Pediatric Graves’ disease: management in the post-propylthiouracil Era

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Pediatric Graves’ disease: management in the post-propylthiouracil Era
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Rivkees, Scott A.
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The most prevalent cause of thyrotoxicosis in children is Graves’ disease (GD), and remission occurs only in a modest proportion of patients. Thus most pediatric patients with GD will need treatment with radioactive iodine (RAI; 131I) or surgical thyroidectomy. When antithyroid drugs (ATDs) are prescribed, only methimazole (MMI) should be administered, as PTU is associated with an unacceptable risk of severe liver injury. If remission does not occur following ATD therapy, 131I or surgery should be contemplated. When 131I is administered, dosages should be greater than 150 uCi/gm of thyroid tissue, with higher dosages needed for large glands. Considering that there will be low-level whole body radiation exposure associated with 131I, this treatment should be avoided in young children. When surgery is performed near total or total-thyroidectomy is the recommended procedure. Complications for thyroidectomy in children are considerably higher than in adults, thus an experienced thyroid surgeon is needed when children are operated on. Most importantly, the care of children with GD can be complicated and requires physicians with expertise in the area. Keywords: Thyroid, Hyperthyroidism, Methimazole, Propylthiouracil, Radioactive iodine, Thyroidectomy, Hepatotoxicity
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Rivkees International Journal of Pediatric Endocrinology 2014, 2014:10 http://www.ijpeonline.com/content/2014/1/10; Pages 1-10
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doi:10.1186/1687-9856-2014-10 Cite this article as: Rivkees: Pediatric Graves’ disease: management in the post-propylthiouracil Era. International Journal of Pediatric Endocrinology 2014 2014:10.

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© 2014 Rivkees; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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REVIEWOpenAccessPediatricGraves ’ disease:managementinthe post-propylthiouracilEraScottARivkeesAbstractThemostprevalentcauseofthyrotoxicosisinchildrenisGraves ’ disease(GD),andremissionoccursonlyina modestproportionofpatients.ThusmostpediatricpatientswithGDwillneedtreatmentwithradioactiveiodine (RAI;131I)orsurgicalthyroidectomy.Whenantithyroiddrugs(ATDs)areprescribed,onlymethimazole(MMI)should beadministered,asPTUisassociatedwithanunacceptableriskofsevereliverinjury.Ifremissiondoesnotoccur followingATDtherapy,131Iorsurgeryshouldbecontemplated.When131Iisadministered,dosagesshouldbe greaterthan150uCi/gmofthyroidtissue,withhigherdosagesneededforlargeglands.Consideringthatthere willbelow-levelwholebodyradiationexposureassociatedwith131I,thistreatmentshouldbeavoidedinyoung children.Whensurgeryisperformedneartotalortotal-thyroidectomyistherecommendedprocedure.Complications forthyroidectomyinchildrenareconsiderablyhigherthaninadults,thusanexperiencedthyroidsurgeonisneeded whenchildrenareoperatedon.Mostimportantly,thecareofchildrenwithGDcanbecomplicatedandrequires physicianswithexpertiseinthearea. Keywords: Thyroid,Hyperthyroidism,Methimazole,Propylthiouracil,Radioactiveiodine,Thyroidectomy,HepatotoxicityGraves ’ diseaseGraves ’ disease(GD)isthemostcommoncauseof hyperthyroidisminchildrenandisaconsiderablymore perniciousconditionthanhypothyroidism.TheprevalenceofGDis1in1,000adults[1]andis1in10,000in thepediatricpopulation[2].GDisduetothyroidgland stimulationbythyroidreceptorantibodies[TRAbs;or thyroidstimulatingimmunoglobulins(TSI)][3].Toxic nodules,toxicmultinodulargoiters,acuteandsubacute thyroiditis,thyroidhormoneingestioncanalsocause childhoodthyrotoxicosis,butmuchlesscommonlythan GD[4]. Symptomsofhyperthyroidismincludeexcessivephysicalactivity,tremor,tachycardia,flushing,palpitations, weightloss, acceleratedlineargrowth,reducedbone mineralization,andpoorschoolperformance[4].In childhoodGD,ophthalmopathyoccursinlessthan50% ofpatientsandisusuallymildwhenpresent[4]. BecauseGDspontaneouslyresolvesuncommonly, hyperthyroidismtreatmentismandatory.TherapeuticapproachesforGDincludetheantithyroiddrugs(ATDs) propylthiouracil(PTU)ormet himazole(MMI),radioactive iodine(131I),orsurgery[4-7].Eachofthesemodalitieshas uniquelyassociatedbenefitsandrisksthatmustbeconsideredwhenchildrenaretreated.AntithyroiddrugsATDswereintroducedinthe1940swiththiouracilbeing thefirstcompoundusedclinically[8].Becauseofthe highincidenceoftoxicreactionsassociatedwiththiouracil,thismedicationwasreplacedforclinicalusebyPTU