ThyroidGlandSalilDSarkarThyroidAnatomy209HormoneSynthesisandSecretion - PDF document

7 ThyroidGlandSalilD.SarkarThyroidAnatomy209HormoneSynthesisandSecretion7.2.1IodideTransport2107.2.2HormoneSynthesis2107.2.3ReleaseofHormoneandThyroglobulin2107.2.4TandT Chapter7 HormoneSynthesisandSecretionIodideTransportThethyroidfollicleconsistsofacolloidcenter,whichactsasastoragesiteforthyroidhormone,surroundedbyepi-thelialcells.Thethyroidepithelialcellhasatransportmechanism,alsoreferredtoastrappingŽoruptakeŽ,thatenablesthyroidconcentrationofiodidefarinexcessofthatintheplasma[3,4].Aplasmamembraneprotein,thesodium/iodidesymporter(NIS),isresponsibleforio-didetransport.Symporteractivityisinfluencedprimari-lybypituitarythyrotropin,alsocalledthyroidstimulat-inghormone(TSH),whichincreasesthetransportofio-dide.Thetrappediodidesubsequentlyundergoesorga-nificationandincorporationintothyroidhormones.Iodideisaccumulated,thoughnotorganified,inotherorgansincludingthesalivaryglands,stomach,mucousglands,skin,breast,andplacenta,whichmaybeassociatedwithundesirableconsequencesfortheclinicaluseofradioiodine.Aftertherapeuticadminis-trationof131Iforthyroidcancer,uptakeinthesalivaryglandsandgastricmucosamaycausesialitisandgas-tritisrespectively,whileactivityintheskinandmucoussecretionsmayincreaseenvironmentalcontaminationandinterferewithimageinterpretation[5…7].Iodideuptakebytheplacentaandmammaryglandsexposesthefetusandthenursingchildtounacceptableamountsofradiationfromboththetherapeuticanddi-agnosticuseofI[8,9].Otheranions,includingpertechnetate,thiocyanate,andperchlorate,alsoareaccumulatedbythethyroidgland.TheuptakeofpertechnetateisthebasisforTc-pertechnetatescintigraphy.Thiocyanate,de-rivedfromcertainfoods,decreasesthyroidaccumula-tionofiodineandmayexacerbateiodinedeficiency.Perchloratehasdiagnosticandtherapeuticapplica-tions,whicharediscussedlater. HormoneSynthesisIodidetransportedviaNISatthebasolateralcellmem-braneisconvertedtoanoxidizedformattheapicalsur-faceofthecellbythyroidperoxidase(TPO)inthepres-enceofhydrogenperoxide.OxidationofiodidepermitsitsbindingtotheaminoacidtyrosineSynthesisofhor-monetakesplaceinthyroglobulin,aglycoprotein,whichisproducedinthethyroidcellandextrudedintothecolloid.Iodinecombineswithtyrosineinthyro-globulintoformmonoiodotyrosine(MIT)anddiiodo-tyrosine(DIT).Subsequently,theiodotyrosinesarecoupled,withtheformationofthyroxine(T)andtriio-dothyronine(T3).Thecouplingreactionalsoismedi-atedbyperoxidase.Decreaseinperoxidase,associatedwithcertaincon-genitalandacquiredthyroiddisorders,impairsorganiciodinationandincreasestheproportionofunboundintrathyroidaliodine.Potassiumperchlorateinphar-macologicaldosesdischargesunboundiodinefromthethyroid.ThisisthebasisforitsuseinthePerchlorateDischargeTestŽtodetectanorganificationdefect[10…12],andinthetreatmentofthyroiddysfunctioncausedbyamiodarone,aniodine-richdrug(seelater). ReleaseofHormoneandThyroglobulinInresponsetoTSH,asmallamountofcolloidisen-gulfedbytheepithelialcellandproteolyzed,withre-leaseofTandT,whichdiffuseintothecirculation.Thyroglobulinnotundergoingproteolysisalsoentersthecirculationinsmallquantities.Theserumthyro-globulinhasbeenusedasatumormarkerindifferenti-atedthyroidcancer.Thyroglobulinbecomesundetect-ablefollowingthyroidectomyand131Iablation,anditssubsequentriseindicatesarecurrence.TSHstimula-tion,bypromotingcolloidendocytosis,increasestheamountofthyroglobulinreleased.Consequently,theserumthyroglobulinisamorereliabletumormarkerathighTSHlevels[13,14]. andTMostofthecirculatingthyroidhormonesareboundtoplasmaproteins,thefreefractioncomprisingabout0.05%ofTand0.2%ofT.Onlythefreehormonehasmetaboliceffects,anditisamoreaccuratemeasureofthyroidfunctionthanthetotalhormone,whichvarieswithplasmaproteinslevels.isconsideredtheactivehormone.About20%…30%ofthecirculatingTissecretedbythethyroidglandandtheremainderisproducedbymonodeiodin-ationofTinextrathyroidtissues,notablytheliver,kidney,brain,andpituitary[14].Decreaseinthepe-ripheralconversionofTtoTisabasisfortheuseofsomeantithyroiddrugs(seebelow).Syntheticformsofthyroidhormonesarecommonlyusedforreplacementand/orsuppressivetherapy.Th

y-roxineispreferredforthispurposebecauseithasalon-gerbiologicalhalf-life(6…7days)comparedwithT(about1…2days).However,Thasamorerapidonsetofactionandmaybeusefulinselectedclinicalsitua-tions. AntithyroidDrugsMostantithyroiddrugsgenerallyblockoneormorestepsinthesynthesisandmetabolismofthyroidhor- 7ThyroidGland