Guidelines of the American Thyroid Association

2022-08-22 来源：易榕旅网

THYROID

Volume21,Number6,2011ªMaryAnnLiebert,Inc.DOI:10.1089/thy.2010.0417

ORIGINALSTUDIES,REVIEWS,

ANDSCHOLARLYDIALOG

HYPERTHYROIDISM,OTHERCAUSESOFTHYROTOXICOSIS,

ANDTHYROIDHORMONEACTION

HyperthyroidismandOtherCausesofThyrotoxicosis:ManagementGuidelinesoftheAmericanThyroidAssociation

andAmericanAssociationofClinicalEndocrinologists

TheAmericanThyroidAssociationandAmericanAssociationofClinicalEndocrinologists

TaskforceonHyperthyroidismandOtherCausesofThyrotoxicosis

RebeccaS.Bahn(Chair),1,*HenryB.Burch,2DavidS.Cooper,3JeffreyR.Garber,4M.CarolGreenlee,5IrwinKlein,6PeterLaurberg,7I.RossMcDougall,8VictorM.Montori,1ScottA.Rivkees,9DouglasS.Ross,10JulieAnnSosa,11andMariusN.Stan1Background:Thyrotoxicosishasmultipleetiologies,manifestations,andpotentialtherapies.Appropriatetreatmentrequiresanaccuratediagnosisandisinﬂuencedbycoexistingmedicalconditionsandpatientpref-erence.Thisarticledescribesevidence-basedclinicalguidelinesforthemanagementofthyrotoxicosisthatwouldbeusefultogeneralistandsubspecialityphysiciansandothersprovidingcareforpatientswiththiscondition.Methods:ThedevelopmentoftheseguidelineswascommissionedbytheAmericanThyroidAssociationinassociationwiththeAmericanAssociationofClinicalEndocrinologists.TheAmericanThyroidAssociationandAmericanAssociationofClinicalEndocrinologistsassembledataskforceofexpertclinicianswhoau-thoredthisreport.ThetaskforceexaminedrelevantliteratureusingasystematicPubMedsearchsupple-mentedwithadditionalpublishedmaterials.Anevidence-basedmedicineapproachthatincorporatedtheknowledgeandexperienceofthepanelwasusedtodevelopthetextandaseriesofspeciﬁcrecommendations.ThestrengthoftherecommendationsandthequalityofevidencesupportingeachwasratedaccordingtotheapproachrecommendedbytheGradingofRecommendations,Assessment,Development,andEvaluationGroup.

Results:Clinicaltopicsaddressedincludetheinitialevaluationandmanagementofthyrotoxicosis;man-agementofGraves’hyperthyroidismusingradioactiveiodine,antithyroiddrugs,orsurgery;managementoftoxicmultinodulargoiterortoxicadenomausingradioactiveiodineorsurgery;Graves’diseaseinchildren,adolescents,orpregnantpatients;subclinicalhyperthyroidism;hyperthyroidisminpatientswithGraves’ophthalmopathy;andmanagementofothermiscellaneouscausesofthyrotoxicosis.

Conclusions:Onehundredevidence-basedrecommendationsweredevelopedtoaidinthecareofpatientswiththyrotoxicosisandtosharewhatthetaskforcebelievesiscurrent,rational,andoptimalmedicalpractice.

Bymutualagreementamongtheauthorsandeditorsoftheirrespectivejournals,thisworkisbeingpublishedjointlyinThyroidandEndocrinePractice.

*Authorsarelistedinalphabeticalorder.1DivisionofEndocrinology,Metabolism,andNutrition,MayoClinic,Rochester,Minnesota.2EndocrinologyandMetabolismDivision,WalterReedArmyMedicalCenter,Washington,DistrictofColumbia.3DivisionofEndocrinology,TheJohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland.4EndocrineDivision,HarvardVanguardMedicalAssociates,Boston,Massachusetts.5WesternSlopeEndocrinology,GrandJunction,Colorado.6TheThyroidUnit,NorthShoreUniversityHospital,Manhassett,NewYork.7DepartmentofEndocrinology,AarhusUniversityHospital,Aalborg,Denmark.8DivisionofNuclearMedicine,DepartmentofRadiologyandDivisionofEndocrinology,DepartmentofMedicine,StanfordUniversitySchoolofMedicine,Stanford,California.

9DepartmentofPediatrics,YalePediatricThyroidCenter,NewHaven,Connecticut.10MassachusettsGeneralHospital,Boston,Massachusetts.11DivisionsofEndocrineSurgeryandSurgicalOncology,YaleUniversitySchoolofMedicine,NewHaven,Connecticut.

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Introduction

BAHNETAL.

MethodsofDevelopmentofEvidence-BasedGuidelinesAdministration

TheATAExecutiveCouncilandtheExecutiveCommitteeofAACEforgedanagreementoutliningtheworkingrela-tionshipbetweenthetwogroupssurroundingthedevelop-mentanddisseminationofmanagementguidelinesforthetreatmentofpatientswiththyrotoxicosis.Achairpersonwasselectedtoleadthetaskforceandthisindividual(R.S.B.)identiﬁedtheother11membersofthepanelinconsulta-tionwiththeATAandtheAACEboardsofdirectors.Membershiponthepanelwasbasedonclinicalexpertise,scholarlyapproach,andrepresentationofadultandpedi-atricendocrinology,nuclearmedicine,andsurgery.ThetaskforceincludedindividualsfrombothNorthAmericaandEurope.Inaddition,thegrouprecruitedanexpertonthedevelopmentofevidence-basedguidelines(V.M.M.)toserveinanadvisorycapacity.Panelmembersdeclaredwhethertheyhadanypotentialconﬂictofinterestattheinitialmeetingofthegroupandperiodicallyduringthecourseofdeliberations.FundingfortheguidelineswasderivedsolelyfromthegeneralfundsoftheATAandthusthetaskforcefunctionedwithoutcommercialsupport.

Todevelopascholarlyandusefuldocument,thetaskforceﬁrstdevelopedalistofthemostcommoncausesofthyrotoxicosisandthemostimportantquestionsthatapractitionermightposewhencaringforapatientwithaparticularformofthyrotoxicosisorspecialclinicalcondition.Twotaskforcememberswereassignedtoreviewtheliter-aturerelevanttoeachofthetopics,usingasystematicPubMedsearchforprimaryreferencesandreviewssupple-mentedwithadditionalpublishedmaterialsavailablebeforeJune2010,anddeveloprecommendationsbasedonthelit-eratureandexpertopinionwhereappropriate.Aprelimi-narydocumentandaseriesofrecommendationsconcerningallofthetopicsweregeneratedbyeachsubgroupandthencriticallyreviewedbythetaskforceatlarge.Thepanelagreedrecommendationswouldbebasedonconsensusofthepanelandthatvotingwouldbeusedifagreementcouldnotbereached.Tworecommendationswerenotunanimousandthedissentingpositionisnoted.Taskforcedeliberationstookplaceduringseverallengthycommitteemeetings,multipletelephoneconferencecalls,andthroughelectroniccommunication.

hyrotoxicosisisaconditionhavingmultipleeti-ologies,manifestations,andpotentialtherapies.Theterm‘‘thyrotoxicosis’’referstoaclinicalstatethatresultsfromin-appropriatelyhighthyroidhormoneactionintissuesgenerallyduetoinappropriatelyhightissuethyroidhormonelevels.Theterm‘‘hyperthyroidism,’’asusedintheseguidelines,isaformofthyrotoxicosisduetoinappropriatelyhighsynthesisandsecretionofthyroidhormone(s)bythethyroid.Appropriatetreatmentofthyrotoxicosisrequiresanaccuratediagnosis.Forexample,thyroidectomyisanappropriatetreatmentforsomeformsofthyrotoxicosisandnotforothers.Additionally,betablockersmaybeusedinalmostallformsofthyrotoxicosis,whereasantithyroiddrugsareusefulinonlysome.

IntheUnitedStates,theprevalenceofhyperthyroidismisapproximately1.2%(0.5%overtand0.7%subclinical);themostcommoncausesincludeGraves’disease(GD),toxicmultinodulargoiter(TMNG),andtoxicadenoma(TA)(1).Scientiﬁcadvancesrelevanttothistopicarere-portedinawiderangeofliterature,includingsubspecialitypublicationsinendocrinology,pediatrics,nuclearmedi-cine,andsurgery,makingitchallengingforclinicianstokeepabreastofnewdevelopments.Althoughguidelinesforthediagnosisandmanagementofpatientswithhy-perthyroidismhavebeenpublishedpreviouslybyboththeAmericanThyroidAssociation(ATA)andAmericanAs-sociationofClinicalEndocrinologists(AACE),inconjunc-tionwithguidelinesforthetreatmentofhypothyroidism(1,2),bothassociationsdeterminedthatthyrotoxicosisrepresentsapriorityareainneedofupdatedevidence-basedpracticeguidelines.

Thetargetaudiencefortheseguidelinesincludesgeneralandsubspecialityphysiciansandothersprovidingcareforpatientswiththyrotoxicosis.Inthisdocument,weoutlinewhatwebelieveiscurrent,rational,andoptimalmedicalpractice.Itisnottheintentoftheseguidelinestoreplaceclinicaljudgment,individualdecisionmaking,orthewishesofthepatientorfamily.Rather,eachrecommendationshouldbeevaluatedinlightoftheseelementsinorderthatoptimalpatientcareisdelivered.Insomecircumstances,itmaybeapparentthatthelevelofcarerequiredmaybebestprovidedincenterswherethereisspeciﬁcexpertise,andthatreferraltosuchcentersshouldbeconsidered.

Table1.GradingofRecommendations,Assessment,Development,andEvaluationSystem

Typeofgrading

Strengthoftherecommendation

Deﬁnitionofgrades

1¼strongrecommendation(fororagainst)

AppliestomostpatientsinmostcircumstancesBeneﬁtsclearlyoutweightherisk(orviceversa)2¼weakrecommendation(fororagainst)

BestactionmaydifferdependingoncircumstancesorpatientvaluesBeneﬁtsandrisksorburdensarecloselybalanced,oruncertain

þþþ¼Highquality;evidenceatlowriskofbias,suchashighqualityrandomizedtrialsshowingconsistentresultsdirectlyapplicabletotherecommendation

þþ¼Moderatequality;studieswithmethodologicalﬂaws,showinginconsistentorindirectevidence

þ¼Lowquality;caseseriesorunsystematicclinicalobservations

Qualityoftheevidence

HYPERTHYROIDISMMANAGEMENTGUIDELINESRatingoftherecommendations

Theseguidelinesweredevelopedtocombinethebestsci-entiﬁcevidencewiththeexperienceofseasonedcliniciansandthepragmaticrealitiesinherentinimplementation.ThetaskforceelectedtoratetherecommendationsaccordingtothesystemdevelopedbytheGradingofRecommendations,As-sessment,Development,andEvaluationGroup(3),withamodiﬁcationinthegradingofevidence(4).AlthoughtheratingsystemwechosediffersfromthoseusedinpreviousATAandAACEclinicalpracticeguidelines,theapproachconformswiththerecentlyupdatedAACEprotocolforstandardizedproductionofclinicalpracticeguidelines(5).Thebalancebetweenbeneﬁtsandrisks,qualityofevidence,applicability,andcertaintyofthebaselineriskareallcon-sideredinjudgmentsaboutthestrengthofrecommendations(6).Gradingthequalityoftheevidencetakesintoaccountstudydesign,studyquality,consistencyofresults,anddi-rectnessoftheevidence.Thestrengthofarecommendationisindicatedbythenumber1or2.Grade1indicatesastrongrecommendation(fororagainst)thatappliestomostpatientsinmostcircumstanceswithbeneﬁtsofactionclearlyout-

595

weighingtherisksandburdens(orviceversa).Incontrast,Grade2indicatesaweakrecommendationorasuggestionthatmaynotbeappropriateforeverypatient,dependingoncontext,patientvalues,andpreferences.Therisksandbene-ﬁtsorburdensassociatedwithaweakrecommendationarecloselybalancedoruncertainandthestatementisgenerallyassociatedwiththephrase‘‘wesuggest’’or‘‘shouldbecon-sidered.’’Thequalityoftheevidenceisindicatedbyplussigns,suchthatþdenoteslowqualityevidence;þþ,mod-eratequalityevidence;andþþþ,highqualityevidence,basedonconsistencyofresultsbetweenstudiesandstudydesign,limitations,andthedirectnessoftheevidence.Table1describesthecriteriatobemetforeachratingcategory.Eachrecommendationisprecededbyadescriptionoftheevidenceand,insomecases,followedbyaremarkssectionincludingtechnicalsuggestionsonissuessuchasdosingandmonitoring.

PresentationandendorsementofrecommendationsTheorganizationofthetaskforce’srecommendationsispresentedinTable2.Thepagenumbersandthelocationkey

Table2.OrganizationoftheTaskForce’sRecommendations

Locationkey[A][B]

Description

Background

Howshouldclinicallyorincidentallydiscoveredthyrotoxicosisbeevaluatedandinitiallymanaged?[B1]Assessmentofdiseaseseverity[B2]Biochemicalevaluation[B3]Determinationofetiology[B4]Symptomaticmanagement

HowshouldoverthyperthyroidismduetoGDbemanaged?

If131ItherapyischosenastreatmentforGD,howshoulditbeaccomplished?[D1]PreparationofpatientswithGDfor131Itherapy[D2]Administrationof131IinthetreatmentofGD[D3]Patientfollow-upafter131ItherapyforGD[D4]TreatmentofpersistentGraves’hyperthyroidismfollowingradioactive

iodinetherapy

IfantithyroiddrugsarechosenasinitialmanagementofGD,howshouldthetherapybemanaged?[E1]InitiationofantithyroiddrugtherapyforthetreatmentofGD[E2]Monitoringofpatientstakingantithyroiddrugs[E3]Managementofallergicreactions[E4]DurationofantithyroiddrugtherapyforGD

IfthyroidectomyischosenfortreatmentofGD,howshoulditbeaccomplished?[F1]PreparationofpatientswithGDforthyroidectomy[F2]Thesurgicalprocedureandchoiceofsurgeon[F3]Postoperativecare

HowshouldthyroidnodulesbemanagedinpatientswithGD?Howshouldthyroidstormbemanaged?

HowshouldoverthyperthyroidismduetoTMNGorTAbetreated?

If131ItherapyischosenastreatmentforTMNGorTA,howshoulditbeaccomplished?[J1]PreparationofpatientswithTMNGorTAfor131Itherapy[J2]Evaluationofthyroidnodulespriortoradioioactiveiodinetherapy[J3]AdministrationofradioactiveiodineinthetreatmentofTMNGorTA[J4]Patientfollow-upafter131ItherapyforTMNGorTA[J5]Treatmentofpersistentorrecurrenthyperthyroidismfollowing131Itherapy

forTMNGorTA

Ifsurgeryischosen,astreatmentforTMNGorTA,howshoulditbeaccomplished?[K1]PreparationofpatientswithTMNGorTAforsurgery

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597597598598599600601601601602603603603604604604605605605605606606607609609609609610610610610(continued)

[C][D]

[E]

[F]

[G][H][I][J]

[K]

596

Table2.(Continued)

Locationkey

[K2][K3][K4]

Description

BAHNETAL.

Page610611611611612612612612612613613614614614615615615615616616617617617617618618619619619621621622623624625625625626626627627628628628628629629629629630630

[L][M][N][O]

[P]

[Q][R]

[S]

[T]

[U]

[V]

[W]

ThesurgicalprocedureandchoiceofsurgeonPostoperativecare

TreatmentofpersistentorrecurrentdiseasefollowingsurgeryforTMNGorTA

IstherearoleforantithyroiddrugtherapyinpatientswithTMNGorTA?

Istherearoleforradiofrequency,thermaloralcoholablationinthemanagementofTAorTMNG?

HowshouldGDbemanagedinchildrenandadolescents?[N1]Generalapproach

IfantithyroiddrugsarechosenasinitialmanagementofGDinchildren,howshouldthetherapybemanaged?[O1]InitiationofantithyroiddrugtherapyforthetreatmentofGDinchildren[O2]SymptomaticmanagementofGraves’hyperthyroidisminchildren[O3]Monitoringofchildrentakingmethimazole[O4]Monitoringofchildrentakingpropylthiouracil[O5]Managementofallergicreactionsinchildrentakingmethimazole[O6]DurationofmethimazoletherapyinchildrenwithGD

IfradioactiveiodineischosenastreatmentforGDinchildren,howshoulditbeaccomplished?[P1]PreparationofpediatricpatientswithGDfor131Itherapy[P2]Administrationof131IinthetreatmentofGDinchildren[P3]Side-effectsof131Itherapyinchildren

IfthyroidectomyischosenastreatmentforGDinchildren,howshoulditbeaccomplished?[Q1]PreparationofchildrenwithGDforthyroidectomyHowshouldSHbemanaged?[R1]Frequencyandcausesofsubclinicalhyperthyroidism[R2]Clinicalsigniﬁcanceofsubclinicalhyperthyroidism[R3]Whentotreatsubclinicalhyperthyroidism[R4]Howtotreatsubclinicalhyperthyroidism[R5]Endpointstobeassessedtodetermineeffectivetherapyofsubclinical

hyperthyroidism

Howshouldhyperthyroidisminpregnancybemanaged?[S1]Diagnosisofhyperthyroidisminpregnancy[S2]Managementofhyperthyroidisminpregnancy[S3]TheroleofTRAblevelsmeasurementinpregnancy[S4]Postpartumthyroiditis

HowshouldhyperthyroidismbemanagedinpatientswithGraves’ophthalmopathy?[T1]Assessmentofdiseaseactivityandseverity[T2]PreventionofGO[T3]TreatmentofhyperthyroidisminpatientswithactiveGOofmildseverity[T4]Treatmentofhyperthyroidisminpatientswithactiveandmoderate-to-severe

orsight-threateningGO

[T5]TreatmentofGDinpatientswithinactiveGOHowshouldovertdrug-inducedthyrotoxicosisbemanaged?[U1]Iodine-inducedthyrotoxicosis[U2]Cytokine-inducedthyrotoxicosis[U3]Amiodarone-inducedthyrotoxicosis

Howshouldthyrotoxicosisduetodestructivethyroiditisbemanaged?[V1]Subacutethyroiditis[V2]Painlessthyroiditis[V3]Acutethyroiditis

Howshouldthyrotoxicosisduetounusualcausesbemanaged?[W1]TSH-secretingpituitarytumors[W2]Strumaovarii[W3]Choriocarcinoma[W4]Thyrotoxicosisfactitia[W5]Functionalthyroidcancermetastases

GD,Graves’disease;GO,Graves’ophthalmopathy;SH,subclinicalhyperthyroidism;TA,toxicadenoma;TMNG,toxicmultinodular

goiter;TRAb,thyrotropinreceptorantibody;TSH,thyroid-stimulatinghormone.

HYPERTHYROIDISMMANAGEMENTGUIDELINEScanbeusedtolocatespeciﬁctopicsandrecommenda-tions.Speciﬁcrecommendationsarepresentedwithinboxesinthemainbodyofthetext.LocationkeyscanbecopiedintotheFindorSearchfunctioninaﬁleorWebpagetorapidlynavigatetoaparticularsection.AlistingoftherecommendationswithouttextisprovidedasAppendixA.

TheﬁnaldocumentwasapprovedbytheATAandAACEonMarch15,2011andofﬁciallyendorsed(inalpha-beticalorder)byAmericanAcademyofOtolaryngology–HeadandNeckSurgery,AssociazioneMediciEndocrinologi,BritishAssociationofEndocrineandThyroidSurgeons,CanadianPaediatricEndocrineGroup–GroupeCanadien

d’EndocrinologiePe

´diatrique(endorsementofpediatricsec-tiononly),EuropeanAssociationofNuclearMedicine,TheEndocrineSociety,EuropeanSocietyofEndocrinology,Eu-ropeanSocietyofEndocrineSurgeons,EuropeanThyroidAssociation,InternationalAssociationofEndocrineSur-geons,LatinAmericanThyroidSociety,PediatricEndocrineSociety,ItalianEndocrineSociety,andSocietyofNuclearMedicine.Results

[A]Background

Ingeneral,thyrotoxicosiscanoccurif(i)thethyroidisinappropriatelystimulatedbytrophicfactors;(ii)thereisconstituitiveactivationofthyroidhormonesynthesisandsecretionleadingtoautonomousreleaseofexcessthyroidhormone;(iii)thyroidstoresofpreformedhormonearepas-sivelyreleasedinexcessiveamountsowingtoautoimmune,infectious,chemical,ormechanicalinsult;or(iv)thereisexposuretoextra-thyroidalsourcesofthyroidhormone,whichmaybeeitherendogenous(strumaovarii,metastaticdifferentiatedthyroidcancer)orexogenous(factitiousthyro-toxicosis).

Subclinicalhyperthyroidism(SH)ismostoftencausedbyreleaseofexcessthyroidhormonebythegland.Thisconditionisdeﬁnedasaloworundetectableserumthyroid-stimulatinghormone(TSH)withvalueswithinthenormalreferencerangeforbothtriiodothyronine(T3)andfreethyroxine(T4)estimates.Bothovertandsub-clinicaldiseasemayleadtocharacteristicsignsandsymptoms.

GDisanautoimmunedisorderinwhichthyrotropinre-ceptorantibodies(TRAbs)stimulatetheTSHreceptor,in-creasingthyroidhormoneproduction.Thenaturalhistoryofnodularthyroiddiseaseincludesgrowthofestablishednodules,newnoduleformation,anddevelopmentofau-tonomyovertime(7).InTAs,autonomoushormonepro-ductioncanbecausedbysomaticactivatingmutationsofgenesregulatingthyroidhormonesysthesis.Germlinemu-tationsinthegeneencodingtheTSHreceptorcancausesporadicorfamilialnonautoimmunehyperthyroidismasso-ciatedwithadiffuseenlargementofthethyroidgland(8).Autonomoushormoneproductioniscausedbysomatic,activatingmutationsofgenesregulatingfollicularcellac-tivities.Hormoneproductionmayprogressfromsubclinicaltooverthyperthyroidism,andtheadministrationofphar-macologicamountsofiodinetosuchpatientsmayresultiniodine-inducedhyperthyroidism(9).GDisoverallthemostcommoncauseofhyperthyroidismintheUnitedStates

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(10,11).AlthoughtoxicnodulargoiterislesscommonthanGD,itsprevalenceincreaseswithageandinthepresenceofiodinedeﬁciency.Therefore,toxicnodulargoitermayactu-allybemorecommonthanGDinolderpatientsfromregionsofiodinedeﬁciency(12).Unliketoxicnodulargoiter,whichisprogressive(unlesstriggeredbyexcessiveiodineintake),remissionofGDhasbeenreportedinupto30%ofpatientswithouttreatment(13).

Themechanismofhyperthyroidisminpainlessandsub-acutethyroiditisisinﬂammationofthyroidtissuewithreleaseofpreformedhormoneintothecirculation.Painlessthyroid-itisistheetiologyofhyperthyroidisminabout10%ofpatients(14),occurringinthepostpartumperiod(postpartumthy-roiditis)(15),duringlithium(16),orcytokine(e.g.,interferon-alpha)(17)therapy,andin5–10%ofamiodarone-treatedpatients(18).Subacutethyroiditisisthoughttobecausedbyviralinfectionandischaracterizedbyfeverandthyroidpain(19).

Thyroidhormoneinﬂuencesalmosteverytissueandorgansysteminthebody.Itincreasestissuethermogenesisandbasalmetabolicrate(BMR)andreducesserumcholesterollevelsandsystemicvascularresistance.Someofthemostprofoundeffectsofincreasedthyroidhormonelevelsareonthecardiovascularsystem(20).Thecomplicationsofuntreatedthyrotoxicosisincludelossofweight,osteoporosis,atrialﬁbrillation,embolicevents,andevencardiovascularcollapseanddeath(21,22).

ThecellularactionsofthyroidhormonearemediatedbyT3,theactiveformofthyroidhormone.T3bindstonuclearreceptorproteinsthatfunctionastranscriptionfactorstoregulatetheexpressionofmanygenes.Nongenomicactionsofthyroidhormonealsoregulateimportantphysiologicpa-rameters.

Thesignsandsymptomsofovertandmild,orsubclinical,thyrotoxicosisaresimilar,butdifferinmagnitude.Overtthyrotoxicosis,whetherendogenousorexogenous,ischar-acterizedbyexcessthyroidhormonesinserumandsup-pressedTSH(<0.01mU/L).Therearealsomeasurablechangesinbasalmetabolicrate,cardiovascularhemody-namics,andpsychiatricandneuropsychologicalfunction(23).Thereisonlymoderatecorrelationbetweentheelevationinthyroidhormoneconcentrationandclinicalsignsandsymp-toms.Symptomsandsignsthatresultfromincreasedadren-ergicstimulationincludetachycardiaandanxietyandappeartobemorepronouncedinyoungerpatientsandthosewithlargergoiters(24).

[B]Howshouldclinicallyorincidentallydiscoveredthyrotoxicosisbeevaluatedandinitiallymanaged?

[B1]Assessmentofdiseaseseverity

Theassessmentofthyrotoxicmanifestations,andespe-ciallypotentialcardiovascularandneuromuscularcompli-cations,isessentialtoformulatinganappropriatetreatmentplan.WhileitmightbeanticipatedthattheseverityofthyrotoxicsymptomsisproportionaltotheelevationintheserumlevelsoffreeT4andT3estimates,inonestudyof25patientswithGD,theHyperthyroidSymptomScaledidnotstronglycorrelatewithfreeT4orT3estimatesandwasin-verselycorrelatedwithage(24).Theimportanceofageasadeterminantoftheprevalenceandseverityofhyperthyroid

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symptomshasbeenrecentlyconﬁrmed(25).Cardiacevalu-ationmaybenecessary,especiallyintheolderpatient,andmayrequireanechocardiogram,electrocardiogram,Holtermonitor,ormyocardialperfusionstudies.Inadditiontotheadministrationofbeta-blockers(26),speciﬁccardiovasculartreatmentmaybedirectedtowardconcomitantmyocardialischemia,congestiveheartfailure,oratrialarrhythmias(20),andanticoagulationmaybenecessaryinpatientsinatrialﬁbrillation(27).Goitersize,obstructivesymptoms,andtheseverityofGraves’ophthalmopathy(GO;theinﬂammatorydiseasethatdevelopsintheorbitinassociationwithauto-immunethyroiddisorderscanbediscordantwiththedegreeofhyperthyroidismorhyperthyroidsymptoms.

Allpatientswithknownorsuspectedhyperthyroidismshouldundergoacomprehensivehistoryandphysicalexamination,includingmeasurementofpulserate,bloodpressure,respiratoryrate,andbodyweight.Inaddition,thyroidsize;presenceorabsenceofthyroidtenderness,symmetry,andnodularity;pulmonary,cardiac,andneuro-muscularfunction(23,26,28);andpresenceorabsenceofpe-ripheraledema,eyesigns,orpretibialmyxedemashouldbeassessed.

[B2]Biochemicalevaluation

SerumTSHmeasurementhasthehighestsensitivityandspeciﬁcityofanysinglebloodtestusedintheevaluationofsuspectedhyperthyroidismandshouldbeusedasaninitialscreeningtest(29).However,whenhyperthyroidismisstronglysuspected,diagnosticaccuracyimproveswhenbothaserumTSHandfreeT4areassessedatthetimeoftheinitialevaluation.TherelationshipbetweenfreeT4andTSH(whenthepituitary-thyroidaxisisintact)isaninverselog-linearrelationship;therefore,smallchangesinfreeT4resultinlargechangesinserumTSHconcentrations.SerumTSHlevelsareconsiderablymoresensitivethandirectthyroidhormonemeasurementsforassessingthyroidhormoneexcess(30).Inoverthyperthyroidism,usuallybothserumfreeT4andT3estimatesareelevated,andserumTSHisundetectable;however,inmilderhyperthyroidism,serumT4andfreeT4estimatescanbenormal,onlyserumT3maybeelevated,andserumTSHwillbe<0.01mU/L(orundectable).Theselabo-ratoryﬁndingshavebeencalled‘‘T3-toxicosis’’andmayrep-resenttheearlieststagesofdiseaseorthatcausedbyanautonomouslyfunctioningthyroidnodule.AsisthecasewithT4,totalT3measurementsareimpactedbyproteinbinding.AssaysforestimatingfreeT3arelesswidelyvalidatedthanthoseforfreeT4,andthereforemeasurementoftotalT3isfrequentlypreferredinclinicalpractice.Subclincialhyper-thyroidismisdeﬁnedasanormalserum-freeT4estimateandnormaltotalT3orfreeT3estimate,withsubnormalserumTSHconcentration.LaboratoryprotocolsthatautomaticallyaddfreeT4estimateandT3measurementswhenscreeningserumTSHconcentrationsarelowavoidtheneedforsubse-quentblooddraws.

IntheabsenceofaTSH-producingpituitaryadenomaorthyroidhormoneresistance,iftheserumTSHisnormal,thepatientisalmostneverhyperthyroid.Theterm‘‘euthyroidhyperthyroxinemia’’hasbeenusedtodescribeanumberofentities,mostlythyroidhormone-bindingproteindisorders,thatcauseelevatedtotalserumT4concentrations(andfre-quentlyelevatedtotalserumT3concentrations)intheabsence

BAHNETAL.

ofhyperthyroidism(31).TheseconditionsincludeelevationsinT4bindingglobulin(TBG)ortransthyretin(TTR)(32),thepresenceofanabnormalalbuminwhichbindsT4withhighcapacity(familialhyperthyroxinemicdysalbuminia),asimi-larlyabnormalTTR,and,rarely,immunoglobulinswhichdirectlybindT4orT3.TBGexcessmayoccurasahereditaryX-linkedtrait,orbeacquiredasaresultofpregnancyorestrogenadministration,hepatitis,acuteintermittentporphyuria,orduringtreatmentwith5-ﬂourouracil,perphenazine,orsomenarcotics.Othercausesofeuthyroidhyperthyroxinemiain-cludethosedrugsthatinhibitT4toT3conversion,suchasamiodarone(18)orhigh-dosepropranolol(26),acutepsy-chosis,extremehighaltitude,andamphetamineabuse.Esti-matesoffreethyroidhormoneconcentrationsfrequentlyalsogiveerroneousresultsinthesedisorders.SpuriousfreeT4elevationsmayoccurinthesettingofheparintherapy.WhenfreethyroidhormoneconcentrationsareelevatedandTSHisnormalorelevated,furtherevaluationisnecessary.

Afterexcludingeuthyroidhyperthyroxinemia,TSH-mediatedhyperthyroidismshouldbeconsidered.ApituitarylesiononMRIandadisproportionatelyhighserumlevelofthealpha-subunitofthepituitaryglycoproteinhormonessupportthediagnosisofaTSH-producingpituitaryadenoma(33).AfamilyhistoryandpositiveresultofgenetictestingformutationsintheT3-receptorsupportadiagnosisofthyroidhormoneresistance(34).RareproblemswithTSHassayscausedbyheterophilicantibodiescancausespuriouslyhighTSHvalues.

[B3]Determinationofetiology

RECOMMENDATION1

AradioactiveiodineuptakeshouldbeperformedwhentheclinicalpresentationofthyrotoxicosisisnotdiagnosticofGD;athyroidscanshouldbeaddedinthepresenceofthyroidnodularity.1/+00

Inapatientwithasymmetricallyenlargedthyroid,recentonsetofophthalmopathy,andmoderatetoseverehyper-thyroidism,thediagnosisofGDissufﬁcientlylikelythatfurtherevaluationofhyperthyroidismcausationisunneces-sary.Aradioactiveiodineuptake(RAIU)isindicatedwhenthediagnosisisinquestion(exceptduringpregnancy)anddistinguishescausesofthyrotoxicosishavingelevatedornormaluptakeoverthethyroidglandfromthosewithnear-absentuptake(Table3).ItisusuallyelevatedinpatientswithGDandnormalorhighintoxicnodulargoiter,unlesstherehasbeenarecentexposuretoiodine(e.g.,radiocontrast).ThepatternofRAIUinGDisdiffuseunlesstherearecoexistentnodulesorﬁbrosis.ThepatternofuptakeinapatientwithasingleTAgenerallyshowsfocaluptakeintheadenomawithsuppresseduptakeinthesurroundingandcontralateralthy-roidtissue.TheimageinTMNGdemonstratesmultipleareasoffocalincreasedandsuppresseduptake,andifautonomyisextensive,theimagemaybedifﬁculttodistinguishfromthatofGD(35).