in1947[8].MMIbecameatreatmentoptionforGDin 1950[8]. ATDsactbyinhibitingoxidationandorganicbinding ofthyroidiodidetoimpairthyroidhormoneproduction [9].MMIisten-totwenty-foldmorepotentthanPTU andhasalongerhalf-life[9].Importantly,thesemedicationsdonotcurethehyperthyroidstate,rathertheypalliatethecondition.Eachofthesemedicationsisassociated withadverseeventsthatmustbeconsideredwhenprescribed.Assuch,priortotheinitiationofATDtherapy,a back-upplanthattakesintoaccountthepatient ’ sageand treatmentrisks,intheeventthatatoxicreactionoccurs, shouldbeconsidered. Correspondence: srivkees@ufl.edu DepartmentofPediatrics,UniversityofFloridaCollegeofMedicine,1600SW ArcherRoad – RoomR1-118,Gainesville,FL,USA 2014Rivkees;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycredited.TheCreativeCommonsPublicDomain Dedicationwaiver(http://creativecommons.org/publicdomain/zero/1.0/)appliestothedatamadeavailableinthisarticle, unlessotherwisestated.Rivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10 http://www.ijpeonline.com/content/2014/1/10

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PropylthiouracilhepatotoxicityIn2008,anumberofseriouscomplicationsassociated withPTUtherapyinchildrenwerebroughttopublic attentionbyRivkees[10-12].PTU-inducedliverinjuryat thattimeaccountedfor15%oflivertransplantsinthe UnitedStates[13].From1990to2007,23PTU-related livertransplantstookplace,and30%ofthePTU-related transplantrecipientswerechildren.Basedonprescribingdata,theriskofPTU-inducedliverfailureleading totransplantationwasestimatedtobe1in2,000children[2]. Despiteacommonperception,becausePTU-induced liverinjuryoccursrapidlyandisoftenirreversible,serial monitoringoftransaminaselevelsinachildonPTU,is notviewedtobeusefulinhelpingtoreducedrughepatotoxicityrisk[2].Assuch,theonlywaytoreducetherisks ofPTU-relatedhepatotoxicityistoavoidtheuseofthe medication. In2009,RivkeesandMadisonrecommendedthatPTU notbeusedinchildren,andthatPTUbestoppedinall childrentakingthemedicationinfavorofalternative treatments[11].InApril,2010,theUSFoodandDrug Administrationissuedabl ackboxregardingtheuseof PTUstatingthatPTUshouldnotbeusedinchildren [10],exceptinspecialsettings,solidifyingthenotion thatthedrugshouldnotbeused.AppropriatelimiteduseofpropylthiouracilAlthoughPTUshouldbeavoidedclinically,thereisa roleforitslimiteduseinspecialcircumstances.PTUcan beusedwhenneitherprompt131Iorsurgicaltreatment areoptionsinapatientwhohashadatoxicreactionto MMI,andATDmedicationisnecessary.Inthissituation, PTUshouldonlybeusedshort-termwhileplansfor131I orsurgeryaredeveloped. WhenPTUisused,patientsandguardiansneedtobe informedoftheriskofliverfailureandtobealertfor signsandsymptomsofliverabnormalities.Thesefeatures includepruritus,jaundice,anorexia,lightcoloredstools, darkurine,andabdominalpain.Iftheseproblemsoccur, thepatientshouldimmediatelystopthemedication,a practitionercontacted,and laboratorytestsobtained (whitebloodcellcount,bilirubin,alkalinephosphatase, ALT/AST).MethimazoleMMIisnowthedrug-of-choiceforGD.Carbimazole, whichisapro-drugthatisconvertedtoMMI,canbeused inplaceofMMIincountrieswhereitisavailable.AlthoughMMIisoftenprescribedindivideddosesoverthe day,onceadaydosingissufficient[14]andisassociated withbettercompliancethanmultipledailydoses[15].The typicalMMIdoseis0.2to0.5mg/kgperday,anddoses canrangefrom0.1to1.0mg/kgperday[3,16-20]. MMIisavailablein5,10,and20mgtablets.When usedinchildren,thefollowingdosesthatarefractionsof tabletscanbeused:infants,1.25mgperday;1to5years, 2.5to5.0mg/day;5to10years,5to10mg/day;and10 to18years,10to20mg/day.Whenthereissevere hyperthyroidism,onecanusedoubletheabovedoses. Becausethehyperthyroidstatecanbeassociatedwith lowwhitecellcountsandpatientswillbetreatedwitha medicationthatcandepressneutrophillevels,itisreasonabletoobtainacompletebloodcountattherapyonset.In addition,weroutinelyobtaintransaminaselevelsandliver functiontestsattherapyonset,toassessforpremorbid liverdisease,aswefindthat1%ofourpatientsmayhave autoimmunehepatitis. TheresponsetoATDsinfluencingcirculatingthyroid hormonelevelsisnotinstantaneous,andseveralmonths areneededforthyroidhormonelevelstonormalize [7,14].Thyroidfunctiontestsshouldthusbeobtained monthlyaftertherapyonset.AfterT4levelsbecome normal,theMMIdosescanbecutbyhalftomaintain euthyroidism[21].BecauseTSHlevelsmaytakemonths tonormalize,theyshouldnotbeusedtoguidechanges inmedicationinearlyphasesoftreatment. RatherthantitratingtheMMIdoselowerwhencirculatingthyroidhormonelevelsfall,somephysiciansprefer theblock-and-replaceapproachandaddlevo-thyroxine whilenotchangingtheMMIdose,however,thereisa greaterriskofadverseeventsusingblockandreplacevs. dosereduction[21,22].Recognizingthatthereisapotentialdose – responserelationshipforsomeMMI-related