU/l)
fT3fT4
Doyoufeel wellnow? N % !0.010.01–0.10.1–0.20.2–4.0 O4.0LNHLNH Yes69780275352257614321 No201607210111800154
ThereferencerangeforserumTSHis0.2–4.0mU/landforfT410–20pmol/l.L,low;N,normalandH,high;L!10pmol/l;NZ10–20;HO20pmol/l.
‘Doyoufeelwellnow’,9/20(45%)hadsuppressedTSH, 7(35%)hadTSHbelow0.1mU/land10hadanormal TSHvalue.Thereisnosignificantdifferenceinthe numberofanswers‘yes’and‘no’betweensuppressed andnormalserumTSH(c2,n.s.)(Table2).Neitherdid theleveloffT3orfT4significantlyinfluencethe‘yes’ versus‘no’responses(c2,n.s.).
QoL2004:multivariateanalyses Asimilaranalysis, asforSF36,wasperformedfortheanswertothe question‘Doyoufeelwellnow’classifiedas‘yes’or‘no’ withthesamevariablesasabove.Nosignificant correlationswereobservedbetweenanyofthevariables andtheanswertothequestion.
Discussion
WehaverecentlyreportedthatGDhasnegative consequencesforthepatients’HRQLevenafter14–21 years,especiallywithregardtomentalperformanceand ‘vitality’ (10).However,themodeoftreatmentfor Graves’hyperthyroidismwhethersurgical,medicalor radioiodine,hadlittleimpactonHRQLinthelong-term. Inthepresentstudy,wehaveanalysedwhetherthe thyroidstateofthesubjectsatthetimeofresponseto thequestionnairescouldexplainwhytheGDpatients hadlowerHRQLcomparedwithalarge,normal Swedishreferencepopulation (10) .Providedthe subjectshavenormalpituitaryandhypothalamic function,andwehavenoreasontobelieveotherwise, anormalserumTSHisthemostvalidandrecognized surrogatemarkerforanormalthyroidstateandhas thereforebeenused.
However,wefoundnoassociationbetweenserum TSHandPCSorMCS.Amongsubjectswithsuppressed TSH,therewasthesameproportionofMCSandPCS scoresaboveasbelowtheaverageof50forthereference population.AndthatalsoholdsforpatientswithTSH withinthereferencerange.Thestepwiselogistic regressionanalysesgavethesameresult.Taken together,PCSorMCSorsubdomainscoredonotseem tobesubstantiallyinfluencedbythyroidhormonestate whenTSHwasusedasanindicator(Figs1–3).
AsserumTSHshowedaskewdistribution,with38% oftheserumTSHconcentrationsbelow0.02mU/l,we alsoanalysedwhetherPCS,MCSandthesubdomain
scores(PF,RP,BP,GHandVT,SF,RE,MH)couldbe predictedbyserum-fT4,totalT3orthefT3concentrations.NoassociationwasseenforfT4,totalT3orfT3 inMCSorPCSbutwedidseeaweakassociation betweenalowserum-fT3andlowerGHscores.
AweakassociationbetweenelevatedTRabandlower PCSwasalsoobserved.TheassociationbetweenTRab andPCSisanewobservationbutdifficulttointerpretate untilfurtherstudiessubstantiatethisfinding.
Consistentevidenceindicatesthatbothexogenous andendogenoussubclinicalhyperthyroidismreduces theHRQL (11).However,inthepresentstudy,the presenceofexogenoussubclinicalhyperthyroidismdid notsignificantlyreducetheHRQLbySF36scoresas outcome.
TheQoL2004questionnairecontainedthequestion ‘Doyoufeelwellnow’statedattheendofGD-related questions (10).AlthoughtheQoL2004questionnaire hasnotbeenvalidated,weassumethattheanswers reflectthesubject’sapprehensionoftheirpresent thyroidstateandthereforeincludedtheresponsein thepresentstudy.Withthisreservationinmind,we foundnorelationbetweenserumTSH,fT4,totalT3or fT3andtheresponsepattern.Again,thethyroid hormonalstatewasnotreflectedbytheQoL2004 instrument.