TheRAIUwillbenearzeroinpatientswithpainless,postpartum,orsubacutethyroiditis,orinthosewithfactitiousingestionofthyroidhormoneorrecentexcessiodineintake.Theradioiodineuptakemaybelowafterexposuretoiodin-atedcontrastinthepreceeding1–2monthsorwithingestion

HYPERTHYROIDISMMANAGEMENTGUIDELINES

Table3.CausesofThyrotoxicosis

ThyrotoxicosisradioiodineuptakeassociatedoverwiththeneckanormalaorelevatedGD

TATrophoblasticorTMNG

TSH-producingdisease

ThyrotoxicosisResistanceuptakeassociatedtothyroidpituitaryhormoneadenomas

(T3receptormutation)bPainlessoverthewithanear-absentradioiodineAmiodarone-induced(silent)neck

thyroiditis

Subacutethyroiditis

Iatrogenic(granulomatous,Factitiousthyrotoxicosis

deQuervain’s)thyroiditisStrumaAcuteovariiingestionofthyroidhormoneExtensivethyroiditis

metastasesfromfollicularthyroidcancer

aIniodine-inducedoriodine-exposedhyperthyroidism(includingamiodaronebtype1),theuptakemaybelow.Patientsarenotuniformlyclinicallyhyperthyroid.T3,triiodothyronine.

ofadietunusuallyrichiniodinesuchasseaweedsouporkelp.However,itisrarelyzerounlesstheiodineexposureisreoccurringasduringtreatmentwithamiodarone.Whenex-posuretoexcessiodineissuspected(e.g.,whentheRAIUislowerthanexpected),butnotwellestablishedfromthehis-tory,assessmentofurinaryiodineconcentrationmaybehelpful.

Technetiumscintigraphy(TcO4)utilizespertechnetatethatistrappedbythethyroid,butnotorganiﬁed.Whilethisre-sultsinalowrangeofnormaluptakeandhighbackgroundactivity,totalbodyradiationexposureislessthanfor123Iscintiscans;eithertypeofscancanbeusefulindeterminingtheetiologyofhyperthyroidisminthepresenceofthyroidnodularity.Ultrasonographydoesnotgenerallycontributetothedifferentialdiagnosisofthyrotoxicosis.Whenradioactiveiodineiscontraindicated,suchasduringpregnancyorbreastfeeding,ornotuseful,suchasfollowingrecentiodineexposure,ultrasoundshowingincreasedcolorDopplerﬂowmaybehelpfulinconﬁrmingadiagnosisofthyroidhyper-activity(36).Dopplerﬂowhasalsobeenusedtodistinguishbetweensubtypesofamiodarone-inducedthyrotoxicosis(seeSection[U3],andbetweenGDanddestructivethyroiditis(seeSection[V1]).

AnalternativewaytodiagnoseGDisbymeasurementofTRAb.Thisapproachisutilizedwhenathyroidscananduptakeareunavailableorcontraindicated(e.g.,duringpregnancyandnursing).TheratiooftotalT3tototalT4canalsobeusefulinassessingtheetiologyofthyrotoxicosiswhenscintigraphyiscontraindicated.SincerelativelymoreT3issynthesizedthanT4inahyperactivegland,theratio(ng/mcg)isusually>20inGDandtoxicnodulargoiter,and<20inpainlessorpostpartumthy-roiditis(37).

Inmostpatients,thedistinctionbetweensubacuteandpainlessthyroiditisisnotdifﬁcult.Subacutethy-roiditisisgenerallypainful,theglandisﬁrmtohardonpalpation,andtheerythrocytesedimentationrate(ESR)isalmostalways>50andsometimesover100mm/h.Pa-tientswithpainlessthyroiditismaypresentinthepost-

599

partumperiod,oftenhaveapersonalorfamilyhistoryofautoimmunethyroiddisease,andtypicallyhavelowtomoderateconcentrationsofantithyroidperoxidaseanti-bodies(38).

Thyroglobulinisreleasedalongwiththyroidhormoneinsubacute,painless,andpalpationthyroiditis,whereasitsreleaseissuppressedinthesettingofexogenousthy-roidhormoneadministration.Therefore,ifnotelucidatedbythehistory,factitiousingestionofthyroidhormonecanbedistinguishedfromothercausesofthyrotoxicosisbyalowserumthyroglobulinlevelandanear-zeroRAIU(39).Inpatientswithantithyroglobulinantibodies,whichin-terferewiththyroglobulinmeasurement,analternativebutnotwidelyavailableapproachismeasurementoffecalT4(40).

Technicalremarks:MostTRAbassaysarespeciﬁcforGD,butthyroid-stimulatingimmunoglobulins(TSI)andﬁrst-generationthyrotropin-bindinginhibitorimmunoglobulin(TBII)assaysarelesssensitive(41,42).Forexample,onestudyfoundasecond-generationTBIIassay,whichutilizeshumanrecombinantTSHreceptors,tohaveaspeciﬁcityof99%andasensitivityof95%comparedtoasensitivityof68%foraﬁrst-generationassay(43).[B4]Symptomaticmanagement

RECOMMENDATION2

Beta-adrenergicblockadeshouldbegiventoelderlypa-tientswithsymptomaticthyrotoxicosisandtootherthyr-otoxicpatientswithrestingheartratesinexcessof90bpmorcoexistentcardiovasculardisease.1/++0

RECOMMENDATION3

Beta-adrenergicblockadeshouldbeconsideredinallpa-tientswithsymptomaticthyrotoxicosis.1/+00

Inpatientsinwhomthediagnosisofthyrotoxicosisisstronglysuspectedorconﬁrmed,treatmentwithpropran-olol,atenolol,metoprolol,orotherbeta-blockersleadstoadecreaseinheartrate,systolicbloodpressure,muscleweakness,andtremor,aswellasimprovementinthede-greeofirritability,emotionallability,andexerciseintoler-ance(24).

Technicalremarks:Sincethereisnotsufﬁcientbeta-1selec-tivityoftheavailablebeta-blockersattherecommendeddo-ses,thesedrugsaregenerallycontraindicatedinpatientswithbronchospasticasthma.However,inpatientswithquiescentbronchospasticasthmainwhomheartratecontrolisessential,orinpatientswithmildobstructiveairwaydiseaseorsymp-tomaticRaynaud’sphenomenon,anonselectivebeta-blockersuchasnadololcanbeusedcautiously,withcarefulmonitoringofpulmonarystatus.Occasionally,veryhighdosesofbeta-blockersarerequiredtomanagesymptomsofthyrotoxicosisandtoreducetheheartratetoneartheupperlimitofnormal(Table4)(26).Calciumchannelblockers,bothverapamilanddiltiazem,whenadministeredorallyandnotintravenously,havebeenshowntoeffectratecontrolinpatientswhodonottolerateorarenotcandidatesforbeta-adrenergicblockingagents.

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Table4.Beta-AdrenergicReceptorBlockadeintheTreatmentofThyrotoxicosis

DrugPropanololaDosage10–40mg

FrequencyTID-QID

Considerations

BAHNETAL.

AtenololMetoprololaNadolol

25–100mg25–50mg40–160mg

QDorBIDQIDQD

EsmololIVpump50–100mg/kg/min

Nonselectivebeta-adrenergicreceptorblockade

Longestexperience

MayblockT4toT3conversionathighdosesPreferredagentfornursingmothersRelativebetaÀ1selectivityIncreasedcompliance

RelativebetaÀ1selectivity

Nonselectivebeta-adrenergicreceptorblockadeOncedaily

Leastexperiencetodate

MayblockT4toT3conversionathighdosesInintensivecareunitsettingofseverethyrotoxicosisorstorm

Eachofthesedrugshasbeenapprovedfortreatmentofcardiovasculardiseases,buttodatenonehasbeenapprovedforthetreatmentofthyrotoxicosis.aAlsoavailableinoncedailypreparations.T4,thyroxine.

[C]HowshouldoverthyperthyroidismduetoGDbemanaged?

RECOMMENDATION4

PatientswithovertGraves’hyperthyroidismshouldbetreatedwithanyofthefollowingmodalities:131Itherapy,antithyroidmedication,orthyroidectomy.1/++0

Onceithasbeenestablishedthatthepatientishyperthy-roidandthecauseisGD,thepatientandphysicianmustchoosebetweenthreeeffectiveandrelativelysafeinitialtreat-mentoptions:131Itherapy(radioactiveiodine),antithyroiddrugs(ATD),orthyroidectomy(44).IntheUnitedStates,radioactiveiodinehasbeenthetherapymostpreferredbyphysicians.InEuropeandJapan,therehasbeenagreaterphysicianpreferenceforATDsand/orsurgery(45).Thelong-termqualityoflife(QoL)followingtreatmentforGDwasfoundtobethesameinpatientsrandomlyallocatedtooneofthethreetreatmentoptions(46).

Technicalremarks:Oncethediagnosishasbeenmade,thetreatingphysicianandpatientshoulddiscusseachofthetreatmentoptions,includingthelogistics,beneﬁts,expectedspeedofrecovery,drawbacks,potentialsideeffects,andcost.Thissetsthestageforthephysiciantomakerecommenda-tionsbasedonbestclinicaljudgmentandallowstheﬁnaldecisiontoincorporatethepersonalvaluesandpreferencesofthepatient.

FactorsthatfavoraparticularmodalityastreatmentforGraves’hyperthyroidism:a.

I:Femalesplanningapregnancyinthefuture(inmorethan4–6monthsfollowingradioiodinetherapy,providedthyroidhormonelevelsarenormal),individ-ualswithcomorbiditiesincreasingsurgicalrisk,andpatientswithpreviouslyoperatedorexternallyirradi-atednecks,orlackofaccesstoahigh-volumethyroidsurgeonorcontraindicationstoATDuse.

131b.ATDs:Patientswithhighlikelihoodofremission(pa-tients,especiallyfemales,withmilddisease,smallgoi-ters,andnegativeorlow-titerTRAb);theelderlyorotherswithcomorbiditiesincreasingsurgicalriskorwithlimitedlifeexpectancy;individualsinnursinghomesorothercarefacilitieswhomayhavelimitedlongevityandareunabletofollowradiationsafetyregulations;patientswithpreviouslyoperatedorirra-diatednecks;patientswithlackofaccesstoahigh-volumethyroidsurgeon;andpatientswithmoderatetosevereactiveGO.

c.Surgery:Symptomaticcompressionorlargegoiters(!80g);relativelylowuptakeofradioactiveiodine;whenthyroidmalignancyisdocumentedorsus-pected(e.g.,suspiciousorindeterminatecytology);largenonfunctioning,photopenic,orhypofunction-ingnodule;coexistinghyperparathyroidismrequir-ingsurgery;femalesplanningapregnancyin<4–6months(i.e.,beforethyroidhormonelevelswouldbenormalifradioactiveiodinewerechosenastherapy),especiallyifTRAblevelsareparticularlyhigh;andpatientswithmoderatetosevereactiveGO.

ContraindicationstoaparticularmodalityastreatmentforGraves’hyperthyroidism:

Itherapy:Deﬁnitecontraindicationsincludepreg-nancy,lactation,coexistingthyroidcancer,orsuspicionofthyroidcancer,individualsunabletocomplywithradiationsafetyguidelinesandfemalesplanningapregnancywithin4–6months.

b.ATDs:Deﬁnitecontraindicationstolong-termATDtherapyincludepreviousknownmajoradversereac-tionstoATDs.

c.Surgery:Factorsthatmaymitigateagainstthechoiceofsurgeryincludesubstantialcomorbiditysuchascardiopulmonarydisease,end-stagecancer,orothera.

131HYPERTHYROIDISMMANAGEMENTGUIDELINES

debilitatingdisorders.Pregnancyisarelativecontrain-dicationandshouldonlybeusedinthiscircumstance,whenrapidcontrolofhyperthyroidismisrequiredandantithyroidmedicationscannotbeused.Thyroidectomyisbestavoidedintheﬁrstandthirdtrimestersofpregnancybecauseofteratogeniceffectsassociatedwithanestheticagentsandincreasedriskoffetallossintheﬁrsttrimesterandincreasedriskofpretermlaborinthethird.Optimally,thyroidectomyisperformedinthelatterportionofthesecondtrimester.Althoughitisthesafesttime,itisnotwithoutrisk(4.5%–5.5%riskofpretermlabor)(47,48).

Factorsthatmayimpactpatientpreference:a.

131Itherapy:Patientschoosing131ItherapyastreatmentforGDwouldlikelyplacerelativelyhighervalueondeﬁnitivecontrolofhyperthyroidism,theavoidanceofsurgery,andthepotentialsideeffectsofantithyroidmedications,aswellasarelativelylowervalueontheneedforlifelongthyroidhormonereplacement,rapidresolutionofhyperthyroidism,andpotentialworseningordevelopmentofGO(49).

b.ATDs:PatientschoosingantithyroiddrugtherapyastreatmentforGDwouldplacerelativelyhighervalueonthepossibilityofremissionandtheavoidanceoflifelongthyroidhormonetreatment,theavoidanceofsurgery,andexposuretoradioactivityandarelativelylowervalueontheavoidanceofATDsideeffects(seesectionE),theneedforcontinuedmonitoringandthepossibilityofdiseaserecurrence.

c.Surgery:PatientschoosingsurgeryastreatmentforGDwouldlikelyplacearelativelyhighervalueonpromptanddeﬁnitivecontrolofhyperthyroidism,avoidanceofexposuretoradioactivity,andthepotentialsideeffectsofATDsandarelativelylowervalueonpotentialsurgicalrisksandneedforlifelongthyroidhormonereplacement.

[D]If131Itherapyischosen,howshoulditbeaccomplished?

[D1]PreparationofpatientswithGDfor

131Itherapy

RECOMMENDATION5

PatientswithGDwhoareatincreasedriskforcomplica-tionsduetoworseningofhyperthyroidism(i.e.,thosewhoareextremelysymptomaticorhavefreeT4estimates2–3timestheupperlimitofnormal)shouldbetreatedwithbeta-adrenergicblockadepriortoradioactiveiodinether-apy.1/+00

RECOMMENDATION6

PretreatmentwithmethimazolepriortoradioactiveiodinetherapyforGDshouldbeconsideredinpatientswhoareatincreasedriskforcomplicationsduetoworseningofhy-perthyroidism(i.e.,thosewhoareextremelysymptomaticorhavefreeT4estimate2–3timestheupperlimitofnor-mal).2/+00

Taskforceopinionwasnotunanimous;onepersonheldtheopinionthatpretreatmentwithmethimazoleisnotnecessaryinthissetting.

601

RECOMMENDATION7

Medicaltherapyofanycomorbidconditionsshouldbeoptimizedpriortoadministeringradioactiveiodine.1/+00

131Ihasbeenusedtotreathyperthyroidismforsixdecades.Thistherapyiswelltoleratedandcomplicationsarerare,ex-ceptforthoserelatedtoophthalmopathy(seesection[T].)Thyroidstormoccursonlyrarelyfollowingtheadministra-tionofradioactiveiodine(50,51).Inonestudyofpatientswiththyrotoxiccardiacdiseasetreatedwithradioactiveiodineasthesolemodality,noclinicalworseninginanyofthecardinalsymptomsofthyrotoxicosiswasseen(52).Thefrequencyofshort-termworseningofhyperthyroidismfollowingpre-treatmentwithATDtherapyisnotknown.However,theuseofmethimazole(MMI)orcarbimazole,thelatterofwhichisnotmarketedintheUnitedStates,beforeandafter131Itreat-mentmaybeconsideredinpatientswithseverethyrotoxicosis(i.e.,thosewhoareextremelysymptomaticorhavefreeT4estimates2–3timestheupperlimitofnormal),theelderly,andthosewithsubstantialcomorbiditythatputsthematgreaterriskforcomplicationsofworseninghyperthyroidism(53,54).Thelatterincludespatientswithcardiovascularcomplicationssuchasatrialﬁbrillation,heartfailure,orpul-monaryhypertensionandthosewithrenalfailure,infection,trauma,poorlycontrolleddiabetesmellitus,andcerebrovas-cularorpulmonarydisease(50).Thesecomorbidconditionsshouldbeaddressedwithstandardmedicalcareandthepa-tientrenderedmedicallystablebeforetheadministrationofradioactiveiodine.Inaddition,beta-adrenergicblockingdrugsshouldbeusedjudiciouslyinthesepatientsinprepa-rationforradioiodinetherapy(20,55).

OnecommitteememberfeltthatMMIuseisnotnecessaryinpreparation,asthereisinsufﬁcientevidenceforradioactiveiodineworseningeithertheclinicalorbiochemicalaspectsofhyperthyroidism,anditonlydelaystreatmentwithradioac-tiveiodine.Inaddition,thereisevidencethatMMIpretreat-mentmayreducetheefﬁcacyofsubsequentradioactiveiodinetherapy(6,52,56).

Technicalremarks:Ifgivenaspretreatment,MMIshouldbediscontinued3–5daysbeforetheadministrationofradioac-tiveiodine,restarted3–7dayslater,andgenerallytaperedover4–6weeksasthyroidfunctionnormalizes.Overseveraldecades,therehavebeenreportsthatpretreatmentwithlithiumreducestheactivityof131InecessaryforcureofGraves’hyperthyroidismandmaypreventthethyroidhor-moneincreaseseenuponATDwithdrawal(57–59).However,thisisnotusedwidely,andthereisinsufﬁcientevidencetorecommendthepractice.[D2]Administrationof

131IinthetreatmentofGD

RECOMMENDATION8

Sufﬁcientradiationshouldbeadministeredinasingledose(typically10–15mCi)torenderthepatientwithGDhy-pothyroid.1/++0

RECOMMENDATION9

Apregnancytestshouldbeobtainedwithin48hourspriortotreatmentinanyfemalewithchildbearingpotentialwhoistobetreatedwithradioactiveiodine.Thetreating

602

physicianshouldobtainthistestandverifyanegativere-sultpriortoadministeringradioactiveiodine.1/+00Thegoalof131Iistocontrolhyperthyroidismbyrenderingthepatienthypothyroid;thistreatmentisveryeffective,providedsufﬁcientradiationisdepositedinthethyroid.Thiscanbeaccomplishedequallywellbyeitheradministeringaﬁxedactivityorbycalculatingtheactivitybasedonthesizeofthethyroidanditsabilitytotrapiodine(44).Theﬁrstmethodissimple,andthereisevidencethat10mCi(370MBq)resultsinhypothyroidismin69%(representingcure)at1year(60)and15mCi(450MBq)resultsinhypothyroidismin75%at6months(61).Thesecondmethodrequiresthreeunknownstobedetermined:theuptakeofradioactiveiodine,thesizeofthethyroid,andthequantityofradiation(mCiorBq)tobedepositedpergram(orcc)ofthyroid(e.g.,activity(mCi)¼glandweight(g)Â150mCi/gÂ[1/24houruptakeon%ofdose]).TheactivityinmCiisconvertedtomCibydividingtheresultby1000.Themostfrequentlyuseduptakeiscal-culatedat24hours,andthesizeofthethyroidisdeterminedbypalpationorultrasound.Onestudyfoundthatthisesti-matebyexperiencedphysiciansisaccuratecomparedwithanatomicimaging(62);however,otherinvestigatorshavenotconﬁrmedthisobservation131(63).ThereiswidevariationintherecommendedquantityofIthatshouldbedeposited(i.e.,between50and200mCi/g).Historically,activitiesatthelowendofthespectrumhaveledtoahigherproportionoftreat-mentfailures(41).

Alternately,amoredetailedcalculationcanbemadetodepositaspeciﬁcnumberofradiationabsorbeddose(rad)orGytothethyroid.Usingthisapproach,itisalsonecessarytoknowtheeffectivehalf-lifeofthe131I(44).Thisrequiresad-ditionaltimeandcomputationand,becausetheoutcomeisnotbetter,thismethodisseldomusedintheUnitedStates.Evidenceshowsthattoachieveahypothyroidstate,>150mCi/gneedstobedelivered(61,64,65).Patientswhoareondialysisorwhohavejejunostomyorgastricfeedingtubesrequirespecialcarewhenbeingadministeredtherapeuticdosesofradioiodine(66).

Propylthiouracil(PTU)treatmentbefore131Iincreasestheradioresistanceofthethyroid(51,67).WhetherMMImayhave131thesameeffectisunclear(51).UseofhigheractivitiesofImayoffsetthereducedeffectivenessof131Itherapyfol-lowingantithyroidmedication(53,54).Aspecialdietisnotrequiredbeforeradioactiveiodinetherapy,butexcessiveamountsofiodine,includingiodine-containingmultivita-mins,shouldbeavoidedforatleast7days.Alow-iodinedietmaybeusefulforthosewithrelativelylowRAIUtoincreasetheproportionofradioactiveiodinetrapped.

Along-termincreaseincardiovascularandcerebrovascu-lardeathshasbeenreportedafter131Itherapy,likelyduetothehyperthyroidismratherthanthetreatment(56).Whilethisstudyalsofoundasmallincreaseincancermortality,long-termstudiesoflargernumbersofpatientshavenotshownastatisticallysigniﬁcantincreaseincancerdeathsfollowingthistreatment(68–74).Insomemen,thereisamodestfallinthetestosteronetoluteinizinghormone(LH)ratioafter131Ither-apythatissubclinicalandreversible(75).Conceptionshouldbedelayedfor4–6monthsinwomentoassurestableeu-thyroidism(onthyroidhormonereplacementfollowingsuc-cessfulthyroidablation)and3–4monthsinmentoallowforturnoverofspermproduction.However,oncethepatient

BAHNETAL.

(bothgenders)iseuthyroid,thereisnoevidenceofreducedfertilityandoffspringoftreatedpatientsshownocongenitalanomaliescomparedtothepopulationatlarge.

Technicalremarks:Renderingthepatienthypothyroidcanbeaccomplishedequallywellbyadministeringeitherasuf-ﬁcientﬁxedactivityorcalculatinganactivitybasedonthesizeof131thethyroidanditsabilitytotrapiodine.FetusesexposedtoIafterthe10thto11thweekofgestationmaybebornathyreotic(76,77)andarealsoatatheoreticalincreasedriskforreducedintelligenceand/orcancer.Inbreast-feedingwomen,radioactiveiodinetherapyshouldnotbeadminis-teredforatleast6weeksafterlactationstopstoensurethattheradioactivitywillnolongerbeactivelyconcentratedinthebreasttissues.

RECOMMENDATION10

Thephysicianadministeringtheradioactiveiodineshouldprovidewrittenadviceconcerningradiationsafetypre-cautionsfollowingtreatment.Iftheprecautionscannotbefollowed,alternativetherapyshouldbeselected.1/+00

Allnationalandregionalradiationprotectionrulesre-gardingradioactiveiodinetreatmentshouldbefollowed(78).IntheUnitedStates,thetreatingphysicianmustensureanddocumentthatnoadultmemberofthepublicisexposedto0.5mSv(500milli-roentgenequivalentinman[mrem])whenthepatientisdischargedwitharetainedactivityof33mCi(1.22GBq)orgreater,oremits!7mrem/h(70mSv/h)at1m.Technicalremarks:Continuityoffollow-upshouldbepro-videdandcanbefacilitatedbywrittencommunicationbetweenthereferringphysicianandthetreatingphysician,includingarequestfortherapyfromtheformerandastatementfromthelatterthatthetreatmenthasbeenadministered.[D3]Patientfollow-upafter

131ItherapyforGD

RECOMMENDATION11

Follow-upwithintheﬁrst1–2monthsafterradioactiveiodinetherapyforGDshouldincludeanassessmentoffreeT4andtotalT3.Ifthepatientremainsthyrotoxic,bio-chemicalmonitoringshouldbecontinuedat4–6weekin-tervals.1/+00

Mostpatientsrespondtoradioactiveiodinetherapywithanormalizationofthyroidfunctiontestsandclinicalsymptomswithin4–8weeks.Hypothyroidismmayoccurfrom4weekson,butmorecommonlybetween2and6months,andthetimingofthyroidhormonereplacementtherapyshouldbedeterminedbyresultsofthyroidfunctiontests,clinicalsymptoms,andphysicalexamination.Transienthypothy-roidismfollowingradioactiveiodinetherapycanrarelyoccur,withsubsequentcompleterecoveryofthyroidfunctionorrecurrenthyperthyroidism(79).Whenthyroidhormonereplacementisinitiated,thedoseshouldbeadjustedbasedonanassessmentoffreeT4.Therequireddosemaybelessthanthetypicalfullreplacement,andcarefultitrationisnec-essaryowingtononsuppressibleresidualthyroidfunction.Overthypothyroidismshouldbeavoided,especiallyinpa-

HYPERTHYROIDISMMANAGEMENTGUIDELINEStientswithactiveGO(seesectionT2).Onceeuthyroidismisachieved,lifelongannualthyroidfunctiontestingisrecommended.

Technicalremarks:SinceTSHlevelsmayremainsuppressedforamonthorlongerafterhyperthyroidismresolves,thelevelsshouldbeinterpretedcautiouslyandonlyinconcertwithfreeT4andT3estimates.

[D4]TreatmentofpersistentGraves’hyperthyroidismfollowingradioactiveiodinetherapy

RECOMMENDATION12

WhenhyperthyroidismduetoGDpersistsafter6monthsfollowing131Itherapy,orifthereisminimalresponse3monthsaftertherapy,retreatmentwith131Iissuggested.2/+00

Technicalremarks:Responsetoradioactiveiodinecanbeas-sessedbymonitoringthesizeofthegland,thyroidfunction,andclinicalsignsandsymptoms.Thegoalofretreatmentistocontrolhyperthyroidismwithcertaintybyrenderingthepa-tienthypothyroid.Patientswhohavepersistent,suppressedTSHwithnormaltotalT3andfreeT4estimatesmaynotrequireimmediateretreatmentbutshouldbemonitoredcloselyforeitherrelapseordevelopmentofhypothyroidism.Inthesmallpercentageofpatientswithhyperthyroidismrefractorytoseveralapplicationsof131I,surgerycouldbeconsidered(80).[E]IfantithyroiddrugsarechosenasinitialmanagementofGD,howshouldthetherapybemanaged?

ATDshavebeenemployedforsixdecades(81).Thegoalofthetherapyistorenderthepatienteuthyroidasquicklyandsafelyaspossible.ThesemedicationsdonotcureGraves’hyperthyroidism.However,whengiveninadequatedoses,theyareveryeffectiveincontrollingthehyperthyroidism;whentheyfailtoachieveeuthyroidism,theusualcauseisnonadherence(82).Thetreatmentmighthaveabeneﬁcialimmunosuppressiverole,butthemajoreffectistoreducetheproductionofthyroidhormonesandmaintainaeuthyroidstatewhileawaitingaspontaneousremission.

[E1]InitiationofantithyroiddrugtherapyforthetreatmentofGD

RECOMMENDATION13

MethimazoleshouldbeusedinvirtuallyeverypatientwhochoosesantithyroiddrugtherapyforGD,exceptduringtheﬁrsttrimesterofpregnancywhenpropylthiouracilispre-ferred,inthetreatmentofthyroidstorm,andinpatientswithminorreactionstomethimazolewhorefuseradioac-tiveiodinetherapyorsurgery.1/++0

RECOMMENDATION14

Patientsshouldbeinformedofsideeffectsofantithyroiddrugsandthenecessityofinformingthephysicianpromptlyiftheyshoulddeveloppruriticrash,jaundice,acolicstoolsordarkurine,arthralgias,abdominalpain,nausea,fatigue,fever,orpharyngitis.Beforestartinganti-thyroiddrugsandateachsubsequentvisit,thepatient

603

shouldbealertedtostopthemedicationimmediatelyandcalltheirphysicianwhentherearesymptomssuggestiveofagranulocytosisorhepaticinjury.1/+00

RECOMMENDATION15

PriortoinitiatingantithyroiddrugtherapyforGD,wesuggestthatpatientshaveabaselinecompletebloodcount,includingwhitecountwithdifferential,andaliverproﬁleincludingbilirubinandtransaminases.2/+00

IntheUnitedStates,MMIandPTUareavailable,andinsomecountries,carbimazole,aprecursorofMMI,iswidelyused.MMIandcarbimazole,whichisrapidlyconvertedtoMMIintheserum(10mgofcarbimazoleismetabolizedtoapproximately6mgofMMI),workinavirtuallyidenticalfashionandwillbothbereferredtoasMMIinthistext.Bothareeffectiveasasingledailydose.AtthestartofMMIther-apy,higherdosesareadvised(10–20mgdaily)torestoreeuthyroidism,followingwhichthedosecanbetitratedtoamaintenancelevel(generally5–10mgdaily)(81,83).MMIhasthebeneﬁtofonce-a-dayadministrationandareducedriskofmajorsideeffectscomparedtoPTU.PTUhasashorterdu-rationofactionandisusuallyadministeredtwoorthreetimesdaily,startingwith50–150mgthreetimesdaily,dependingontheseverityofthehyperthyroidism.Astheclinicalﬁnd-ingsandthyroidfunctiontestsreturntonormal,reductiontoamaintenancePTUdoseof50mgtwoorthreetimesdailyisusuallypossible.Higherdosesofantithyroidmedicationaresometimesadministeredcontinuouslyandcombinedwithl-thyroxineindosestomaintaineuthyroidlevels(so-calledblockandreplacetherapy).However,thisapproachisnotgenerallyrecommended,asithasbeenshowntoresultinahigherrateofATDsideeffects(81,84).

PTUmayrarelycauseagranulocytosis,whereaslowdosesofMMImaybelesslikelytodoso(85,86).PTUveryinfre-quentlycausesantineutrophilcytoplasmicantibody(ANCA)-positivesmallvesselvasculitis(87,88),withariskthatappearstoincreasewithtimeasopposedtootheradverseeffectsseenwithATDsthattypicallyoccurearlyinthecourseoftreatment(89,90).PTUcancausefulminanthepaticnecrosisthatmaybefatal;livertransplantationhasbeennecessaryinsomepa-tientstakingPTU(91).ItisforthisreasonthattheFDAre-centlyissuedasafetyalertregardingtheuseofPTU,notingthat32(22adultand10pediatric)casesofseriousliverinjuryhavebeenassociatedwithPTUuse(92,93).

MMIhepatotoxicityistypicallycholestatic,buthepatocel-lulardiseasemayrarelybeseen(94,95).AplasiacutisofthescalpisrarelyfoundinbabiesborntomotherstakingMMI(96).MMItakenbythemotherintheﬁrsttrimesterisalsoassociatedwithasyndromeofMMIembryopathy,includingchoanalandesophagealatresia(97,98).Arthropathyandalupus-likesyn-dromerarelycanoccurwitheitherMMIorPTU.