complications[23,24],itispreferabletousethelowest MMIdosethatachievescontrol,ratherthanusingthe blockandreplaceapproach. AlthoughMMIisthedrugofchoiceforGD,MMI therapyisnotwithoutrisks.Minorsideeffectsmay affectupto17%ofchildren[25].Themostcommon minoradversesideeffectsrelatedtoMMIarehives,arthralgia,andneutropenia[25].Childrenmayalsodevelop majorsideeffects,includingStevens-Johnsonsyndrome andvasculitis[25].MMIadverseeventsmostcommonly occurwithin6monthsoftherapyonset[25].Yet,4%of childrenwilldevelopadverseevents18monthsofMMI therapy,highlightingtheneedforconstantvigilancewhile ontreatment. AgranulocytosisisanotherpotentialseriousATD adverseeventandoccursin0.3%ofadultstakingPTU orMMI[7,26].WithMMI,agranulocytosisisdosedependentandisrareatlowdoses[7,26].Ifanindividual receivingMMIfeelsill,becomesfebrileordevelops pharyngitis,MMIshouldbestoppedimmediately,a practitionercontacted,andacompletebloodcellcount obtained. Agranulocytosistypicallydevelopsfirst3monthsof therapy[7,26].Thus,whereasitistemptingtotreatwithRivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10Page2of10 http://www.ijpeonline.com/content/2014/1/10

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high-dosesofATDtherapyatonset,thisapproachshould beavoided.Rather,relativelylowerdosesofMMIshould beemployedinitially,andsymptomsmanagedwithbetablockers.Furthermore,thetimetonormalizationofthyroidfunctiontestsisonlymodestlydifferentinindividuals treatedwithhighvs.lowATDdoses[14]. AlthoughATDscanbeusedlong-term,reportsdescribe thedevelopmentofanti-neutr ophil-cytoplasmicantibodies (ANCAs),whichareassociatedwithvasculitisandmay limitprolongedmedicaltherapyofGD[27-29].Inadults upto15%ofindividualstreatedwithPTU,developANCAs after2yearsoftherapy[27,28].MMIuseisalsoassociated withANCA-positivityconversion,albeitwithalower incidencethanwithPTU[27,28]. Inthepediatricpopulation,ANCA-mediateddiseasehas beenobservedwitheitherPTUorMMI[30,31].Because theseantibodiescantriggerseriousvasculitisevents,antithyroidmedicationsshouldbestoppedanddefinitive therapyconsideredwhenANCAantibodiesaredetected [32].Totestforthispotentialproblemitisreasonable toperformannualassessmentofANCAsonchildrenon prolongedATDtherapy,i.e.morethantwoyears.DurationoftherapyRemissionofGDisdefinedasbeingbiochemicallyeuthyroidorhypothyroidforoneyearormoreafterthediscontinuationofATDs.Thecollectiveliteratureindicatesthat remissionratesinchildrenarelessthan25%following manyyearsofATDtherapy[33-37](Table1). AlthoughprolongedATDtreatmentwillcontrolbiochemicalhyperthyroidism,itisnotclearthatprolonged ATDuseincreasesthelikelihoodoflastingspontaneous remission[38].InaFrenchstudyof94patients,following treatmentfor6or18months,remissionrateswere42% and62%respectively,aftertwoyearsoftreatment[39]. In52Spanishpatients,followingtreatmentfor12or 24months,remissionrateswere46%and54%,respectively,2yearsaftercessation oftherapy[40];at5-years, therelapseratewas85%.Anotherstudyof134French patientsfoundnobenefitof18vs.43monthsoftreatment[41].Thustreatingbeyond18monthsdoesnot increaseremissionlikelihoodinadults. Inthepediatricagegroup,remissionratesrangefrom 20to30%followingATDsusefortwoyearsormore [18,35,36,42,43].Morethan25yearsago,Lippeandcoworkersestimatedthat25%ofchildrengointoremission foreverytwoyearsoftreatment[44].Ofthe63patients followedonATDs,36(57%)remittedafteranaverageof fouryearsoftherapy[44].Yet,therewerelittledatato showifthepatientswhocameoffATDsremainedin remission[44]. OtherlargecohortstudiesofATDuseformanyyears [33,34]showlowremissionrates.Ofmorethan200childrenwithGDinMinnesota,25%wereinremissionafter oneyear;25%after2years;26%after4years;and15% after10years.Inaddition,30%oftheboysandgirlswho wentintoremissionhaddiseaserecurrence[33]. When184pediatricchildreninCaliforniawerefollowed forupto4years,theoverallremissionratewas23%[34]. AfteroneyearofATDs,10%wereinremission;after 2years,14%wereinremission;after3years,20%)werein remission;andafter4years,23%wereinremission. InastudyofchildreninArgentina,113patientsreceivedATDsforprolongedperiods[45].After10years oftreatment,33%ofpatientstreatedwithATDswent intoremission[45]. Mostrecently,astudyperformedinFrancereported thatprolongeddrugtherapywasassociatedwith50% remissionratesinchildren[37].One-hundredfifty-four childrenwithGDdiagnosedbetween1997and2002were examinedfollowingtreatmentwithcarbimazole.Theestimatedratesofremissionwere20%,37%,45%,and49%, after4,6,8,and10yearsoftherapy,respectively[37]. Age-relatedfactorsalsoinfluenceremissionlikelihood. Inastudyof32prepubertalvs.68pubertalchildrenwith GD,remissionoccurredin17%ofprepubertalchildren treatedfor6yearsvs.30%ofpubertalchildren[42].In anotherreportwithpre-andpost-pubertalcohorts,remissionoccurredin28%ofchildren[46],butthetime