mone.Thethioureaderivatives(thionamidesŽ),in-cludingpropylthiouracil(PTU)andmethimazole,arethemostcommonantithyroidagentsinuse[14,15].Bothdecreasehormonesynthesisprimarilybyblock-ingiodineorganification,whilePTUalonedecreasesthemonodeiodinationofTtoT.Thesedrugsalsolowerserumlevelsofthyrotropinreceptorautoanti-bodies(TRAB),whichareresponsibleforGraveshy-perthyroidism.MethimazoleorPTUmaybeusedtocontrolhyperthyroidisminGravesdiseaseandtoxicnodulargoiterbeforetreatmentwithI.Inselectedpatients,thesedrugsalsomaybeusedasprimaryther-apyforGravesdisease.Remissionoccursinaminorityofpatientsafterthionamidetreatmentfor1…2years.Otherdrugsusedfortheirantithyroidactionsin-cludeglucocorticoids,iodides,lithium,andpotassiumperchlorate[14].Glucocorticoidshavearapidinhibito-ryeffectontheperipheralconversionofTtoT,andareausefuladjunctinthyroidstorm.Theiranti-in-flammatoryandcellmembranestabilizingactionshavebeenutilizedinGravesophthalmopathyandprotract-edsubacutethyroiditis.Iodideinpharmacologicalamountsdecreasesthesynthesisofthyroidhormones,permittingrapidcontrolofhyperthyroidisminthyroidstorm(seeThyroidAutoregulationŽ).Italsoblocksthyroiduptakeofradioiodine,andisrecommendedasaprophylacticmeasureafteranuclearreactoraccident[16].Lithiumblocksthereleaseofthyroidhormone,andmaybeusedasanadjunctforthecontrolofseverehyperthyroidism.Lithiumprolongsiodineretentioninthyroidtissue,andincreasestheabsorbedradiationdosefromI,anadvantageinthetreatmentofdiffer-entiatedthyroidcancer[17].Potassiumperchloratede-creasesthyroidiodineuptakeanddischargesunboundiodine.Itmaybeusedforthetreatmentofthyroiddys-functioncausedbyamiodarone,adrugwithahighio-dinecontent,andafteraccidentalexposuretoradioac-tiveiodine. SummarySynthesisandsecretionofthyroidhormoneareregu-latedprimarilybythyrotropin.Circulatingiodideistrappedbythethyroidepithelialcell,oxidized,andboundtotyrosine.CouplingofiodotyrosinesyieldsTandT.Thyroidperoxidasepromotesoxidationofio-dide,anecessarystepforiodinationoftyrosine,aswellascouplingofiodotyrosines.ThyroidhormoneactionismediatedbyT.About20%…30%ofthecirculatingissecretedbythethyroid,andtheremainderisde-rivedfromtheperipheralmonodeiodinationofTAmongthedrugswithantithyroidactions,PTUandmethimazolearemostcommonlyused.Bothdrugsde-creasehormonesynthesisandTRABlevels,whilePTUalonedecreasestheconversionofTtoT7.3ThyroidHandlingofRadiotracersTechnetium-99m-pertechnetateTechnetium-99m-pertechnetateiswidelyusedforim-agingthethyroidgland[18,19].Thepopularityofthisradiotracerstemsfromitseasyavailability(frompor-tablemolybdenum-99generators)andlowabsorbedradiationdose(shorthalf-lifeof6handabsenceofbetaemissions).99mTc-pertechnetateistrappedbythethyroid,butunlikeiodine,itdoesnotundergoorganificationandremainsintheglandforarelativelyshortperiod.Therefore,imagingisdoneabout20…30minafterad-ministrationoftheradiotracer.Approximately5…10mCi(185…370MBq)isused.Thethyroid-to-backgroundactivityratioisnotashighasthatwithra-dioiodine,sothat99mTc-pertechnetateisunsuitableforimagingofmetastaticthyroidcarcinoma,whichusual-lyfunctionspoorlycomparedwithnormaltissue.Im-agingofectopicmediastinalthyroidtissuealsomaybesuboptimalduetohighbloodandsofttissueback-groundactivity. Iodine-123hasidealcharacteristicsforimagingthethyroidgland,withashortphysicalhalf-lifeof13h,ab-senceofbetaemissions,andhighuptakeinthyroidtis-suerelativetobackground.However,itislessreadilyavailableandmoreexpensivethan99mTc-pertechneta-Iundergoesorganicbindinginthethyroidgland,andimagingisusuallydone4…24haftertheadminis-trationof200…400µCi(7.4…14.8MBq)ofradiotracer[18,19].Becauseofitssuperiorbiodistributioncharac-teristics,IispreferredoverTc-pertechnetateforimagingofpoorlyfunctioningandectopicthyroidglands.123Ialsomay

beusedforwholebodyimagingindifferentiatedthyroidcancer(seebelow).Approxi-mately2…4mCi(74…148MBq)oftheradiotracerareusedforthispurpose. Iodine-131maybeusedforthemeasurementofthy-roiduptake,whichrequiresonlysmallamountsofra-diotracer.Itisnolongerusedforroutineimagingofthethyroidglandbecauseofahighabsorbedradiationdoserelatedtothelongphysicalhalf-lifeof8daysandbetaemissions.131I,however,continuestobevaluableforthedetectionofmetastasesandrecurrencesindif-ferentiatedthyroidcancer[13,19,20].Followingap-propriatepatientpreparationtoincreaseTSHlevels7.3ThyroidHandlingofRadiotracers (seeManipulationofThyrotropinLevelsŽ),2…4mCi(74…148MBq)of131Iisadministeredandimagingisperformed48…96hlater.Radioiodineimaginghasdi-agnosticaswellasprognosticvalue.Iodine-avidtu-morstendtohavewell-differentiatedhistologicalfea-turesandafavorableprognosis,whereastumorsthatdonotaccumulateiodinearelikelytobelessdifferenti-atedandmoreaggressive[13,21,22].Iodine-131deliversahighradiationabsorbeddosetothethyroid,withrelativesparingofnon-thyroidtis-sues.Itisthereforeidealforthetreatmentofthyroiddisease,andusedextensivelyinthemanagementofGravesdisease,toxicnodulargoiter,anddifferentiatedthyroidcancer. Fluorine-18-fluorodeoxyglucosePositronemissiontomography(PET)withF-fluor-odeoxyglucose(FDG)isusedinevaluatingavarietyofneoplasmsincludingdifferentiatedthyroidcancer.Im-agingispossiblefortworeasons.First,malignanttu-morsderiveenergyfromahigherrateofglycolysis,sothattheuptakeofglucose(andFDG)isincreased.Sec-ond,unlikeglucose,FDGisnotmetabolizedcomplete-lyandretainedlongerwithinthetumor.Indifferentiat-edthyroidcancer,FDGmaybeusedtoidentifymetas-tasesnotvisualizedatradioiodineimaging,andtoas-sessprognosis.LesionsthataccumulateFDGtendtofollowamoreaggressivecoursethanlesionsthatarenotFDG-avid[23,24].WholebodyFDG-PET,there-fore,isusefulinevaluatinghigh-riskthyroidcancer.Patientpreparationissimilartothatforradioiodinescintigraphy,sincetheuptakeanddiagnosticsensitivi-tyofFDGareincreasedbyTSHstimulation[25,26].FocaluptakeofFDGwithinthethyroidgland,anocca-sionalfindingatevaluationofnon-thyroidcancers,mayberelatedtoabenignormalignantpathology. SummaryTc-pertechnetateistrappedbutnotorganifiedbythyroidtissue.Imagingwiththisradiotracerislimitedtotheintactthyroidgland.123Iand131Iaretrappedandorganified,andprovidehigherthyroid-to-backgrounduptakeratios.Bothtracersareusedtodetectthyroidcancermetastases,while123Iisalsousedforimagingthethyroidgland.Ideliversahighabsorbedradia-tiondosetothyroidtissue,andisamainstayinthemanagementofGravesdisease,toxicnodulargoiter,anddifferentiatedthyroidcancer.Imagingandtreat-mentofthyroidcancermetastaseswithIrequirehighTSHlevels.F-FDG,aglucoseanalogue,isaccu-mulatedinvariousmalignanttumorsincludingdiffer-entiatedthyroidcancer.FDG-PETisparticularlyusefulinhighriskthyroidcancer,whereitmaydetectmetas-tasesnotvisualizedatradioiodineimagingandprovideprognosticinformation.TumoruptakeofFDGisin-creasedbyTSHstimulation. 7.4TSHandThyroidFunctionTSHSecretionThyrotropin-releasinghormone(TRH),atripeptideoriginatingfromthehypothalamicmedianeminence,stimulatesthesecretionandsynthesisofthyroidstimu-latinghormone(TSH,thyrotropin),aglycoprotein,bytheanteriorpituitary.TSHcomprisesanalphaunit,alsopresentinotheranteriorpituitaryhormones(FSH,LH),andabetaunitresponsibleforitsspecificactions.Itactsonspecificmembrane-boundreceptorsofthethyroidepithelialcell,activatingtheadenylatecyclasesystemandincreasingsodium/iodidesymporterexpression.Asaresult,thetransportofiodide,synthesisofhormone,andreleaseofT,andthyroglobulinareincreased.TheproductionandreleaseofTSHareinfluencedbytheconcentrationofTwithinthepituitary.WhentheconcentrationfallsbelowasetpointŽ,TSHsecre-tionincreases,andsynthesisandreleaseofthyroidhor-monesareaccelerated.Conversely,whentheTlevelrisesabovethesetpoint,TSHreleaseisinhibited.Inad-ditiontoitspituitaryeffect,TinhibitshypothalamicTRHrelease.Othermechanismsreportedmorerecent-lyincludetheinhibitoryactionsofthereleasedTSHonTRHsecretion,andonTSHreceptorsinthepituitaryitse

lf.Insum,TSHsecretionisinfluencedbythyroid-to-pituitary,thyroid-to-hypothalamus,pituitary-to-hypothalamus,andpituitary-to-pituitaryfeedbackcontrolmechanisms,whichcombinetoreducefluctua-tionsincirculatingTandT[14,27…28].Intherareconditionofpartialtissueresistancetothyroidhor-mone,thepituitaryfailstorespondtoincreasingTlevels,sothatTSHcontinuestobesecretedandserumTSHandthyroidhormonesarebothelevated.Individ-ualswiththisconditionmaybecomehyperthyroidiftissueresistanceislimitedtothepituitaryorremaineuthyroidifresistanceisgeneralized[29].Inadditiontoregulationofthyroidfunction,TSHpromotesthyroidgrowth.Ifthyroidhormonesynthe-sisischronicallyimpaired,asiniodinedeficiencyandautoimmunethyroiddisease,chronicTSHstimulationeventuallymayleadtothedevelopmentofagoiter. SerumTSHinThyroidDisordersTheserumTSHisasensitivemarkerofthyroidfunc-tion.NormalserumTSHisabout0.45…4.5µunits/ml, 7ThyroidGland andlevelsupto20µunits/mlareconsiderednormalinnewbornsbecauseofthecontributionofmaternalTSH.Duringearlygestation,TSHtendstobeatlownormal(attimesbelownormal)levels,whichcoincidewithasurgeinhumanchorionicgonadotropin(hCG)release.SerumTSHisincreasedinprimaryhypothy-roidismanddecreasedinhyperthyroxinemiaofalleti-ologiesexceptfortheuncommonentityofthyrotropin-inducedhyperthyroidism.Theavailabilityofhighsensitivityassays,whichcanaccuratelymeasureverylowTSHlevels,hassignificant-lyimprovedtheabilitytodiagnosemildhyperthyroid-ism.Third-generationassayscandetectlevelsaslowas0.01…0.03µunits/mlandareparticularlyhelpfulines-tablishingsubclinicalhyperthyroidisminnodulargoiterandathyroticpersonsreceivingreplacementlevothy-roxinetherapy[27,30].Subclinicalhyperthyroidisminolderindividualshasbeenassociatedwithadverseef-fectsontheheartandbonemineraldensity[31…34].TheserumTSHisalsoasensitivemarkerofhypo-thyroidism.Assuchitiscommonlyusedtodetecthy-pothyroidisminHashimotosdisease,newborns,andhyperthyroidpatientstreatedwithI.TheTRHStim-ulationTestmeasurestheTSHresponsetoTRH.Itwasusedinthepastforthediagnosisofsubtlethyroiddys-functionincludingcentralhypothyroidism,buthasbeenlargelyabandonedwiththeemergenceofhigh-sensitivityTSHassays[35]. ManipulationofTSHLevels7.4.3.1SuppressingTSHLevelsThesecretionofTSHissuppressedwithexogenousthyroidhormonetoavoidstimulationoftumorgrowthinpatientswithdifferentiatedthyroidcancer,andtodecreasethyroidsizeorarrestthyroidgrowthintheearlystagesofgoiterdevelopment.Whilelevothyroxine)isthetraditionalthyroidhormonepreparationforthispurpose,regimenscombiningTandTarecur-rentlyunderinvestigation.Notinfrequently,patientsreceivinglevothyroxinearereferredforanuclearup-takeandscan,requiringhormonewithdrawaltoallowtherecoveryofthehypothalamus-pituitary-thyroidax-is.Itmaytakeaslongas8weeksforrecoveryandforre-turnofradioiodineuptakestobaselinevalues;howev-er,shorterperiodsofupto3weeksmaysufficeforeval-uatingnodularfunction.7.4.3.2IncreasingTSHLevelsStimulationwithTSHincreasesthyroidfunctionandthyroiduptakeofradioiodine.Thisprincipleisusedindifferentiatedthyroidcancerforthedetectionandtreat-mentofthyroidremnantsandthyroidcancermetastaseswithradioiodine[13,19,36].Thyroidstimulatinghor-monelevelsareallowedtoriseto30…50µunits/mlorhigherafterwithholdingthyroidhormonesupplements,orafteradministeringrecombinanthumanTSH.Thelatterisgaininginpopularitysinceitshortenstheprepa-rationtimeandavoidsaperiodofhypothyroidism[37…41].Currently,recombinantTSHisapprovedpri-marilyfordiagnosticuse,i.e.,priortoscintigraphyandserumthyroglobulinmeasurement.Itappearstobeef-fectiveinmonitoringthyroidcancer,especiallythelow-riskpapillarytype,thoughtheradioiodineuptakeandserumthyroglobulinusuallyarelowerthanafterhor-monewithdrawal.Asnotedearlier,PETwithfluorode-oxyglucoseisoptimalathighTSHlevels,anditmaybecombinedwithradioiodineimagingandthyroglobulinmeasurementinselectedpatients[23…26].RecombinanthumanTSHmayhavethepotentialtofacilitatethetreatmentoflargenodulargoiterswith131I.Radioiodineuptakeinthesegoitersisusuallylowandheterogeneous.Asaresult,largeandmultiplether-apeuticIdosesmaybeneededtore

ducegoitervol-umeandcuretheassociatedhyperthyroidism.Inre-centstudies,asmalldoseofrecombinantTSHresultedinamoreuniformIdistribution,ahigher24-hup-take,andincreasedtherapeuticefficacy[42,43]. SummaryThyroidstimulatinghormone(thyrotropin)promotesiodidetransport,andthesynthesisandreleaseofthy-roidhormoneandthyroglobulin.ThesecretionofTSHismodulatedbythehypothalamus-pituitary-thyroidaxis.TheserumTSHlevelisasensitiveandspecificmarkerofprimaryhyperthyroidismandhypothyroid-ism,andisparticularlyvaluablefordiagnosingsub-clinicalthyroiddysfunction.SuppressionofTSHsecre-tionwithexogenousthyroidhormonemayhelpreducegoitersizeandlimitthegrowthofthyroidcancer.Inathyroticpatientswithdifferentiatedthyroidcancer,ahighserumTSHisneededforradioiodine/FDGimag-ing,thyroglobulinmeasurement,and131Itreatment.TheserumTSHmaybeincreasedbywithdrawingthy-roidhormone,orbyadministeringrecombinanthu-manTSH. 7.5IodineIntakeandThyroidFunctionIodineDeficiencyThedailyrequirementforiodineisabout150µg,in-creasingtoroughly200…250µgduringpregnancy.Io-dinedeficiencyismostprevalentinthemountainous7.5IodineIntakeandThyroidFunction regionsoftheHimalayas,Alps,andAndes,andinsomelowlandsremotefromtheocean.Iodinedeficiencyaloneorincombinationwithgoitrogenspresentincer-tainfoodsresultsindecreasedthyroidhormonesyn-thesis[44,45].Seleniumdeficiencymaybeacontribut-ingfactor.Reducedsynthesisofthyroidhormoneiscompensated,atleastinpart,byincreasedTSHsecre-tion,resultingeventuallyingoiterformation.Becauseanadequatesupplyofthyroidhormoneisneededforfetalneurologicaldevelopment,maternalandfetalhy-pothyroidismresultingfromiodinedeficiencyisasso-ciatedwithvaryingdegreesofneuropsychologicaldefi-citsincludingcretinism[46…50]. IodineExcess7.5.2.1ThyroidAutoregulationThyroidhormonehomeostasisismaintainedbyanin-trathyroidautoregulatorymechanisminadditiontothehypothalamus-pituitary-thyroidaxis.Whenintra-thyroidiodineconcentrationsaresignificantlyin-creased,therateofthyroidhormonesynthesisisde-creased,withareductioniniodothyroninesynthesisanddecreaseintheDIT/MITratio.Thisresponseisre-ferredtoastheWolff-Chaikoffeffect[51].TheamountofintrathyroidiodineneededtotriggertheWolff-Chaikoffeffectvaries,dependingonpriorlong-termiodineintakeandthyroidfunction.Barringothermechanisms,continuedexposuretolargeamountsofiodinewouldeventuallyleadtohypothy-roidism,withcompensatoryincreaseinTSHanddevel-opmentofgoiter.Whilethisdoesoccuroccasionally(seebelow),adaptationorescapeŽfromtheeffectsofchroniciodideexcessismorelikely.Adaptationap-pearstobetheresultofanabsolutedecreaseiniodidetransport,sothatintrathyroidiodineisreducedtolev-elsthatallowresumptionofhormonesynthesis.Theinhibitoryeffectofiodidesonthyroidfunctionisutilizedclinicallyforpromptcontrolofseverehyper-thyroidismandthyroidstorm.InGravesdisease,largedosesofiodidedecreasenotonlyhormonesynthesisbutalsohormonerelease[52].Sinceescapefromtheinhibitoryeffectislikely,iodidetherapyisonlyashort-termmeasureforloweringthyroidhormonelevelsrap-idly.7.5.2.2ThyroidDysfunctionIodineexcessmayleadtohyperthyroidismorhypothy-roidism[51…54].Iodine-inducedhyperthyroidism,re-ferredtoasjodbasedow,characteristicallyoccursinpersonswithnodularthyroidglands.Hyperthyroidismoccurringafteriodinesupplementationinendemicgoiterareasisaclassicalexample.Iodine-containingmedicalproducts,includingamiodarone,radiographicdyes,andkelp,alsohavethepotentialtocausejodbase-dow[51,55…58].Amiodarone,acardiacantiarrhyth-micdrug,isperhapsthecommonestsourceofiodinetoday.Each200mgtabletyieldsabout7mgfreeiodine,whilethedailyrequirementisonly0.15mg[55,56].Amiodarone-relatedhyperthyroidismmayberelatedtoanothermechanism.Thedrugmaycausethyroiditis,whichisdiscussedlater(seeDestructive(Subacute)ThyroiditisŽ].HypothyroidismrelatedtoincreasediodineintakeresultsfromtheinabilitytoescapefromtheWolff-Chaikoffeffect.Itismorefrequentiniodine-sufficientareas,whereautoimmunediseaseismorecommonthannodulardisease[53,54].Inthepast,iodidegoi-terŽwithorwithouthypothyroidismwasrelatedtotheuseofiodinesolutionsasmucolyticagentsinbron