Thepresentstudyrepresentsasubgroupofthe previouslyreportedGDgroupusedinthefirstvalidly performedcomparisonofHRQLandinwhichno differencesbetweenthethreetreatmentmodalities werefound (10).Theinclusionofsubjectsinthe presentstudywasbasedontheavailabilityofserum thyroidhormoneanalysesandresponsetoSF36and QoL2004.However,theresultsfromthepresent subgroupcorroborateourpreviousresultsofsimilar HRQLpatterndespitethemodeoftreatment (10).
Severalquestionscanberaised.Firstofall,theabsent relationbetweenthethyroidhormonalstateandthe SF36andQoL2004scoresindicatesthatthediminished HRQLonlong-terminGDarenotrelatedtothethyroid hormonelevelsandthereforemayhaveotherexplanations.ItisconceivablethatGDpatients,forexample, aremoresusceptibletovariousformsofstress(whichis awell-knownelicitingfactorforGD),whichexpectedly mayimpactQoLandHQRLdespitetreatmentforGD. Alternatively,itcanbeimaginedthatthepersonalityof thesubjectassuchmayimplydifficultiesinadaptingto
manyaspectsoflifeevenbeforeGDandperhapsthisis partlyresponsiblefortheGD,sothatthesubjectmany yearsaftertreatmenthaslowerHRQLscores,asinthe presentstudy.Itisthereforeaquestionwhetherthe lowerHQRLscoreslateronarediseasespecificormay becausedbyconfoundingfactors,whicharenotrelated tothepatient’shistoryofGDassuch.Recently,lower HRQLusingSF36hasalsobeenobserved,forexample inasymptomatic,untreatedprimaryhyperparathyroidismwithborderlinehypercalcaemia,whichsupports thisview (16) .Secondly,measuringHRQLina particulardiseasesuchasGDposeseveralproblems. ItispossiblethatthevalidatedbutgenericMOSSF36 andunvalidatedQoL2004aretooinsensitiveinstrumentsforaproperevaluationofHRQLinpatientswitha historyofGD.ThegenericMOSSF36posesgeneral questionsonhealthstatusandcanbeusedfor comparisonofHRQLaspectsindifferentdiseases (12) SF36doesnotcovertheadequatephysical,mental, cognitive,socialwell-beingandotherGD-specificitems inparticularaswellasathyroiddisease-specific questionnairewouldhavedone.Onesuchthyroid disease-specificinstrumentisthe‘Hyperthyroid ComplaintQuestionnaire’(HCQ)buttheHCQand otherinstruments,however,arenotavailablein SwedishandhasnotbeenvalidatedinaSwedish referencepopulation (5,6)
Conclusions
OurpreviousobservationsofreducedHRQLinpatients withahistoryofGDcomparedwithage-andsexmatchedhealthySwedesseemnottobeexplainedby thepatient’sthyroidhormonestatusatthetimeof follow-up.HRQLscoresbySF36beloworabovethe averagevaluefortheSwedishreferencepopulationwas seenindependentlyoftheserumconcentrationsofTSH, fT4ortotalT3.fT3wasweaklycorrelatedwithGH.The findingsaresomewhatunexpectedandcouldindicate thatGDpatientsmayrepresentaspecialgroupof subjects,whowouldhaveproducedalowSF36score independentlyoftheirpreviousGD.Alternatively,the SF36andQoL2004instruments,whicharenotthyroid diseasespecific,maynotbesensitiveenough.
Acknowledgements
WewishtothankProfessorBHambergerforhis interest,importantandvaluablehelpthroughoutthe study.WewishalsotothankElisabethBerg,LIME KarolinskaInstitutestetforvaluablestatisticalassistance.ThestudywassupportedbytheSwedishResearch CouncilandtheKarolinskaInstitutet.
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