toremissionwasthree-timeslongerinthepre-pubertal childrenthanpubertalchildren[46].Ofnote,adverse reactionstoATDsoccurred withgreaterfrequencyin prepubertalchildren(71%)thaninpubertal(28%)and postpubertal(25%)children[46]. Inadditiontopuberty,TRAblevelsandglandsizeinfluenceremissionrates.TheefficacyofATDsisinversely relatedtocirculatinglevelsofTRAbs.Remissionratesof GDinadultsareabout15%inpatientshighTRAblevels atdiagnosis,and50%whenthepretreatmentlevelsare normal[47].Largeglandsatpresentationarealsoassociatedwithmuchlowerremissionratesthanwhengland sizeisnormal[48-50].SymptomaticmanagementInpatientstreatedwithATDsforGD,itmaytakeoneor twomonthsuntilbiochemicalhyperthyroidismresolves Table1Studiesofratesofremissionrelatedto antithyroiddruguseAuthorDateSampleOutcome*Reference Hamburger198526214%[ 54 ] Glaser199718424%[ 34 ] Glaser20085829%[ 35 ] Kaguelidou200815428%[ 36 ] Leger201215448%[ 37 ]*Remissionrate.Rivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10Page3of10 http://www.ijpeonline.com/content/2014/1/10

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[14].Intheinterim,treatmentwithbetablockers,including propranolol,atenololormetoprolol,canbeusedtocontrol GDsymptoms.Whenthepatienthasasthma,metoprololis preferredovernon-selectivebe ta-blockers,withthepatient carefullymonitored[51].Whenthyroidhormonelevels normalize,betablockerscanbestopped.MetaboliccomplicationsofGDIncreasingevidenceshowsthatGDcanbeassociated metaboliccomplications.GDcanbeassociatedwitheither hyper-orhypoglycemiaatpresentation[52,53].Myopathy hasbeenobservedbothatinitialpresentationandwhen hypothyroidismoccursaftertherapy[54].Excessiveweight gainhasbeenobservedafterinitiationoftherapy,leading totherecommendationthatdietarycounselingtakeplace whentreatmentisinitiated[55].RadioactiveiodineRadioactiveiodineuptakebythethyroidisnotdistinguishablefromordinaryiodin e,thusradioactiveiodine istrappedinthyroidcells[56].Afterbeingtakenupby thyroidcells,beta-emissi onsbringaboutthedestructionoftheiodinetrapping-cellsandthoseinclose proximity[56]. Aroundtendifferentisotopesofiodinehavebeenused inmedicine.123Iistheisotopemostfrequentlyusedfor diagnosticstudiesofthyroidstructureandfunction[56].121Ihasashorthalf-life(13.3hrs)andemitsx-raysand gamma-photons,butnobetaparticles.Bycomparison,131Ihasahalf-lifeof6 – 8daysandemitsbetaparticlesand gammarays. Radioactiveiodineuseforthyroidablationwasintroducedinthe1940 ’ sattheMassachusettsInstituteof TechnologyandMassachusettsGeneralHospital[6,57]. WhentheUSAtomicEnergyCommissionwaspermitted tosupplyuraniumfissionproductsformedicalusage,131I, withaneight-dayhalf-lifebecameavailableforGDtreatment.Becauseoftheintrinsicadvantagesalongerhalf-life isotope,131Iquicklybecamethefavorediodineisotopefor treatingthyroidcancerandhyperthyroidism.TreatmentapproachThegoalfor131ItherapyforGDistoinduce hypothyroidism.Radioactiveiodineshouldnotbegivento causeeuthyroidisminchildren, asthisresultsinpartiallyirradiatedresidualthyroidti ssuethatwillbeassociatedwith ariskofthyroidneoplasm[58,59].Ithasbeensuggested thatdosagesdelivering30,000to40,000cGy(rad)tothe thyroidarenecessarytoablatethethyroidgland[60,61]; however,dosesdelivering10,000to20,000cGytothethyroidaremoreoftenusedandresultinpartialorcomplete destructionofthethyroid[4,62,63]. Typically,administeredthyroiddosesof150uCi/gm (5.5MBq/gm)generateradiationdosesof12,000cGyto thethyroid[64].After131Itreatment,radiationexposure tothestomach,marrow,liver,andgonadsisabout14, 6.8,4.8,and2.5cGyperorgan,respectively,withtotal bodyexposureatabout4.0cGy[64].Becauseoffetalrisks,131Ishouldnotbegiventowomenwhoarepregnant. Therateofiodineuptakeandtheamountofthyroid tissuepresentinfluencesthyroiddestructionpotential. Dosagesofradioiodineadministeredarethusbasedon iodineuptakeandglandsizeusingtheQuimby-Marinelli equation:dosage(radiation;inGy)=90oraliodine-131 dose( Ci)oral24-hruptake(%)/glandmass(gm) 100%).ThiscalculationassumesaneffectiveT/1/2of 6.0daysfor131I.Thyroidsizeisestimatedbypalpationor ultrasound(ultrasoundvolume=0.48lengthdepth width)[65].Ifapatientistakingantithyroidmedication, treatmentshouldbestopped3 – 5daysbeforeradioactive iodineisadministered.After131Iadministration,thecirculatinglevelsofthyroidhormonesmayincreasewithin4to 10days,asthyroidhormoneisreleasedfromdegenerating follicularcells[66].Thusifantithyroidmedicationisdiscontinuedtoosoon,therecanbeaccumulationofexcess thyroidhormonewithinthegland,leadingtoanincreased riskofthyroidstormfollowingtreatment[67]. Itusuallytakes6to12weeksafter131Itreatmentforthe patienttobecomebiochemical lyeuthyroidorhypothyroid. Untilthen,symptomsofhyperthyroidismcanbecontrolled usingbeta-blockers[66,68,69].TheuseofSSKIorLugol ’ s solutiononeweekafter131Iwillalsoquicklyattenuatebiochemicalhyperthyroidismwit houtadverselyaffectingthe outcomeofradioiodinetherapy[69]. Inasmanyas5%ofpatients,receivingproperlycalculateddosages,hyperthyroidismwillpersistafter131I.Itis recommendedthatthesepatientsreceiveaseconddose ofradioiodine[62],whichcanbegiven6monthsafter initialtherapy.Furthermore,sometimesinthosepatients withresidualthyroidtissues,asindicatedbybeingeuthyroidorborderlinehypothyroid,hyperthyroidismmay recurrequiringadditionaltherapy. Cureratesarehigherinpatientstreatedwithlarger thansmalleramountsof131I.Whentreatedwithrelatively lowdosages(50 – 75uCi/gm),hyperthyroidismpersistsin 30to50%ofadultsoneyearaftertherapy[70-73].By comparison,aftertreatmentwithhigherdosages(150 – 250 uCi/gm),only5-10%ofpatientswillremainhyperthyroid atoneyear[64,74,75]. Radioiodinetherapy ’ ssuccessisinfluencedbythethyroidglandsizeandbycirculatinglevelsofTRAb.Patients withverylargeglands(>80gm)andhighTRAblevels havelowerresponsesto131Itherapythanpatientswith smallerglands[63,76-79].Becauseofpoorresponserates withverylargeglands,thyroidectomyshouldbeconsideredforindividualswithglandsgreaterthan80gm.But,if131Iisusedinthissetting,patientsshouldbecounseled thattheriskofneedinganadditionaldose,willbehigherRivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10Page4of10 http://www.ijpeonline.com/content/2014/1/10

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thanforpatientswithasmallergland.Furthermore,surgicalremovalofverylargeglandswillbeassociatedwith greaterriskthanremovalofasmallergland. Consideringtheabove,patientstreatedforGDneed tobeconstantlymonitoredforprogressivethyromegaly, whichcanchangeapatientsfrombeinganexcellent candidateforgood131Ioutcome,tooneinwhichoutcomes ispoororassociatedwithincreasedrisksoftherapy.Gland sizecanbegrosslyestimatedbypalpation,withtheexaminerstandingbehindthepatientandfeelingeachlobeof thethyroidglandwiththeirindexfingerstoestimatethe sizeofeachloberelativetoateaspoon(5gm)ortablespoon (15gm),ormultiplesthereof.Forexampleifeachlobeof thethyroidisaboutoneteaspoon,theestimatedglandsize is10gm.Yet,whenthereareabouttwotablespoonsor moreforeachlobe,glandsizewillbe60gmormore. Whentheglandislarge,thyroidultrasoundisrecommendedtomoreaccuratelyassessglandsize.Byultrasoundglandsizeis0.6lengthwidthdepth[80,81].RadioactiveiodineuseinchildrenSeveralstudieshavereportedthedetailsof131Itherapy forchildhoodGD[33,82-88].Childrenasyoungasone yearoldhavebeentreatedwith131Iwithexcellentresults [88,89].But,treatmentofsuchyoungchildrenisnotcommon,norisrecommended.131Idosagesinchildrenand teenagershaverangedfrom100to400uCi/gmofthyroid tissue[4].Similartothatfoundinadults,responsesto131I therapyarerelatedtoglandsizeanddose.25to40%of childrentreatedwith50 – 100uCiof131Ipergmofthyroid tissuearehyperthyroidseveralyearsaftertherapy[58].In childrentreatedwith150 – 200uCiof131Ipergmthyroid, hyperthyroidismremainsin5-20%,and60-90%become hypothyroid[4,62,83,89]. Ourgroupanalyzedoutcomesofthechildrentreated withradioactiveiodinetherapytoassesstheeffectiveness oftherapyasrelatedtoglandsizeanddose[90].Following treatment,whentreatedwith80 – 120uCiof131Iper gmofthyroidtissue,28%ofchildrenwerehyperthyroid,28%ofchildrenwereeuthyroid,and42%of childrenwerehypothyroid.Followingtreatmentwith 200 – 250uCipergmofthyroidtissue,37%ofchildrenwerehyperthyroidand62%werehypothyroid. Following,treatmentwith300 – 400uCipergmofthyroid tissue,0%ofchildrenwerehyperthyroid,euthyroid,and 93%werehypothyroid.Comparingthesepediatricdata withthosefromadults[63,65,90],thyroidtissueofchildrenappearstobemoresensitiveto131Iinducedablation thanadults. Asinadults,wefindthatglandsizeinfluencestherapy outcomes.Ingeneral,higherdosagespergmofthyroid tissueareneededwithlargerthansmallerglands.Yet, withglandslargerthan80gm,131Iefficacyislowandis notrecommended. Asinadults,whenchildrenaretobetreatedwith131I, ATDsshouldbestopped3to5dayspriortotreatment [90].Patientsarethenplacedonbeta-blockersuntilT4 and/orfreeT4levelsnormalizepost-therapy.Whereas somecliniciansrestartATDsaftertreatmentwith131I, thisisrarelyrequiredinchildren[4,62,90,91].Thyroid hormonelevelsbegintodecreaseabout7daysafter radioiodinetherapyinchildrenandcontinuedATDusecan makeitdifficulttoassessifpo st-treatmenthypothyroidism istheresultof131IortheATD. Somecentersgiveafixedadministereddosageof10or 15mCi131Itoallchildren[91]ratherthanindividually calculatedadministeredactivation.Therearenostudies comparingoutcomesoffixeddosesvs.calculateddosesin children.Inadults,thetwodifferentapproachesleadto similaroutcomes[92,93];however,inchildren,apotential advantageofcalculatedvs.fixeddosing,isthatitmightbe possibletouselowerdosagesof131Iiftheadministered