chialasthma,oftenwithreversalofclinicalmanifestationsafterstoppingthedrug.Asimilarconditionhasbeenreportedfromingestionoflargequantitiesof(iodine-rich)seaweedinthecoastalregionsofJapan[59].7.5.2.3IodineandAutoimmuneThyroidDiseaseIodineappearstohaveanother,moreinsidiouseffectonthethyroid.Inregionsthatwerepreviouslyiodine-deficient,ariseinautoimmunethyroiddiseasehasbeenobservedaftertheinstitutionofiodinesupple-mentationinfoods[60].Experimentalworkinanimalsconfirmsanassociationbetweeniodineandautoim-munity,probablyrelatedinparttothegreaterantigenicpotentialofhighlyiodinatedthyroglobulin[61].Auto-immunethyroiddiseaseandassociateddisordersarediscussedunderHashimotosDiseaseŽ. SummaryExcessiveamountsofiodinemaycausehypothyroid-ismorhyperthyroidism.Asignificantincreaseinthy-roidconcentrationofiodinemayinitiateanautoregu-latoryresponse,theWolff-Chaikoffeffect,whichde-creaseshormonesynthesis.Althoughthiseffectisusu-allytemporary,occasionallyitmaybesustainedandleadtohypothyroidism.Iodine-inducedhypothyroid-ismismorefrequentiniodine-repleteregionswithahighprevalenceofautoimmunethyroiddisease.Exces-siveiodinealsomayleadtohyperthyroidism.Thismayoccurinindividualswithnodularthyroidglands,anditismorecommoniniodine-deficientareas.Inadditiontoitseffectsonthyroidfunction,iodineisbelievedtopromotethedevelopmentofautoimmunethyroiddis-ease,aviewsupportedbyepidemiologicalandexperi-mentalevidence. 7ThyroidGland EndemicGoiterEndemicgoiterisattributedprimarilytoiodinedefi-ciency,possiblyinassociationwithseleniumdeficien-cyorgoitrogens.Goitrogensarepresentincertainfoodsandchemicalsandcauseeitherdecreasedsyn-thesisorincreasedmetabolismofthyroidhormone. Certainfoodsincludingcassavaandbambooshootscontaincyanogeniccompounds,whichmayinterferewiththyroidaccumulationofiodineandexacerbateio-dinedeficiency[62].Otherfoodswithgoitrogenicpo-tentialincludepearlmilletandplantsfromthebrassicafamily[63].Variouschemicalsmayalterthyroidhormonemetab-olismandleadtothedevelopmentofgoiter.Contamina-tionofdrinkingwaterwithammoniumperchloratefromdiscardedrocketfuelisaconcern.However,thesuggestedregulatorylimitforperchlorateconcentrationinwateriswellbelowtheamountneededtoblockiodineuptake[64].Cigarettesmokinghasbeenlinkedtothy-roiddiseaseandaggravationofGravesophthalmopa-thy.Theeffectspresumablyaremediatedinpartbythio-cyanate[65].Otherindustrialchemicalsanddrugsmayinducehepaticenzymesthatacceleratethemetaboliceliminationofthyroidhormone[66,67]. PathophysiologyThethyroidenlargesprimarilyinresponsetoTSHstimulationresultingfrominefficienthormonesynthe-sis.ThereisnaturalheterogeneityincellulargrowthandresponsetoTSH,andrapidproliferationofthyro-cyteswithagrowthadvantageleadseventuallytothedevelopmentofnodules.Anadditionalmechanismfornoduleformationinvolvestheactivationoftheadeny-latecyclasesystem,usuallybysomaticmutationsoftheTSHreceptor,withincreaseincellreplicationrates[68…71].Evidenceofsuchmutationshasbeenfoundinbothsolitarynodulesandnodulesassociatedwithmul-tinodulargoiters.Thedevelopmentoftoxicnodulargoiteroccursoveraperiodofyears,ifnotdecades,withgradualtransitionofcellclonestomicronodules,andsubsequentlytomacronodulesofsufficientsizetocausehyperthyroidism.Thedisorder,therefore,istypi-callyseeninolderindividuals.Hyperthyroidismassociatedwithnodulargoiterisoftensubclinical,withasuppressedTSHandanormalfreeT4.Nonetheless,treatmentwithIorsurgeryisgenerallyrecommendedintheelderlybecauseofin-creasedriskofosteopenia,andofadversecardiovascu-larsequelaeincludingatrialfibrillation[31…34].Sup-pressivelevothyroxinetherapyisoftenattemptedtoar-restnodulargrowthineuthyroidpatients,butisrarelysuccessfulsincethenodulesarelargelyindependentofTSHcontrol[72].HyperfunctioningnodulesmaybecomecoldŽornon-functionalduetohemorrhageandnecrosis.Coldnodulesalsomaybecausedbythefailureofiodidetransportwithaging,rapidproliferationofcellswithdecreasedfunction,andmalignanttransformation. RadionuclideProceduresToxicmultinodulargoiterstypicallyshowirregulardis-tributionofradioiodineortechnetiumpertechnetate,andano

rmalormildlyelevated24-hradioiodineup-take.Theirregulartracerdistributionisconsistentwithheterogeneityincellfunctionandgrowth,andthepresenceofmicro-andmacronodules(Fig.7.2).Largeanddiscretehyperfunctioningnodulesmaybeassoci-atedwithpooruptakeintheextranodularthyroidtis-sue.ThelatterconsistsofsuppressedŽnormaltissue,and/orsmallautonomousnoduleswithrelativelylesstraceraccumulation.FollowingItreatment,theareasthatwerepreviouslycoldŽmayappearmoreactive.Adominantnonfunctioningnodulemayberelatedtoanumberofcauses,butmayrequireadditionaldiagnos-ticwork-uptoexcludemalignancy.Nodulardiseasemaybetreatedwith131Iorsurgery.Forlargemultinodulargoiters,thegoalofItreat-mentistoreducethyroidvolumeandcurehyperthy-roidism.Butthetreatmentmayfailbecauseradioio-dinedistributionisheterogeneousandthe24-huptakeisnotsignificantlyelevated.Stimulationwithrecombi-nanthumanTSHcausesaglobalincreaseinthyroiduptakeof131I,andappearstoimprovethetherapeuticoutcome[42,43]. SummaryEndemicgoiteristheresultofiodinedeficiency,occa-sionallyinassociationwithgoitrogens,withdecreaseinhormoneproductionandcompensatoryincreaseinTSHsecretion.Hyperfunctioningnodulesmayresultfromagrowthadvantageofsomecellsorgain-of-func-tionmutationsoftheTSHreceptor.Nodularthyroiddiseaseisacommoncauseofsubclinicalhyperthyroid-ismintheelderly,anditmaybeassociatedwithatrialfibrillationandosteopenia.Radionuclidestudiestypi-callyshowheterogeneoustracerdistributioninthethy-roidgland,withanormalormildlyelevated24-hra-dioiodineuptake.RecombinanthumanTSHincreasesthethyroiduptakeglobally,andmayfacilitatethetreat-mentofnodulargoiterswith1317.6EndemicGoiter