Technicalremarks:Baselinebloodteststoaidintheinter-pretationoffuturelaboratoryvaluesshouldbeconsideredbeforeinitiatingantithyroiddrugtherapy.ThisissuggestedinpartbecauselowwhitecellcountsarecommoninpatientswithautoimmunediseasesandinAfricanAmericans,andabnormalliverenzymesarefrequentlyseeninpatientswiththyrotoxicosis.Inaddition,abaselineabsoluteneutro-philcount<500/mm3orlivertransaminaseenzymelevelselevatedmorethanﬁvefoldtheupperlimitofnormalare

604

contraindicationstoinitiatingantithyroiddrugtherapy.ItisadvisabletoprovideinformationconcerningsideeffectsofATDstothepatientbothverballyandinwritingtoassuretheircomprehension,anddocumentthatthishasbeendone.ThisinformationcanbefoundontheUpToDateWebsite(99).[E2]MonitoringofpatientstakingantithyroiddrugsThereisaneedforperiodicclinicalandbiochemicaleval-uationofthyroidstatusinpatientstakingATDs,anditisessentialthatthepatientunderstanditsimportance.Anas-sessmentofserumfreeT4shouldbeobtainedabout4weeksafterinitiationoftherapy,andthedoseofmedicationadjustedaccordingly.SerumT3alsomaybemonitored,sincetheesti-matedserumfreeT4levelsmaynormalizewithpersistentelevationofserumT3.Appropriatemonitoringintervalsareevery4–8weeksuntileuthyroidlevelsareachievedwiththeminimaldoseofmedication.Oncethepatientiseuthyroid,biochemicaltestingandclinicalevaluationcanbeundertakenatintervalsof2–3months.AnassessmentofserumfreeT4andTSHarerequiredbeforetreatmentandatintervalsafterstartingthetreatment.SerumTSHmayremainsuppressedforseveralmonthsafterstartingtherapyandisthereforenotagoodparametertomonitortherapyearlyinthecourse.

RECOMMENDATION16

Adifferentialwhitebloodcellcountshouldbeobtainedduringfebrileillnessandattheonsetofpharyngitisinallpatientstakingantithyroidmedication.Routinemonitor-ingofwhitebloodcountsisnotrecommended.1/+00

Thereisnoconsensusconcerningtheutilityofperiodicmonitoringofwhitebloodcellcountsandliverfunctiontestsinpredictingearlyonsetofadversereactiontothemedication(100).Whileroutinemonitoringofwhitebloodcellcountsmaydetectearlyagranulocytosis,thispracticeisnotlikelytoidentifycases,asthefrequencyisquitelow(0.2%–0.5%)andtheconditionsuddeninonset.Becausepatientsaretypicallysymptomatic,measuringwhitebloodcellcountsduringfe-brileillnessesandattheonsetofpharyngitishasbeenthestandardapproachtomonitoring.Inapatientdevelopingagranulocytosisorotherserioussideeffectswhiletakingei-therMMIorPTU,useoftheothermedicationisabsolutelycontraindicatedowingtoriskofcross-reactivitybetweenthetwomedications(101).

RECOMMENDATION17

Liverfunctionandhepatocellularintegrityshouldbeas-sessedinpatientstakingpropylthiouracilwhoexperiencepruriticrash,jaundice,light-coloredstoolordarkurine,jointpain,abdominalpainorbloating,anorexia,nausea,orfatigue.1/+00

Hyperthyroidismcanitselfcausemildlyabnormalliverfunctiontests,andPTUmaycausetransientelevationsofserumtransaminasesinuptoone-thirdofpatients.Signiﬁcantelevationstothreefoldabovetheupperlimitofnormalareseeninupto4%ofpatientstakingPTU(102),aprevalencehigherthanwithMMI.Asnotedabove,PTUcanalsocausefatalhepaticnecrosis,leadingtothesuggestionbysomethatpatientstakingthisATDhaveroutinemonitoringoftheirliverfunction,especiallyduringtheﬁrst6monthsoftherapy.

BAHNETAL.

Itisdifﬁculttodistinguishtheseabnormalitiesfromtheeffectofpersistentthyrotoxicosisunlesstheyarefollowedprospec-tively.Inpatientswithimprovingthyrotoxicosis,arisingal-kalinephosphatasewithnormalizationofotherliverfunctiondoesnotindicateworseninghepatictoxicity.TheonsetofPTU-inducedhepatotoxicitymaybeacute,difﬁculttoappreciateclinically,andrapidlyprogressive.Ifnotrecognized,itcanleadtoliverfailureanddeath(92,103–105).Routinemonitoringofliverfunctioninallpatientstakingantithyroidmedicationhasnotbeenfoundtopreventseverehepatotoxicity.

Technicalremarks:PTUshouldbediscontinuediftrans-aminaselevels(eitherelevatedatonsetoftherapy,foundincidentallyormeasuredasclinicallyindicated)reach2–3timestheupperlimitofnormalandfailtoimprovewithin1weekwithrepeattesting.Afterdiscontinuingthedrug,liverfunctiontestsshouldbemonitoredweeklyuntilthereisevidenceofresolution.Ifresolutionisnotevident,promptreferraltoagastroenterologistorhepatologistiswarranted.ExceptincasesofseverePTU-inducedhepatotoxicity,MMIcanbeusedtocontrolthethyrotoxicosiswithoutilleffect(106,107).

[E3]Managementofallergicreactions

RECOMMENDATION18

Minorcutaneousreactionsmaybemanagedwithconcur-rentantihistaminetherapywithoutstoppingtheantithy-roiddrug.Persistentminorsideeffectsofantithyroidmedicationshouldbemanagedbycessationofthemedi-cationandchangingtoradioactiveiodineorsurgery,orswitchingtotheotherantithyroiddrugwhenradioactiveiodineorsurgeryarenotoptions.Inthecaseofaseriousallergicreaction,prescribingthealternativedrugisnotrecommended.1/+00

Minorallergicsideeffects,suchasalimited,minorrash,mayoccurinupto5%ofpatientstakingeitherMMIorPTU(81).[E4]DurationofantithyroiddrugtherapyforGD

RECOMMENDATION19

IfmethimazoleischosenastheprimarytherapyforGD,themedicationshouldbecontinuedforapproximately12–18months,thentaperedordiscontinuediftheTSHisnormalatthattime.1/+++

RECOMMENDATION20

MeasurementofTRAblevelspriortostoppingantithyroiddrugtherapyissuggested,asitaidsinpredictingwhichpatientscanbeweanedfromthemedication,withnormallevelsindicatinggreaterchanceforremission.2/+00&

RECOMMENDATION21

IfapatientwithGDbecomeshyperthyroidaftercomplet-ingacourseofmethimazole,considerationshouldbegiventotreatmentwithradioactiveiodineorthyroidectomy.Low-dosemethimazoletreatmentforlongerthan12–18monthsmaybeconsideredinpatientsnotinremissionwhopreferthisapproach.2/+00

HYPERTHYROIDISMMANAGEMENTGUIDELINESApatientisconsideredtobeinremissioniftheyhavehadanormalserumTSH,FT4,andT3for1yearafterdiscontinuationofATDtherapy.Theremissionratevariesconsiderablybe-tweengeographicalareas.IntheUnitedStates,about20%–30%ofpatientswillhavealastingremissionafter12–18monthsofmedication(44).TheremissionrateappearstobehigherinEuropeandJapan;along-termEuropeanstudyindicateda50%–60%remissionrateafter5–6yearsoftreatment(108).Ameta-analysisshowstheremissionrateinadultsisnotim-provedbyacourseofATDslongerthan18months(84).Alowerremissionratehasbeendescribedinmen,smokers(es-peciallymen),andthosewithlargegoiters(!80g)(109–113).PersistentlyhighlevelsofTRAbandhighthyroidbloodﬂowidentiﬁedbycolorDopplerultrasoundarealsoassociatedwithhigherrelapserates(112,114–116),andthesepatientsshouldbeassessedmorefrequentlyandatshorterintervalsafteranti-thyroiddrugsarediscontinued.Conversely,patientswithmilddisease,smallgoiters,andnegativeTRAbhavearemissionrateover50%,makingtheuseofantithyroidmedicationspoten-tiallymorefavorableinthisgroupofpatients(117).

Technicalremarks:WhenMMIisdiscontinued,thyroidfunctiontestingshouldcontinuetobemonitoredat1–3-monthintervalsfor6–12monthstodiagnoserelapseearly.Thepatientshouldbecounseledtocontactthetreatingphy-sicianifsymptomsofhyperthyroidismarerecognized.[F]IfthyroidectomyischosenfortreatmentofGD,howshoulditbeaccomplished?

[F1]PreparationofpatientswithGDforthyroidectomy

RECOMMENDATION22

Wheneverpossible,patientswithGDundergoingthy-roidectomyshouldberenderedeuthyroidwithmethima-zole.Potassiumiodideshouldbegivenintheimmediatepreoperativeperiod.1/+00

RECOMMENDATION23

Inexceptionalcircumstances,whenitisnotpossibletoren-derapatientwithGDeuthyroidpriortothyroidectomy,theneedforthyroidectomyisurgent,orwhenthepatientisal-lergictoantithyroidmedication,thepatientshouldbeade-quatelytreatedwithbeta-blockadeandpotassiumiodideintheimmediatepreoperativeperiod.Thesurgeonandanes-thesiologistshouldhaveexperienceinthissituation.1/+00

Thyroidstormmaybeprecipitatedbythestressofsurgery,anesthesia,orthyroidmanipulationandmaybepreventedbypretreatmentwithATDs.Wheneverpossible,thyrotoxicpa-tientswhoareundergoingthyroidectomyshouldberenderedeuthyroidbyMMIbeforeundergoingsurgery.Preoperativepotassiumiodide,saturatedsolutionofpotassiumiodide(SSKI)orinorganiciodine,shouldbeusedbeforesurgeryinmostpatientswithGD.Thistreatmentisbeneﬁcialasitde-creasesthyroidbloodﬂow,vascularity,andintraoperativebloodlossduringthyroidectomy(118,119).Inaddition,rapidpreparationforemergentsurgerycanbefacilitatedbytheuseofcorticosteroids(120).

Technicalremarks:Potassiumiodidecanbegivenas5–7drops(0.25–0.35mL)Lugol’ssolution(8mgiodide/drop)or

605

1–2drops(0.05–0.1mL)SSKI(50mgiodide/drop)threetimesdailymixedinwaterorjuicefor10daysbeforesurgery.[F2]Thesurgicalprocedureandchoiceofsurgeon

RECOMMENDATION24

IfsurgeryischosenastheprimarytherapyforGD,near-totalortotalthyroidectomyistheprocedureofchoice.1/++0

Thyroidectomyhasahighcurerateforthehyperthyroid-ismofGD.Totalthyroidectomyhasanearly0%riskofre-currence,whereassubtotalthyroidectomymayhavean8%chanceofpersistenceorrecurrenceofhyperthyroidismat5years(121).

Themostcommoncomplicationsfollowingnear-totalortotalthyroidectomyarehypocalcemia(whichcanbetransientorpermanent),recurrentorsuperiorlaryngealnerveinjury(whichcanbetemporaryorpermanent),postoperativebleeding,andcomplicationsrelatedtogeneralanesthesia.

RECOMMENDATION25

IfsurgeryischosenastheprimarytherapyforGD,thepatientshouldbereferredtoahigh-volumethyroidsur-geon.1/++0

Improvedpatientoutcomehasbeenshowntobeinde-pendentlyassociatedwithhighthyroidectomysurgeonvol-ume;speciﬁcally,complicationrate,lengthofhospitalstay,andcostarereducedwhentheoperationisperformedbyasurgeonwhoconductsmanythyroidectomies.Asigniﬁcantassociationisseenbetweenincreasingthyroidectomyvolumeandimprovedpatientoutcome;theassociationisrobustandismorepronouncedwithanincreasingnumberofthyroid-ectomies(122,123).

Thesurgeonshouldbethoroughlytrainedintheproce-dure,haveanactivepracticeinthyroidsurgery,andhaveconductedasigniﬁcantnumberofthyroidectomieswithalowfrequencyofcomplications.Thereisarobust,statisticallysigniﬁcantassociationbetweenincreasingsurgeonvolumeandsuperiorpatientoutcomesforthyroidectomy.Datashowthatsurgeonswhoperformmorethan30thyroidsurgeriesperyearhavesuperiorpatientclinicalandeconomicout-comescomparedtothosewhoperformfewer,andsurgeonswhoperformatleast100peryearhavestillbetteroutcomes(46,123).FollowingthyroidectomyforGDinthehandsofhigh-volumethyroidsurgeons,therateofpermanenthypo-calcemiahasbeendeterminedtobe<2%,andpermanentrecurrentlaryngealnerve(RLN)injuryoccursin<1%(124).Thefrequencyofbleedingnecessitatingreoperationis0.3%–0.7%(125).Mortalityfollowingthyroidectomyisbetween1in10,000and5in1,000,000(126).[F3]Postoperativecare

RECOMMENDATION26

FollowingthyroidectomyforGD,wesuggestthatserumcalciumorintactparathyroidhormonelevelsbemeasured,andthatoralcalciumandcalcitriolsupplementationbeadministeredbasedontheseresults.2/+00

Successfulpredictionofcalciumstatusaftertotalthyroid-ectomycanbeachievedusingtheslopeof6-and12-hour

606

postoperativecalciumlevelsorthepostoperativeintactparathyroidhormone(iPTH)level(127–132).Patientscanbedischargediftheyareasymptomaticandtheirserumcalciumlevelsare7.8mg/dL(1.95mmol/L)oraboveandarenotfalling(133).Theuseofionizedcalciummeasurements(orserumcalciumcorrectedforalbuminlevel)arepreferredbysome,andareessentialifthepatienthasabnormallevelsofserumproteins.LowiPTHlevels(<10–15pg/mL)intheim-mediatepostoperativesettingappeartopredictsymptomatichypocalcemiaandneedforcalciumandcalcitriol(1,25vita-minD)supplementation(134,135).

Postoperativeroutinesupplementationwithoralcal-ciumandcalcitrioldecreasesdevelopmentofhypocalcemicsymptomsandintravenouscalciumrequirement,allowingforsaferearlydischarge(136).Intravenouscalciumgluconateshouldbereadilyavailableandmaybeadministeredifpa-tientshaveworseninghypocalcemicsymptomsdespiteoralsupplementationand/ortheirconcomitantserumcalciumlevelsarefallingdespiteoralrepletion.Persistenthypocalce-miainthepostoperativeperiodshouldpromptmeasurementofserummagnesiumandpossiblemagnesiumrepletion(137,138).Followingdischarge,serumiPTHlevelsshouldbemeasuredinthesettingofpersistenthypocalcemiatodeter-mineifpermanenthypoparathyroidismistrulypresentorwhether‘‘bonehunger’’isongoing.IfthelevelofcirculatingiPTHisappropriateforthelevelofserumcalcium,calciumandcalcitrioltherapycanbetapered.

Technicalremarks:Prophylacticcalciumsupplementationcanbeaccomplishedwithoralcalcium(usuallycalciumcar-bonate,1250–2500mg)fourtimesdaily,taperedby500mgevery2days,or1000mgevery4daysastolerated.Inaddi-tion,calcitriolmaybestartedatadoseof0.5mcgdailyandcontinuedfor1–2weeks(133)andincreasedortaperedaccordingtothecalciumand/oriPTHlevel.Patientscanbedischargediftheyareasymptomaticandhavestableserumcalciumlevels.Postoperativeevaluationisgenerallycon-ducted1–2weeksfollowingdismissalwithcontinuationofsupplementationbasedonclinicalparameters.

RECOMMENDATION27

Antithyroiddrugsshouldbestoppedatthetimeofthy-roidectomyforGD,andbeta-adrenergicblockersshouldbeweanedfollowingsurgery.1/+00

RECOMMENDATION28

FollowingthyroidectomyforGD,L-thyroxineshouldbestartedatadailydoseappropriateforthepatient’sweight(0.8mg/lbor1.7mg/kg),andserumTSHmeasured6–8weekspostoperatively.1/+00

Technicalremarks:Oncestableandnormal,TSHshouldbemeasuredannuallyormorefrequentlyifclinicallyindicated.[G]HowshouldthyroidnodulesbemanagedinpatientswithGD?

RECOMMENDATION29

IfathyroidnoduleisdiscoveredinapatientwithGD,thenoduleshouldbeevaluatedandmanagedaccordingtorecentlypublishedguidelinesregardingthyroidnodulesineuthyroidindividuals.1/++0

BAHNETAL.

ThyroidcanceroccursinGDwithafrequencyof2%orless(139).Thyroidnoduleslargerthan1–1.5cmshouldbeeval-uatedbeforeradioactiveiodinetherapy.Ifaradioactiveiodinescanisperformed,anynonfunctioningorhypo-functioningnodulesshouldbeconsideredforﬁneneedleas-piration(FNA),asthesemayhaveahigherprobabilityofbeingmalignant(46).Ifthecytopathologyisindeterminate(suspicious)orisdiagnosticofmalignancy,surgeryisadvisedafternormalizationofthyroidfunctionwithATDs.Disease-freesurvivalat20yearsisreportedtobe99%afterthyroid-ectomyforGDinpatientswithsmall( 1cm)coexistingthyroidcancers(140).

TheuseofthyroidultrasonographyinallpatientswithGDhasbeenshowntoidentifymorenodulesandcancerthandoespalpationand123Iscintigraphy.However,sincemostofthesecancersarepapillarymicrocarcinomaswithminimalclinicalimpact,furtherstudyisrequiredbeforeroutineultrasound(andthereforesurgery)canberecommended(141,142).Technicalremarks:BoththeATAandAACE,thelatterinconjunctionwiththeEuropeanThyroidAssociationandAs-sociazioneMediciEndocrinologi,haverecentlypublishedupdatedmanagementguidelinesforpatientswiththyroidnodules(143,144).

[H]Howshouldthyroidstormbemanaged?

RECOMMENDATION30

Amultimodalitytreatmentapproachtopatientswiththyroidstormshouldbeused,includingbeta-adrenergicblockade,antithyroiddrugtherapy,inorganiciodide,corti-costeroidtherapy,aggressivecoolingwithacetaminophenandcoolingblankets,volumeresuscitation,respiratorysupportandmonitoringinanintensivecareunit.1/+00

Life-threateningthyrotoxicosisorthyroidstormisarare,occasionallyiatrogenicdisordercharacterizedbymultisysteminvolvementandahighmortalityrateifnotimmediatelyrec-ognizedandtreatedaggressively(20).Ahighindexofsuspicionforthyroidstormshouldbemaintainedinpatientswiththy-rotoxicosisassociatedwithanyevidenceofsystemicdecom-pensation.Precisecriteriaforthyroidstormhavebeendeﬁned(Table5)(21)andincludetachycardia,arrhythmias,congestiveheartfailure,hypotension,hyperpyrexia,agitation,delirium,psychosis,stuporandcoma,aswellasnausea,vomiting,di-arrhea,andhepaticfailure.Precipitantsofthyroidstorminapatientwithpreviouslycompensatedthyrotoxicosisincludeabruptcessationofantithyroiddrugs,thyroid,ornonthyroidalsurgeryinapatientwithunrecognizedorinadequatelytreatedthyrotoxicosis,andanumberofacuteillnessesunrelatedtothyroiddisease(145).Thyroidstormalsooccursrarelyfollow-ingradioactiveiodinetherapy.Exposuretoiodinefromtheuseofiodine-containingcontrastagentsmaybeanadditionalfactorinthedevelopmentofthyroidstorminpatientswithillnessesunrelatedtothyroiddisease.Eachpharmacologicallyaccessiblestepinthyroidhormoneproductionandactionistargetedinthetreatmentofpatientswiththyroidstorm(Table6).

Technicalremarks:Treatmentwithinorganiciodine(SSKI/Lugol’ssolution,ororalradiographiccontrast)leadstorapiddecreasesinbothT4andT3levelsandcombinedwithantithy-

HYPERTHYROIDISMMANAGEMENTGUIDELINES

Table5.PointScalefortheDiagnosisofThyroidStorm

Criteria

ThermoregulatorydysfunctionTemperature(8F)99.0–99.9100.0–100.9101.0–101.9102.0–102.9103.0–103.9!104.0Cardiovascular

Tachycardia(beatsperminute)100–109110–119120–129130–139!140

AtrialﬁbrillationAbsentPresent

CongestiveheartfailureAbsentMild

ModerateSevereScorestotaled>4525–44<25

Points

Criteria

Gastrointestinal-hepaticdysfunctionManifestationAbsent

Moderate(diarrhea,abdominalpain,nausea/vomiting)Severe(jaundice)

607

Points

51015202530

01020

510152025010051020

ThyroidstormImpendingstormStormunlikely

CentralnervoussystemdisturbanceManifestationAbsent

Mild(agitation)

Moderate(delirium,psychosis,extremelethargy)Severe(seizure,coma)

0102030

PrecipitanthistoryStatusPositiveNegative

010

Source:BurchandWartofsky,1993(21).Printedwithpermission.

roidmedication,resultsinrapidcontrolofGraves’hyperthy-roidism,andcanaidinseverelythyrotoxicpatients(146).Un-fortunately,theoralradiographiccontrastagentsipodateandiopanoicacidarenotcurrentlyavailableinmanycountries.[I]HowshouldoverthyperthyroidismduetoTMNGorTAbemanaged?

occasion,long-term,low-dosetreatmentwithmethimazolemaybeappropriate.2/++0

Therearetwoeffectiveandrelativelysafetreatmentop-tions,131Itherapyandthyroidectomy.Thedecisionregardingtreatmentshouldtakeintoconsiderationanumberofclinicalanddemographicfactors,aswellaspatientpreference.Thegoaloftherapyistherapidanddurableeliminationofthehyperthyroidstate.

ForpatientswithTMNG,theriskoftreatmentfailureorneedforrepeattreatmentis<1%followingnear-total/total

RECOMMENDATION31

WesuggestthatpatientswithovertlyTMNGorTAbetreatedwitheither131Itherapyorthyroidectomy.On

Table6.ThyroidStorm:DrugsandDoses

Drug

PropylthiouracilMethimazolePropranololaDosing

500–1000mgload,then250mgevery4hours60–80mg/day

60–80mgevery4hours

Comment

BlocksnewhormonesynthesisBlocksT4-to-T3conversionBlocksnewhormonesynthesis

Considerinvasivemonitoringincongestiveheartfailurepatients

BlocksT4-to-T3conversioninhighdosesAlternatedrug:esmololinfusion

Donotstartuntil1hourafterantithyroiddrugsBlocksnewhormonesynthesisBlocksthyroidhormonereleaseMayblockT4-to-T3conversion

ProphylaxisagainstrelativeadrenalinsufﬁciencyAlternativedrug:dexamethasone

Iodine(saturatedsolutionofpotassiumiodide)Hydrocortisone

5drops(0.25mLor250mg)orallyevery6hours

300mgintravenousload,then100mgevery8hours

aMaybegivenintravenously.

608

thyroidectomy(147,148),comparedwitha20%riskoftheneedforretreatmentfollowing131Itherapy(147,149).Eu-thyroidismwithouttheneedforantithyroiddrugtherapyisachievedwithindaysaftersurgery(147,148);afterradioactiveiodine,theresponseis50%–60%by3months,and80%by6months(147,149).Ontheotherhand,theriskofhypothyroidismandtherequirementforexogenousthyroidhormonetherapyis100%afternear-total/totalthyroidectomy.InalargestudyofpatientswithTMNGtreatedwith131I,theprevalenceofhypothyroidismwas3%at1yearand64%at24years(150).Hypothyroidismwasmorecommonamongpatientsunder50yearsofage(61%after16years),comparedwiththoseover70years(36%after16years).

ForpatientswithTA,theriskoftreatmentfailureis<1%aftersurgicalresection(ipsilateralthyroidlobectomyoristhmusectomy)(151),whereasfollowing131Ithereisa6%–18%riskofpersistenthyperthyroidismanda5.5%riskofrecurrenthyperthyroidism(152).Typically,euthyroid-ismwithouttheneedforantithyroiddrugtherapyisachievedwithindaysaftersurgery.131Thereisa75%re-sponserateby3monthsfollowingItherapyforTA(152).Theprevalenceofhypothyroidismis2.3%followinglobectomyforTA(151,153),andlowerafteristhmu-sectomyintheuniquecircumstancewheretheTAiscon-ﬁnedtothethyroidisthmus.Incontrast,theprevalenceofhypothyroidismafterradioactiveiodineisprogressiveandhastenedbythepresenceofantithyroidantibodiesoranonsuppressedTSHatthetimeoftreatment(152,154,155).Astudyfollowing684patientswithTAtreatedwith131Ireportedaprogressiveincreaseinovertandsubclinicalhypothyroidism(154).At1year,theinvestigatorsnoteda7.6%prevalence,with28%at5years,46%at10years,and60%at20years.TheyobservedafasterprogressiontohypothyroidismamongpatientswhowereolderandwhohadincompleteTSHsuppression(correlatingwithonlypartialextranodularparenchymalsuppression)duetopriortherapywithATDs.

Inlargeretrospectiveseries’ofpatientswithTMNGpre-sentingwithcompressivesymptoms,allpatientsundergo-ingtotalthyroidectomyhadresolutionofthesesymptomsaftertreatment,whereasonly46%ofpatientsundergoingradioactiveiodinehadimprovementinsuchsymptoms(156).Thismaybedueinparttothefactthatverylargegoiterstreatedwithhigh-activityradioactiveiodineonlydecreaseinsizeby30%–50%(157).ThenoduleisrarelyeradicatedinpatientswithTAundergoing131Itherapy,whichcanleadtotheneedforcontinuedsurveillance(152,155).

Potentialcomplicationsfollowingnear-total/totalthy-roidectomyincludetheriskofpermanenthypoparathyroid-ism(<2.0%)orRLNinjury(<2.0%)(158,159).Thereisasmallriskofpermanent131RLNinjurywithsurgeryforTA(151).FollowingItherapy,therehavebeenreportsofnew-onsetGD(upto4%prevalence)(160),aswellasconcernforthyroidmalignancy(68)andaveryminimalincreaseinlatenon-thyroidmalignancy(161).

BAHNETAL.

baseduponbestclinicaljudgmentandfortheﬁnaldecisiontoincorporatethepersonalvaluesandpreferencesofthepatient.

FactorsthatfavoraparticularmodalityastreatmentforTMNGorTA:a.

131I:Advancedpatientage,signiﬁcantcomorbidity,priorsurgeryorscarringintheanteriorneck,smallgoitersize,RAIUsufﬁcienttoallowtherapy,andlackofaccesstoahigh-volumethyroidsurgeon(thelatterfactorismoreimportantforTMNGthanforTA).

b.Surgery:Presenceofsymptomsorsignsofcompressionwithintheneck,concernforcoexistingthyroidcancer,coexistinghyperparathyroidismrequiringsurgery,largegoitersize(>80g),substernalorretrosternalex-tension,RAIUinsufﬁcientfortherapy,orneedforrapidcorrectionofthethyrotoxicstate(156).ContraindicationstoaparticularmodalityastreatmentforTMNGorTA:a.

131I:Deﬁnitecontraindicationstotheuseofradioactiveiodineincludepregnancy,lactation,coexistingthyroidcancer,individualsunabletocomplywithradiationsafetyguidelines,andfemalesplanningapregnancywithin4–6months.

b.Surgery:Factorsweighingagainstthechoiceofsurgeryincludesigniﬁcantcomorbiditysuchascardiopulmo-narydisease,end-stagecancer,orotherdebilitatingdisorders.Pregnancyisarelativecontraindicationandshouldonlybeusedinthiscircumstancewhenrapidcontrolofhyperthyroidismisrequiredandantithyroidmedicationscannotbeused.Thyroidectomyisbestavoidedintheﬁrstandthirdtrimestersofpregnancybecauseofteratogeniceffectsassociatedwithanestheticagentsandincreasedriskoffetallossintheﬁrsttri-mester,andincreasedriskofpretermlaborinthethird.Optimally,thyroidectomyshouldbeperformedinthelatterportionofthesecondtrimester.Althoughitisthesafesttime,itisnotwithoutrisk(4.5%–5.5%riskofpretermlabor)(47,48).Factorsthatmayimpactpatientpreference:a.

131I:PatientswitheitherTMNGorTAchoosing131Itherapywouldlikelyplacerelativelyhighervalueontheavoidanceofsurgeryandattendanthospitaliza-tionorcomplicationsarisingfromeithersurgeryoranesthesia;also,patientswithTMNGwouldplacegreater131valueonthepossibilityofremainingeuthyroidafterI.

b.Surgery:Patientschoosingsurgerywouldlikelyplacearelativelyhighervalueonpromptanddeﬁnitivecontrolofhyperthyroidsymptomsandavoidanceofexposuretoradioactivityandalowervalueonpotentialsurgicalandanestheticrisks;patientswithTAwhochoosesurgerywouldplacegreatervalueonthepossibilityofachievingeuthyroidismwithouthormonereplacement,whereaspatientswithTMNGchoosingsurgerywouldplacealowervalueonthecertainneedforlifelongthyroidhormonereplacement.

HYPERTHYROIDISMMANAGEMENTGUIDELINES[J]If131Itherapyischosen,howshoulditbeaccomplished?

[J1]PreparationofpatientswithTMNGorTAfor131Itherapy

RECOMMENDATION32

PatientswithTMNGorTAwhoareatincreasedriskforcomplicationsduetoworseningofhyperthyroidism,in-cludingtheelderlyandthosewithcardiovasculardiseaseorseverehyperthyroidism,shouldbetreatedwithbeta-blockadepriortoradioactiveiodinetherapyanduntileu-thyroidismhasbeenachieved.1/+00

Medicalmanagementbefore131Itherapyshouldbetailoredtothevulnerabilityofthepatientbasedontheseverityofthehyperthyroidism,patientage,andcomorbidconditions.Worsenedchemicalhyperthyroidismwithincreasedheartrateandrarecasesofsupraventriculartachycardia,includingatrialﬁbrillationandatrialﬂutter,havebeenobservedinpatientstreatedwith131IforeitherTMNGornontoxicmul-tindoulargoiter(MNG)(162–164).Insusceptiblepatientswithpre-existingcardiacdiseaseorintheelderly,thismayproducesigniﬁcantclinicalworsening(163).Therefore,theuseofbeta-blockerstopreventpost-treatmenttachyarrhyth-miasshouldbeconsideredinallpatientswithTMNGorTAwhoareolderthan60yearsofageandthosewithcardio-vasculardiseaseorseverehyperthyroidism(26).ThedecisionregardingtheuseofMMIpretreatmentismorecomplexandisdiscussedbelow.

RECOMMENDATION33

PretreatmentwithmethimazolepriortoradioactiveiodinetherapyforTMNGorTAshouldbeconsideredinpatientswhoareatincreasedriskforcomplicationsduetowors-eningofhyperthyroidism,includingtheelderlyandthosewithcardiovasculardiseaseorseverehyperthyroidism.2/+00

Taskforceopinionwasnotunanimous;onememberheldtheopinionthatpretreatmentwithmethimazoleinpatientsalreadytreatedwithbetaadrenergicblockadeisnotindicatedinthissetting.

Theminoritypositionregardingtheaboverecommen-dationheldthatpretreatingTMNGpatientswithMMIbe-foreradioactiveiodinetherapyisnotnecessaryanddelaysthetimetodeﬁnitivetreatmentandcure.Beta-blockadealonewasthoughttobesufﬁcienttopreventthemajorityofadverseeventsrelatedtoworseningofchemicalhyperthyroidismthatcanoccurfollowing131ItreatmentforTMNG.Youngandmiddle-agedpatientswithTMNGorTAgenerallydonotrequirepretreatmentwithATDs(MMI)beforereceivingra-dioactiveiodine,butmaybeneﬁtfrombeta-blockadeifsymptomswarrantandcontraindicationsdonotexist.Technicalremarks:Ifmethimazoleisusedinprepara-tionforradioactiveiodinetherapyinpatientswithTMNGorTA,cautionshouldbetakentoavoidradio-iodinetherapy131whentheTSHisnormalorelevatedtopreventdirectItreatmentofperinodularandcontra-lateralnormalthyroidtissue,whichincreasestheriskofdevelopinghypothyroidism.