doseiscalculated. Sideeffectsof131Itherapyareunusual.Lessthan10% ofchildrenwillcomplainofmildtendernessoverthe thyroidinthefirstweekafter131Itherapy.Thiscanbe treatedwitheitheracetami nophenornon-steroidal, anti-inflammatoryagentsfor24to48hrs[62,90]. Therearerarereportsofchildrenwithseverehyperthyroidismdevelopingthyroidstormafter131I[67].Ingeneral, thesechildrenwereseverelyhyperthyroidwhen131Iwas rendered.Thus,ifT4levelsare>20ug/dl(200nmol/l)or freeT4levelsare>5ng/dl(60pmol/l),childrenshouldbe treatedwithMMIuntilT4and/orfreeT4levelsnormalize beforeproceedingwith131Itherapy[90].Itisimportantto recognizethatmostchildrenwithGDhavebeenhyperthyroidformonthspriortodiagnosis;thereisnoneedtorush to131Itherapy. Following131I,T3,T4and/orfreeT4levelsshouldbe obtainedmonthly.BecauseTSHlevelsmaybesuppressed forseveralmonthsafterthehyperthyroidstateiscorrected. Thus,TSHdeterminationmaynotbeusefulpost-therapy. Typically,hypothyroidismdevelopsby2to3monthsafter treatment[90,91].WhenT4levelsfallbelownormal,levothyroxineisprescribed.OphthalmopathyThedevelopmentofprogressionofophthalmopathyfollowing131Iinadultshasbeenreported.However,unlike adults,childrenrarelydevelopsevereophthalmopathy andproptosisismild. StudiesshowthatdiseaseworsensinonlyasmallpercentageofchildrenwithGD,irrespectiveoftherapytype. Of87childrentreatedwith131IforGDatonecenter, proptosisimprovedin90%ofchildren,didnotchangein 7.5%,andworsenedin3%post-therapy[75,89].In45childrenwhohadophthalmopathyattheonsetoftreatment atanothercenter,eyediseaseimprovedin73%andRivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10Page5of10 http://www.ijpeonline.com/content/2014/1/10

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worsenedin2%afteroneyearormoreofdrugtherapy [94].Aftersubtotalthyroidectomyin80children,eye diseasewasworsenedin9%[95],andwasstablein75% aftertotalsurgicalthyroidectomy[95]. Inadults,ithasbeenshownthatprogressionof ophthalmopathycanbepreventedbytreatmentwith prednisonefor3monthsfollowing131Itherapy[96]. Adjunctiveprednisonetherapyisnotroutinelyrecommendedforthemajorityofchildren,asmostdonot havesignificanteyedisease.Theprolongedadministrationofprednisoneisalsoassociatedwithgrowthfailure, weightgainandimmunesuppression.Nevertheless, prednisonemaybeusefulforthechildwhohassevere eyediseaseandwillbetreatedwith131I.TherisksofgeneticdamagewithradioactiveiodineThereisnoevidenceshowingadverseeffectstooffspring ofchildrentreatedwith131I.Birthdefectswerenothigher in500offspringborntoabout370individualstreated with131Iforhyperthyroidismduringchildhoodoradolescence[4].Additionally,theratesofbirthdefectsare nothigherinchildrentreatedwith80 – 700mCiof131I forthyroidcancer,whicharedosagesthataremuch higherthanthoseusedforGD[97].ThyroidneoplasmriskwithradioactiveiodineThethyroidglandisuniqueinitsdevelopmentalsensitivity tomalignancyafterlow-level radiationexposure[98-101]. Thereisanincreasedriskofthyroidcancerinindividuals lessthan20yearsofageatthetimeoflow-levelthyroidirradiation,andtheyoungeroneis,thegreaterthe thyroidcancerrisk[98-100].Incontrast,individuals whoareolderthan20yearsofage,donotexhibitan increasedriskofthyroidcancerwhenexposedtolow-level thyroidirradiation[98-101]. Importantly,theriskofthyroidneoplasmsisgreatestwithexposuretolow-levelexternalradiation (0.1-25Gy;~0.09-30uCi/gm)[98-102]andnotwith thehigherdosagesusedtotreatGD.Atpresent,weare notawareofanycasesofthyroidcancerthatdevelopedin pediatricpatientstreatedwith>150uCiof131Ipergm ofthyroidtissueforchildhoodGDthatcanbeattributedto131Itherapy.Thus,itisimportantthatlowdosages beavoided.Non-thyroidcancerriskswithradioactiveiodineAlongwiththeriskofthyroidcancer,thepotentialinfluencesof131Itherapyonothercancersmustbeconsideredsince131Itherapyresultsinlow-level,whole bodyradiationexposure.Severalstudiesinadultshave examinedpotentialrisksof131ItherapyforGDoncancers(Table2).Thesestudieshavenotrevealedincreased mortalityorincreasedratesofcancerfollowing131Ifor GD[103-109]. Incomparisonwithstudiesinadults,fewstudieshave focusedonoutcomesof131ItherapyforchildhoodGD. Themostextensivestudyofpediatricpatientsinvolved 36yearoutcomesof116patientswhowerelessthan 20-yearsoldwhentreatedwith131ItherapyforGD [110].Therewasnoevidenceforincreasecancerriskin thispopulation. Thetotal-bodyradiationdoseafter131Ivarieswith age,andthesameabsolutedoseof131Iwillresultin moreradiationexposureinayoungchildthaninan adolescentoradult[111,112].Currently,wedonothave dosimetrydataon131IuseinpediatricpatientswithGD toassesstotalbodyexposureinpediatricpatients.Based onphantommodeling,itisestimatedthatat0,1,5,10, 15years,andadulthood,respectivetotalbodyradiation doseswillbe11.1,4.6,2.41.45,0.90,and0.85rem (0.01Sv)permCiof131Iadministered[111,112].Basedon