Fig.7.2a…d.Scintigraphicim-agesinfourtypesofhyper-thyroidismshow:multino-dulargoiter,solitaryhy-perfunctioningthyroidnod-ule,thyroiditis,GravesdiseaseDestructive(SubacuteŽ)ThyroiditisDestructivethyroiditis,alsoreferredtoassubacutethyroiditisŽorsimplythyroiditisŽ,ischaracterizedbycellmembranebreakdownandreleaseofexcessiveamountsofthyroidhormoneintothecirculation.Se-rumthyroglobulinlevelsalsoareincreased.Theusualcausesareautoimmunethyroiddisease,viralinfection,andamiodaronetreatment.Thesearediscussedbelow.Lesscommonly,thyroiditismayberelatedtotreatmentwithinterferonalpha,interleukin-2,lymphokine-acti-vatedkiller(LAK)cells,andlithium.Thesetherapeuticagentsprobablyexacerbateexistingautoimmunethy-roiddisease[73…77].Bacterialthyroiditisisrarelyen-counteredtoday.Thyroiditistendstoresolvespontaneously.Hyper-thyroidismintheactivephaseisfollowedbytransienthypothyroidismbeforerestorationoftheeuthyroidstate,usuallyin6…12months.Treatmentusuallycon-sistsof-adrenergicblockersinthehyperthyroidphase,withanalgesicsforpain.Protractedthyroiditismayrequireglucocorticoids.PostpartumThyroiditisPostpartumthyroiditis,alsoknownaspainlessŽorsubacutelymphocyticŽthyroiditis,istheprincipalthyroiddisorderinpostpartumwomen.Itmaybecon-sideredanacceleratedformofautoimmunethyroiddisease,attributedtosuppressionofimmune-relateddisordersduringpregnancywithareboundafterchild-birth[78…82].Forthesamereason,Gravesdiseaseal-somayoccurinthepostpartumperiod,thoughlessfrequently,andastrongassociationwithinsulin-de-pendentdiabetesmellitus,anautoimmunecondition,hasbeennotedPostpartumthyroiditis,likeotherformsofdestruc-tivethyroiditis,isaself-limiteddisease,buttendstore-occurinsubsequentpregnancies.Permanenthypothy-roidismoccursin20%…25%ofpatientsoveraperiodof5years.Theincidenceisgreateriniodine-repletere-gionswithahigherprevalenceofautoimmunethyroiddisease.Elevatedthyroidperoxidase(anti-microsom-alŽ)antibodiesduringpregnancyareassociatedwithasharpincreaseinpostpartumthyroiditis. 7ThyroidGland ViralThyroiditisViralsubacutethyroiditis,alsoknownasdeQuer-vainsŽthyroiditis,usuallyoccursafteranupperrespi-ratorytractinfection.Thedisordertendstobeseasonalandmayoccurinclusters,occasionallycausingminiepidemics[83].Itusuallypresentsasapainfulandten-dergoiter,associatedwithgeneralmalaiseandpossiblyfever.Inflammationfrequentlybeginsinonelobeofthethyroidandgraduallyspreadstoinvolvetheentiregland.Permanenthy

pothyroidismisuncommon. ThyroiditisandOtherEffectsofAmiodaroneAmiodaroneisaniodine-richbenzofuranderivativeusedtotreatandpreventcardiacarrhythmias.Itmayprecipitateanumberofthyroidconditionsincludingthyroiditis,whichappearstoberelatedtoacytotoxiceffect[55,56].Sinceamiodaroneanditsmetabolitede-sethylamiodaronehavelonghalf-livesofupto100days,thethyroid-relatedeffectscanbeprotractedandoccasionallymaybeginafterstoppingthedrug.Amiodarone-inducedthyroiditisgenerallyrequirestreatmentwithaglucocorticoid.Permanenthypothy-roidismisuncommon.Othersideeffectsofamiodaronestemfromitshighiodinecontent(seeSect.7.5,IodineIntakeandThy-roidFunctionŽ).Thyroidhormonesynthesismayin-creaseordecrease.Increasedhormonesynthesis(jod-basedow)typicallyoccursinnodularthyroidglands,whicharecommoniniodine-deficientareas.De-creasedhormonesynthesis,resultingfromapersistentWolff-Chaikoffeffect,ismorefrequentiniodine-suffi-cientregionswithahigherincidenceofautoimmunethyroiddisease.Treatmentofamiodarone-inducedhyperthyroidismdependsonthecause,althoughthismaybedifficulttodetermine.Thyroiditis,asnotedearlier,respondstoglucocorticoidtherapy.Jodbasedowistreatedwithathionamide,andifneededwithpotassiumperchloratetodepletethyroidiodinecontent.Acleardistinctionbetweenthyroiditisandjodbasedowisfrequentlynotpossible,andtreatmentshouldbeinitiatedwithbothaglucocorticoidandathionamide.Inresistantcases,treatmentmaybefeasibleiftheradioiodineuptakeisadequate.Thyroidectomymaybeanalternativeinre-fractorycases,orwhencontinuedamiodaronetreat-mentandpromptreliefofhyperthyroidismarere-quired.Otheractionsofamiodaroneareworthnoting.ItblocksperipheralconversionofT4toT3,bindingofT3toitsreceptors,andthyroidreleaseofT3andT4.Theseeffectsmaypermittheuseofamiodaroneinveryse-lectedcasesofhyperthyroidism[84].RadionuclideProceduresPoorradioiodine/99mTc-pertechnetateuptakeinthethyroidglandisthehallmarkofsubacutethyroiditisofanyetiology(Fig.7.2).Decreasedtraceruptakeisrelat-edtoTSHsuppressionbyexcessivethyroidhormonereleasedfromdamagedfollicles