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[J2]Evaluationofthyroidnodulesbeforeradioactiveiodinetherapy

RECOMMENDATION34

Nonfunctioningnodulesonradionuclidescintigraphyornoduleswithsuspiciousultrasoundcharacteristicsshouldbemanagedaccordingtorecentlypublishedguidelinesregardingthyroidnodulesineuthyroidindividuals.1/++0

ThoroughassessmentofsuspiciousnoduleswithinaTMNG,accordingtotherecentlypublishedguidelines(143,144),shouldbecompletedbeforeselectionofradioactiveiodineasthetreatmentofchoice.TheprevalenceofthyroidcancerinTMNGhistoricallyhasbeenestimatedtobeabout3%(148).Morerecently,ithasbeenestimatedtobeashighas9%,whichissimilartothe10.6%prevalencenotedinnontoxicMNG(165).

Technicalremarks:BoththeATAandAACE,thelatterinconjunctionwiththeEuropeanThyroidAssociationandAs-sociazioneMediciEndocrinologi,haverecentlypublishedupdatedmanagementguidelinesforpatientswiththyroidnodules(143,144).

[J3]AdministrationofradioactiveiodineinthetreatmentofTMNGorTA

RECOMMENDATION35

ForradioactiveiodinetreatmentofTMNG,sufﬁcientra-diationshouldbeadministeredinasingledosetoalleviatehyperthyroidism.1/++0

Thegoalofradioactiveiodinetherapy,especiallyinolderpatients,iseliminationofthehyperthyroidstate.Higherac-tivitiesof131I,evenwhenappropriatelycalculatedforthespeciﬁcvolumeormassofhyperthyroidtissue,resultinmorerapidresolutionofhyperthyroidismandlessneedforre-treatment,butahigherriskforearlyhypothyroidism.Onestudyshoweda64%prevalenceofhypothyroidism24yearsafterradioactiveiodinetherapyforTMNG,withahigherprevalenceamongpatientswhorequiredmorethanonetreatment131(150).TheprevalenceofhypothyroidismfollowingItherapyisincreasedbynormalizationorelevationofTSHatthetimeoftreatmentresultingfromATDpretreatmentandbythepresenceofantithyroidantibodies(166).

TheactivityofradioiodineusedtotreatTMNG,calculatedonthebasisofgoitersizetodeliver150–200mCipergramoftissuecorrectedfor24-hourRAIU,isusuallyhigherthanthatneededtotreatGD.Inaddition,theRAIUvaluesforTMNGmaybelower,necessitatinganincreaseinthetotaldoseofradioactiveiodine.Radiationsafetyprecautionsmaybeonerousifhighactivitiesof131Iareneededforlargegoiters.PretreatmentwithMMItoaslightlyelevatedTSHincreasedRAIUenoughtoallowmoreefﬁcacyfromaﬁxedactivity(30mCi)of131IinarecentstudyofpatientswithTMNG(167).UseofrecombinanthumanTSHisnotindicatedinTMNGduetoriskofexacerbatingthepatient’shyperthy-roidism(168).

131Technicalremarks:SwellingofthethyroidisveryrareafterItreatment.However,patientsshouldbeadvisedto

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immediatelyreportanytighteningoftheneck,difﬁcultybreathing,orstridorfollowingtheadministrationofradio-activeiodine.Anycompressivesymptoms,suchasdiscom-fort,swelling,dysphagia,orhoarseness,whichdevelopfollowingradiotherapy,shouldbecarefullyassessedandmonitored,andifclinicallynecessary,corticosteroidscanbeadministered.Respiratorycompromiseinthissettingisex-tremelyrareandrequiresmanagementasanyothercauseofacutetrachealcompression.

RECOMMENDATION36

ForradioactiveiodinetreatmentofTA,sufﬁcientradiationtoalleviatehyperthyroidismshouldbeadministeredinasingledose.1/++0

RadioactiveiodineadministeredtotreatTAcanbegiveneitherasaﬁxedactivity(approximately10–20mCi)oranactivitycalculatedonthebasisofnodulesizeusing150–200mCi131Ipergramcorrectedfor24-hourRAIU(169).Along-termfollow-upstudyofpatientswithTA,wherepa-tientswithsmall(<4cm)noduleswereadministeredanav-erageof13mCiandthosewithlargernodulesanaverageof17mCi,showedaprogressiveincreaseinhypothyroidismovertimeinbothgroups,suggestingthathypothyroidismdevelopsovertimeregardlessofactivityadjustmentfornodulesize(154).Arandomizedtrialof97patientswithTAcomparedtheeffectsofhigh(22.5mCi)orlow(13mCi)ﬁxedactivityradioactiveiodine,withacalculatedactivitythatwaseitherhigh(180–200mCi/g)orlow(90–100mCi/g)andcor-rectedfor24-hourRAIU(169).Thisstudyconﬁrmedpreviousreportsshowinganearlierdisappearanceofhyperthyroidismandearlierappearanceofhypothyroidismwithhigheractiv-ity131treatments.UseofacalculatedactivityallowedforalowerIactivitytobeadministeredforasimilarefﬁcacyinthecureofhyperthyroidism.

[J4]Patientfollow-upafter

131ItherapyforTMNGorTA

RECOMMENDATION37

Follow-upwithintheﬁrst1–2monthsafterradioactiveiodinetherapyforTMNGorTAshouldincludeanas-sessmentoffreeT4,totalT3andTSH.Thisshouldbere-peatedat1–2monthintervalsuntilstableresultsareobtained,thenatleastannuallythereafteraccordingtoclinicalindication.1/+00

RadioactiveiodinetherapyforTMNGresultsinresolutionofhyperthyroidisminapproximately55%ofpatientsat3monthsand80%ofpatientsat6months,withanaveragefailurerateof15%(147–149).Goitervolumeisdecreasedby3months,withfurtherreductionobservedover24months,foratotalsizereductionof40%(149).ForTA,75%ofpatientswerenolongerhyperthyroidat3months,withnodulevol-umedecreasedby35%at3monthsandby45%at2years(152).Riskofpersistentorrecurrenthyperthyroidismrangedfrom0%to30%,dependingontheseries(147–149,152).Long-termfollow-upstudiesshowaprogressiveriskofclinicalorsubclinicalhypothyroidismofabout8%by1yearand60%by20yearsforTA(154),andanaverageof3%by1yearand64%by24yearsforTMNG(150).

BAHNETAL.

Technicalremarks:Ifthyroidhormonetherapyisnecessary,thedoserequiredmaybelessthanfullreplacementduetounderlyingpersistentautonomousthyroidfunction.[J5]Treatmentofpersistentorrecurrenthyperthyroidismfollowing131ItherapyforTMNGorTA

RECOMMENDATION38

Ifhyperthyroidismpersistsbeyond6monthsfollowing131ItherapyforTMNGorTA,retreatmentwithradioactiveiodineissuggested.2/+00

Technicalremarks:InsevereorrefractorycasesofpersistenthyperthyroidismduetoTMNGorTA,surgerymaybecon-sidered.Assomepatientswithmildhyperthyroidismfol-lowingradioactiveiodineadministrationwillcontinuetoimproveovertime,useofMMIwithclosemonitoringmaybeconsideredtoallowcontrolofthehyperthyroidismuntiltheradioactiveiodineiseffective.

[K]Ifsurgeryischosen,howshoulditbeaccomplished?

[K1]PreparationofpatientswithTMNGorTAforsurgery

RECOMMENDATION39

IfsurgeryischosenastreatmentforTMNGorTA,patientswithoverthyperthyroidismshouldberenderedeuthyroidpriortotheprocedurewithmethimazolepretreatment(intheabsenceofallergytothemedication),withorwithoutbeta-adrenergicblockade.Preoperativeiodineshouldnotbeusedinthissetting.1/+00

Risksofsurgeryareincreasedinthepresenceofthyrotox-icosis.Thyrotoxiccrisisduringoraftertheoperationcanre-sultinextremehypermetabolism,hyperthermia,tachycardia,hypertension,coma,ordeath.Therefore,preventionwithcarefulpreparationofthepatientisofparamountimportance(170,171).Theliteraturereportsaverylowriskofanesthesia-relatedmortalityassociatedwiththyroidectomy(151,172).Inpatientswhowishtoavoidgeneralanesthesia,orwhohavesigniﬁcantcomorbidities,thisriskcanbeloweredfurtherwhencervicalblockanesthesiawithsedationisemployedbythyroidsurgeonsandanesthesiologistsexperiencedinthisapproach(173).However,thistechniqueisnotwidelyavail-ableintheU.S.Preoperativeiodinetherapyisnotindicatedduetoriskofexacerbatingthehyperthyroidism(174).[K2]Thesurgicalprocedureandchoiceofsurgeon

RECOMMENDATION40

IfsurgeryischosenastreatmentforTMNG,near-totalortotalthyroidectomyshouldbeperformed.1/++0

RecurrencecanbeavoidedinTMNGifanear-totalortotalthyroidectomyisperformedinitially.Thisprocedurecanbeperformedwiththesamelowrateofcomplicationsasasub-totalthyroidectomy(175–178).Reoperationforrecurrentorpersistantgoiterresultsina3-to10-foldincreaseinriskforpermanentvocalcordparalysisorhypoparathyroidism(179,180).

HYPERTHYROIDISMMANAGEMENTGUIDELINES

RECOMMENDATION41

SurgeryforTMNGshouldbeperformedbyahigh-volumethyroidsurgeon.1/++0

Dataregardingoutcomesfollowingthyroidectomyinelderlypatientshaveshownconﬂictingresults.Overall,however,studiesconductedatthepopulationlevelhavedemonstratedsigniﬁcantlyhigherratesofpostoperativecomplications,longerlengthofhospitalstay,andhighercostsamongelderlypatients(122).Datashowingequivalentout-comesamongtheelderlyusuallyhavecomefromhigh-volumecenters(181).Therearerobustdatademonstratingthatsurgeonvolumeofthyroidectomiesisanindependentpredictorofpatientclinicalandeconomicoutcomes(i.e.,in-hospitalcomplications,lengthofstay,andtotalhospitalcharges)followingthyroidsurgery(122,123,182).Thereisarobust,statisticallysigniﬁcantassociationbetweenincreasingsurgeonvolumeandsuperiorpatientoutcomesforthyroid-ectomy.Datashowthatsurgeonswhoperformmorethan30thyroidsurgeriesperyearhavesuperiorpatientclinicalandeconomicoutcomescomparedtothosewhoperformfewer,andsurgeonswhoperformatleast100peryearhavestillbetteroutcomes.Itisforthisreasonthatnear-totalortotalthyroidectomyforTMNGisbestperformedbyahigh-volumethyroidsurgeon(123,181,182).

RECOMMENDATION42

IfsurgeryischosenasthetreatmentforTA,anipsilateralthyroidlobectomy,oristhmusectomyiftheadenomaisinthethyroidisthmus,shouldbeperformed.1/++0

Apreoperativethyroidultrasoundisuseful,asitwillde-tectthepresenceofcontralateralnodularitythatissuspiciousinappearanceorthatwillnecessitatefuturesurveillance,bothcircumstancesinwhichatotalthyroidectomymaybemoreappropriate.LobectomyremovestheTAwhileleavingnormalthyroidtissue,allowingresidualnormalthyroidfunctioninthemajorityofpatients.OnelargeclinicalseriesforTAdemonstratednosurgicaldeathsandlowcomplica-tionrates(151).Patientswithpositiveantithyroidantibodiespreoperativelyhaveahigherriskofpostoperativehypothy-roidism(166).

RECOMMENDATION43

WesuggestthatsurgeryforTAbeperformedbyahigh-volumesurgeon.2/++0

WhilesurgeonexperienceinthesettingofTAisofsome-whatlessimportancethaninTMNG,itremainsafactortoconsiderindecidingbetweensurgeryandradioactiveiodine.High-volumethyroidsurgeonstendtohavebetteroutcomesfollowinglobectomythanlow-volumesurgeons,butthedif-ferencesarenotstatisticallysigniﬁcant(122).[K3]Postoperativecare

RECOMMENDATION44

FollowingthyroidectomyforTMNG,wesuggestthatserumcalciumorintactparathyroidhormonelevelsbemeasured,andthatoralcalciumandcalcitriolsupple-mentationbeadministeredbasedontheseresults.2/+00

611

Technicalremarks:Themanagementofhypocalcemiafol-lowingthyroidectomyforTMNGisessentiallythesameasthatdescribedinsectionF3forpostoperativemanagementinGD.Severeorprolongedpreoperativehyperthyroidism,andlargersizeandgreatervascularityofthegoiter(moretypicallyseeninGD)increasestherisksofpostoperativehypocalcemia.

RECOMMENDATION45

MethimazoleshouldbestoppedatthetimeofsurgeryforTMNGorTA.Beta-adrenergicblockadeshouldbeslowlydiscontinuedfollowingsurgery.1/+00

RECOMMENDATION46

FollowingsurgeryforTMNG,thyroidhormonereplace-mentshouldbestartedatadoseappropriateforthepatient’sweight(0.8mcg/lbor1.7mcg/kg)andage,withelderlypatientsneedingsomewhatless.TSHshouldbemeasuredevery1–2monthsuntilstable,andthenannu-ally.1/+00

Technicalremarks:Ifasigniﬁcantthyroidremnantremainsfollowingthyroidectomy,becausesucharemnantmaydemonstrateautonomousproductionofthyroidhormone,immediatepostoperativedosesofthyroidhormoneshouldbeinitiatedatsomewhatlessthanfullreplacementdosesandsubsequentlyadjustedbasedonthyroidfunctiontesting.

RECOMMENDATION47

FollowingsurgeryforTA,TSHandestimatedfreeT4levelsshouldbeobtained4–6weeksaftersurgery,andthyroidhormonesupplementationstartedifthereisapersistentriseinTSHabovethenormalrange.1/+00

Technicalremarks:AfterlobectomyforTA,serumcalciumlevelsdonotneedtobeobtained,andcalciumandcalcitriolsupplementsdonotneedtobeadministered.

[K4]TreatmentofpersistentorrecurrentdiseasefollowingsurgeryforTMNGorTA

RECOMMENDATION48

Radioactiveiodinetherapyshouldbeusedforretreatmentofpersistentorrecurrenthyperthyroidismfollowingin-adequatesurgeryforTMNGorTA.1/+00

Persistentorrecurrenthyperthyroidismfollowingsurgeryisindicativeofinadequatesurgery.Asremedialthyroidsur-gerycomesatsigniﬁcantlyincreasedriskofhypoparathy-roidismandRLNinjury,itshouldbeavoidedifpossibleinfavorofradioactiveiodinetherapy(179,180).Ifthisisnotanoption,itisessentialthatthesurgerybeperformedbyahigh-volumethyroidsurgeon.

[L]IstherearoleforantithyroiddrugtherapyinpatientswithTMNGorTA?

ATDsdonotinduceremissioninpatientswithnodularthyroiddisease.Therefore,discontinuationoftreatmentre-sultsinrelapse(117,159).However,prolonged(life-long)ATDtherapymaybethebestchoiceforsomeindividuals

612

withlimitedlongevityandincreasedsurgicalrisk,includingresidentsofnursinghomesorothercarefacilitieswherecompliancewithradiationsafetyregulationsmaybedifﬁcult.

RECOMMENDATION49

Wesuggestthatlong-termmethimazoletreatmentofTMNGorTAbeavoided,exceptinsomeelderlyoroth-erwiseillpatientswithlimitedlongevitywhoareabletobemonitoredregularly,andinpatientswhopreferthisoption.2/+00

Technicalremarks:Becauselong-term,low-doseATDtreat-mentinnodularhyperthyroidismcanbedifﬁculttoregulate,frequent(every3months)monitoringisrecommended,especiallyintheelderly(183).

[M]Istherearoleforradiofrequency,thermal,oralcoholablationinthemanagementofTAorTMNG?

Alternativetechniqueshavebeenemployedfortheablationofhyperfunctioningthyroidnodules;theseincludepercuta-neousethanolinjection(PEI)undersonographicguidance,aswellasthermalandradiofrequencyablation.DatasupportingthesafetyandefﬁcacyofsuchtechniquescomelargelyfromoutsidetheUnitedStates(184–186).Long-termfollow-upexiststo5years,showingthatPEIiseffectiveandsafe.Inalargeseriesof125patients,Tarantinoetal.demonstratedanoverallcurerate(absentuptakeinthenodule)of93%,andamajorcomplicationrateof3%(184).Theseincludedtransientlaryn-gealnervedamage,abscess,andhematoma.Allpatientsre-mainedeuthyroid(low/normalTSHandnormalfreeT3andfreeT4estimates)duringfollow-up.TheaveragereductioninthevolumeofnodulesafterPEIwas66%.Giventherelativelackofexperiencewiththesealternativetechniques,131Ither-apyandsurgeryremainthemainstayoftreatment.PEIoral-ternativetreatmentsshouldbeemployedonlyintheveryraresituationwhenstandardtherapieshavefailed,orarecontra-indicatedorrefused.

[N]HowshouldGDbemanagedinchildrenandadolescents?[N1]Generalapproach

RECOMMENDATION50

ChildrenwithGDshouldbetreatedwithmethimazole,131Itherapy,orthyroidectomy.131Itherapyshouldbeavoidedinveryyoungchildren(<5years).131Itherapyinpatientsbetween1315and10yearsofageisacceptableifthecalculatedIadministeredactivityis<10mCi.131Itherapyinpa-tientsolderthan10yearsofageisacceptableiftheactivityis>150mCi/gofthyroidtissue.Thyroidectomyshouldbechosenwhendeﬁnitivetherapyisrequired,thechildistooyoungfor131I,andsurgerycanbeperformedbyahigh-volumethyroidsurgeon.1/++0

ThetreatmentofpediatricpatientswithGDvariescon-siderablyamonginstitutionsandpractitioners.ItisimportanttorecognizethatlastingremissionafterATDtherapyoccursinonlyasmallminorityofpediatricpatientswithGD,includingchildrentreatedwithATDsformanyyears.In

BAHNETAL.

determiningtheinitialtreatmentapproach,thepatient’sage,clinicalstatus,andlikelihoodofremissionshouldbeconsidered.

Becausesomechildrenwillgointoremission,MMItherapyfor1–2yearsisstillconsideredﬁrst-linetreatmentformostchildren.However,themajorityofpediatricpatientswithGDwilleventuallyrequireeitherradioactiveiodineorsurgery.WhenATDsareusedinchildren,onlyMMIshouldbeused,exceptinexceptionalcircumstances.Ifclinicalcharacteristicssuggest131alowchanceofremissionatinitialpresentation,MMI,I,orsurgerymaybeconsideredinitially.IfremissionisnotachievedafteracourseoftherapywithATDs,131Iorsurgeryshouldbeconsidered.Alternatively,MMItherapymaybecontinueduntilthechildisconsideredoldenoughforsurgeryorradioactiveiodine.

Properlyadministered,radioactiveiodineisaneffectivetreatmentforGDinthepediatricpopulation(187–189).131Iiswidelyusedinchildren,butstillviewedascontroversialbysomepractitionersowingprimarilytoconcernovercancerrisks(190).AlthoughtherearesparseclinicaldatarelatingtoradioactiveiodineuseinchildrenwithGDandsubsequentthyroidcancer(191),itisknownthatrisksofthyroidcancerafterexternalirradiationarehighestinchil-dren<5yearsofage,andthey131declinewithadvancingage(192,193);seediscussionofItherapyandcancerriskin[P3]below.Incomparison,activitiesofradioactiveiodineusedwithcontemporarytherapyarenotknowntobeas-sociatedwithanincreasedriskofthyroidneoplasminchildren.

ThyroidectomyisaneffectivetreatmentforGD,butisas-sociatedwithahighercomplicationrateinchildrenthanadults(194,195).Thyroidectomyshouldbeperformedinthosechildrenwhoaretooyoungforradioactiveiodine,providedthatsurgerycanbeperformedbyahigh-volumethyroidsurgeon,preferablywithexperienceinconductingthyroidectomiesinchildren.

Technicalremarks:Theremaybecircumstancesinwhich131Itherapyisindicatedinveryyoungchildren,suchaswhenachildhasdevelopedareactiontoATDs,propersurgicalex-pertiseisnotavailable,orthepatientisnotasuitablesurgicalcandidate.

[O]IfantithyroiddrugsarechosenasinitialmanagementofGDinchildren,howshouldthetherapybemanaged?

[O1]InitiationofantithyroiddrugtherapyforthetreatmentofGDinchildren

RECOMMENDATION51

Methimazoleshouldbeusedinvirtuallyeverychildwhoistreatedwithantithyroiddrugtherapy.1/++0

Technicalremarks:MMIcomesin5or10mgtabletsandcanbegivenoncedaily,eveninpatientswithseverehyperthy-roidism.AlthoughmanypractitionersgiveMMIindivideddoses,datainadultsdonotsupportaneedforsuchandshowthatcompliancewithonce-dailyMMItherapyissuperiortomultipledailydosesofPTU(83%vs.53%)(196).TheMMIdosetypicallyusedis0.2–0.5mg/kgdaily,witharangefrom0.1–1.0mg/kgdaily(197–204).Oneapproachistoprescribe

HYPERTHYROIDISMMANAGEMENTGUIDELINESthefollowingwholetabletorquartertohalf-tabletdoses:in-fants,1.25mg/day;1–5years,2.5–5.0mg/day;5–10years,5–10mg/day;and10–18years,10–20mg/day.Withsevereclinicalorbiochemicalhyperthyroidism,dosesthatare50%–100%higherthantheabovecanbeused.

Whenthyroidhormonelevelsnormalize,MMIdosescanbereducedby50%ormoretomaintainaeuthyroidstate(205).Alternatively,somephysicianselectnottoreducetheMMIdoseandaddlevothyroxinetomakethepatienteu-thyroid,apracticereferredtoas‘‘blockandreplace.’’How-ever,becausemeta-analysessuggestahigherprevalenceofadverseeventsusingblock-and-replaceregimensthandosetitration(81,84,206),andtheremaybedose-relatedcompli-cationsassociatedwithMMI(207),wesuggestthatthispracticeingeneralbeavoided.

RECOMMENDATION52

Pediatricpatientsandtheircaretakersshouldbeinformedofsideeffectsofantithyroiddrugsandthenecessityofstoppingthemedicationimmediatelyandinformingtheirphysicianiftheydeveloppruriticrash,jaundice,acolicstoolsordarkurine,arthralgias,abdominalpain,nausea,fatigue,fever,orpharyngitis.1/+00

RECOMMENDATION53

Priortoinitiatingantithyroiddrugtherapy,wesuggestthatpediatricpatientshave,asabaseline,completebloodcellcount,includingwhitebloodcellcountwithdifferential,andaliverproﬁleincludingbilirubin,transaminases,andalkalinephosphatase.2/+00

PTUisassociatedwithanunacceptableriskofhepatotox-icityinchildren,withariskofliverfailureof1in2000–4000childrentakingthemedication(208–210).PTUcancausefulminanthepaticnecrosisthatmaybefatal;livertransplan-tationhasbeennecessaryinsomepatientstakingPTU(91).ItisforthisreasonthattheFDArecentlyissuedasafetyalertregardingtheuseofPTU,notingthat32(22adultand10pediatric)casesofseriousliverinjuryhavebeenassociatedwithPTUuse(92,93).

BecausePTU-inducedliverinjuryisofrapidonsetandcanberapidlyprogressive,biochemicalmonitoringofliverfunctiontestsandtransaminaselevelsisnotexpectedtobeusefulinmanagingthehepatotoxicityriskinaPTU-treatedpatient131(210).However,whenneitherpromptsurgerynorItherapyareoptions,andATDtherapyisnecessaryinapatientwhohasdevelopedaminortoxicreactiontoMMI,ashortcourseofPTUusecanbeconsidered.WhensurgeryistheplannedtherapyandMMIcannotbeadministered,ifthepatientisnottoothyrotoxic(andthehyperthyroidismisduetoGD),thehyperthyroidstatecanbecontrolledbeforesurgerywithbetablockadeandSSKI(50mgiodide/drop)3–7drops(0.15–0.35mL)bymouth,giventhreetimesadayfor10daysbeforesurgery).Alternatively,ifthesurgerycannotbeperformedwithinafewweeks,ashortcourseofPTUmaybeadministeredwiththechildcloselymonitored.

Technicalremarks:ItisadvisabletoprovideinformationconcerningsideeffectsofATDstothepatientinwriting.ThisinformationcanbefoundontheUpToDateWebsite(99).See

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TechnicalremarksfollowingRecommendation15foradiscussionregardingtheutilityofobtainingcompletebloodcountandliverproﬁlebeforeinitiatingmethimazoletherapy.

[O2]SymptomaticmanagementofGraves’hyperthyroid-isminchildren

RECOMMENDATION54

Betaadrenergicblockadeisrecommendedforchildrenexperiencingsymptomsofhyperthyroidism,especiallythosewithheartratesinexcessof100beatsperminute.1/+00

InchildreninwhomthediagnosisofGraves’hyperthy-roidismisstronglysuspectedorconﬁrmed,andwhoareshowingsigniﬁcantsymptoms,including,butnotlimitedto,tachycardia,muscleweakness,tremor,orneuropsychologicalchanges,treatmentwithatenolol,propranolol,ormetoprololleadstoadecreaseinheartrateandsymptomsofGD.Inthosewithreactiveairwaydisease,cardioselectivebeta-blockerscanbeused(211),withthepatientmonitoredforexacerbationofasthma.

[O3]Monitoringofchildrentakingmethimazole

AfterinitiationofMMItherapy,thyroidfunctiontests(estimatedfreeT4,totalT3,TSH)areobtainedmonthlyatﬁrst,andthenevery2–4months.Dependingontheseverityofhyperthyroidism,itcantakeseveralmonthsforelevatedthyroidhormonelevelstofallintothenormalrangeonATDs.

RECOMMENDATION55

Antithyroidmedicationshouldbestoppedimmediately,andwhitebloodcountsmeasuredinchildrenwhodevelopfever,arthralgias,mouthsores,pharyngitis,ormalaise.1/+00

AlthoughMMIhasabetteroverallsafetyproﬁlethanPTU,MMIisassociatedwithminoradverseeventsthatmayaffectupto20%ofchildren(212).MMI-relatedadverseeventsin-cludeallergicreactions,rashes,myalgias,andarthralgias(188,213,214),aswellashypothyroidismfromovertreatment.SideeffectstoMMIusuallyoccurwithintheﬁrst6monthsofstartingtherapy,butadverseeventscanoccurlater.Inchil-dren,therisksofcholestasisandhepatocellularinjuryappeartobemuchlessthanthatobservedinadults.

Agranulocytosishasbeenreportedinabout0.3%ofadultpatientstakingMMIorPTU(81,207,215).Dataontheprev-alenceofagranulocytosisinchildrenareunavailable,butitisestimatedtobeverylow.Inadults,agranulocytosisisdosedependentwithMMI,andrarelyoccursatlowdoses(207,215).Whenagranulocytosisdevelops,95%ofthetimeitoccursintheﬁrst100daysoftherapy(207,215).TheoverallrateofsideeffectstoATDs(bothmajorandminor)inchildrenhasbeenreportedtobe6%–35%(214,216).

Technicalremarks:Whileroutinemonitoringofwhitebloodcountsmayoccasionallydetectearlyagranulocytosis,itisnotrecommendedbecauseoftherarityoftheconditionanditssuddenonset,whichisgenerallysymptomatic.Itisforthisreasonthatmeasuringwhitecellcountsduringfebrileill-nessesandattheonsetofpharyngitishasbecomethestan-dardapproachtomonitoring.

614

[O4]Monitoringofchildrentakingpropylthiouracil

RECOMMENDATION56

Whenpropylthiouracilisusedinchildren,themedicationshouldbestoppedimmediatelyandliverfunctionandhepatocellularintegrityassessedinchildrenwhoexperi-enceanorexia,pruritis,rash,jaundice,light-coloredstoolordarkurine,jointpain,rightupperquadrantpainorab-dominalbloating,nausea,ormalaise.1/+00

Technicalremarks:PTUshouldbediscontinuediftransam-inaselevels(obtainedinsymptomaticpatientsorfoundinci-dentally)reach2–3timestheupperlimitofnormalandfailtoimprovewithinaweekwithrepeattesting.Afterdis-continuingthedrug,liverfunctiontests(i.e.,bilirubin,alka-linephosphatase,andtransaminases)shouldbemonitoredweeklyuntilthereisevidenceofresolution.Ifthereisnoev-idenceofresolution,referraltoagastroenterologistorhepa-tologistiswarranted.

[O5]Managementofallergicreactionsinchildrentakingmethimazole

RECOMMENDATION57

Persistentminorcutaneousreactionstomethimazoletherapyinchildrenshouldbemanagedbyconcurrentantihistaminetreatmentorcessationofthemedicationandchangingtotherapywithradioactiveiodineorsurgery.Inthecaseofaseriousallergicreactiontoanantithyroidmedication,prescribingtheotherantithyroiddrugisnotrecommended.1/+00

IfchildrendevelopseriousallergicreactionstoMMI,ra-dioactiveiodineorsurgeryshouldbeconsideredbecausetherisksofPTUareviewedtobegreaterthantherisksofradioactiveiodineorsurgery.PTUmaybeconsideredforshort-termtherapyinthissettingtocontrolhyperthyroidisminpreparationforsurgery.

[O6]DurationofmethimazoletherapyinchildrenwithGD

RECOMMENDATION58

Ifmethimazoleischosenastheﬁrst-linetreatmentforGDinchildren,itshouldbeadministeredfor1–2yearsandthendiscontinued,orthedosereduced,toassesswhetherthepatientisinremission.1/++0

TheissueofhowlongATDsshouldbeusedinchildrenbeforeconsideringeitherradioactiveiodineorsurgeryisatopicofcontroversyandwarrantsfurtherstudy.Prospectivestudiesinadultsshowthatifremissiondoesnotoccurafter12–18monthsoftherapy,thereislittlechanceofremissionoccurringwithprolongedtherapy(217).Inchildren,whenATDsareusedfor1–2years,remissionratesaregenerally20%–30%,withremissiondeﬁnedasbeingeuthyroidfor1yearaftercessationoftherapy(187,199,214,218,219).Retro-spectivestudieshavesuggestedthatthechanceofremissionafter2yearsofATDsislowifthethyroidglandislarge(morethan2.5timesnormalsizeforage),thechildisyoung(<12years)(214,219)ornotcaucasian,serumTRAblevelsare

BAHNETAL.

abovenormalontherapy,orFT4estimatesaresubstantiallyelevatedatdiagnosis(>4ng/dL;50pmol/L)(214).Onepro-spectivestudysuggestedthatlikelihoodofremissioncouldbestbepredictedbytheinitialresponsetoantithyroidmed-ication,withachievementofeuthyroidstatewithin3months,suggestinghigherlikelihood.Youngerchildrenandthosewithhighinitialthyroidhormonelevelswerealsofoundtobelesslikelytoachieveremissionwithin2yearsinthepro-spectivestudy(214).

RemissionratesinchildrentreatedwithATDsforlongerthan2yearshavebeenreported.Althoughtwodecadesagoitwassuggestedthat25%ofchildrenwithGDgointore-missionwithevery2yearsofcontinuedtreatment(220),otherstudiesoflargercohortsofpediatricpatientswithGDtreatedwithATDsforextendedperiodshavenotrevealedsimilarremissionrates(213,216,221).Of120pediatricpa-tientstreatedwithATDsatonecenter,after1yearoftherapywithATDs,25%wereinremission;after2years,26%;after4years,37%;andafter4–10years,15%.Importantly,30%ofthechildrenwhowentintoremissioneventuallyrelapsed(213).Inanotherlargecohortof184medicallytreatedchil-dren,after1yearoftherapywithATDs,10%wereinre-mission;after2years,14%;after3years,20%;andafter4years,23%(221).