theBiologicalEffectsofIonizingRadiationCommitteeV (BEIRVII)analysisoflow-level,acuteexposuretoradiation[113],theoreticallifetimeattributableriskofcancer mortalityandallcancerincidencecanbeprojected.Based onthesetheoreticalcalculations,wefeelthatitisprudent toavoidradioactiveiodinetherapyinchildrenunder 5yearsofageandtoavoid>10mCiinpatientslessthan 10yearsold.Yet,theserecommendationsarebasedon theoreticalconcernsandnotonharddata. Werecognizethattheremaybecircumstances when131Itherapyisnecessaryforyoungchildren.The needfor131Iinayoungchildmayoccurwhenthechild developsatoxicreactiontoanATD,propersurgicalexpertiseisnotaccessible,orthechildisnotasuitablesurgicalcandidate.SurgeryTheoldestformofdefinitiveGDtherapyissurgery,with theNobelPrizeinPhysiologyandMedicineawardedin 1909toKokerfordevelopmentsinthisarea.Whensurgeryisconsidered,neartotalortotal-thyroidectomyis indicated,assubtotalthyroidectomyisassociatedwitha Table2Totalcancerandcancermortalityrelatedto131I therapyforhyperthyroidisminadultsAuthorDateSiteSampleOutcomeReference Ron1998US23,020NoEffect***[ 109 ] Holm1991SW10,000NoEffect**[ 107 ] Franklyn1998UK7,209NoEffect[ 104 ] Flynn2006UK3,888NoEffect[ 103 ] Metso2007FN2,793NoEffect*[ 108 ] Franklyn2005UK2,668NoEffect[ 105 ] Goldman1982US1,762NoEffect[ 106 ]***IncreaseinthyroidCAwithNodularDisease. **20%increaseinstomachCA. *15%IncreaseinstomachCAinElderlyMenwithNodularDisease.Rivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10Page6of10 http://www.ijpeonline.com/content/2014/1/10

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higherrelapserate[95].Hypothyroidismisnearlyuniversalinchildrenandadultswhoundergototalthyroidectomy[95,114-116].Incomparison,aftersubtotal thyroidectomy,hyperthyroidismrecursin10-15%of patients[95,114,115]. Surgeryispreferredinchildrenyoungerthan5years whendefinitivetherapyisneededANDcanbeperformed byaskilledthyroidsurgeon.Inindividualswhohave largethyroidglands(>80gm),theresponseto131Iis poor[63,117].Thus,surgeryisrecommendedforthese patients. Inpreparationforsurgery,thepatientshouldberenderedeuthyroid.Typically,thisisdonebycontinuing MMIuntilT4levelsnormalize.Aweekbeforesurgery, iodinedropsarestarted(5to10drops,t.i.d.),whichinhibitsthyroidhormoneproductionandcausesthegland tobecomefirmandlessvascular,facilitatingsurgery. Postoperatively,youngerped iatricpatientsareatahigher riskfortransienthypoparathyroidismthanadolescents oradults[118].Tomitigatepost-operativehypocalcemia,wetreatchildrenwith0.5mcgofcalcitriol,twicea day,for3dayspriortosurgery.Post-operatively,the calcitriolisweanedover15days(0.5mcgbid5days; 0.5mcgqd5days;0.5mcgqodx5days)[119].Using thisapproachonly5%ofpatientsrequirepost-operative calciuminfusionsvs.40%ofpatientswithoutpreoperativetreatment[119].ComplicationsofsurgeryAcutecomplicationsthatfollowthyroidectomyinclude hemorrhage,hypocalcaemia,andrecurrentlaryngeal nerveparesis[118,120-123].Inchildren,ratesfrom0 – 6 yearswere22%,from7 – 12years,11%;andfrom13to 17years,11%[118].Theseratesarehigherthanthosein adults. Complicationratesarealsorelatedtothetypeof surgeon.Whenperformedbypediatricsurgeons,the complicationratefortotalthyroidectomyisapproximately 15%.Incomparison,thecomplicationrateinchildrenfor high-volumethyroidsurgeons(>30thyroidectomies/year) isapproximately4%. Consideringthesedata,iflocalpediatricthyroidsurgeryexpertiseisunavailable,referralofachildwithGD toahigh-volume,thyroidsurgerycenterwithpediatric experienceshouldbeconsidered[124,125].Verylow complicationratesforchildrenundergoingthethyroidectomiesforGDhavebeenreportedwiththistypeof multidisciplinarymodel[119,124].ConclusionsBasedonwhatweknowaboutboththerisksofdifferent treatmentsandthepathogenesisofGD,wecanbediscriminatinginourapproachtotherapy.Toreducethe risksoftreatmentandtoexpeditecure,treatmentshould beguidedbythepatient ’ sage,thenatureoftheintrinsic autoimmunedisease,andbyexpertise. Forchildrenlessthan5yearsold,MMIshouldbe consideredasafirst-linetherapy.Whileradioactive iodinehasbeensuccessfullyusedinthisagegroup withoutanapparentincreaseincancerrates[89,126], itmaybewisesttodeferradioactiveiodinetherapy untilolder. Becauseyoungchildrenarelesslikelytohaveremission ondrugtreatmentvs.olderchildren[42,46],prolonged drugtherapymaybenecessary.Assumingthereareno toxiceffects,continuingMMIissensibleuntilthechildis oldenoughfor131I.Ifreactionstomedicationdevelop,or thereisthedesiretoavoidprolongeddruguse,thyroidectomyor131Icanbeconsidered.Fortunately,lessthan5% ofchildrenwithGDpresentat5yearsoryounger[127]. ItisimportanttoemphasizethatwhenATDsareused, onlyMMIshouldbeprescribed.PTUuseshouldberestrictedtospecialcircumstanceswhenneitherprompt surgerynor131Itreatmentsarepossibilitiesinapatient whohasdevelopedatoxicreactiontoMMI,andATD