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Testes defunçãotireoidiana;tireotropina;triiodotironina;tiroxina;hipotireoidismo; hipertireoidismo Descritores ferramentas diagnósticasnapráticaclínica. cotidiano dessestestesesãoapresentadasrecomendaçõesparaotimizarautilizaçãodessas dados doMedline,sãodiscutidasasprincipaisarmadilhaseinterferênciasrelacionadasaouso mônios tireoidianos e dos anticorpos antitireoidianos. Mediante um levantamento na basede tireoidiana, entreelesadosagemséricadohormônioestimulantedatireoide(TSH),doshor desteartigotivo éfazer umaanálisecríticadousoapropriadodosprincipaistestesdefunção e inespecífica,deformaqueapenastestesbioquímicospodemdetectarotranstorno.Oobje apenas confirmamodiagnóstico.Noentanto,na maioriadospacientes, a sintomatologia ésutil dasdisfunçõestireoidianas.Quandoháalta suspeita clínica,asdosagenshormonais -efetivo Exames laboratoriais são fundamentais para o diagnóstico acurado e o monitoramento custo RESUMO mendations arepresentedtooptimize theuseofthesediagnostictoolsinclinicalpractice. to theroutineuseofthesetestsarediscussedbasedonaMedlinedatabasesurvey, andrecom (TSH), and antithyroid antibodies. The pitfallsof and impediments dard thyroid functiontests,which includemeasuringthelevelsofserumthyroid-stimulating cessary toidentifythedisorder. The purposeofthisarticle istocriticallyanalyze theuseofstan suspicion. For mostpatients,symptoms arenonspecificandsubtle,sobiochemical testsarene dysfunction. Hormonelevelscanonlyconfirmadiagnosiswhenthereishighlevelofclinical Laboratory testsareessentialfortheaccuratediagnosisandcost-effective monitoringofthyroid ABSTRACT Gisah Amaral deCarvalho Utilização dostestes defunçãotireoidiana naprática clínica function tests The clinical useofthyroid Thyroid functiontests;thyrotropin;;thyroxine;; Keywords Bras EndocrinolMetab. 2013;57(3):193-204 Arq Bras Metab. Endocrinol 2013;57/3 the re andhowto interpret tests quest laboratory todetectdisease. making biochemicaltestsnecessary subtle orabsentinmostpatients, disease are thyroid becausethesignsandsymptomsof disorders thyroid essentialfortheaccurate diagnosisof testsare ratory T INTRODUCTION Therefore, allphysicians mustknowwhentore Therefore, and hassignificantconsequences.Qualitylabo in clinical practice dysfunction is prevalent hyroid 1 , CamilaLuhmSilva Perez Arq BrasEndocrinolMetab. 2013;57(3):193-204 - - - 1 , Laura Sterian Ward ce upon which they are based (Tablece uponwhich theyare 1). of the eviden categorized by the strength topic and are test. Recommendationsemphasize keypointsforeach andlimitations ofeach ble adiscussionofthestrengths functiontestsandtoena commonly utilizedthyroid onthe anoverview to provide reviewed Med) were dysfunction. thyroid manage diagnoseandcost-effectively sults tocorrectly All of the articles intheMedlinedatabase(Pub All ofthearticles 2 Arq Arq Thyroid consensus ------2 1 Campinas, SP, Brazil Campinas (FCM/Unicamp), Universidade de Estadual SEMPR), Curitiba,PR,Brazil (HC-UFPR/ e Metabologia deEndocrinologia Paraná, Serviço Clínicas, Universidade Federal do das Hospital and , Accepted onMar/7/2013 Received onJan/30/2013 [email protected] 80030-110 –Curitiba,PR,Brazil Rua Agostinho Leão Júnior, 285 Gisah Amaral deCarvalho Correspondence to: Faculdade deCiênciasMédicas, DepartmentofEndocrinology