Dataalsosuggestthatthereareage-relateddifferencesinresponsivenesstoATDs.Inonestudythatcomparedout-comesof32prepubertaland68pubertalchildren,remissionoccurredinonly17%ofprepubertalchildrentreated5.9Æ2.8years,comparedwith30%ofpubertalindividualstreated2.8Æ1.1years(219).Inanotherreport,thecourseofGDwascomparedin7prepubertal,21pubertal,and12postpubertalchildren(216).Remissionwasachievedin10patients(28%)withsimilarratesamongthethreegroups,whereasthetimetoremissiontendedtobelongerinthesmallproportionofprepubertalchildren(medianage,6years)(216).

PersistenceofGDinchildreniscorrelatedwiththeper-sistenceofTRAbs.ArecentstudyfoundthatTRAblevelsnormalizedafter24monthsinonly18%ofpediatricpa-tientsonATDs(204).TherewerenodatashowingthattherewasnormalizationofTRAblevelswhenpatientswereonATDsforalongertime.Therefore,itappearsthatTRAblevelspersistlongerinchildrenthaninadults(204).WhereasmonitoringofTRAblevelswhileonATDshasbeenshowntobeusefulinadultpatientsforpredictingthelikelihoodofremissionorrelapseofGDafterstoppingthemedication(222),thisapproachhasyettobevalidatedinchildren.

RECOMMENDATION59

PediatricpatientswithGDwhoarenotinremissionfollowing1–2yearsofmethimazoletherapyshouldbeconsideredfortreatmentwithradioactiveiodineorthy-roidectomy.1/+00

IfafterstoppingMMIafter1or2years’remissionisnotachieved,131Iorsurgeryshouldbeconsidered,dependingontheageofthechild.Alternatively,practitionerscancontinueMMIforextendedperiods,aslongasadversedrugeffectsdonotoccurandthehyperthyroidstateiscontrolled.Thisap-proachcanbeusedasabridgeto131Itherapyorsurgeryatalaterageifremissiondoesnotoccur.Inselectedsituationswhereitmightnotbesuitableorpossibletoproceedwith131I

HYPERTHYROIDISMMANAGEMENTGUIDELINESorsurgery,low-doseMMIcanbecontinued,althoughthelikelihoodofremissionisnotgreat.

[P]Ifradioactiveiodineischosenastreatment

forGDinchildren,howshoulditbeaccomplished?[P1]PreparationofpediatricpatientswithGDfor131I

therapy

RECOMMENDATION60

WesuggestthatchildrenwithGDhavingtotalT4levelsof>20ug/dL(260nmol/L)orfreeT4estimates>5ng/dL(60pmol/L)whoaretoreceiveradioactiveiodinetherapybepretreatedwithmethimazoleandbeta-adrenergicblockadeuntiltotalT4and/orfreeT4estimatesnormalizebeforeproceedingwithradioactiveiodine.2/+00

Althoughthefrequencyofshort-termworseningofhy-perthyroidismfollowingpretreatmentwithATDtherapyisnotknown,therearerarereportsofpediatricpatientswithseverehyperthyroidismwhohavedevelopedthyroidstormafterreceiving131I(223).

Technicalremarks:WhenchildrenreceivingMMIaretobetreatedwith131I,themedicationisstopped3–5daysbeforetreatment(224).Atthattime,patientsareplacedonbeta-blockers,whichtheycontinuetotakeuntiltotalT4and/orfreeT4estimatelevelsnormalizefollowingradioactiveiodinetherapy.AlthoughsomephysiciansrestartATDsaftertreat-mentwith131I(225),thispracticeisseldomrequiredinchil-dren(188,189,224,226).Thyroidhormonelevelsinchildrenbegintofallwithintheﬁrstweekfollowingradioactiveiodinetherapy.ATDscancomplicateassessmentofpost-treatmenthypothyroidism,131sinceitcouldbetheresultoftheMMIratherthantheItherapy.[P2]Administrationof131IinthetreatmentofGD

inchildren

RECOMMENDATION61

If131ItherapyischosenastreatmentforGDinchildren,sufﬁcient131Ishouldbeadministeredinasingledosetorenderthepatienthypothyroid.1/++0

Thegoalof131ItherapyforGDistoinducehypothy-roidism,rather131thaneuthyroidism,asloweradministeredactivitiesofIresultinresidual,partiallyirradiatedthy-roidtissuethatisatincreasedriskforthyroidneoplasmdevelopment(69,227).Becauseofanincreasedriskofthyroidnodulesandcancerassociatedwithlow-levelthy-roidirradiationinchildren(192–194,228,229),andpoorremissionrateswithlow-administeredactivitiesof131I(61,64,65,188),itisimportantthatlarger(>150mCiof131Iper131gramofthyroidtissue)ratherthansmalleractivitiesofIbeadministeredtoachievehypothyroidism(230).Withlargeglands(50–80g),higheradministeredactivitiesof131I(200–300mCiof131Ipergram)maybeneeded(224).Theadministeredactivityof131Itopatientswithverylargegoitersishigh,andthereisatendencytounderestimatethesizeofthegland(andtherebyadministerinsufﬁcientra-

615

diationtothesepatients)(64).Therefore,surgeryinpatientswithgoiterslargerthan80gmaybepreferabletoradio-activeiodinetherapy.

Physiciansatsomecentersadministeraﬁxeddoseofabout15mCi131Itoallchildren(226),whereasotherscalculatetheactivity123fromestimationordirectmeasurementofglandsizeandIuptake(224).Toassessthyroidsize,particularlyinthesettingofalargegland,ultrasonograhyisrecommended(231).Therearenodatacomparingoutcomesofﬁxedversuscalculatedactivitiesinchildren;inadults,similaroutcomeshavebeenreportedwiththetwoapproaches(232).Onepo-tentialadvantageofcalculatedversusﬁxeddosingisthatitmaybepossibletouseloweradministeredactivitiesof131I,especiallywhenuptakeishighandthethyroidissmall.Cal-culateddosingalsowillhelpassurethatanadequatead-ministeredactivityisgiven.

Whenactivities>150mCiof131Ipergramofthyroidtissueareadministered,hypothyroidismratesareabout95%(188,233,234).Whiletherearereportsthathyperthyroidismcan131relapseinpediatricpatientsrenderedhypothyroidwithI,thisisveryinfrequent.Technicalremarks:Radioactiveiodineisexcretedbysa-liva,urine,andstool.Signiﬁcantradioactivityisretainedwithinthethyroidforseveraldays.Itisthereforeimportantthatpatientsandfamiliesbeinformedofandadheretolocalradiationsafetyrecommendationsfollowing131Itherapy.After131Itherapy,T3,T4,and/orestimatedfreeT4levelsshouldbeobtainedeverymonth.BecauseTSHlevelsmayremainsuppressedforseveralmonthsaftercorrectionofthehyperthyroidstate,TSHdeterminationsmaynotbeusefulinthissettingforassessinghypothyroidism.Hy-pothyroidismtypicallydevelopsby2–3monthspost-treatment(224,226),atwhichtimelevothyroxineshouldbeprescribed.

[P3]Side-effectsof

131Itherapyinchildren

Sideeffectsof131Itherapyinchildrenareuncommonapartfromthelifelonghypothyroidismthatisthegoaloftherapy.Lessthan10%ofchildrencomplainofmildtender-nessoverthethyroidintheﬁrstweekaftertherapy;itcanbetreatedeffectivelywithacetaminophenornonsteroidalanti-inﬂammatoryagentsfor24–48hours(189,224).

Ifthereisresidualthyroidtissueinyoungchildrenafterradioactiveiodinetreatment,thereisatheoreticalriskofde-velopmentofthyroidcancer.Detractorsoftheuseof131ItherapyinchildrenpointtotheincreasedratesofthyroidcancerandthyroidnodulesobservedinyoungchildrenexposedtoradiationfromnuclearfalloutatHiroshimaoraftertheChernobylnuclearreactorexplosion.However,thesedatadonotapplydirectlywhenassessingrisksof131Ither-apy.Theriskofthyroidneoplasiaisgreatestwithexposuretolowlevelexternalradiation(0.1–25Gy;*0.09–30mCi/g)(192,193,228,235,236),notwiththehigheradministeredac-tivitiesusedtotreatGD.Itisalsoimportanttonotethatiodinedeﬁciencyandexposuretoradionuclidesotherthan131ImayhavecontributedtotheincreasedriskofthyroidcancerinyoungchildrenaftertheChernobylreactorexplosion(192).Notably,thyroidcancerrateswerenotincreasedamong3000childrenexposedto131IfromtheHanfordnuclearreactorsiteinaniodine-repleteregion(237).Increasedthyroidcancer

616

Table7.TheoreticalProjectionsofCancerIncidenceorCancerMortalityRelatedto

forHyperthyroidismasRelatedtoAge

Lifetimeattributableriskofcancermortality

Ageatexposure

PermCiPer15mCiMalesFemaleAverageMalesFemaleAverageCasesper100,000(year)0

151015204060

aBAHNETAL.

131ITherapy

Total-body131Idose

(remorrad)

Per100,000per0.1GyorSVPer100,000perradorremLifetimecancerriskfor15mCi131I

%23.99.93.961.971.020.810.560.46

Relativelifetimecancerriskfor15mCi131Ia1.961.401.161.081.041.031.021.02

11.14.62.41.450.90.850.850.8516769.036.021.813.512.812.812.810991099852712603511377319177017701347110491476250740914351435110090875963744236411011085716051383217717713511091765141143143110917664443623,8849898395819751024812564464

Usingagrossaverageofdyingfromaspontaneouscancerof25%dataanalysisbyDr.PatrickZanzonico,MemorialSloanKetteringCancerCenter(NewYork,NY).

ratesalsowerenotseenin6000childrenwhoreceived131Iforthepurposeofdiagnosticscanning(238).

ThereisnoevidencetosuggestthatchildrenoradultstreatedforGDwithmorethan150mCiof131Ipergramofthyroidtissuehaveanincreasedriskofthyroidcancerdirectlyattributabletotheradioactiveiodine.WhilethereareseveralstudiesofthisissueinadultstreatedwithradioactiveiodineforGD(seesec-tionD2),fewstudieshavefocusedonpopulationsexposedto131IforthetreatmentofGDinchildhoodoradolescence.

Inonestudy,ananalysiswascarriedoutof602individualsexposedto131Ibelow20yearsofageinSwedishandU.S.populations(239).Theaveragefollow-upperiodwas10years,andthemeanadministeredactivityofradioactiveiodinetothethyroidwas88Gy(approximately80mCi/gequivalent),anactivityknowntobeassociatedwiththyroidneoplasiaandbelowthatrecommendedfortreatmentofGD.Twocasesofthyroidcancerwerereportedcomparedto0.1casesexpectedoverthatperiodoftime.Effectsonthedevelopmentofnon-thyroidcancerswerenotexamined.

Thepediatricstudywiththelongestfollow-upreported36-yearoutcomesof116patients,treatedwith131Ibetween1953and1973(240).Thepatientsrangedinageattreatmentfrom3to19years.Nopatientdevelopedthyroidcancerorleukemia.Therewasnoincreaseintherateofspontaneousabortionorinthenumberofcongenitalanomaliesinoffspring.Itisimpor-tanttonotethatsamplesizewassmall;thus,thestatisticalpowerwasinadequatetoaddressthisissuefully.

Totalbodyradiationdoseafter131Ivarieswithage,andthesameabsoluteactivitiesof131Iwillresultinmoreradiationexposuretoayoungchildthantoanadolescentoradult(241).Atpresent,wedonothavedosimetryinformationregarding131IuseinchildrenwithGDtoassesstotalbodyexposureinchildren.Usingphantommodeling,ithasbeenestimatedthatat0,1,5,10,and15yearsofage,andadulthood,respectivetotalbodyradiationactivitiesare11.1,4.6,2.4,1.45,0.90,and0.85rem(1rem¼0.1Sv)permCiof131Iadministered(241).BasedontheBiologicalEffectsofIonizingRadiationCom-mitteeVIIanalysisofacute,low-levelradiationexposure(242),thetheoreticallifetimeattributableriskofall-cancerincidenceandall-cancermortalityforalargepopulationoftreatedchildrencanbeestimated(Table7).

Todate,long-termstudiesofchildrentreatedwith131IforGDhavenotrevealedanincreasedriskofnonthyroid

malignancies(239).Ifasmallriskexists,asamplesizeofmorethan10,000childrenwhoweretreatedat<10yearsofagewouldbeneededtoidentifytherisk,likelyexceedingthenumberofsuchtreatedchildren.Basedoncancerriskprojectionsfromes-timatedwhole-body,low-levelradiationexposureasrelatedtoage,itistheoreticallypossiblethattheremaybealowriskofmalignanciesinveryyoungchildrentreatedwith131I.Thus,werecommendedabovethatradioactiveiodinetherapybeavoidedinveryyoungchildren(<5years)andthatradioactiveiodinebeconsideredinthosechildrenbetween5and10yearsofagewhentherequiredactivityfortreatmentis<10smCi.Itisimportanttoemphasizethattheserecommendationsarebasedontheoreticalconcernsandfurtherdirectstudyofthisissueisneeded.Thetheoreticalrisksof131IusemustthereforebeweighedagainsttheknownrisksinherentinthyroidectomyorprolongedATDusewhenchoosingamongthethreedifferenttreatmentoptionsforGDinthepediatricagegroup.

Theactivityofradioactiveiodineadministeredshouldbebasedonthyroidsizeanduptake,andnotarbitrarilyreducedbecauseofageinyoungindividuals.Attemptstominimizetheradioactiveiodineactivitywillresultinundertreatmentandthepossibleneedforadditionalradioactiveiodinether-apyandradiationexposure.

[Q]Ifthyroidectomyischosenastreatment

forGDinchildren,howshoulditbeaccomplished?[Q1]PreparationofchildrenwithGDforthyroidectomy

RECOMMENDATION62

ChildrenwithGDundergoingthyroidectomyshouldberenderedeuthyroidwiththeuseofmethimazole.Po-tassiumiodideshouldbegivenintheimmediatepreop-erativeperiod.1/+00

SurgeryisanacceptableformoftherapyforGDinchildren.ThyroidectomyisthepreferredtreatmentforGDinyoungchildren(<5years)whendeﬁnitivetherapyisrequired,andthesurgerycanbeperformedbyahigh-volumethyroidsur-geon.Inindividualswithlargethyroidglands(>80g),theresponseto131Imaybepoor(64,65);surgeryalsomaybepreferableforthesepatients.Whenperformed,near-totalortotalthyroidectomyistherecommendedprocedure(243).

HYPERTHYROIDISMMANAGEMENTGUIDELINESTechnicalremarks:MMIistypicallygivenfor1–2monthsinpreparationforthyroidectomy.Tendaysbeforesurgery,po-tassiumiodide(SSKI;50mgiodide/drop)canbegivenas3–7drops(i.e.,0.15–0.35mL)threetimesdailyfor10daysbeforesurgery.

RECOMMENDATION63

IfsurgeryischosenastherapyforGDinchildren,totalornear-totalthyroidectomyshouldbeperformed.1/++0&

RECOMMENDATION64

Thyroidectomyinchildrenshouldbeperformedbyhigh-volumethyroidsurgeons.1/++0

Surgicalcomplicationratesarehigherinchildrenthaninadults,withhigherratesinyoungerthaninolderchildren(194).Postoperatively,youngerchildrenalsoappeartobeathigherriskfortransienthypoparathyroidismthanadoles-centsoradults(194).

Inaddition,complicationratesaretwofoldhigherwhenthyroidectomyisperformedbypediatricorgeneralsurgeonswhodonothaveextensivecurrentexperienceinthisproce-durethanwhenperformedbyhigh-volumethyroidsurgeons(194).FurthersupportforthenotionthatthyroidectomyforGDinchildrenshouldbeperformedbyexperiencedthyroidsurgeonscomesfromreportsofinstitutionalexperienceshowinglowcomplicationratesathigh-volumecenters(190,244).Incircumstanceswherelocalpediatricthyroidsurgeryexpertiseisnotavailable,referralofachildwithGDtoahigh-volumethyroidsurgerycenterthatalsohaspedi-atricexperienceisindicated,especiallyforyoungchildren.Amultidisciplinaryhealth-careteamthatincludespediatricendocrinologistsandexperiencedthyroidsurgeonsandan-esthesiologistsisoptimal.

[R]HowshouldSHbemanaged?[R1]FrequencyandcausesofSH

SHhasaprevalenceofabout1%inthegeneralpopulation(245).Inolderpersons,TMNGisprobablythemostcommoncauseofSH,withotheretiologiesofendogenousSH,in-cludingGD,solitaryautonomouslyfunctioningnodules,andvariousformsofthyroiditis(246,247),thelatterofwhichwouldbemorestrictlytermed‘‘subclinicalthyrotoxicosis.’’SomeotherwisehealthyolderpersonsmayhavelowserumTSHlevels,lownormalserumlevelsoffreeT4estimatesandT3,andnoevidenceofthyroidorpituitarydisease,suggestinganalteredsetpointofthepituitary-thyroidaxis(248,249).ThissituationcanmimicSHbiochemically,anditmaybedifﬁculttoruleoutclinically,althoughscintigraphicstudiessuggestingautonomousthyroidfunctionwouldfavorSH.OthercausesofasuppressedTSHbutnormalestimatedfreeT4andT3includecorticosteroidtherapy,centralhypothyroidism,andnon-thyroidalillness.

OnceSHhasbeendetected,itisimportanttodocumentthatitisapersistentproblembyrepeatingtheserumTSHat3or6months.SomereportssuggestthatasubnormalserumTSHmayspontaneouslyresolve,especiallyifthelevelsare>0.05mU/L(250–252).PatientswithGDratherthanaTMNGasthecauseofSHmaybemorelikelytospontane-ouslyremit(253).

617

[R2]ClinicalsigniﬁcanceofSH

SinceSHisamildformofhyperthyroidism,deleteriousef-fectsonthecardiovascularsystemandtheskeletonmightbeexpectedinsomepatients,andsubtlesymptomsofthyro-toxicosisoralteredcognitionmightalsobepotentialproblems.Regardingcardiaccomplications,onestudyfounda2.8-foldriskofatrialﬁbrillationinpersonsoverage60yearswithSH(254),whichhasbeenconﬁrmedinanotherpopulationoverage65years(255).Smalluncontrolledstudieshaveshownimprove-mentincardiacparameters,withrestorationofaeuthyroidstate(256,257)ortheuseofbetaadrenergicblockingdrugs(258).PostmenopausalwomenwithSHmayhaveincreasedfrac-tureratesevenwithonlymildlysuppressedserumTSHlevels(259),aswellasimprovementinbonemineraldensitywiththerapyofSHwithantithyroiddrugsorradioactiveiodineincontrolledbutnonrandomizedinterventionstudies(260,261).Therearealsopreliminarydatasuggestinganincreaseinboneturnover(262)andlowerbonedensityinpremenopausalwo-menwithSH(263).Anotheruncontrolledstudyhasshownanincreaseinmusclemassandmusclestrengthinmiddle-agedwomenwithSHaftertreatmentwithradioactiveiodineorthyroidectomy(264).Forpatientsreceivinglevothyroxinere-placementtherapy,onlythosewithasuppressedTSHhadanincreasedriskofcardiacorbonedisease,whereasthosewithalow,butunsuppressedleveldidnot(265).

Onecross-sectional(266)andonelongitudinal(267)studyofolderindividualsshowednochangesincognitivefunction,whereastwootherssuggestedanassociationbetweenSHanddementiainolderpersons(268,269).Finally,thereisthepo-tentialriskofprogressiontooverthyperthyroidismifSHisleftuntreated.Thisriskisprobablysomewherebetween0.5%and1%peryear(270,271).

DataontheeffectsofSHonmortalityareconﬂicting.Inonestudy,all-causeandcardiovascularmortalitywerehigherinagroupofindividualswithSH(serumTSH<0.5mU/L)aged60yearsandolderat1,2,and5yearsoffollow-up,butnotafter10yearsoffollow-up(271).Anotherstudyalsofoundanincreaseinmortalityover4yearsoffollow-upamongpersonsaged85yearsandabove(267),inathirdstudy,individualswithSHandconcomitantheartdiseasehadanincreaseincardiovas-cularandall-causemortality(272).Incontrast,twootherlon-gitudinalpopulation-basedstudiesreportednoincreaseinoverallmortalityinpersonswithSH(255,273).Arecentmeta-analysissuggestedthatall-causemortalityriskinSHprogres-sivelyincreaseswithage(274),whichmightexplainthecon-ﬂictingreports.Anothermeta-analysis,however,didnotﬁndastatisticallysigniﬁcantincreaseinmortalityinSH(275).[R3]WhentotreatSH

RECOMMENDATION65

WhenTSHispersistently<0.1mU/L,treatmentofSHshouldbestronglyconsideredinallindividuals!65yearsofage,andinpostmenopausalwomenwhoarenotonestrogensorbisphosphonates;patientswithcardiacriskfactors,heartdiseaseorosteoporosis;andindividualswithhyperthyroidsymptoms.2/++0

TreatmentofSHiscontroversial,sincenocontrolledin-terventionstudiestoshowbeneﬁthavebeenperformed.However,apanelofexpertsdeterminedthattheevidencefor

618

beneﬁtwassufﬁcienttowarranttherapyofSHinolderin-dividualswhoseserumTSHlevelwas<0.1mU/L(276).Thiswasbasedprimarilyonthestudiesshowinganincreasedrateofatrialﬁbrillationandalteredskeletalhealthwithasup-pressedlevelofTSHdescribedabove.

ThereareinsufﬁcientdatafororagainsttreatmentofSHinyoungerpersonsorpremenopausalwomenwithSHandse-rumTSH<0.1mU/L.Oneuncontrolledstudyofmiddle-agedpatientsshowedanimprovementinhyperthyroidsymptomswiththerapy(256).Althoughthisstudydidnotincludeyoungerindividuals,thetaskforceelectedtorecommendtreatmentofallSHpatientsyoungerthan65yearsofagewithpersistentTSH<0.1mU/Landhyperthyroidsymptoms.Technicalremarks:ATSHlevelof<0.1mU/Lonrepeatedmeasurementovera3–6-monthperiodisconsideredtobepersistent,effectivelyrulingouttransientthyroiditisasacause.ThethyroiddisorderunderlyingSHshouldbediag-nosed,andismostcommonlyTMNG,GD,orTA.

BAHNETAL.

tientswithtransient,functionaldisordersrelatedtoacuteill-ness,drugs,andothercausesoflowTSH.AsummaryoffactorstoconsiderwhendecidingwhetherornottotreatapatientwithSHisprovided(Table8).

[R4]HowtotreatSH

RECOMMENDATION67

IfSHistobetreated,thetreatmentshouldbebasedontheetiologyofthethyroiddysfunctionandfollowthesameprinciplesasoutlinedforthetreatmentofoverthyperthy-roidism.1/+00

RECOMMENDATION66

WhenTSHispersistentlybelowthelowerlimitofnormalbut!0.1mU/L,treatmentofSHshouldbeconsideredinindividuals!65yearsofageandinpatientswithcardiacdiseaseorsymptomsofhyperthyroidism.2/+00

Sincethepublicationoftheexpertpanelreportdiscussedabove,asubsequentstudyshowedthatahigherriskofatrialﬁbrillationmayextendtopersonsoverage65yearswhohaveserumTSHlevelsbetween0.1and0.5mU/L(where0.5mU/Listhelowerlimitofthenormalrangefortheassay)(255).Therefore,justiﬁcationfortherapyinpatientswiththishigherTSHthresholdlevelrestswiththosedata,aswellasameta-analysisshowingaprogressiveincreaseinmortalityinin-dividualsolderthan60yearsofage(274).Incontrast,anobservationalcohortstudyofT4-treatedpatientscouldﬁndnosuchrelationshipwithTSHlevelsbetween0.04and0.4mU/L.Therearenodatafororagainsttreatmentofindividualsyoungerthanmiddle-agedwithserumTSHlevelsbetween0.1and0.5mU/L.Inpatientswithsymptomsofhyperthyroidism,atrialofbeta-adrenergicblockersmaybeusefultodeterminewhethersymptomatictherapymightsufﬁce.

Technicalremarks:ATSHlevelbetween0.1and0.5mU/Lonrepeatedmeasurementovera3–6-monthperiodisconsideredpersistent,effectivelyrulingouttransientthyroiditisasacause.ThethyroiddisorderunderlyingSHwithTSHpersistentlywithinthisrangeshouldbediagnosedtoavoidtreatingpa-

ThetreatmentofSHissimilartothetreatmentofoverthy-perthyroidism.Radioactiveiodineisappropriateformostpa-tients,especiallyinolderpatientswhenTMNGisafrequentcauseofSH.Therearenodatatoinformwhetherelderlypa-tientswithSHwouldbeneﬁtfrompretreatmentwithATDstonormalizethyroidfunctionbeforeradioactiveiodinetherapy.Giventhelowriskofexacerbation(51),therisksofATDther-apymayoutweighanypotentialsmallbeneﬁt.Long-termATDtherapyisareasonablealternativetoradioactiveiodineinpatientswithGDandSH,especiallyinyoungerpatients,sinceremissionratesarehighestinpersonswithmilddisease(81).SomepatientswithSHduetoGDmayremitspontaneouslywithouttherapy,sothatcontinuedobservationwithoutther-apyisreasonableforyoungerpatientswithSHduetoGD.AsmallsubsetofelderlypatientswithpersistentlylowTSHandnoevidenceoftruethyroiddysfunctioncanbefollowedwithoutintervention,especiallywhentheserumFT4estimateandT3levelsareinthelowerhalfofthenormalrange.Treat-mentwithbeta-adrenergicblockademaybesufﬁcienttocon-trolthecardiovascular-relatedmorbidityfromSH,especiallythatofatrialﬁbrillation(258).

Technicalremarks:SomepatientswithSHduetomildGDmayremitspontaneouslyandmaybefollowedwithouttherapywithfrequent(every3months)monitoringofthyroidfunction.InselectpatientswithSHduetoTMNGwhohavecompressivesymptoms,orinwhomthereisconcernformalignancy,surgeryisalsoanoption.

[R5]EndpointstobeassessedtodetermineeffectivetherapyofSH

ThegoaloftherapyforSHistorenderthepatienteuthyroidwithanormalTSH.SincetherationalefortherapyofSHistoa

Table8.SubclinicalHyperthyroidism:WhentoTreat

Factor

Age>65

Age<65withcomorbiditiesHeartdiseaseOsteoporosisMenopausal

HyperthyroidsymptomsAge<65,asymptomatic

aTSH(<0.1mU/L)Yes

YesYes

ConsidertreatingYes

Considertreating

TSH(0.1–0.5mU/L)aConsidertreatingConsidertreatingNo

ConsidertreatingConsidertreatingNo

Where0.5mU/Listhelowerlimitofthenormalrange.

HYPERTHYROIDISMMANAGEMENTGUIDELINESlargedegreepreventive,therearefewendpointsthatcanbeusedtodocumentthattherapyhasbeensuccessful.Therearenostudiestoshowthattherapypreventstheonsetofatrialﬁbrillationordecreasesmortality.SeveralstudieshaveshownstabilizationorimprovementinbonemineraldensitywiththerapyofSHinpostmenopausalwomen(260,261,277).OneuncontrolledstudyreportedanimprovementinhyperthyroidsymptomswithantithyroiddrugtherapyofSH(256)andasecondreportshowedimprovementinthehyperthyroidsymptomsofSHaftertreatmentwithbeta-adrenergicblock-ade(258).

[S]Howshouldhyperthyroidisminpregnancybemanaged?

HyperthyroidismduetoGDiscommoninwomeninthereproductiveagerangeandboththethyrotoxicosisandtherapyofthediseasemaycomplicatethecourseandout-comeofpregnancy.Further,normalpregnancyisaccompa-niedbychangesinthyroidphysiology,andalteredthyroidfunctiontestingwillreﬂectthis.Inearlypregnancy,physio-logicalchangescanmimicbiochemicalhyperthyroidismthatdoesnotrequiretherapy.Intheseguidelines,wewilladdressonlythemostcommonissuesrelatedtohyperthyroidisminpregnancy,pendingfullguidelinesonthyroiddiseaseandpregnancycurrentlybeingdevelopedbytheATA.[S1]Diagnosisofhyperthyroidisminpregnancy

RECOMMENDATION68

ThediagnosisofhyperthyroidisminpregnancyshouldbemadeusingserumTSHvalues,andeithertotalT4andT3withtotalT4andT3referencerangeadjustedat1.5timesthenonpregnantrangeorfreeT4andfreeT3estimationswithtrimester-speciﬁcnormalreferenceranges.1/+00

Thediagnosisofhyperthyroidisminpregnancycanbechallenging.Inthevastmajorityofpatients,thediseaseiscausedbyaprimarythyroidabnormality,andtheprincipalﬁndingwillbeasuppressedserumTSH,withestimatedse-rumfreeT4and/orfreeT3levelsabovethereferencerange(overthyperthyroidism),orwithinthereferencerange(SH).Akeypointisthatreferencerangesforthyroidfunctiontestsaredifferentduringvariousstagesofpregnancy,andforsometypesofassays,thechangemaybeassay-dependent.GDisthemostcommoncauseofhyperthyroidismduringpreg-nancy(278);nodularthyroiddiseaseislesscommon.Hy-perthyroidismcausedbyahumanchorionicgonadotropin(hCG)-producingmolarpregnancyorachoriocarcinomapresentswithadiffusehyperactivethyroidsimilartoGD,butwithouteyesignsandwithoutserumTRAb.Inthesepatients,serumhCGwillbehigherthanexpected,andthecausecanbeidentiﬁedbyobstetricalinvestigation.

Anunderstandingofpregnancy-relatedvariationsinthy-roidfunctiontestsisimportantinmakingthediagnosisofhyperthyroidisminpregnancy.SerumTSHlevelsmaybebelowthenonpregnantreferencerangeintheﬁrsthalfofanormal-termpregnancy(279,280),presumablytheresultofstimulationofthenormalthyroidbyhighlevelsofserumhCG(281).Therefore,lowserumTSHlevelswithnormalfreeT4valuesinearlypregnancydonotindicateabnormalthyroidfunction.Duringthesecondhalfofpregnancy,the

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lowerlimitforTSHinthenonpregnantpopulationcanbeused(282).

FreeT4andT3measuredinanequilibriumdialysateoranultraﬁltrateofserummaybeslightlyhigher(5%–10%)thannonpregnancyvaluesaroundweek10ofpregnancy,correspondingtotheperiodofhighserumhCGandlowserumTSH.Fromthisnormalorslightlyhighlevel,agradualdecreaseoccursduringpregnancy,andlatethirdtrimesterreferencevaluesare10%–30%belownon-pregnancyvalues(283).

SerumtotalT4andT3increaseinearlypregnancy.Fromthelateﬁrsttrimester,theyremainstable,withreferencerangescloseto1.5timesnonpregnancyrangesduringthesecondandthirdtrimesters(283,284).TotalT4andT3valuesmaybecombinedwithaT3uptaketestormeasurementsofTBGtoadjustforpregnancy-associatedvariationsinTBG.Such‘‘freeT4index’’or‘‘TBGadjustedT4’’valuesmaybeusefulfordi-agnosinghyperthyroidisminpregnancy.However,trimester-speciﬁcnormalreferencerangesshouldbeestablishedforeachindividualtestandassayused.

Technicalremarks:Thereliabilityofautomatedanalog-basedassaysforfreeT4andfreeT3estimationshasbeenquestionedformorethan25years(285),buttheseestimatesarecurrentlywidelyused;inmanyclinics,theyarethestan-dardofmeasurementinpregnancy.Becausepregnancymayinﬂuenceresultsoftheseassaysfromdifferentmanufacturersindifferentways(286),method-speciﬁcreferencerangesforeachtrimesterofpregnancyshouldbeemployedbythemanufacturer(287,288).