therapyisrequired.Inthissetting,theuseofPTU shouldbeshort-term. FifteenpercentofchildrenwithGDwillpresentbetween6yearsand10yrsofage[127].Itisreasonable toconsiderMMItherapyasafirstlinemeasureforthis agegroup.As10yearsofageisapproached,either drugtherapyorradioactiveiodinecanbeconsidered asaninitialtherapy. Childrenwhoare10yearsandolderaccountfor80% ofthepediatricGDcases.RadioactiveiodineorMMI canbeconsideredasfirstlinetreatmentoptionsforthis agegroup.TRAblevelsandthyroidsizemaybepredictive ofremissionrates.ThepresenceoflowTRAblevelsanda smallthyroidissuggestiveofthepossibilityofspontaneousremissionafteratleastoneyearofmedicaltherapy. Yet,ifthethyroidislargeandTRAblevelsarehigh,the oddsofspontaneousremissionarelow[47,128,129]. ForthosepatientswhohavenormalTRAblevelsand asmallthyroid,itisreasonabletotreatforonetotwo yearsandstopthedrugwhenclinicalremissionis achieved.Ifrelapseoccurs,medicaltreatmentcanbe resumedoranalternativeformoftherapychosen.For patientswithelevatedTRAblevelsandalargethyroid size,itislesslikelythatremissionwilloccuraftermedical therapy.Thus,definitivetreatmentsoonaftereuthyroidismisachievedcanbeconsidered. Whenradioactiveiodineisused,itisimportantthat theappropriatedosagebeadministered.Theobjective ofradioactiveiodinetherapyinpediatricpatients shouldbetoablatethethyroidglandandachieve hypothyroidism.Theriskof thyroidcancerwillbevery small,ifpresentatall,ifnothyroidtissueremains,To achievethisobjective,dosesof131I>150uCi/gmofRivkees InternationalJournalofPediatricEndocrinology 2014, 2014 :10Page7of10 http://www.ijpeonline.com/content/2014/1/10

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thyroidtissueareneeded,w ithhigherdosesneededfor largerglands. Finally,regardlessofthetreatmentoptionselected, carefulfollowupisessentialforallpatientstreatedfor GD.Long-termfollow-upshouldinclude,onceortwice ayear,regularexaminationofthethyroidglandand measurementofcirculatinglevelsofthyroidhormones. SelectingatreatmentapproachforchildhoodGDcan bechallengingandpersonaldecision.Itisessentialthat physiciansdiscusstheadvantagesandrisksofeachtherapeuticoptiontohelpthepatientandfamilyselectthe treatmentplantheyfeelcomfortablewith.Competinginterests Theauthordeclaresthattherearenocompetinginterests. Acknowledgement SupportedinpartbyNIHgrant7R01FD003707. Received:10April2014Accepted:4June2014 Published:16June2014 References1.Abraham-NordlingM,TorringO,LantzM,HallengrenB,OhrlingH,Lundell G,CalissendorffJ,JrneskogG,WallinG: Incidenceofhyperthyroidismin Stockholm,Sweden,2003 – 2005. EurJEndocrinol/EurFedEndocrSoc 2008, 158: 823 – 827. 2. 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AnnRheumDis 2002, 61: 90 – 91. 29.RadiceA,SinicoRA: Antineutrophilcytoplasmicantibodies(ANCA). Autoimmunity 2005, 38: 93 – 103. 30.PoomthavornP,MahachoklertwattanaP,Tapaneya-OlarnW,ChuansumritA, ChunharasA: Antineutrophiliccytoplasmicantibody-positivesystemic vasculitisassociatedwithpropylthiouraciltherapy:reportof2children withGraves'disease. JMedAssocThai 2002, 85 (Suppl4):S1295 – S1301. 31.FujiedaM,SuzukiK,SatoH,HattoriM,WadaN,TsuchiyaM,OkamotoN, MurataT,MatsudairaM,ShimizuM,OhtaK,NaruseK,SugiharaS,WakiguchiH: Epitopeanalysisofmyeloperoxidase-specificantineutrophilcytoplasmic autoantibodies(MPO-ANCA)inchildhoodonsetGraves'diseasetreated withpropylthiouracil. ClinNephrol 2005, 63: 437 – 445. 32.MerkelPA: Drugsassociatedwithvasculitis. CurrOpinRheumatol 1998, 10: 45 – 50. 33.HamburgerJI: Managementofhyperthyroidisminchildrenand adolescents. JClinEndocrinolMetab 1985, 60: 1019– 1024. 34.GlaserNS,StyneDM: Predictorsofearlyremissionofhyperthyroidismin children. 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39.AllannicH,FauchetR,OrgiazziJ,MadecAM,GenetetB,LorcyY,LeGuerrier AM,DelambreC,DerennesV: AntithyroiddrugsandGraves'disease:a prospectiverandomizedevaluationoftheefficacyoftreatment duration. JClinEndocrinolMetab 1990, 70: 675 – 679. 40.Garcia-MayorRV,ParamoC,LunaCanoR,PerezMendezLF,GalofreJC, AndradeA: AntithyroiddrugandGraves'hyperthyroidism.Significance oftreatmentdurationandTRAbdeterminationonlastingremission. JEndocrinolInvest 1992, 15: 815 – 820. 41.MaugendreD,GatelA,CampionL,MassartC,GuilhemI,LorcyY, LescouarchJ,HerryJY,AllannicH: AntithyroiddrugsandGraves' disease – prospectiverandomizedassessmentoflong-termtreatment. ClinEndocrinol(Oxf) 1999, 50: 127 – 132. 42.ShulmanDI,MuharI,JorgensenEV,DiamondFB,BercuBB,RootAW: Autoimmunehyperthyroidisminprepubertalchildrenandadolescents: comparisonofclinicalandbiochemicalfeaturesatdiagnosisand responsestomedicaltherapy. Thyroid 1997, 7: 755 – 760. 43.MaC,KuangA,XieJ,LiuG: RadioiodinetreatmentforpediatricGraves' disease. 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