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Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 194 routinely. generationassays are thethird the diagnosticcertainty available,sincetheydonotincrease currently assays are TSH 7%to24%.Fourth-generation from tic certainty Conversely, thediagnos first-generationassaysincrease 37%, respectively, disease. inpopulations withprevalent 4%to36%- 1%to12%andfrom from nostic certainty thediag assaysincrease Second- andthird-generation in18minutes(9)(B). results 6.78-28.33) butprovides ty, andmaintainsasimilarLR+value(13.86,95%CI: nostic certainty, with97%sensitivityand93%specifici thediag assayslightlyincreases The third-generation LR+of13.71(95%CI:6.71-28.05)(8)(B). increased respectively,and specificityof 96%and93%, withan becausetheyhaveasensitivity the diagnosticcertainty 4.12-13.65) (7) (B). Second-generationassaysincrease ting ina7.50positivelikelihoodratio(LR+,95%CI: resul have asensitivityof75%andspecificity90%, ration TSHassays(6)(D).First-generation (functionalsensitivity:0.01-0.02mIU/L)-gene third second- (functional sensitivity: 0.1-0.2 mIU/L) and canbedetectedusing Hyperthyroidism pothyroidism. (5)(D). production thyroid TSHisthebestindicatorofsubtlechanges in refore, concentrationofTSH;the large changesintheserum in (TH)result hormone thyroid concentration offree smallchanges inthe (B,B). Duetothisrelationship, (3,4) thyrotrophs -linear negativefeedbackonpituitary log whichexert , and T3(triiodothyronine) (D,D). especiallyinoutpatientsettings(1,2) hyperthyroidism, hypo- and testfordiagnosing primary most reliable (TSH)assayisthe hormone The thyroid-stimulating thyroid d WHAT ISTHEBESTSCREENINGTESTFOR Table 1. Recommendationgradeandstrengthofevidence Thyroid functiontests inclinical practice D C B A Recommendation First-generation TSHassayscanonlydiagnosehy T4(thyroxine) regulates TSHsecretion Pituitary y sfunction? consensus, physiologicalstudiesoranimalmodels Opinions withoutcriticalevaluationbasedon Case reports(uncontrolledstudies) studies The leastconsistentexperimentalandobservational studies experimental andobservational Systematic reviewsandthemostconsistent Strength ofevidence ------TSH foradultsis0.4-4.5mIU/L(12,13)(D,D).Ho (11)(B). secretion nocturnal TSHlevelscanbeattributedto itspulsatileand serum an upperlimitof3.9-5.5mIU/L(10)(B).Changesin 1.4 mIU/L,withalowerlimitof0.3-0.5mIU/Land 1.3- approximately and 4a.m.,themeanlevelsare pulsesoccurbetween10p.m. rhythm. Majorsecretory ispulsatileandfollowsacircadian TSH secretion WHAT TSHVALUES ARECONSIDEREDNORMAL? ≤ 0.002μIU/ml. withsensibility -generation assayshouldbeperformed described methods. Third the other two previously than lessdiagnosticcertainty ded (B)becausetheyoffer however, first-generationTSHassaysshouldbeavoi (B)assays; tween thesecond-(B)andthird-generation be nosignificantdifferences are function (B).There The TSHassayisthebestforinitiallyevaluatingthyroid Recommendation above 7mIU/L (20)(A).Somestudies suggestthat andpatientswithTSH levels agegroups ted tocertain benefitislimi 4.5 mIU/L.Evidencefor a treatment levelsbetween2.5 and exhibit TSHserum thyroiditis and those with suspected Hashimoto’s thyroidism because somepatientsin the initialstagesofhypo tion hasTSHlevels≤2.5mIU/L(16,17)(B). popula than95%ofthenormal pulation andthatmore 1.5mIU/Linthehealthypo approximately levels are by ultrasound;thesestudiesestablishedthatmeanTSH ofauto-antibodies,andchangesdetected the presence basedonclinicaldata, excluded)thatwere disease were dies withstrictselectioncriteria(patientsthyroid 2.5 mIU/L (15) (B). between 0.5 and with subjectswhoseTSHlevelsare patients withTSHlevelsabove2.5mIU/Lcompared antibodiesin ofanti-thyroid presence and theincreased