[S2]Managementofhyperthyroidisminpregnancy

RECOMMENDATION69

TransienthCG-mediatedthyrotropinsuppressioninearlypregnancyshouldnotbetreatedwithantithyroiddrugtherapy.1/+00

Oncethediagnosisofhyperthyroidismismadeinapreg-nantwoman,attentionshouldbefocusedondeterminingtheetiologyofthedisorderandwhetheritwarrantstreatment.Clinicalfeaturesthatmayindicatethepresenceofsigniﬁcanthyperthyroidismincludefailuretogainweight,heatintoler-ance,excessivesweating,andtachycardia,beyondthatnor-mallyassociatedwithpregnancy.

Thetwomostcommontypesofbiochemicalhyper-thyroidismthatoccurduringpregnancyaregestationalhyperthyroidism(e.g.,hCG-mediatedtransientTSHsup-pression)andGD.Gestationalhyperthyroidismisagen-erallyasymptomatic,mildbiochemicalhyperthyroidismthatmaybeobservedintheﬁrsttrimesterofnormalpregnancy.ItispresumablycausedbythehighserumhCGofearlypregnancy(281)andisnotassociatedwithadversepregnancyoutcomes(289).Pregnantwomenhavingges-tationalhyperthyroidismwithemesis,andparticularlyhyperemesis,maydevelopmoreprofoundabnormalitiesinthyroidfunction,withbiochemicallyoverthyperthyroid-ismandclinicalsymptomsandsignsofhyperthyroidism.Complicatedcasesofgestationalhyperthyroidismshouldbereferredtomedicalcenterswithspeciﬁcexpertiseintreatingthesepatients.

620

Technicalremarks:ThereisnoevidencethattreatmentofgestationalhyperthyroidismwithATDsisbeneﬁcial.Inthesepatients,physicalexaminationandrepeatthyroidfunctiontestsatintervalsof3–4weeksisrecommended.Ifthediffer-entialdiagnosisofthetypeofhyperthyroidismisunclear(i.e.,ifthereissuspicionofGD)orinthecaseofverysymptomaticdisease,atrialofATDtherapymaybeconsideredifsigniﬁ-cantclinicalhyperthyroidismisevident.

RECOMMENDATION70

Antithyroiddrugtherapyshouldbeusedforhyper-thyroidismduetoGDthatrequirestreatmentduringpregnancy.Propylthiouracilshouldbeusedwhenanti-thyroiddrugtherapyisstartedduringtheﬁrsttrimester.Methimazoleshouldbeusedwhenantithyroiddrugther-apyisstartedaftertheﬁrsttrimester.1/+00

Untreatedorinsufﬁcientlytreatedhyperthyroidismmayseriouslycomplicatepregnancy(290–292),andpatientswiththisdisordershouldbetreatedatcenterswithspeciﬁcex-pertiseinthisarea.GDasthecauseofhyperthyroidisminpregnancymaybediagnosedfromtypicalclinicalﬁndings,includingthepresenceofGOand/orserumTRAbinahy-perthyroidpatient.Approximately5%ofpatientswithnewlydiagnosedGraves’hyperthyroidismareTRAbnegative(43,293),especiallythosewithmilderdisease.

AwomanfoundtohaveGDbeforepregnancyandtreatedwithATDwhogoesintoremissionandiseuthyroidoffmedicationhasalowriskofrecurrenthyperthyroidismdur-ingpregnancy.However,herriskofrelapse(aswellastheriskofpostpartumthyroiditis)duringthepostpartumperiodisrelativelyhigh(294).Antithyroiddrugshavemuchthesameeffectonthyroidfunctioninpregnantasinnonpregnantwomen.BothATDsandTRAbpasstheplacentaandcanaf-fectfetalthyroid.Ontheotherhand,T4andT3crosstheplacentaonlyinlimitedamounts.

PTUgenerallyhasbeenpreferredinpregnancybecauseofconcernsaboutrarebutwell-documentedteratogenicityassociatedwithMMI,namely,aplasiacutisandchoanaloresophagealatresia(81).However,recentconcernsaboutrarebutpotentiallyfatalPTUhepatotoxicityhaveledtoare-examinationoftheroleofPTUinthemanagementofhyperthyroidisminpregnancy(92).TheU.S.FoodandDrugAdministrationrecentlyrecommendedthatPTUbereservedforpatientswhoareintheirﬁrsttrimesterofpregnancy,orwhoareallergictoorintolerantofMMI(92,93).

MMIandPTUbothappearinbreastmilkinsmallcon-centrationsandstudiesofbreast-fedinfantsofmotherstakingATDshavedemonstratednormalthyroidfunctionandsub-sequentintellectualdevelopment(81).However,becauseofthepotentialforhepaticnecrosisineithermotherorchildfrommaternalPTUuse,MMIisthepreferredATDinnursingmothers.

RECOMMENDATION71

Wesuggestthatpatientstakingmethimazolewhodecidetobecomepregnantobtainpregnancytestingattheearliestsuggestionofpregnancyandbeswitchedtopropylthiour-acilassoonaspossibleintheﬁrsttrimesterandchangedbacktomethimazoleatthebeginningofthesecondtrimes-ter.Similarly,wesuggestthatpatientsstartedonpro-

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pylthiouracilduringtheﬁrsttrimesterbeswitchedtomethimazoleatthebeginningofthesecondtrimester.2/+00ConcernisthatchangingbackandforthbetweenMMIandPTUmightleadtopoorlycontrolledthyroidfunctionbecauseofdifferencesinpharmacokineticsanduncertaintyaboutdoseequivalencybetweenthetwodrugs.ThissituationiscomplicatedbythechanginglevelsofTRAbinpregnancy.Ingeneral,apotencyratioofMMItoPTUofatleast20–30:1isrecommendedwhenchangingfromonedrugtoanother,al-thoughtherearenostudiesthathaveexaminedthispotencyratiodirectly.Forexample,300mgofPTUwouldberoughlyequivalentto10to15mgofMMI(81).Alternatively,ratherthanswitchingtoMMIattheendoftheﬁrsttrimester,thepatientcouldremainonPTUduringthesecondandthirdtrimesters,andhavehepaticenzymesmeasuredevery4weeks,atthesametimethatthyroidfunctionisassessed.However,therearenoprospectivedatathatshowthatthistypeofmonitoringiseffectiveinpreventingfulminantPTU-relatedhepatotoxicity.

RECOMMENDATION72

GDduringpregnancyshouldbetreatedwiththelowestpossibledoseofantithyroiddrugsneededtokeepthemother’sthyroidhormonelevelsslightlyabovethenor-malrangefortotalT4andT3valuesinpregnancyandtheTSHsuppressed.FreeT4estimatesshouldbekeptatorslightlyabovetheupperlimitofthenonpregnantreferencerange.Thyroidfunctionshouldbeassessedmonthly,andtheantithyroiddrugdoseadjustedasre-quired.1/+00

EvenifthemotheriseuthyroidduringATDtherapy,thereisariskofinducingfetalhypothyroidismduringthesecondandthirdtrimesterswhenthefetalthyroidhasbeguntofunction(295,296).Thus,thedoseofATDshouldbekeptaslowaspossible.Block-replacementtherapyconsistingofATDpluslevothyroxineshouldnotbeusedinpregnancy.Ifawomanreceivingsuchtherapybecomespregnant,therapyshouldbechangedtoanATDalone(278).

Technicalremarks:FreeT4istheparameterthathasbeenmostcloselycorrelatedwithgoodfetaloutcome.SerumTSHmaystillbesuppressedinthesepatientsandshouldnotbeusedasthesoleguideintreatment,althoughnormalizationofmaternalTSHduringATDtherapymayindicateaneedtoreducethedoseofATD(278).

RECOMMENDATION73

Whenthyroidectomyisnecessaryforthetreatmentofhy-perthyroidismduringpregnancy,thesurgeryshouldbeperformedifpossibleduringthesecondtrimester.1/+00

Pregnancyisarelativecontraindicationtothyroidectomyandshouldonlybeusedinthiscircumstancewhenaggressivemedicalmanagementhasnotobviatedtheneedforimmedi-atetreatmentofthehyperthyroidismandantithyroidmedi-cationscannotbeused.Thyroidectomyisbestavoidedintheﬁrstandthirdtrimestersofpregnancybecauseofteratogeniceffectsassociatedwithanestheticagentsandincreasedriskoffetallossintheﬁrsttrimesterandincreasedriskofpreterm

HYPERTHYROIDISMMANAGEMENTGUIDELINESlaborinthethird.Optimally,thyroidectomywouldbeper-formedinthelatterportionofthesecondtrimester.Althoughitisthesafesttime,itisnotwithoutrisk(4.5%–5.5%riskofpretermlabor)(47,48).

Evaluationbyahigh-riskobstetricianisadvisedalongwithcounselingbeforesurgeryregardingrisksinvolved(48).ThyroidectomycuresthehyperthyroidconditionandisoftenfollowedbyagradualreductioninTRAbfromthecirculation(297).Untilsuchremissiontakesplace,TRAbproducedbythemothermaystimulatethethyroidofthefetusornewbornandinducehyperthyroidism.InthesettingwherethemotherstillharbourshighlevelsofTRAbafterthyroidectomy,closefetalmonitoringforbothcardiovascularandskeletalchanges(fetalultrasound)mustbeestablished.

TherearenodataconcerningwhetherSSKIoriodineshouldbeusedtopreparepregnantpatientsforthyroidec-tomy.Theriskofiodidetherapytothefetusisinhibitionofiodineorganiﬁcation,theWolff-Chaikoffeffect.Thefetalthyroidglandisparticularlysusceptibletotheinhibitoryef-fectsofexcessiodineattheendofgestation,andfetalgoitercanoccurwithchronictherapy(298).However,thereisnoevidencethatbriefiodinepreparationofthemotherdonepreoperativelytoreducethyroidbloodﬂowandcontrolhy-perthyroidismisharmfultothefetus.

Technicalremarks:Preoperativepreparationforthyroidec-tomyduringthesecondtrimesterofpregnancyincludes10–14daysofiodine,alongwithATDtherapyandbeta-blockerstocontrolhyperthyroidism(299–301).

[S3]TheroleofTRAblevelsmeasurementinpregnancy

RECOMMENDATION74

TRAblevelsshouldbemeasuredwhentheetiologyofhyperthyroidisminpregnancyisuncertain.1/+00

ThetwobestindicatorsoftheactivityofGDduringpreg-nancyarethyroidfunctionintheuntreatedpatientandmea-surementofTRAblevelsintheserum.TRAbmeasurementisusefulinthediagnosisofGDinpregnantwomenwithnewlydiagnosedhyperthyroidismwhodonothaveclinicalsignsspeciﬁcforGD,keepinginmindthatthediagnosticsensitivityofgoodassaysisaround95%,andthespeciﬁcityis99%(43).

RECOMMENDATION75

Patientswhoweretreatedwithradioactiveiodineorthy-roidectomyforGDpriortopregnancyshouldhaveTRAblevelsmeasuredusingasensitiveassayeitherinitiallyat22–26weeksofgestation,orinitiallyduringtheﬁrsttri-mesterand,ifelevated,againat22–26weeksofgestation.1/+00

MeasurementofTRAblevelscandetectpersistentTSH-receptorautoimmunityinapregnantwomanpreviouslytrea-tedwithablativetherapy(radioactiveiodineorthyroidectomy)forGDwhoisnoweuthyroidwithorwithoutthyroidhormonereplacement(297,302).IfthemotherstillproducesTRAb,theywillcrosstheplacentaandmayaffectfetalthyroidfunctioninthelasthalfofthepregnancy.BecauseoftheslowclearanceofmaternalimmunoglobulinG(IgG)fromtheneonatalcircula-

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tion,thyroiddysfunctioninthechildmaylastforseveralmonthsafterbirth.Toevaluatetheriskofsuchcomplications,aTRAblevelshouldbemeasuredinthepregnantwomaneitherinitiallyat22–26weeksofgestation,orinitiallyduringtheﬁrsttrimesterand,ifelevated,againat22–24weeksofgestation.Ifthelevelishigh,aprogramoffetalandneonatalsurveillanceforthyroiddysfunctionshouldbeinitiated(303).Whilemea-suringTRAblevelsonlyat22–26weeksismorecosteffective,theadvantagetoinitialmeasurementduringtheﬁrsttrimesteristhatthisallowsmoretimetoinitiatespecialtyconsultationand,ifthelevelsarefoundtobeespeciallyhighatthattime,interventionmayberequiredbeforethethirdtrimester.TRAbmeasurementisnotnecessaryinaeuthyroidpregnantpatientpreviouslyfoundtohaveGDifshehasanintactthyroid(i.e.,notpreviouslytreatedwithsurgeryorradioactiveiodine)andisnotcurrentlytakingATDs(295,297).

RECOMMENDATION76

PatientsfoundtohaveGDduringpregnancyshouldhaveTRAblevelsmeasuredatdiagnosisusingasensitiveassayand,ifelevated,againat22–26weeksofgestation.1/+00&

RECOMMENDATION77

TRAblevelsmeasuredat22–26weeksofgestationshouldbeusedtoguidedecisionsregardingneonatalmonitoring.1/+00

TRAb(TBIIorTSI)measurementisalsousefultoassistintheevaluationofdiseaseactivityinawomanbeingtreatedwithATDsforGDduringpregnancy(297).Inmanypatients,GDgraduallyremitsduringpregnancy.DisappearanceofTRAbisanindicationthatATDtherapymaynolongerbenecessary,andthatitscontinuationmayputthefetusatriskforhypo-thyroidism.TRAbmeasurementalsocanbeusedduringthethirdtrimestertoassesstheriskofdelayedneonatalhyper-thyroidismwhenthemothercontinuestoneedMMItocontrolhyperthyroidismuptoterm.Afterdelivery,MMIdeliveredtothefetusviaplacentalpassageisrapidlymetabolizedbytheneonate,whereasthematernalTRAbdisappearsmoreslowly,withahalf-lifeofaround3weeks.Thus,ahighlevelofTRAbinthemotherinlatepregnancyisanindicatorthattheneonatemayneedtobemonitoredfortheonsetofneonatalhyper-thyroidismstartingafewdaysafterbirth.

Technicalremarks:AsensitiveTBIIassayorTSIassayshouldbeusedtodetectTRAbduringpregnancy.AsummaryofTRAbmeasurementandmanagementofhyperthyroidismcausedbyGDduringpregnancyispresentedinTable9.[S4]Postpartumthyroiditis

RECOMMENDATION78

Inwomenwiththyrotoxicosisafterdelivery,selectivedi-agnosticstudiesshouldbeperformedtodistinguishpost-partumthyroiditisfrompostpartumGD.1/+00

Postpartumthyroiddysfunctionoccursinupto10%ofpregnanciesintheUnitedStates.Postpartumthyroiditisisanautoimmunedisorderunmaskedinpredisposedwomenasimmunesurveillancereboundsafterpregnancy.Theclassictriphasicpatternisthyrotoxicosisat1–6monthspostpartum,

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Table9.SummaryofRecommendationsConcerningManagementofGraves’DiseaseinPregnancy

TimingofdiagnosisGDdiagnosed

duringpregnancy

Speciﬁccircumstances

Diagnosedduringﬁrsttrimester

Recommendations

BeginpropylthiouracilaMeasureTRAbatdiagnosisand,ifelevated,repeatat22–26weeksofgestationbIfthyroidectomyisrequired,itisoptimallyperformedduringthesecondtrimesterBeginmethimazolecMeasureTRAbatdiagnosisand,ifelevated,repeatat22–26weeksofgestationbIfthyroidectomyisrequired,itisoptimallyperformedduringthesecondtrimester

SwitchtopropylthiouracilassoonaspregnancyisconﬁrmedwithearlytestingaMeasureTRAbeitherinitiallyat22–26weeksofgestation,or

initiallyduringtheﬁrsttrimesterand,ifelevated,againat22–26weeksofgestationbTRAbmeasurementnotnecessaryMeasureTRAbeitherinitiallyat22–26weeksofgestation,or

initiallyduringtheﬁrsttrimesterand,ifelevated,againat22–26weeksofgestationbDiagnosedafterﬁrsttrimester

GDdiagnosedandtreatedpriortopregnancy

Currentlytakingmethimazole

InremissionafterstoppingantithyroidmedicationPrevioustreatmentwithradioiodineorsurgery

SeeremarksunderRecommendation71fordiscussionregardingswitchingfromoneantithyroiddrugtotheotherduringpregnancy.IfaTRAb-positivewomanbecomesTRAb-negativeduringpregnancy,thismayindicateaneedtoreduceorstopantithyroiddrugtherapytoavoidfetalhypothyroidism.IftheantithyroiddrugtreatedmotherhashighTRAbvaluesinlatepregnancythisindicatesariskofdelayedneonatalhyperthyroidism(seeremarkstoRecommendation77).Ifthemotherhasundergonesometypeofthyroidablation(radioactiveiodineorsurgery)forGDandTRAbishigh,evaluatefetuscarefullyforhyperthyroidisminsecondhalfofpregnancyandadjustorbeginantithyroiddrugtherapyaccordingly.cAvoidfetalhypothyroidism,especiallyinsecondhalfofpregnancy(seerecommendation75fordetails).

bafollowedbyhypothyroidismandreturntoeuthyroidismat9–12monthspostpartum(304,305).However,thissequenceisnotobservedineverypatient.Among371casesin13studies,25%ofpatientswerefoundtohaveatriphasicpattern,43%hadhypothyroidismwithoutprecedingthyrotoxicosis,and32%hadthyrotoxicosiswithoutsubsequenthypothyroidism(305).Inaprospectivestudyofpregnantwomen,thosewithpositivethyroperoxidase(TPO)antibodiesintheﬁrsttri-mesterwere27timesmorelikelytodeveloppostpartumthyroiditisthanwerethosewithnegativeserology(306).Inthisstudy,tobaccosmokingandbottlefeeding(maybebe-causeofhigherexposureofthematernalthyroidtoiodine,whichisnotexcretedintobreastmilk)alsoincreasedtheriskofdevelopingthyroiditis.

PostpartumthyroiditismustbedistinguishedfromGDtorecommendpropertherapy.Goiterisgenerallymorepro-nouncedinGD,andthyroidbruitorGOstronglysuggestGDaswell.TRAbmaybemeasurableinpatientswithpostpar-tumthyroiditis,buthighertitersaresuggestiveofGD.Wheninvivotestingisrequiredtomakethisdistinction,123Iortechnetiumshouldbeusedratherthan131Iinwomenwhoarenursing,sincetheshorterhalf-lifeoftheseagentswillallowbreastmilktobepumpedanddiscardedforseveraldaysandnursingresumed,whereasbreast-feedingshouldnotbere-sumedif131IisgivenastreatmentforGD(307).TotalT3toT4ratios(ng/dL:mcg/dL)tendtobehigher(>20)inpatientswithGDthaninthosewithpostpartumthyroiditis.

RECOMMENDATION79

Inwomenwithsymptomaticpostpartumthyrotoxicosis,thejudicioususeofbeta-adrenergicblockingagentsisre-commended.1/+00

Treatmentforpostpartumthyroiditisisgenerallysupportiveinnature,withtheuseofbeta-adrenergicblockerssuchaspropranolol(lowestlevelinbreastmilk)(308)ormetroprololtocontrolpulserateandhyperadrenergicsymptomsduringthethyrotoxicstage.Levothyroxinetherapymaybebeneﬁcial,atleasttransiently,forwomenwithsymptomatichypothyroid-ismorhavingTSHlevels>10mU/L(305).

Technicalremarks:Becausebetablockersaresecretedintobreastmilkinverylowlevels,nospecialmonitoringisneededforbreastfedinfantsofmothersonthesemedications(308).[T]HowshouldhyperthyroidismbemanagedinpatientswithGraves’ophthalmopathy?

GOisaninﬂammatoryeyediseasethatdevelopsintheorbitinassociationwithautoimmunethyroiddisorders(309).

HYPERTHYROIDISMMANAGEMENTGUIDELINES

Table10.AssessmentofGraves’Ophthalmopathy:ClinicalActivityScoreElements

ElementsaPainfulfeelingbehindtheglobeoverlast4weeksPainwitheyemovementduringlast4weeksRednessoftheeyelidsRednessoftheconjunctivaSwellingoftheeyelids

Chemosis(edemaoftheconjunctiva)

Swollencaruncle(ﬂeshybodyatmedialangleofeye)Increaseinproptosis!2mm

Decreasedeyemovements!58anydirectionDecreasedvisualacuity!1lineonSnellenchart

a623

Eachvisit

XXXXXXX

ComparisonwithpreviousvisitScore1111111111

XXX

A7-pointscale(excludingthelastthreeelements)isusedwhennopreviousassessmentisavailable.GOisconsideredactiveinpatientswithaCAS!3.

Sources:AdaptedfromMouritsetal.,1989(310);andMouritsetal.,1997(311).

Inthemajorityofcases,itoccursinpatientswithcurrentorpastGD.Thyroid-associatedorbitopathy,thyroideyedisease,andGraves’orbitopathyareothernamesusedforGO.Ap-proximatelyhalfofpatientswithGraves’hyperthyroidismhavesignsand/orsymptomsofGO,and5%sufferfromse-veredisease.

[T1]AssessmentofdiseaseactivityandseverityThenaturalhistoryofthediseaseisoneofrapiddeterio-rationfollowedbygradualimprovementtowardthebaseline.ThisactivephaseisbestdescribedbytheClinicalActivityScore(CAS)(310,311).TheCASisgeneratedbytheadditionofonepointforeachofthefollowingfeaturesifpresent:paininprimarygaze,painwitheyemovement,chemosis,eyelidswelling,eyeliderythema,conjunctivalredness,carunculaswelling,and,overtheprior3months,decreasedvisualacuity,increaseddiplopia,andproptosis(Table10).Thescorerangesfrom0to10andpredictsresponsetoanti-inﬂamma-torytherapies(310,311).A7-pointscale,lackingthelastthreeelements,isusedwhennopreviousassessmentisavailable.GOisconsideredactiveinpatientswithaCAS!3.Therefore,hyperthyroidpatientshavingonlylidretractionalone,orinconjunctionwithmildconjunctivalerythemaandeyelidswelling,arenotconsideredtohaveactiveGO.Theseverityofthediseaseisbestassessedusingobjective,quantiﬁableparametersandisausefultoolfordirectingtherapy.Themaingradationsofdiseaseseverityaremild,moderatetosevere,andsightthreatening(312).Table11liststheelementsasagreeduponinaconsensusstatementbytheEuropeanGrouponGraves’Orbitopathy(EUGOGO)(312).Bothactivityandseverityofthediseasemustbeconsideredintherapeuticdecisionsregardingtreatmentoftheeyediseaseitself,aswellastreatmentofhyperthyroidism.TheoverallevaluationandmanagementofGOisbestdoneinamulti-disciplinarycliniccombiningendocrinologistsandophthal-mologistswithexpertiseintheconditionandotherspecialtiesinconsultation(e.g.,ENT,radiationtherapy,plasticsurgery,andendocrinesurgery).

QoLisclearlyimpairedbythedisease,butonlyalimitednumberofarticleshavebeenpublishedinthisarea.TheU.S.FoodandDrugAdministrationhasendorsedQoLinforma-tionasacomponentofanytherapeuticapplication.TheQoLcorrelationwithdiseaseseverityhasbeenfairtoexcellentfortheoneinstrumentpublishedtodateinaNorthAmericanpopulation(316),thoughitlacksprospectivedata.TwonewvalidatedinstrumentsassessingQoLintheU.S.populationaresoontobepublishedandwillbeuseful,astheinstrumentcommonlyusedinEurope(317)hasnotbeentestedintheNorthAmericanpopulation.

Table11.Graves’OphthalmopathySeverityAssessment

GradeaLidretraction

Softtissues

ProptosisbDiplopia

CornealexposureOpticnervestatus

AbsentMildMildSevere

NormalNormalNormal

Compression

Mild<2mmModerate!2mmSevere!2mmSightthreatening—UpperlimitsofnormalAfricanAmericanWhiteAsian

aMildinvolvement<3mmTransientorabsentModerateinvolvement!3mmInconstantSevereinvolvement!3mmConstant

———F/M¼23/24mm

F/M¼19/21mm

F/M¼16/17mm(Thai)or18.6mm(Chinese)

MildGO:patientswhosefeaturesofGOhaveonlyaminorimpactondailylife,generallyinsufﬁcienttojustifyimmunosuppressiveorsurgicaltreatment.Moderate-to-severeGO:patientswithoutsight-threateningGOwhoseeyediseasehassufﬁcientimpactondailylifetojustifytherisksofimmunosuppression(ifactive)orsurgicalintervention(ifinactive).Sight-threateningGO:patientswithdysthyroidopticneuropathyand/orcornealbreakdown.Thiscategorywarrantsimmediateintervention.bProptosisreferstothevariationcomparedtotheupperlimitofnormalforeachrace/sexorthepatient’sbaseline,ifavailable.

Sources:AdaptedfromdeJuanetal.,1980(313);Sarinnapakornetal.,2007(314);Tsaietal.,2006(315);andBartalenaetal.,2008(312).

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Table12.UseofOralGlucocorticoidsforPreventionofGraves’OphthalmopathyDevelopment

orProgressionWhenRadioactiveIodineIsUsedtoTreatGraves’Hyperthyroidism

RAIwithoutglucocorticoids

RAIwithoralglucocorticoidsRecommendagainst

AcceptableaRecommend

Insufﬁcientdatatorecommendfororagainst

Recommendagainst

NoGO(nonsmoker)NoGO(smoker)

GOpresent-activeandmild(nonsmoker)GOpresent-activeandmild(smoker)

GOpresent-activeandmoderate-to-severeorsight-threatening(smokerornonsmoker)GOpresent-inactive(smokerornonsmoker)

Recommend

InsufﬁcientdatatorecommendfororagainstAcceptableaRecommendagainstRecommendagainstRecommend

Methimazoleorthyroidectomyarealsorecommendedtreatmentoptionsineachofthesescenarios,andtheyarethepreferredchoiceoftherapyinpatientswithactiveandmoderate-to-severeorsight-threateningGO.aThedecisionregardinguseofconcurrentglucocorticoidsshouldbemadeinlightoftherisk-beneﬁtratiorelativetothepatient’soverallhealth.RiskfactorsforGOdeterioration(highT3level,highTRAblevel,smoking)increasethebeneﬁtofglucocorticoidsinpreventingGOdeterioration.Poorlycontrolleddiabetes,osteoporosis,psychiatricillness,highriskforinfectionsincreasethelikelihoodofcomplicationsfromglucocorticoids.

IntheremainderofsectionT,wediscussthepreventionofGOandthemanagementofhyperthyroidisminpatientshavingestablishedGO.Inparticular,wefocusonrecom-mendationsregardingtheconcurrentuseofcorticosteroidsinpatientschoosingradioactiveiodineastreatmentforhyper-thyroidism(Table12).[T2]PreventionofGO

CurrenttherapeuticapproachestoGO,includinglocalmeasures,corticosteroids,orbitalradiation,andsurgery(312),oftenfailtosigniﬁcantlyimprovetheQoLofpatientswiththisdebilitatingcondition.Therefore,effortsshouldbemadetopreventthedevelopmentorprogressionofGOinpatientswithGraves’hyperthyroidism.IdentiﬁedriskfactorsforGOincluderadioiodinetherapyforhyperthy-roidism(318,319),smoking,highpretreatmentT3values(!325ng/dLor!5nmol/L)(319),highserumpretreatmentTRAblevels(>50%TBIIinhibitionorTSI>8.8IU/Liter)(320),andhypothyroidismfollowingradioiodinetreatment(321).

RECOMMENDATION81

InnonsmokingpatientswithGraves’hyperthyroidismwhohavenoclinicallyapparentophthalmopathy,131Itherapywithoutconcurrentsteroids,methimazole,orthyroidectomyshouldbeconsideredequallyacceptabletherapeuticoptions.1/++0

RECOMMENDATION80

EuthyroidismshouldbeexpeditiouslyachievedandmaintainedinhyperthyroidpatientswithGOorriskfac-torsforthedevelopmentofophthalmopathy.1/++0

Anumberofstudieshavesuggestedthatdevelopmentofpersistent,untreatedhypothyroidismaftertherapyforhy-perthyroidismplaysadetrimentalroleintheprogressionofGO.Anearlystudynotedthatpatientswhowereeitherhypo-orhyperthyroidhadmoresevereGOthaneuthyroidpatients(322).Subsequently,twocohortstudiesinwhichpatientsre-ceivedlevothyroxinetherapyearlyafterradioactiveiodinewiththespeciﬁcintentofpreventinghypothyroidismnotedthatdeteriorationofGOrarelyoccurred(0%–2%)(321,323).ArandomizedstudyofnewlydiagnosedGDfoundthatra-dioactiveiodinedidnotincreasetheriskofworseningGOcomparedtotherapywithMMI(RRof0.95)inthesettingwherehypothyroidismwasactivelypreventedbyadminis-trationofthyroidhormoneat2weeksafterradioactiveiodineadministration(49).

SeveralretrospectivecohortstudiesandrandomizedtrialshaveidentiﬁedtheriskofGOdevelopmentorprogressionaftertherapyforhyperthyroidismtobebetween15%and33%.Tworandomizedcontrolledtrialsfoundthatrisktobe23/150(15%)forradioactiveiodine,comparedwith4/148(3%)forATDs(318)inonestudy,and13/39(33%)forradioactiveio-dinecomparedwith4/38(10%)forATDsand6/37(16%)forsurgery(319)intheotherstudy.Incontrast,oneprospectivebutnonrandomizedcohortstudyidentiﬁednodifferenceamongATD,surgery,andradioactiveiodinetreatment,withanoverall4.9%–7.1%frequencyofGOdevelopment(324).ThehigherriskofGOworseningafterradioactiveiodinetherapyinthemajorityofstudiesmayberelatedtotheuniqueincreaseinTRAblevelsobservedfollowingthistherapy(222).Experi-mentalevidencesuggeststhattheseantibodiesmaybedirectlyinvolvedinGOpathogenesis(309).

ThereisevidencethatcorticosteroidsgivenconcurrentlywithradioiodinetherapymaypreventworseningofGOinpatientswithmildactiveeyedisease(318).However,thereisinsufﬁcientevidencetorecommendprophylactictreatmentwithcorticosteroidsinnonsmokingpatientswhodonothaveclinicallyapparentGO.Therelativelylowabsoluteriskofnonsmokersdevelopingnew-onsetsevereGOsuggeststhatGOpreventionshouldnotbeafactorintheselectionoftherapyforhyperthyroidisminthisgroupofpatients(318).ThereisinsufﬁcientevidencetorecommendfororagainsttheuseofprophylacticcorticosteroidsinsmokerswhohavenoevidenceofGO.However,intwodifferentstudies,activesmokerswhoreceivedradioactiveiodinerepresentedthegroupwiththehighestincidence(23%–40%)ofnewGOordeteriora-tionofpre-existingGOduring1yearoffollow-up(49,318).

RECOMMENDATION82

CliniciansshouldadvisepatientswithGDtostopsmokingandreferthemtoastructuredsmokingcessationprogram.