,andtodecreasedhor-monesynthesisinthedamagedgland.Thethyroidup-takeandscannormalizewithresolutionofthyroiditis.Thenuclearstudyisfrequentlyusedinhyperthyroidindividualstodifferentiatethyroiditis,withlowuptake,fromGravesdisease,withhighuptake.Athyroidup-take/scanalsomaybeworthwhileinamiodarone-relat-edhyperthyroidism,whichmaybeduetojodbasedoworthyroiditis.Asuppressedthyroiduptakeisnon-di-agnostic,whileanormalorhighuptakesuggeststhatjodbasedowislikely.Thethyroiduptakemeasurementalsohelpsdeterminethefeasibilityof131Itreatmentinrefractorycases. SummarySubacutethyroiditisisusuallycausedbyexacerbationofautoimmunedisease,viralinfection,andamiodaro-netherapy.Itischaracterizedbyaninitialthyroid-de-structivephase,withreleaseofstoredhormoneintothecirculation.Nuclearstudiesinthisphaseshowpoorra-diotraceruptake,andhelpdifferentiatethyroiditisfromothercausesofhyperthyroidism.Thedisorderisself-limitedandtreatedsymptomatically,thoughami-odarone-relatedthyroiditistendstolastlongerandgenerallyrequiresaglucocorticoid.Amiodaronemaybeassociatedwithotherthyroiddisordersrelatedtoitshighiodinecontent,includingjodbasedow(iodine-in-ducedhyperthyroidism)andhypothyroidism. 7.8AutoimmuneThyroidDiseaseEtiologicalFactorsAutoimmunethyroiddiseasecomprisestwomajoren-tities,Hashimotosdisease(alsoknownaschronicau-toimmunethyroiditis)andGravesdisease.VariantsofHashimotosdiseaseincludesubacuteŽthyroiditis,whichoccurstypicallyinthepostpartumperiod,andatrophicthyroiditis.Thereisageneticpredispositiontothedisease,withcontributionfromenvironmentalfactors[65,85…89].Asdiscussedearlier,iodineexcesshasbeenassociatedwithautoimmunethyroiddisease.CigarettesmokinghasbeenlinkedtoexacerbationofautoimmunethyroidconditionsincludingGravesoph-thalmopathy,andincreasedoccurrenceinwomenim-7.8AutoimmuneThyroidDisease pliesaroleofsexsteroids.TherelationshipbetweenpsychologicalstressandGravesdiseasepresumablyisrelatedtoimmunesuppressionandrebound.Asimilarmechanismisbelievedtoapplytopostpartumthyroiddysfunction.Theoccasio

naloccurrenceofGravesdis-easeincouplessuggeststhatinfectionmaybeaprecipi-tatingfactor.Insupportofthishypothesis,antibodiestocertainmicrobialproteinshavebeenfoundtocross-reactwiththehumanTSHreceptor.Rarely,Gravesdis-easemaybeprecipitatedbyItreatmentofnodulargoiterinpatientswithunderlyingautoimmunethyroiddisease[90].Folliculardisruptionandreleaseofthy-roidantigensisbelievedtobetheinitiatingeventintheseinstances.OnsetofGravesdiseaseaftersubacutethyroiditisprobablyrepresentsananalogoussituation[91,92]. PathophysiologyElevationofthyroidperoxidaseantibodiesischaracter-isticofHashimotosdisease.Antithyroglobulinanti-bodiesalsomaybeelevated.Hormonesynthesisisim-pairedwithcompensatoryincreaseinTSHsecretion,whichstimulatesthyroidfunctionandgrowth.Eventu-ally,manypatientsbecomehypothyroid.Bothovertandsubclinicalhypothyroidismrelatedtoautoimmunediseasearewidelyprevalentiniodine-sufficientre-gions[93…95].ExacerbationofHashimotosdisease,frequentlyoccurringinthepostpartumperiod,isacauseofsubacutethyroiditis(seePostpartumThy-roiditisŽ).Gravesdiseaseisassociatedwithhighlevelsofthyrotropinreceptorautoantibodies(TRAB)thatstimulatethyroidgrowth,andthyroidhormonesyn-thesisandrelease[86…89].Mostorgansystemsareaf-fectedbyGravesdisease,thecardiovascularmanifesta-tionsbeingthemostapparent[31…33].Increasedheartrateandcontractilityincreasesthecardiacoutput.TheseeffectsarerelatedtoadirectinotropiceffectofT3,decreasedsystemicvascularresistance,increasedpreloadrelatedtoahigherbloodvolume,andheight-enedsensitivitytosympatheticstimulation.Bloodvol-umeisincreasedbyactivationoftherenin-angioten-sin-aldosteronesystemcausedbythereductioninsys-temicvascularresistance,andbyincreasederythropoi-etinactivity.Overtcardiacfailuremayresultfromse-vereandprolongedhyperthyroidism,butisrarelyseentoday.Atrialfibrillationisnotanuncommoncomplica-tion,occurringinupto15%ofpatientswithhyperthy-roidism. RadionuclideProceduresNuclearstudiesarenon-specificinHashimotosdis-ease.Thethyroidglandisusuallysymmetricallyen-largedwithuniformtracerdistribution,andthe24-huptakeisnormal.InsubacutethyroiditisresultingfromexacerbationofHashimotosdisease,tracerup-takeistypicallyabsentorverylow.Gravesdiseasetypicallyshowsuniformlyincreasedtraceruptakeinadiffuselyenlargedthyroidgland,frequentlywithvisualizationofapyramidallobe(Fig.7.2).However,atypicalappearances,particularlyinGravesdiseasesuperimposedonnodulargoiter,areoccasionallyencountered.Ifneeded,TRABmeasure-mentmayassistinconfirmingthediagnosis.The24-huptakeiselevatedand,onaverage,muchhigherthanintoxicnodulargoiter.ItreatmentandantithyroiddrugsremaintheprimarymeansofmanagementofGravesdisease. SummaryAutoimmunethyroiddisorders,includingHashimotosdiseaseandGravesdisease,arerelatedprimarilytoge-neticsusceptibility,withcontributionsfromenviron-mentalfactorsincludingchroniciodineexcess.Elevat-edserumanti-TPOantibodiesarecharacteristicofHashimotosdisease.ExacerbationofHashimotosdis-ease,usuallyobservedinpostpartumwomen,maycausesubacutethyroiditiswithhyperthyroidism.Scin-tigraphyinsuchcasesshowspoortraceruptakeinthethyroidgland.Gravesdiseaseischaracterizedbyele-vatedTSHreceptorantibodies(TRAB).Itaffectsmostorgansystems,butthecardiovascularmanifestationsgenerallyarethemostpronounced,andcardiaccom-plicationsarenotuncommon.ThethyroiduptakeandscanmaybeusedtoconfirmthediagnosisofGravesdiseaseanddifferentiateitfromadestructivethyroid-itis. 