hypothyroidism toovert the higherrateofprogression by 2.5 mIU/L(14)(D).Thispositionissupported thislimitto advocatereducing and someresearchers beenquestioned, 4.5mIU/L)hasrecently proximately ofglycosylationandbiologicalactivity(12)(D). terms in TSH is heterogeneous cific tests utilized, and serum range becausevariationsoccurdependingonthespe reference toestablishauniversal wever, itisdifficult Currently, the normal reference range of serum Currently, rangeofserum reference thenormal However, (18,19)(D,D) agree notallresearchers rangeforTSH(ap The upper limit of the normal This change is supported by stu This change is supported Arq Bras Metab. Endocrinol 2013;57/3 ------

Arq Bras Metab. Endocrinol 2013;57/3 dysfunction, including the follo ased risk of thyroid nant women(33)(D). isnoconsensusonthisindicationinpreg though there andtoxemia(31)(B),al associated withhypertension (30)(B)andis (29)(B)andsurvival rodevelopment fetal neu canaffect duringpregnancy pothyroidism becauseundetectedhy women isalsorecommended 35 yearsold(1)(D).RoutineTSHtestinginpregnant fiveyearsinsubjectsover every ting isrecommended TSH tes (subclinicalhypothyroidism). failure thyroid dysfunction,especiallyincasesofminimal of thyroid The TSHtesthasbeenusedfortriageinthediagnosis PERFORMED? IN WHAT SITUATIONS SHOULDTSHTESTINGBE (B). age group foreach rangesproposed tothenormal ted according levels(A).Pediatricpatientsmustbeevalua hormone byfollowingchangesintheir evaluated andmonitored should be carefully levels (subclinical hypothyroidism) T4 free serum tween 4.5 and 10 mIU/L and normal tive autoantibodies(B).PatientswithTSHlevelsbe thosewithposi particularly mIU/L isrecommended, tomatic patientswithTSHlevelsbetween3.0and4.5 to2.5 mIU/L. lowering thecutoff potentially before TSH is required with high normal patients the positiveimpactofidentifyingandtreating 0.4-4.5 mIU/L(D).Aconvincingdemonstrationof TSHis rangeforserum adultreference The normal Recommendation period untiltheendofadolescence(24-28)(B). TSH levels continuously decrease inpediatricpatients; tothoseobserved not correspond values​​ age-dependentandthatadultreference are (23) (A). would bediagnosedin35%ofthesamepopulation to 2.5 mIU/L, hypothyroidism is lowered of normal 12.9% ofthesubjectsover65,butifupperlimit diagnosisin9.7%- inahypothyroidism mIU/L results ding theNHANESstudy, rangeof0.4-4.5 anormal inclu range isasfollows:inlarge populationgroups, (21,22)(A,B).Theriskofchangingthenormal groups ethnic ticularly thoseover80yearsold,andincertain intheelderly, TSHlevelsmaybenormal increased par Triage forpatientswithanincre isalsoappropriate TSH levels that serum Consistent studies confirm Monitoring asymp from the neonatal ​​from do ------school performance ofunknowncause (36,37)(C,C). school performance (ADHD)oradeclinein deficit hyperactivitydisorder andadolescentswithsuspected attention and children (34,35)(B,B); developmentdisorders with pubertal rate (34,35) (B,B); children and/orlowgrowth stature andadolescents withshort de thefollowing:children dysfunction andjustifytriageinpediatricpatientsinclu anddementia. including sleepapnea,depression of comorbidities, and the presence hyperprolactinemia; and phosphokinase and lactate dehydrogenase creatine anemia,increased hyponatremia, hypercholesterolemia, teststhatsuggesthypothyroidism: disease; laboratory diseaseorother autoimmune ofthyroid mily history andcontrastagents;fa , cytokines, : use ofparticular insufficiency); adrenal anemiaand primary betes mellitus, vitiligo,pernicious