HYPERTHYROIDISMMANAGEMENTGUIDELINESPatientsexposedtosecondhandsmokeshouldbeidenti-ﬁedandadvisedofitsnegativeimpact.1/++0

SmokingisthemostimportantknownriskfactorforthedevelopmentorworseningofGO,unrelatedtotypeofther-apyforGO(322),andconsistentdatafromseveralstudiesshowadetrimentaleffectofsmokingonGOinpatientstreatedwithradioactiveiodine(49,318).Theriskispropor-tionaltothenumberofcigarettessmokedperdayandformersmokershavesigniﬁcantlylowerriskthancurrentsmokers,evenafteradjustingforlifetimecigaretteconsumption(325).Technicalremarks:Cliniciansshouldconsultguidelinesoneffectiveandevidence-basedapproachestoaidinsmokingcessationandavoidanceofsecondhandsmoke(326,327).[T3]TreatmentofhyperthyroidisminpatientswithactiveGOofmildseverity(seeTables10and11fordeﬁnitionsofdiseaseactivityandseverity)

RECOMMENDATION83

InpatientswithGraves’hyperthyroidismwhohavemildactiveophthalmopathyandnoriskfactorsfordeteriorationoftheireyedisease,131Itherapy,methimazole,andthy-roidectomyshouldbeconsideredequallyacceptablether-apeuticoptions.1/++0

RECOMMENDATION84

PatientswithGraves’hyperthyroidismandmildactiveophthalmopathywhohavenootherriskfactorsfordete-riorationoftheireyediseaseandchooseradioactiveiodinetherapyshouldbeconsideredforconcurrenttreatmentwithcorticosteroids.2/++0

Technicalremarks:Thedecisionwhetherornottoadmin-isterconcurrentglucocorticoidsinaparticularpatientchoosing131Itherapyshouldbemadeinlightoftherisk–beneﬁtratio(i.e.,theirpersonalriskofworseningGO,balancedagainsttheirriskofdevelopingglucocorticoidsideeffects).Riskfactorsforsideeffectsoforalcorticosteroidsincludepoorlycontrolleddiabetes,hypertension,osteopo-rosis,psychiatricdisease,andpredispositiontoinfections.Smokersinwhomtherisk–beneﬁtratiofortheconcurrentuseofcorticosteroidsishighmaybebettertreatedwithmethimazoleorsurgery.Besidessmoking,riskfactorsfordeteriorationofGOfollowingradioiodinetherapyincludehighpretreatmentT3values(!325ng/dLor!5nmol/L)(319),activeandprogressiveGOoverthepreceding3months,highserumpretreatmentthyrotropinantibodylevels(>50%TBIIinhibitionorTSI>8.8IU/L),anddevel-opmentofhypothyroidismfollowingthetreatment(321).TherecommendedcorticosteroiddoseforGOprophylaxisistheequivalentofprednisone0.4–0.5mg/kg/day,started1–3daysafterradioactiveiodinetreatment,continuedfor1month,andthentaperedover2months(312).However,arecentretrospectivecohortstudysuggestedthatlowerdosesandshorterdurationoforalprednisone(about0.2mg/kg/dayfor6weeks)maybeequallyeffectiveforpreventionofGOexacerbationinpatientswithinitiallymildorabsenteyedisease,ifsupportedbyfuturerandomizedclinicaltrials(328).

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RECOMMENDATION85

PatientswithGraves’hyperthyroidismandmildactiveophthalmopathywhoaresmokersorhaveotherriskfac-torsforGOandchooseradioactiveiodinetherapyshouldreceiveconcurrentcorticosteroids.1/++0

Arandomizedstudyofpatientshavingpre-existingGOofmildseverityfoundtherelativeriskfordeteriorationofeyediseasetobe2.2forsurgeryand1.9forradioactiveiodinecomparedwithATDs,thoughthepatientswerenotran-domizedwithrespecttotheirbaselineGOstatus(319).Anearlierprospectivecohort(alsonotrandomizedastobaselineGOorsmokingstatusandinwhichpost-treatmenthypo-thyroidismwasnotactivelyprevented)identiﬁednodiffer-enceindeteriorationofpre-existingGObetweenthethreemodesoftherapy(324).Neithersurgerynorradioactiveio-dinetherapywasassociatedwithdeteriorationinpre-existingGOin48patientsinanotherearlystudy(329).

OnelargerandomizedcontrolledtrialstudyingmainlypatientswithpreviouslytreatedGDshowedradioactiveio-dinetherapytobeassociatedwithanincreasedriskofGOprogression(RRof5.8incomparisonwithATDs)andfoundthatrisktobeeliminatedwithconcurrentcorticosteroidad-ministration(318).

[T4]Treatmentofhyperthyroidisminpatientswithactiveandmoderate-to-severeorsight-threateningGO(seeTables10and11fordeﬁnitionsofdiseaseactivityandseverity)

RECOMMENDATION86

PatientswithGraves’hyperthyroidismandactivemoderate-to-severeorsight-threateningophthalmopathyshouldbetreatedwitheithermethimazoleorsurgery.1/+00

Weareawareofnotrialsinpatientswithmoderate-to-severeandactiveeyediseasethatcomparehyperthyroid-ismtherapiesforimpactonGO.However,acomparisonoftwodifferentsurgicalapproaches(totalthyroidectomyvs.subtotalthyroidectomy)forpatientswithmoderate-to-se-vereGOshowedthattheeyediseaseimprovedover3yearsoffollow-upinallpatients(330).Inanotherseriesof42patientswithprogressiveGOtreatedwithtotalthyroidec-tomy,exophthalmoswasstablein60%ofcasesandim-provedintheremainder(331),suggestingthatsurgeryisnotdetrimentaltoGOandmaybeassociatedwithim-provementinsomepatients.OtherstudiessuggestthatATDsmaynotadverselyimpactmildactiveGO,butdonotaddresssevereGO(318).

Technicalremarks:Radioactiveiodinetherapyisalessde-sirableoptioninthesepatientsand,ifused,concurrentste-roidsshouldbeadministered.

[T5]TreatmentofGDinpatientswithinactiveGO(seeTable10fordeﬁnitionofdiseaseinactivity)

RECOMMENDATION87

InpatientswithGraves’hyperthyroidismandinactiveophthalmopathy,wesuggestthat131Itherapywithoutconcurrentcorticosteroids,methimazole,andthyroidec-tomyareequallyacceptabletherapeuticoptions.2/++0

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Aseriesof72patientswithinactiveGOaccordingtotheCASweretreatedwithradioactiveiodinewithoutconcurrentglucocorticoidadministration(323).Inthosewhomhypo-thyroidismwaspreventedbyearlythyroxinetherapy,nodeteriorationineyediseasewasreported(323).SmokinghistorydidnotimpactGOoutcomeinthiscohort.

Arecentretrospectivestudyexaminedtheimpactofcon-currentoralorintravenousglucocorticoidtherapyonthepre-valenceofreactivationofGOafterradioiodinetherapyinpatientshavinginactiveGO(332).TheyidentiﬁedGOactiva-tioninapproximately7%ofpatientsconsideredatlowriskwhoweregivennosteroidprophylaxis.Despiteprophylaxis,33%ofpatientsconsideredathighriskwhoweretreatedwithoralglucocorticoidshadworseningofGO.OnlyintravenousglucocorticoidswereeffectiveinpreventingGOreactivation.However,becauseoftheretrospectivenatureofthisstudyandthelackofprespeciﬁedcriteriafordoseandrouteofsteroiduseinthoseconsideredatrisk,wedidnotincludethesedatainourdeliberationsregardingtheaboverecommendation.[U]Howshouldovertdrug-inducedthyrotoxicosisbemanaged?

Althoughnumerousmedicationsmayaffectthyroidfunc-tionorcauseabnormalthyroidtestingresults(333),relativelyfewoftheseactuallycausethyrotoxicosis.Forthosethatdo,threemechanismsareinvolved:(i)iodine-inducedthyrotox-icosis;(ii)destructivethyroiditis;and(iii)inductionofthyroidautoimmunity(GDorpainlessthyroiditis).Morethanonepathwayhasbeenidentiﬁedforseveralmedications.Asummaryofdrugscausingthyrotoxicosis,theproposedmechanism(s),approximatetimingofonset,duration,andtherapeuticoptionsisprovidedinTable13.

[U1]Iodine-inducedhyperthyroidism

BAHNETAL.

Iodine-inducedhyperthyroidismisbelievedtooccurinpatientswithunderlyingthyroidautonomy,especiallythoselivinginareaswithmild-to-moderateiodinedeﬁciency.Inonestudyof788patientsundergoingcardiacangiography,noneofthe27withasuppressedTSHatbaselinedevelopedoverthyperthyroidism,andonly2patientswithnoapparentriskfactorsbecamehyperthyroid(334).Aretrospectivestudyfoundthat7of28elderlypatientswithhyperthyroidismhadahistoryofrecentiodineexposure(335),andaprospectivestudyfoundthat2of73patientsdevelopedhyperthyroidismafterradiographiccontrast(336).HighiodineintakemayalsobefollowedbyrelapseofhyperthyroidisminpatientswithpreviousGDwhoareinremissionafterATDtherapy.Inasmallstudyof10patients,2hadrelapseofoverthyperthy-roidism,and2developedSHafterstoppinghighiodinein-take(337).

RECOMMENDATION88

Beta-adrenergicblockingagentsaloneorincombinationwithmethimazoleshouldbeusedtotreatovertiodine-inducedhyperthyroidism.1/+00

Iodine-inducedhyperthyroidism(theJod-Basedowphe-nomenon)isusuallyself-limited,lasting1–18months(335,338).Treatmentincludesavoidanceofadditionaliodineandadministrationofbeta-blockersaloneorwithATDs,de-pendingontheseverityofhyperthyroidism.Radioactiveio-dineisnotanoptionuntiltheiodineloadhasbeencleared,whichmaytakeseveralmonthsdependingonthelengthofexposuretoiodine.Surgerymaybeusedinpatientsallergicorresistanttoantithyroiddrugs.

Table13.CausesofDrug-AssociatedThyrotoxicosis

DrugAmiodarone

Mechanism(s)Iodineinduced(type1)Thyroiditis(type2)

LithiumInterferonaInterleukin-2IodinatedcontrastRadioactiveiodine,earlyRadioactiveiodineforTMNG,late

aTimingofonsetfollowinginitiationofthedrugMonthstoYearsOften>1yearOften>1yearMonthsMonths

Weekstomonths1–4weeks3–6months

Therapy

SupportivecareaAntithyroiddrugs;perchloratebSurgery

SupportivecareaCorticosteroidsSurgery

SupportivecareaAntithyroiddrugsSupportivecareaAntithyroiddrugsand/orradioactiveiodine(GDonly)SupportivecareaAntithyroiddrugsand/orradioactiveiodine(GDonly)Antithyroiddrugs

Observation;ifsevere,administercorticosteroidsAntithyroiddrugs

RepeatradioactiveiodineSurgery

PainlessthyroiditisPainlessthyroiditis;GDPainlessthyroiditis;GDUnderlyingthyroidautonomyDestructionGD

bSupportivecaremayincludebeta-adrenergicblockersduringthethyrotoxicstageandlevothyroxineifhypothyroidismdevelops.NotavailableintheUnitedStates.

HYPERTHYROIDISMMANAGEMENTGUIDELINESTechnicalremarks:DosingofMMIforiodine-inducedthy-rotoxicosisis20–40mgdaily,giveneitherasadailyortwice-dailydosing.Theremayberelativeresistancetoantithyroiddrugsinpatientswithiodine-inducedhyperthyroidism.Ur-inaryiodinemaybemonitoredtoassesstherateofclearanceoftheiodineload.

[U2]Cytokine-inducedthyrotoxicosis

RECOMMENDATION89

Patientswhodevelopthyrotoxicosisduringtherapywithinterferon-aorinterleukin-2shouldbeevaluatedtodeter-mineetiology(thyroiditisvs.GD)andtreatedaccordingly.1/+00

Interferon-a(IFN-a)-andinterleukin-2-treatedpatientsareatincreasedriskfordevelopingthyrotoxicosis,especiallythosewithpre-existingthyroidautoimmunity.ThyrotoxicosisinthissettingcanbeduetoeitherpainlessthyroiditisorGD(339).Inaliteraturereview,69%ofpatientswithIFN-a-associatedthyrotoxicosisweredeemedtohaveGDastheetiology(340).

Ameta-analysisfoundthat46%ofpatientswithpositivepretreatmentthyroidperoxidaseantibodies(TPOAb)devel-opedthyroiddysfunctionafterIFN-atherapyforhepatitisCinfection,comparedtoonly5%ofthosewithnegativeanti-bodies(341).

[U3]Amiodarone-inducedthyrotoxicosis

RECOMMENDATION90

Wesuggestmonitoringthyroidfunctiontestsbeforeandat1and3monthsfollowingtheinitiationofamiodaronetherapy,andat3–6monthintervalsthereafter.2/+00

Amiodaroneisadrugfrequentlyusedinthetreatmentofrefractoryatrialorventriculartachyarrhymias.Amiodarone-inducedthyrotoxicosis(AIT)occursinupto6%ofpatientstakingthismedicationiniodine-sufﬁcientareasoftheworld(18,342,343)andinupto10%iniodine-deﬁcientareas,suchaspartsofEurope(344).

RECOMMENDATION91

Wesuggesttestingtodistinguishtype1(iodine-induced)fromtype2(thyroiditis)varietiesofamiodarone-inducedthyrotoxicosis.1/+00

Twobasicmechanismshavebeenidentiﬁedinthedevel-opmentofAIT,includinganiodine-inducedformofhyper-thyroidism(type1AIT,orgoitrousAIT)duetothehighiodinecontentofamiodarone(37%bymolecularweight),andtype2AIT,whichisadestructivethyroiditis.Type1AITtendstooccurinpatientswithunderlyingthyroidautonomyinanodulargoiter,butthetermisalsousedwhenamiodar-oneuseisassociatedwithGD,whereastype2AITisduetoadirectdestructiveeffectofamiodaroneonthyrocytes.RAIUisoccasionallymeasurableintype1AIT(particularlyinregionsofiodinedeﬁciency),butnotintype2AIT.Increasedvascularﬂowoncolor-ﬂowDopplerultrasoundstudymaybeseeninpatientswithtype1AIT,butnottype2AIT.Measurementofseruminterleukin-6levelsdoesnotreliablydistinguishbe-

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tweenthetwotypesofAIT(345).Thedistinctionbetweentype1AITandtype2AITisnotalwaysclear,andsomepatientshaveelementsofbothtypes(18).

RECOMMENDATION92

Thedecisiontostopamiodaroneinthesettingofthyro-toxicosisshouldbedeterminedonanindividualbasisinconsultationwithacardiologist,basedonthepresenceorabsenceofeffectivealternativeantiarrhythmictherapy.1/+00

Theneedforamiodaronediscontinuationiscontroversialbecause(i)thisdrugisfrequentlytheonlymedicationabletocontrolcardiacarrhythmia,(ii)theeffectsofthisfatsolubledrugmaypersistformanymonths,and(iii)amiodaronemayhaveT3-antagonisticpropertiesatthecardiaclevelandinhibitT4toT3conversion,suchthatwithdrawalmayactuallyag-gravatecardiacmanifestationsofthyrotoxicosis(18,342).Inaddition,type2AITtypicallyresolvesevenifamiodaronetherapyiscontinued.

RECOMMENDATION93

Methimazoleshouldbeusedtotreattype1amiodarone-inducedthyrotoxicosisandcorticosteroidsshouldbeusedtotreattype2amiodarone-inducedthyrotoxicosis.1/+00&

RECOMMENDATION94

Combinedantithyroiddrugandanti-inﬂammatoryther-apyshouldbeusedtotreatpatientswithovertamiodar-one-inducedthyrotoxicosiswhofailtorespondtosinglemodalitytherapy,andpatientsinwhomthetypeofdiseasecannotbeunequivocallydetermined.1/+00

Type1AITisbesttreatedwithMMI(40mgdaily)topre-ventnewhormonesynthesisand,rarely,withaddedpotas-siumperchlorate(250mgfourtimesdaily;notavailableintheUnitedStates)(346).Type2AITisbettertreatedwithanti-inﬂammatorytherapysuchasprednisone(40mgdaily)withimprovementoccasionallyseenasearlyas1week,andusu-allywithinafewweeks(346).

Inonestudy,20patientswithAIT,includingbothtype1andtype2subtypes,weretreatedwithperchloratefor1monthtoinhibitthyroidiodidetransport,resultingineuthyroidismin12patients(7withtype1AITand5withtype2AIT).Corticosteroidswerethengiventotheeightnonre-sponders,andeuthyroidismwasachievedinallafteranaverageofapproximately6weeks(347).Whenacleardis-tinctionbetweentype1AITandtype2AITisnotpossible,acombinationofprednisoneandmethimazoleshouldbeuseduntilthepatienthasstabilized,atwhichtimethedrugsmaybeindividuallytapered.Thyroidectomymayberequiredinpatientswhoproverefractorytomedicaltherapy(348).Technicalremarks:ThesuggestedstartingdoseofMMIinthissettingis40mgoncedailyuntilthepatientiseuthyroid(generally3–6months).IfhighdosesofMMIcontinuetoberequired,splittingthedosemaybemoreeffective.Thesug-gesteddoseofcorticosteroidsinthissettingisequivalentto40mgprednisonegivenoncedailyfor2–4weeks,followedbyagradualtaperover2–3months,basedonthepatient’sclin-icalresponse.

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BAHNETAL.

failingtorespondorthosewithmoderate-to-severesymptomsshouldbetreatedwithcorticosteroids.1/+00Subacutethyroiditisistreatedwithbeta-blockersandanti-inﬂammatorytherapy.Nonsteroidalanti-inﬂammatoryagents(NSAIDs)providepainreliefinpatientswithmildsymptomsduetosubacutethyroiditis,andshouldbeconsideredﬁrst-linetherapyinsuchpatients.PatientswhofailtorespondtofulldosesofNSAIDsoverseveraldaysshouldbetreatedinsteadwithcorticosteroidtherapy,suchasprednisone40mgdailyfor1–2weeksfollowedbyagradualtaperover2–4weeksorlonger,dependinguponclinicalresponse.Aretrospectivere-viewofpatientsreceivingcareforsubacutethyroiditisfoundthatpatientstreatedwithcorticosteroidshadmorerapidres-olutionofpain(meanduration,8days)comparedwiththosetreatedwithNSAIDs(meanduration,35days).However,symptomscanrecurasthedoseofcorticosteroidisreduced(19).Aswithpainlessandpostpartumthyroiditis,levothyr-oxinemaybeemployedduringthehypothyroidstage,butshouldbewithdrawnafter3–6monthswithrecoveryofnormalfunctionveriﬁedbythyroidfunctiontesting.[V2]Painlessthyroiditis

Painlessorsilentthyroiditisisanautoimmunediseasemanifestedbypositiveanti-TPOantibodiesinthemajorityofpatients,andatriphasicpatterninsomecases.Thepostpar-tumperiodisthemostcommontimewhenpainlessthy-roiditisisseen,butpainlessthyroiditiscanalsooccurinnonpregnantpatientsandmen.Painlessthyroiditishasbeendescribedinsometypesofdrug-inducedthyroiddysfunction,includingthatassociatedwithlithiumorcytokinetherapy.ThelatterincludesIFN-aorinterleukin-2(discussedelse-where),butnotIFN-btherapy.Beta-adrenergicblockerscanbeusedtotreatthyrotoxicsymptomsinpatientswithpainlessthyroiditis,butantithyroiddrugshavenoutility,sincenewhormonesynthesisisalreadylowinthesepatients.Rarely,corticosteroidshavebeenusedtoamelioratetheseverityandthetimecourseofthyrotoxicosisduetopainlessthyroiditis(350),buttheyshouldbereservedonlyformoreseverecases.Somepatientsmayhaverecurrentepisodesofpainlessthy-roiditis,separatedbyyears.[V3]Acutethyroiditis

Patientswithacutethyroiditis(alsoreferredtoassuppu-rativethyroiditisorthyroidabscess)aregenerallyeuthyroid.However,onoccasion,theconditionpresentsasdestructivethyrotoxicosis(351).Theetiologyofacutethyroiditisismostfrequentlyabacterialinfectionaffectingthethyroid,either

RECOMMENDATION95

Patientswithamiodarone-inducedthyrotoxicosiswhoareunresponsivetoaggressivemedicaltherapywithmethi-mazoleandcorticosteroidsshouldundergothyroidec-tomy.1/+00

Technicalremarks:PatientswithAITwhofailtorespondtomedicaltherapyshouldbeofferedthyroidectomybeforetheybecomeexcessivelydebilitatedfrominadequatelycontrolledthyrotoxicosis.Thepatientshouldbecounseledthatwhilethyroidectomyinthissettingcarrieswithitsigniﬁcantmor-bidityandahighmortalityrate(9%),delayordeferralofsurgeryimpartsanevenhigherriskofdeath(348).Thyr-oidectomydoneunderregionalanesthesiawhenavailablemaybepreferred(18,349).

[V]Howshouldthyrotoxicosisduetodestructivethyroiditisbemanaged?

Severalvarietiesofthyroiditiscanpresentwiththyrotoxi-cosis,includingpostpartumthyroiditis,painlessthyroiditis,drug-inducedthyroiditis,subacutethyroiditis,traumaticthy-roiditis,andacutethyroiditis.Ingeneral,thyroiddysfunctioncausedbythyroiditisislessseverethanthatseenwithotherformsofendogenousthyrotoxicosis;RAIUisuniversallylowduringthethyrotoxicstage,owingtoleakingofthyroidhor-monewithsuppressionofserumTSHconcentrations.[V1]Subacutethyroiditis

Thediagnosisofsubacutethyroiditisinathyrotoxicpatientshouldbemadebasedonclinicalhistory,physicalexamina-tion,andRAIU.Subacutethyroiditispresentswithmoderate-to-severepaininthethyroid,oftenradiatingtotheears,jaw,orthroat.Thepainmaybeginfocallyandspreadthroughouttheglandoverseveralweeks.Patientsmayhavemalaise,low-gradefever,andfatigueinadditiontothesymptomsofthy-rotoxicosis.Thethyroidisﬁrmandpainfultopalpation.Inadditiontolaboratoryevidenceofthyrotoxicosis,theeryth-rocytesedimentationrateorC-reactiveproteiniselevated,andmildanemiaiscommon.RAIUislow,andthyroidul-trasonographyshowsdiffuseheterogeneityanddecreasedornormalcolor-ﬂowDoppler,ratherthantheenhancedﬂowcharacteristicofGD.

RECOMMENDATION96

Patientswithmildsymptomaticsubacutethyroiditisshouldbetreatedinitiallywithbeta-adrenergic-blockingdrugsandnonsteroidalanti-inﬂammatoryagents.Those

Table14.UnusualCausesofThyrotoxicosis

Disorder

TSH-producingadenomaStrumaovariiChoriocarcinoma

Thyrotoxicosisfactitia

(surreptiousLT4orLT3)Functionalthyroidcancermetastases

Diagnosis

PituitaryMRI,alpha-subunittoTSHratioRadioiodineuptakeoverpelvis

Elevationintheabsenceofpregnancy

Absenceofgoiter;suppressedthyroglobulinWhole-bodyradioiodinescanning

Primarymanagement

SurgicalremovalSurgicalremovalSurgicalremoval

Psychosocialevaluation

Radioiodineablation,embolizationand/orsurgicalremoval

HYPERTHYROIDISMMANAGEMENTGUIDELINESthroughhematogenousspreadordirectextensionthroughaﬁstulafromaninfectedpyriformsinus.Therapyinvolvessys-temicantibioticsaswellasabscessdrainageorremoval,andexcisionorocclusionoftheoffendingpyriformsinus.Thyr-otoxicosisshouldbetreatedsymptomaticallywithbeta-block-ingagents.Asinotherformsofdestructivethyroiditis,thereisnoroleforantithyroiddrugs.

[W]Howshouldthyrotoxicosisduetounusualcausesbemanaged?

Theseareseveralunusualcausesofthyrotoxicosisthatshouldbeconsideredinthedifferentialdiagnosis(Table14).Sinceeffectivetreatmentdependsonaccuratediagnosis,itisimportanttoclearlyidentifytheetiologyineverypatientpresentingwiththyrotoxicosis.[W1]TSH-secretingpituitarytumors

FunctionalpituitarytumorssecretingTSHarerare.Inamulticenterreviewof4400pituitarytumorsseenovera25-yearperiod,43(1%)wereTSH-secretingadenomas(33).Themajorityofpatientspresentwithdiffusegoiterandclinicalsignsofthyrotoxicosis.Inaddition,serumTSHlevelsmaybeelevatedor,especiallyinpatientswhohavenothadthyroidablation,theymaybeinappropriatelynormal.Cosecretionofeitherprolactinorgrowthhormoneoccursinupto25%ofcases;1%–2%secretebothgrowthhormoneandprolactin,andasimilarpercentagecosecretegonadotropins.MostTSH-producingadenomasarelargerthan1cm,andap-proximately40%ofpatientshaveassociatedvisualﬁelddeﬁcits(352).

RECOMMENDATION97

ThediagnosisofTSH-secretingpituitarytumorshouldbebasedonaninappropriatelynormalorelevatedserumTSHlevelassociatedwithelevatedfreeT4estimatesandT3concentrations,usuallyassociatedwiththepresenceofapituitarytumoronMRIandtheabsenceofafamilyhistoryorgenetictestingconsistentwiththyroidhormoneresis-tanceinathyrotoxicpatient.1/+00

DistinctionbetweenaTSH-secretingadenomaandthyroidhormoneresistanceisimportant,sincethyroidfunctiontestresultsaresimilar,yetmanagementisquitedifferentforthesetwodisorders.TSH-secretingadenomasaremorelikelytohaveconcurrentalpha-subunitelevation(notusefulinpostmenopausalwomenduetoconcurrentgonadotropinelevation),abluntedTSHresponsetothyrotropin-releasinghormone(TRH)(whenavailable),elevatedsex-hormone-bindingglobulinandrestingenergyexpenditure,andclinicalevidenceofthyrotoxicosis,aswellasananatomicabnor-malityonMRIofthepituitary.

Technicalremarks:Genetictestingforthyroidhormonere-sistanceiscommerciallyavailableandmaybeusefulinequivocalcases,especiallyinthosepatientswithoutfamilymembersavailableforthyroidfunctiontesting.

SurgeryisgenerallythemainstayoftherapyforTSH-pro-ducingpituitarytumors.Thepatientshouldbemadeeuthy-roidpreoperatively.Long-termATDtherapyshouldbeavoided.Preoperativeadjunctivetherapywithoctreotideand

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dopamineagonisttherapyhasbeenexamined.Treatmentwithoctreotideresultsina>50%reductioninserumTSHvaluesinthemajorityofpatientstreated,andaconcurrentreturntoeuthyroidisminmost(33).Areductionintumorsizehasbeenobservedin20%–50%ofpatientstreatedwithoctreotide(33,352),butlessimpressiveresultshavebeenobtainedwithbromocriptinetherapy(352).Sterotacticorconventionalra-diotherapyhasalsobeenusedincasesthatproverefractorytomedicaltherapy.ForpatientswithTSH-producingadenomaswhoareconsideredpoorsurgicalcandidates,primarymedicaltherapywithoctreotidecanbeconsidered.

RECOMMENDATION98

PatientswithTSH-secretingpituitaryadenomasshouldundergosurgeryperformedbyanexperiencedpituitarysurgeon.1/+00

Technicalremarks:Postoperativeadjunctivetherapywithoctreotideand/orexternalbeamradiationtherapymaybeusefulinmanagingpatientswithpersistentcentralhyper-thyroidismafteradebulkingprocedurefornonresectableTSH-secretingadenomas(33).[W2]Strumaovarii

RECOMMENDATION99

Patientswithstrumaovariishouldbetreatedinitiallywithsurgicalresection.1/+00

Strumaovarii,deﬁnedasectopicthyroidtissueexistingasasubstantialcomponentofanovariantumor,isquiterare,re-presenting<1%ofallovariantumors.Approximately5%–10%ofpatientswithstrumaovariipresentwiththyrotoxicosis(353)duetoeitherautonomousectopicthyroidfunctionorthecoexistenceofGD,andupto25%ofstrumaovariitumorscontainelementsofpapillarythyroidcancer.Patientsprevi-ouslytreatedforGDmayhavepersistentorrecurrenthy-perthyroidismduetotheactionofTRAbontheectopicthyroidtissue(354).Treatmentofstrumaovariigenerallyin-volvessurgicalremoval,performedlargelyduetotheriskofmalignancywithinthestrumatissueandofcuringthehy-perthyroidism.Preoperativetreatmentwithbeta-adrenergic-blockingagentsandantithyroiddrugsiswarrantedtorestoreeuthyroidismbeforesurgery.

Technicalremarks:Incasesofsuspectedmetastaticmalig-nantstrumaovarii,radioactiveiodineisgenerallygivenfol-lowingsurgicalremovalofboththeovariantumorandthepatient’sthyroidtofacilitatedeliveryofisotopetoanypo-tentialresidualmalignantcells.[W3]Choriocarcinoma

RECOMMENDATION100

Treatmentofhyperthyroidismduetochoriocarcinomashouldincludebothmethimazoleandtreatmentdirectedagainsttheprimarytumor.1/+00

Patientswithchoriocarcinoma,includingmolarpregnancyandtesticularcancer,maypresentwiththyrotoxicosisduetotheeffectoftumor-derivedhCGupontheTSHreceptor

630

(355,356).Thiscross-stimulationonlyoccursatveryhighlevelsofhCG,sincehCGisonlyaweakagonistfortheTSHreceptor.Treatmentofhyperthyroidismduetochoriocarcinomain-volvesbothtreatmentdirectedagainsttheprimarytumorandtreatmentdesignedtopreventthethyroidfromrespondingtohCGstimulation,suchaswithantithyroiddrugs.[W4]Thyrotoxicosisfactitia

Thyrotoxicosisfactitiaincludesallcausesofthyrotoxicosisduetotheingestionofthyroidhormone.Thismayincludeintentionalingestionofthyroidhormoneeithersurrepti-tiouslyoriatrogenically,aswellasunintentionalingestioneitheraccidentally,suchasinpediatricpoisoningorphar-macyerror,orthroughingestionofsupplementsthatcontainthyroidextracts.Historically,accidentalthyroidhormoneingestionhasoccurredasaresultofeatingmeatcontaminatedwithanimalthyroidtissue(‘‘hamburgerthyrotoxicosis’’)(357).Whereasiatrogeniccausesofthyrotoxicosisfactitiaareeasilyidentiﬁed,surreptitioususeofthyroidhormonemaypresentadiagnosticquandary.Cluestothisdiagnosisareanabsenceofgoiter,asuppressedserumthyroglobulinlevel,andadecreaseduptakeofradioactiveiodine.Adis-proportionatelyelevatedT3levelsuggeststhatthepatientmaybeingestingliothyronineoracombinationT4/T3preparation.[W5]Functionalthyroidcancermetastases

Thyrotoxicosisduetofunctionalmetastasesinpatientswiththyroidcancerhasbeendescribedinahandfulofcases.Typically,patientshaveeitheraverylargeprimaryfollicularcancerorwidelymetastaticfollicularthyroidcancer,andmayhavecoexistingTRAbastheproximatecauseofthethyro-toxicosis(358).Morerecently,thyrotoxicosishasbeenre-portedfollowingmultipleinjectionsofrecombinanthumanTSHinpatientswithmetastaticthyroidcancerinpreparationforimaging.Ingeneral,functioningmetastasisaretreatedwithradioactiveiodinewiththeadditionofATDsasneededforpersistenthyperthyroidism.RecombinanthumanTSHshouldbeavoidedinthesepatients.Acknowledgments

ThetaskforcewishestothankMs.BobbiSmith,ExecutiveDirector,ATA,andMs.SheriSlaughter,Assistanttothetaskforce,fortheirexperthelpandsupport.DisclosureStatement

DisclosureInformationfor2yearsbeforeMay2010andtheknownfutureasofMay2010.

D.R.isaconsultantforAbbottLaboratoriesandhasre-ceivedresearchgrantsupportfromGenzyme.Forallotherauthors,nocompetingﬁnancialinterestsexist.References

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EnglJMed333:1688–1694.

334.HintzeG,BlombachO,FinkH,BurkhardtU,KobberlingJ

1999Riskofiodine-inducedthyrotoxicosisaftercoronaryangiography:aninvestigationin788unselectedsubjects.EurJEndocrinol140:264–267.