7.9ThyroidDysfunctionDuringGestationHyperthyroidismHyperthyroidismduringpregnancyisusuallycausedbygestationaltransientthyrotoxicosis(GTT)orGravesdisease[48,49].Gestationaltransientthyrotox-icosisappearstoberelatedtotheTSH-likeeffectsofhumanchorionicgonadotropin(hCG),whichincreasesinearlygestation.Theconditionresolvesspontaneous-lyinthesecondhalfofpregnancy.TheincidenceandseverityofGTTarevariable.Itisoccasionallyassociat-edwithhyperemesisgravidarum.Asinotherhyper-thyroidconditions,theserumTSHislowandfreeT4maybeelevated,butthyroidautoantibodiesincludingTSHreceptorantibodies(TRAB)areabsent,sinceGTTisnotanautoi

mmunecondition. 7ThyroidGland Gravesdiseaseinpregnancyisamoreseriouscon-ditionassociatedwithsignificantmaternalandfetalrisks,includingpre-eclampsia,prematuredelivery,lowinfantbirthweight,neonatalGravesdisease,andcen-tralcongenitalhypothyroidism[48,49,96].Character-istically,TRABlevelsareelevated.Managementofges-tationalGravesdiseaseposesseveralchallenges.Io-dine-131therapyiscontraindicated,andthyroidecto-myisinherentlyriskyforboththemotherandthefe-tus.Leftuntreatedorinadequatelytreated,Gravesdis-easeinpregnancyincreasestheriskoffetalhyperthy-roidismbecauseofthetransplacentalpassageofmater-nalTRAB.Oftheavailabletreatmentoptions,thiona-mides…eitherPTUormethimazole…appeartobethesafest.ThesedrugshelpcontrolhyperthyroidismandreduceTRABlevels,butshouldbeusedonlyinsmalldosessincetheycrosstheplacentaandmaydecreasefetalthyroidfunction[15,49].Gravesdiseasetendstoimproveinthelaterstagesofpregnancy,probablyduetoimmunesuppression,allowingthionamidestobeta-peredordiscontinued.Buttherapyshouldberesumedafterchildbirthbecauseoftheriskofrecurrencerelat-edtopostpartumimmunerebound. HypothyroidismNormalneurologicaldevelopmentisdependentonad-equatematernalandfetalthyroidfunction,andonthy-roidhormonesufficiencyintheearlyneonatalperiod[45…50,97].Iodinedeficiency,presentinregionsofen-demicgoiter,maybeassociatedwithhypothyroidisminboththemotherandthefetus,andmaycausevary-ingseveritiesofneurologicalandgrowthretardationincludingcretinism.Fortunately,theincidenceofthesedisordershasdeclinedduetoiodinesupplementationprograms.Maternalthyroidhormoneisincreasinglyrecog-nizedasanimportantfactorinfetaldevelopmentinthesecondandthirdtrimesters.Maternalhypothyroidismalone,i.e.,withoutfetalhypothyroidism,hasbeenlinkedtoneuropsychologicaldeficitsintheoffspring,andtoincreasedriskoffetallossandpretermdelivery.Autoimmunethyroiddiseaseisthemostfrequentcauseofhypothyroidisminthemother.Whileovertiodinedeficiencyisrelativelyuncommontoday,iodineintakehasgraduallydeclinedinmanyiodine-sufficientŽar-easandmayactuallyfallshortofrequirementduringpregnancy.Thismayhavethepotentialtoaggravateau-toimmunehypothyroidism. SummaryHyperthyroidisminpregnancyisgenerallycausedbyGTTorGravesdisease.ManagementofGravesdiseaseremainsachallenge,withthionamidetreatmentasthebestoption.Patientsshouldbemonitoredcloselybe-causeundertreatment,withpersistentlyhighmaternalTRAB,increasestheriskoffetalhyperthyroidism,whileovertreatmentmaycausefetalhypothyroidism.Gestationalhypothyroidismisusuallyrelatedtoauto-immunethyroiddisease,andlessfrequentlytoiodinedeficiency.Thelattermaybeassociatedwithfetalhy-pothyroidismaswell.Neurologicaldevelopmentisin-fluencedbymaternalthyroidfunction,fetalthyroidfunction,andthyroidhormonelevelsinthenewborn. References1.PankowBG,MichalakJ,McGeeMK(1985)Adulthumanthyroidweight.HealthPhysics49:1097…11032.MochizukiY,MowafyR,PasternackB(1963)WeightsofhumanthyroidsinNewYorkCity.HealthPhysics9:1299…13013.WolffJ(1964)Transportofiodideandotheranionsinthethyroidgland.PhysiolRev44:454.DelaViejaA,DohanO,LevyO,CarrascoN(2000)Molecu-laranalysisofthesodium/iodidesymporter:Impactonthyroidandextrathyroidpathophysiology.PhysiolRev80:1083…11055.AlexanderC,BaderJB,ShaeferA,etal(1998)Intermediateandlong-termsideeffectsofhigh-doseradioiodinethera-pyforthyroidcarcinoma.JNuclMed39:1551…15546.KappesRS,SarkarSD,Har-ElG,etal(1994)Iodine-131therapyofthyroidcancer:extensivecontaminationofthehospitalroominapatientwithtracheostomy.JNuclMed35:2053…20547.MitchellG,PrattBE,ViniL,etal(2000)Falsepositive131Iwholebodyscansinthyroidcancer.BrJRadiol73:627…6358.RomneyB,NickoloffEL,EsserPD(1989)Excretionofra-dioiodineinbreastmilk.JNuclMed30:124…1269.StofferSS,HamburgerJI(1975)InadvertentI-131therapyforhyperthyroidisminthefirsttrimesterofpregnancy.JNuclMed17:146…14910.RotiE,MinelliR,GardiniE,etal(1994)Theiodineper-chloratedischargetestbeforeandafteroneyearofmet-himazoletreatmentofhyperthyroidGravesdisease.JClinEndocrinolMetab78:795…79911.BijayeswarV,CoffeyR,CoyleRetal(1999)ConcurrenceofPendredsyndrome,autoimmunethyr

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