335.MartinFI,TressBW,ColmanPG,DeamDR1993Iodine-inducedhyperthyroidismduetononioniccontrastradi-ographyintheelderly.AmJMed95:78–82.

336.ConnJJ,SebastianMJ,DeamD,TamM,MartinFI1996A

prospectivestudyoftheeffectofnonioniccontrastmediaonthyroidfunction.Thyroid6:107–110.

337.RotiE,GardiniE,MinelliR,BianconiL,SalviM,Gavaruzzi

G,BravermanLE1993Effectsofchroniciodineadminis-trationonthyroidstatusineuthyroidsubjectspreviouslytreatedwithantithyroiddrugsforGraves’hyperthyroid-ism.JClinEndocrinolMetab76:928–932.

338.FradkinJE,WolffJ1983Iodide-inducedthyrotoxicosis.

Medicine(Baltimore)62:1–20.

339.CarellaC,MazziottiG,AmatoG,BravermanLE,RotiE

2004Clinicalreview169:Interferon-alpha-relatedthyroiddisease:pathophysiological,epidemiological,andclinicalaspects.JClinEndocrinolMetab89:3656–3661.

340.PrummelMF,LaurbergP2003Interferon-alphaandauto-immunethyroiddisease.Thyroid13:547–551.

341.KohLK,GreenspanFS,YeoPP1997Interferon-alphain-ducedthyroiddysfunction:threeclinicalpresentationsandareviewoftheliterature.Thyroid7:891–896.

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342.BasariaS,CooperDS2005Amiodaroneandthethyroid.

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LenziardiM,FayM,PacchiarottiA,AroninN,MacchiaE,HaffajeeC,etal.1984Enviromentaliodineintakeandthyroiddysfunctionduringchronicamiodaronetherapy.AnnIntMed101:28–34.

345.EatonSE,EuintonHA,NewmanCM,WeetmanAP,Bennet

WM2002Clinicalexperienceofamiodarone-inducedthy-rotoxicosisovera3-yearperiod:roleofcolour-ﬂowDopplersonography.ClinEndocrinol(Oxf)56:33–38.

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MartinoE1996Treatmentofamiodarone-inducedthyro-toxicosis,adifﬁcultchallenge:resultsofaprospectivestudy.JClinEndocrinolMetab81:2930–2933.

347.ErdoganMF,GulecS,TutarE,BaskalN,ErdoganG2003A

stepwiseapproachtothetreatmentofamiodarone-inducedthyrotoxicosis.Thyroid13:205–209.

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ThompsonGB,GrantCS2004Surgicalmanagementofamiodarone-associatedthyrotoxicosis:MayoClinicexperi-ence.WorldJSurg28:1083–1087.

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anesthesiaincriticallyillpatientswithamiodarone-in-ducedthyrotoxicosis:areviewanddescriptionofthetechnique.Thyroid12:523–525.

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Jr.1982Treatmentoflymphocyticthyroiditiswithsponta-neouslyresolvinghyperthyroidism(silentthyroiditis).ArchInternMed142:2281–2283.

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patientassociatedwithexcesshumanchorionicgonado-tropinproductionbygermcelltumor.Thyroid10:611–619.

357.HedbergCW,FishbeinDB,JanssenRS,MeyersB,McMil-lenJM,MacDonaldKL,WhiteKE,HussLJ,HurwitzES,FarhieJR,etal.1987Anoutbreakofthyrotoxicosiscausedbytheconsumptionofbovinethyroidglandingroundbeef.NEnglJMed316:993–998.

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Addresscorrespondenceto:

RebeccaS.Bahn,M.D.

DivisionofEndocrinology,Metabolism,andNutrition

MayoClinic200FirstSt.SWRochester,MN55905

E-mail:bahn.rebecca@mayo.edu

(Appendixfollows?)

642

AppendixA.HyperthyroidismManagementGuidelinesoftheAmericanThyroidAssociationandAmericanAssociationofClinicalEndocrinologists:SummaryofRecommendations[A][B]

BAHNETAL.

Background

Howshouldclinicallyorincidentallydiscoveredthyrotoxicosisbeevaluatedandinitiallymanaged?Recommendation1Aradioactiveiodineuptakeshouldbeperformedwhentheclinicalpresentationof

thyrotoxicosisisnotdiagnosticofGD;athyroidscanshouldbeaddedinthepresenceofthyroidnodularity.1/+00

Recommendation2Beta-adrenergicblockadeshouldbegiventoelderlypatientswithsymptomaticthyrotoxi-cosisandtootherthyrotoxicpatientswithrestingheartratesinexcessof90bpmor

coexistentcardiovasculardisease.1/++0

Recommendation3Beta-adrenergicblockadeshouldbeconsideredinallpatientswithsymptomaticthyrotox-icosis.1/+00HowshouldoverthyperthyroidismduetoGDbemanaged?Recommendation4PatientswithovertGraves’hyperthyroidismshouldbetreatedwithanyofthefollowing

modalities:131Itherapy,antithyroidmedication,orthyroidectomy.1/++0If131Itherapyischosen,astreatmentforGD,howshoulditbeaccomplished?Recommendation5PatientswithGDwhoareatincreasedriskforcomplicationsduetoworseningof

hyperthyroidism(i.e.,thosewhoareextremelysymptomaticorhavefreeT4estimates2–3timestheupperlimitofnormal)shouldbetreatedwithbeta-adrenergicblockadepriortoradioactiveiodinetherapy.1/+00

Recommendation6*PretreatmentwithmethimazolepriortoradioactiveiodinetherapyforGDshouldbe

consideredinpatientswhoareatincreasedriskforcomplicationsduetoworseningofhyperthyroidism(i.e.,thosewhoareextremelysymptomaticorhavefreeT4estimate2–3timestheupperlimitofnormal).2/+00

Recommendation7Medicaltherapyofanycomorbidconditionsshouldbeoptimizedpriortoadministering

radioactiveiodine.1/+00

Recommendation8Sufﬁcientradiationshouldbeadministeredinasingledose(typically10–15mCi)torender

thepatientwithGDhypothyroid.1/++0

Recommendation9Apregnancytestshouldbeobtainedwithin48hourspriortotreatmentinanyfemalewith

childbearingpotentialwhoistobetreatedwithradioactiveiodine.Thetreatingphysicianshouldobtainthistestandverifyanegativeresultpriortoadministeringradioactiveiodine.1/+00

Recommendation10Thephysicianadministeringtheradioactiveiodineshouldprovidewrittenadviceconcerning

radiationsafetyprecautionsfollowingtreatment.Iftheprecautionscannotbefollowed,alternativetherapyshouldbeselected.1/+00

Recommendation11Follow-upwithintheﬁrst1–2monthsafterradioactiveiodinetherapyforGDshouldinclude

anassessmentoffreeT4andtotalT3.Ifthepatientremainsthyrotoxic,biochemicalmonitoringshouldbecontinuedat4–6weekintervals.1/+00

Recommendation12WhenhyperthyroidismduetoGDpersistsafter6monthsfollowing131Itherapy,orifthereis

minimalresponse3monthsaftertherapy,retreatmentwith131Iissuggested.2/+00IfantithyroiddrugsarechosenasinitialmanagementofGD,howshouldthetherapybemanaged?Recommendation13Methimazoleshouldbeusedinvirtuallyeverypatientwhochoosesantithyroiddrugtherapy

forGD,exceptduringtheﬁrsttrimesterofpregnancywhenpropylthiouracilispreferred,inthetreatmentofthyroidstorm,andinpatientswithminorreactionstomethimazolewhorefuseradioactiveiodinetherapyorsurgery.1/++0

Recommendation14Patientsshouldbeinformedofsideeffectsofantithyroiddrugsandthenecessityofinforming

thephysicianpromptlyiftheyshoulddeveloppruriticrash,jaundice,acolicstoolsordarkurine,arthralgias,abdominalpain,nausea,fatigue,fever,orpharyngitis.Beforestartingantithyroiddrugsandateachsubsequentvisit,thepatientshouldbealertedtostopthemedicationimmediatelyandcalltheirphysicianwhentherearesymptomssuggestiveofagranulocytosisorhepaticinjury.1/+00

Recommendation15PriortoinitiatingantithyroiddrugtherapyforGD,wesuggestthatpatientshaveabaseline

completebloodcount,includingwhitecountwithdifferential,andaliverproﬁleincludingbilirubinandtransaminases.2/+00

Recommendation16Adifferentialwhitebloodcellcountshouldbeobtainedduringfebrileillnessandattheonset

ofpharyngitisinallpatientstakingantithyroidmedication.Routinemonitoringofwhitebloodcountsisnotrecommended.1/+00

Recommendation17Liverfunctionandhepatocellularintegrityshouldbeassessedinpatientstaking

propylthiouracilwhoexperiencepruriticrash,jaundice,lightcoloredstoolordarkurine,jointpain,abdominalpainorbloating,anorexia,nausea,orfatigue.1/+00

Recommendation18Minorcutaneousreactionsmaybemanagedwithconcurrentantihistaminetherapywithout

stoppingtheantithyroiddrug.Persistentminorsideeffectsofantithyroidmedicationshouldbemanagedbycessationofthemedicationandchangingtoradioactiveiodineorsurgery,orswitchingtotheotherantithyroiddrugwhenradioactiveiodineorsurgeryare

[C]

[D]

[E]

*Taskforceopinionwasnotunanimous;onepersonheldtheopinionthatpretreatmentwithmethimazoleisnotnecessaryinthissetting.

HYPERTHYROIDISMMANAGEMENTGUIDELINES643

Recommendation19Recommendation20Recommendation21

notoptions.Inthecaseofaseriousallergicreaction,prescribingthealternativedrugisnotrecommended.1/+00

IfmethimazoleischosenastheprimarytherapyforGD,themedicationshouldbecontinuedforapproximately12–18months,thentaperedordiscontinuediftheTSHisnormalatthattime.1/+++

MeasurementofTRAblevelspriortostoppingantithyroiddrugtherapyissuggested,asitaidsinpredictingwhichpatientscanbeweanedfromthemedication,withnormallevelsindicatinggreaterchanceforremission.2/+00

IfapatientwithGDbecomeshyperthyroidaftercompletingacourseofmethimazole,considerationshouldbegiventotreatmentwithradioactiveiodineorthyroidectomy.Low-dosemethimazoletreatmentforlongerthan12–18monthsmaybeconsideredinpatientsnotinremissionwhopreferthisapproach.2/+00

[F]

IfthyroidectomyischosenfortreatmentofGD,howshoulditbeaccomplished?Recommendation22Wheneverpossible,patientswithGDundergoingthyroidectomyshouldberendered

euthyroidwithmethimazole.Potassiumiodideshouldbegivenintheimmediatepreoperativeperiod.1/+00

Recommendation23Inexceptionalcircumstances,whenitisnotpossibletorenderapatientwithGDeuthyroid

priortothyroidectomy,theneedforthyroidectomyisurgent,orwhenthepatientisallergictoantithyroidmedication,thepatientshouldbeadequatelytreatedwithbeta-blockadeandpotassiumiodideintheimmediatepreoperativeperiod.Thesurgeonandanesthesiologistshouldhaveexperienceinthissituation.1/+00

Recommendation24IfsurgeryischosenastheprimarytherapyforGD,near-totalortotalthyroidectomyisthe

procedureofchoice.1/++0

Recommendation25IfsurgeryischosenastheprimarytherapyforGD,thepatientshouldbereferredtoahigh-volumethyroidsurgeon.1/++0Recommendation26FollowingthyroidectomyforGD,wesuggestthatserumcalciumorintactparathyroid

hormonelevelsbemeasured,andthatoralcalciumandcalcitriolsupplementationbeadministeredbasedontheseresults.2/+00

Recommendation27AntithyroiddrugsshouldbestoppedatthetimeofthyroidectomyforGD,andbeta-adrenergicblockersshouldbeweanedfollowingsurgery.1/+00Recommendation28FollowingthyroidectomyforGD,L-thyroxineshouldbestartedatadailydoseappropriate

forthepatient’sweight(0.8mg/lbor1.7mg/kg),andserumTSHmeasured6–8weekspostoperatively.1/+00HowshouldthyroidnodulesbemanagedinpatientswithGD?Recommendation29IfathyroidnoduleisdiscoveredinapatientwithGD,thenoduleshouldbeevaluatedand

managedaccordingtorecentlypublishedguidelinesregardingthyroidnodulesineuthyroidindividuals.1/++0Howshouldthyroidstormbemanaged?Recommendation30Amultimodalitytreatmentapproachtopatientswiththyroidstormshouldbeused,

includingbeta-adrenergicblockade,antithyroiddrugtherapy,inorganiciodide,cortico-steroidtherapy,aggressivecoolingwithacetaminophenandcoolingblankets,volumeresuscitation,respiratorysupportandmonitoringinanintensivecareunit.1/+00HowshouldoverthyperthyroidismduetoTMNGorTAbetreated?Recommendation31WesuggestthatpatientswithovertlyTMNGorTAbetreatedwitheither131Itherapyor

thyroidectomy.Onoccasion,longterm,low-dosetreatmentwithmethimazolemaybeappropriate.2/++0If131ItherapyischosenastreatmentforTMNGorTA,howshoulditbeaccomplished?Recommendation32PatientswithTMNGorTAwhoareatincreasedriskforcomplicationsduetoworseningof

hyperthyroidism,includingtheelderlyandthosewithcardiovasculardiseaseorseverehyperthyroidism,shouldbetreatedwithbeta-blockadepriortoradioactiveiodinetherapyanduntileuthyroidismhasbeenachieved.1/+00{Recommendation33PretreatmentwithmethimazolepriortoradioactiveiodinetherapyforTMNGorTAshould

beconsideredinpatientswhoareatincreasedriskforcomplicationsduetoworseningofhyperthyroidism,includingtheelderlyandthosewithcardiovasculardiseaseorseverehyperthyroidism.2/+00

Recommendation34Nonfunctioningnodulesonradionuclidescintigraphyornoduleswithsuspiciousultrasound

characteristicsshouldbemanagedaccordingtorecentlypublishedguidelinesregardingthyroidnodulesineuthyroidindividuals.1/++0

Recommendation35ForradioactiveiodinetreatmentofTMNG,sufﬁcientradiationshouldbeadministeredina

singledosetoalleviatehyperthyroidism.1/++0

Recommendation36ForradioactiveiodinetreatmentofTA,sufﬁcientradiationtoalleviatehyperthyroidism

shouldbeadministeredinasingledose.1/++0

Recommendation37Follow-upwithintheﬁrst1–2monthsafterradioactiveiodinetherapyforTMNGorTA

shouldincludeanassessmentoffreeT4,totalT3andTSH.Thisshouldberepeatedat1–2monthintervalsuntilstableresultsareobtained,thenatleastannuallythereafteraccordingtoclinicalindication.1/+00

[G]

[H]

[I]

[J]

Taskforceopinionwasnotunanimous;onememberheldtheopinionthatpretreatmentwithmethimazoleinpatientsalreadytreatedwithbetaadrenergicblockadeisnotindicatedinthissetting.

{644

Recommendation38[K]

Ifhyperthyroidismpersistsbeyond6monthsfollowingretreatmentwithradioactiveiodineissuggested.2/+00

131BAHNETAL.

ItherapyforTMNGorTA,

IfsurgeryischosenfortreatmentofTMNGorTA,howshoulditbeaccomplished?Recommendation39IfsurgeryischosenastreatmentforTMNGorTA,patientswithoverthyperthyroidism

shouldberenderedeuthyroidpriortotheprocedurewithmethimazolepretreatment(intheabsenceofallergytothemedication),withorwithoutbeta-adrenergicblockade.Preoperativeiodineshouldnotbeusedinthissetting.1/+00

Recommendation40IfsurgeryischosenastreatmentforTMNG,near-totalortotalthyroidectomyshouldbe

performed.1/++0

Recommendation41SurgeryforTMNGshouldbeperformedbyahigh-volumethyroidsurgeon.1/++0Recommendation42IfsurgeryischosenasthetreatmentforTA,anipsilateralthyroidlobectomy,or

isthmusectomyiftheadenomaisinthethyroidisthmus,shouldbeperformed.1/++0

Recommendation43WesuggestthatsurgeryforTAbeperformedbyahigh-volumesurgeon.2/++0Recommendation44FollowingthyroidectomyforTMNG,wesuggestthatserumcalciumorintactparathyroid

hormonelevelsbemeasured,andthatoralcalciumandcalcitriolsupplementationbeadministeredbasedontheseresults.2/+00

Recommendation45MethimazoleshouldbestoppedatthetimeofsurgeryforTMNGorTA.Beta-adrenergic

blockadeshouldbeslowlydiscontinuedfollowingsurgery.1/+00

Recommendation46FollowingsurgeryforTMNG,thyroidhormonereplacementshouldbestartedatadose

appropriateforthepatient’sweight(0.8mcg/lbor1.7mcg/kg)andage,withelderlypatientsneedingsomewhatless.TSHshouldbemeasuredevery1–2monthsuntilstable,andthenannually.1/+00

Recommendation47FollowingsurgeryforTA,TSHandestimatedfreeT4levelsshouldbeobtained4–6weeks

aftersurgery,andthyroidhormonesupplementationstartedifthereisapersistentriseinTSHabovethenormalrange.1/+00

Recommendation48Radioactiveiodinetherapyshouldbeusedforretreatmentofpersistentorrecurrent

hyperthyroidismfollowinginadequatesurgeryforTMNGorTA.1/+00IstherearoleforantithyroiddrugtherapyinpatientswithTMNGorTA?Recommendation49Wesuggestthatlong-termmethimazoletreatmentofTMNGorTAbeavoided,exceptin

someelderlyorotherwiseillpatientswithlimitedlongevitywhoareabletobemonitoredregularly,andinpatientswhopreferthisoption.2/+00Istherearoleforradiofrequency,thermaloralcoholablationinthemanagementofTAorTMNG?HowshouldGDbemanagedinchildrenandadolescents?Recommendation50ChildrenwithGDshouldbetreatedwithmethimazole,131Itherapy,orthyroidectomy.131I

therapyshouldbeavoidedinveryyoungchildren(<5years).131Itherapyinpatientsbetween5and10yearsofageisacceptableifthecalculated131Iadministeredactivityis<10mCi.131Itherapyinpatientsolderthan10yearsofageisacceptableiftheactivityis>150uCi/gofthyroidtissue.Thyroidectomyshouldbechosenwhendeﬁnitivetherapyisrequired,thechildistooyoungfor131I,andsurgerycanbeperformedbyahigh-volumethyroidsurgeon.1/++0IfantithyroiddrugsarechosenasinitialmanagementofGDinchildren,howshouldthetherapybemanaged?Recommendation51Methimazoleshouldbeusedinvirtuallyeverychildwhoistreatedwithantithyroiddrug

therapy.1/++0

Recommendation52Pediatricpatientsandtheircaretakersshouldbeinformedofsideeffectsofantithyroiddrugs

andthenecessityofstoppingthemedicationimmediatelyandinformingtheirphysicianiftheydeveloppruriticrash,jaundice,acolicstoolsordarkurine,arthralgias,abdominalpain,nausea,fatigue,fever,orpharyngitis.1/+00

Recommendation53Priortoinitiatingantithyroiddrugtherapy,wesuggestthatpediatricpatientshave,asa

baseline,completebloodcellcount,includingwhitebloodcellcountwithdifferential,andaliverproﬁleincludingbilirubin,transaminases,andalkalinephosphatase.2/+00

Recommendation54Betaadrenergicblockadeisrecommendedforchildrenexperiencingsymptomsofhyperthy-roidism,especiallythosewithheartratesinexcessof100beatsperminute.1/+00Recommendation55Antithyroidmedicationshouldbestoppedimmediately,andwhitebloodcountsmeasuredin

childrenwhodevelopfever,arthralgias,mouthsores,pharyngitis,ormalaise.1/+00

Recommendation56Whenpropylthiouracilisusedinchildren,themedicationshouldbestoppedimmediately

andliverfunctionandhepatocellularintegrityassessedinchildrenwhoexperienceanorexia,pruritis,rash,jaundice,light-coloredstoolordarkurine,jointpain,rightupperquadrantpainorabdominalbloating,nauseaormalaise.1/+00

Recommendation57Persistentminorcutaneousreactionstomethimazoletherapyinchildrenshouldbemanaged

byconcurrentantihistaminetreatmentorcessationofthemedicationandchangingtotherapywithradioactiveiodineorsurgery.Inthecaseofaseriousallergicreactiontoanantithyroidmedication,prescribingtheotherantithyroiddrugisnotrecommended.1/+00

Recommendation58Ifmethimazoleischosenastheﬁrst-linetreatmentforGDinchildren,itshouldbe

administeredfor1–2yearsandthendiscontinued,orthedosereduced,toassesswhetherthepatientisinremission.1/++0

[L]

[M][N]

[O]

HYPERTHYROIDISMMANAGEMENTGUIDELINES

Recommendation59[P]

645

PediatricpatientswithGDwhoarenotinremissionfollowing1–2yearsofmethimazolether-apyshouldbeconsideredfortreatmentwithradioactiveiodineorthyroidectomy.1/+00

IfradioactiveiodineischosenastreatmentforGDinchildren,howshoulditbeaccomplished?Recommendation60WesuggestthatchildrenwithGDhavingtotalT4levelsof>20ug/dL(200nmol/L)orfree

T4estimates>5ng/dL(60pmol/L)whoaretoreceiveradioactiveiodinetherapybepretreatedwithmethimazoleandbeta-adrenergicblockadeuntiltotalT4and/orfreeT4estimatesnormalizebeforeproceedingwithradioactiveiodine.2/+00131Recommendation61IfItherapyischosenastreatmentforGDinchildren,sufﬁcient131Ishouldbeadministered

inasingledosetorenderthepatienthypothyroid.1/++0IfthyroidectomyischosenastreatmentforGDinchildren,howshoulditbeaccomplished?Recommendation62ChildrenwithGDundergoingthyroidectomyshouldberenderedeuthyroidwiththeuse

ofmethimazole.Potassiumiodideshouldbegivenintheimmediatepreoperativeperiod.1/+00

Recommendation63IfsurgeryischosenastherapyforGDinchildren,totalornear-totalthyroidectomyshouldbe

performed.1/++0

Recommendation64Thyroidectomyinchildrenshouldbeperformedbyhigh-volumethyroidsurgeons.1/++0HowshouldSHbemanaged?Recommendation65WhenTSHispersistently<0.1mU/L,treatmentofSHshouldbestronglyconsideredinall

individuals!65yearsofage,andinpostmenopausalwomenwhoarenotonestrogensorbisphosphonates;patientswithcardiacriskfactors,heartdiseaseorosteoporosis;andindividualswithhyperthyroidsymptoms.2/++0

Recommendation66WhenTSHispersistentlybelowthelowerlimitofnormalbut>0.1mU/L,treatmentofSH

shouldbeconsideredinindividuals!65yearsofageandinpatientswithcardiacdiseaseorsymptomsofhyperthyroidism.2/+00

Recommendation67IfSHistobetreated,thetreatmentshouldbebasedontheetiologyofthethyroiddysfunction

andfollowthesameprinciplesasoutlinedforthetreatmentofoverthyperthyroidism.1/+00Howshouldhyperthyroidisminpregnancybemanaged?Recommendation68ThediagnosisofhyperthyroidisminpregnancyshouldbemadeusingserumTSHvalues,

andeithertotalT4andT3withtotalT4andT3referencerangeadjustedat1.5timesthenonpregnantrangeorfreeT4andfreeT3estimationswithtrimester-speciﬁcnormalreferenceranges.1/+00

Recommendation69TransienthCG-mediatedthyrotropinsuppressioninearlypregnancyshouldnotbetreated

withantithyroiddrugtherapy.1/+00

Recommendation70AntithyroiddrugtherapyshouldbeusedforhyperthyroidismduetoGDthatrequires

treatmentduringpregnancy.Propylthiouracilshouldbeusedwhenantithyroiddrugtherapyisstartedduringtheﬁrsttrimester.Methimazoleshouldbeusedwhenantithyroiddrugtherapyisstartedaftertheﬁrsttrimester.1/+00

Recommendation71Wesuggestthatpatientstakingmethimazolewhodecidetobecomepregnantobtain

pregnancytestingattheearliestsuggestionofpregnancyandbeswitchedtopropylthiouracilassoonaspossibleintheﬁrsttrimesterandchangedbacktomethimazoleatthebeginningofthesecondtrimester.Similarly,wesuggestthatpatientsstartedonpropylthiouracilduringtheﬁrsttrimesterbeswitchedtomethimazoleatthebeginningofthesecondtrimester.2/+00

Recommendation72GDduringpregnancyshouldbetreatedwiththelowestpossibledoseofantithyroiddrugs

neededtokeepthemother’sthyroidhormonelevelsslightlyabovethenormalrangefortotalT4andT3valuesinpregnancyandtheTSHsuppressed.FreeT4estimatesshouldbekeptatorslightlyabovetheupperlimitofthenonpregnantreferencerange.Thyroidfunctionshouldbeassessedmonthly,andtheantithyroiddrugdoseadjustedasrequired.1/+00

Recommendation73Whenthyroidectomyisnecessaryforthetreatmentofhyperthyroidismduringpregnancy,

thesurgeryshouldbeperformedifpossibleduringthesecondtrimester.1/+00

Recommendation74TRAblevelsshouldbemeasuredwhentheetiologyofhyperthyroidisminpregnancyis

uncertain.1/+00

Recommendation75PatientswhoweretreatedwithradioactiveiodineorthyroidectomyforGDpriorto

pregnancyshouldhaveTRAblevelsmeasuredusingasensitiveassayeitherinitiallyat22–26weeksofgestation,orinitiallyduringtheﬁrsttrimesterand,ifelevated,againat22–26weeksofgestation.1/+00

Recommendation76PatientsfoundtohaveGDduringpregnancyshouldhaveTRAblevelsmeasuredatdiagnosis

usingasensitiveassayand,ifelevated,againat22–26weeksofgestation.1/+00

Recommendation77TRAblevelsmeasuredat22–26weeksofgestationshouldbeusedtoguidedecisions

regardingneonatalmonitoring.1/+00

Recommendation78Inwomenwiththyrotoxicosisafterdelivery,selectivediagnosticstudiesshouldbeperformed

todistinguishpostpartumthyroiditisfrompostpartumGD.1/+00

Recommendation79Inwomenwithsymptomaticpostpartumthyrotoxicosis,thejudicioususeofbeta-adrenergic

blockingagentsisrecommended.1/+00

[Q]

[R]

[S]

646[T]

BAHNETAL.

HowshouldhyperthyroidismbemanagedinpatientswithGraves’ophthalmopathy?Recommendation80Euthyroidismshouldbeexpeditiouslyachievedandmaintainedinhyperthyroidpatients

withGraves’ophthalmopathyorriskfactorsforthedevelopmentofophthalmopathy.1/++0

Recommendation81InnonsmokingpatientswithGraves’hyperthyroidismwhohavenoclinicallyapparent

ophthalmopathy,131Itherapywithoutconcurrentsteroids,methimazoleorthyroidectomyshouldbeconsideredequallyacceptabletherapeuticoptions.1/++0

Recommendation82CliniciansshouldadvisepatientswithGDtostopsmokingandreferthemtoastructured

smokingcessationprogram.Patientsexposedtosecondhandsmokeshouldbeidentiﬁedandadvisedofitsnegativeimpact.1/++0

Recommendation83InpatientswithGraves’hyperthyroidismwhohavemildactiveophthalmopathyandnorisk

factorsfordeteriorationoftheireyedisease,131Itherapy,methimazole,andthyroidectomyshouldbeconsideredequallyacceptabletherapeuticoptions.1/++0

Recommendation84PatientswithGraves’hyperthyroidismandmildactiveophthalmopathywhohavenoother

riskfactorsfordeteriorationoftheireyediseaseandchooseradioactiveiodinetherapyshouldbeconsideredforconcurrenttreatmentwithcorticosteroids.2/++0

Recommendation85PatientswithGraves’hyperthyroidismandmildactiveophthalmopathywhoaresmokersor

haveotherriskfactorsforGraves’ophthalmopathyandchooseradioactiveiodinetherapyshouldreceiveconcurrentcorticosteroids.1/++0

Recommendation86PatientswithGraves’hyperthyroidismandactivemoderate-to-severeorsight-threatening

ophthalmopathyshouldbetreatedwitheithermethimazoleorsurgery.1/+00

Recommendation87InpatientswithGraves’hyperthyroidismandinactiveophthalmopathy,wesuggestthat131I

therapywithoutconcurrentcorticosteroids,methimazole,andthyroidectomyareequallyacceptabletherapeuticoptions.2/++0Howshouldovertdrug-inducedthyrotoxicosisbemanaged?Recommendation88Beta-adrenergicblockingagentsaloneorincombinationwithmethimazoleshouldbeusedto

treatovertiodine-inducedhyperthyroidism.1/+00

Recommendation89Patientswhodevelopthyrotoxicosisduringtherapywithinterferon-aorinterleukin-2should

beevaluatedtodetermineetiology(thyroiditisvs.GD)andtreatedaccordingly.1/+00

Recommendation90Wesuggestmonitoringthyroidfunctiontestsbeforeandat1and3monthsfollowingthe

initiationofamiodaronetherapy,andat3–6-monthintervalsthereafter.2/+00

Recommendation91Wesuggesttestingtodistinguishtype1(iodine-induced)fromtype2(thyroiditis)varietiesof

amiodarone-inducedthyrotoxicosis.1/+00

Recommendation92Thedecisiontostopamiodaroneinthesettingofthyrotoxicosisshouldbedeterminedonan

individualbasisinconsultationwithacardiologist,basedonthepresenceorabsenceofeffectivealternativeantiarrhythmictherapy.1/+00

Recommendation93Methimazoleshouldbeusedtotreattype1amiodarone-inducedthyrotoxicosisand

corticosteroidsshouldbeusedtotreattype2amiodarone-inducedthyrotoxicosis.1/+00

Recommendation94Combinedantithyroiddrugandanti-inﬂammatorytherapyshouldbeusedtotreatpatients

withovertamiodarone-inducedthyrotoxicosiswhofailtorespondtosinglemodalitytherapy,andpatientsinwhomthetypeofdiseasecannotbeunequivocallydetermined.1/+00

Recommendation95Patientswithamiodarone-inducedthyrotoxicosiswhoareunresponsivetoaggressive

medicaltherapywithmethimazoleandcorticosteroidsshouldundergothyroidectomy.1/+00Howshouldthyrotoxicosisduetodestructivethyroiditisbemanaged?Recommendation96Patientswithmildsymptomaticsubacutethyroiditisshouldbetreatedinitiallywithbeta-adrenergic-blockingdrugsandnonsteroidalanti-inﬂammatoryagents.Thosefailingto

respondorthosewithmoderate-to-severesymptomsshouldbetreatedwithcorticoste-roids.1/+00Howshouldthyrotoxicosisduetounusualcausesbemanaged?Recommendation97ThediagnosisofTSH-secretingpituitarytumorshouldbebasedonaninappropriately

normalorelevatedserumTSHlevelassociatedwithelevatedfreeT4estimatesandT3concentrations,usuallyassociatedwiththepresenceofapituitarytumoronMRIandtheabsenceofafamilyhistoryorgenetictestingconsistentwiththyroidhormoneresistanceinathyrotoxicpatient.1/+00

Recommendation98PatientswithTSH-secretingpituitaryadenomasshouldundergosurgeryperformedbyan

experiencedpituitarysurgeon.1/+00

Recommendation99Patientswithstrumaovariishouldbetreatedinitiallywithsurgicalresection.1/+00

Recommendation100Treatmentofhyperthyroidismduetochoriocarcinomashouldincludebothmethimazoleand

treatmentdirectedagainsttheprimarytumor.1/+00

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Guidelines of the American Thyroid Association