other autoimmunediseases(forexample,type1dia radiationtherapy; ofcervical history previous gery; sur of thyroid history incidence ofgoiter;previous dysfunction; ofthyroid history wing (1)(D):previous vels, TSH testing may not accurately reflect thecondi vels, TSHtesting maynotaccuratelyreflect T3andT4le two monthstoayearafter normalizing Inthesesituations,whichcanlastfor hyperthyroidism. or hypothyroidism T4 levelsinpatientswith chronic limits itsutility. function,whichsomewhat testing toevaluatethyroid solelyonTSH situations,wecannotrely In numerous CONSIDERED WHENPERFORMINGTSHTESTING? WHAT SPECIALSITUATIONS SHOULDBE (D treatment levels shouldbetestedpriortostarting T4 sampleincludingTSHandfree second confirmatory function (D dys in patientsofallageswithriskfactorsforthyroid womenand 5years,inpregnant over 35yearsoldevery inpatients TSHlevelsshouldbedetermined Serum Recommendation (38) (D). thedoseofT4 the bestmarkertoevaluateandcontrol andis hypothyroidism ment inpatientswithprimary (1,12)(D,D ). therapywithlevothyroxine replacement starting before med, andtestingshouldberepeated In all situations, increased TSHshould beconfir In allsituations,increased ariskforthyroid Medical conditionsthatmayreflect TSH may remain abnormal despite normalizing free free despitenormalizing abnormal TSH mayremain replace T4 TSH concentrationaccuratelyreflects ). If the results indicate high TSH levels, a indicate high TSH levels, a ). If the results Thyroid functiontests inclinical practice 195 ). ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 196 a critically ill uncommon for endocrinologists to treat disease. It is not thyroid from and changes thatresult systemic disease from function that result in thyroid betweenchanges significant datafordifferentiating contains themost (40,41) (B,D).Amedicalhistory orelevateTSH usecansuppress and cause stress solelyonTSHtesting beand cliniciansshouldnotrely comorbidities is challenging, tient with one or more (48)(C ( (46) T4(44,45)(B,B);firsttrimesterofpregnancy free withlow that causestransientcentralhypothyroidism (39)(B hyperthyroidism from disease,includingthefollowing:recovery thyroid 0.1 mIU/L(1,2)(D,D). indicated toevaluatepatientswithTSHlevelsbelow typically tobelow0.1mIU/L.T4andT3testingis TSH, in clinicalpracticeisaccompaniedbydecreased observed toTH,hyperthyroidism resistance pituitary hypothyroidism. TSHelevationsandtrue reversible cancausebothtransient and bythesedrugs production (43)(D),becauseinhibitionofTH and amiodarone (B,D); andmedications,includinglithium(42)D) illness (40,41) nonthyroidal from xinemia resulting hypothyro from the following(1,2)(D,D):recovery medications. CausesofisolatedTSHelevationinclude dysfunction andmaybecausedbyotherconditions withthyroid TSHdonotalwayscorrespond in serum TSH(1,2)(D,D). notofserum hormones, of free shouldbemadebasedonthe measurement vothyroxine therapywithle suspected, adiagnosisandreplacement or hypothalamic diseaseis this disorder. When pituitary vels canbelow, orslightlyelevatedinpeoplewith normal becauseTSHle (central)hypothyroidism for secondary test butisnot areliable hypothyroidism cases ofprimary orelevated FT4levels(4)(B elevated despitenormal adjustmentsinT4.Inthesepatients,TSHcanbe recent themost FT4testingreports 8 weeksofT4treatment, thesteadystateachievedafter6to TSH testingreflects atment compliance and use T4 intermittently. Whereas whohavepoortre vels inpatientswithhypothyroidism (4,39)(B,B). respectively or priorsuppression, hypertrophy becauseofthyrotroph tion ofthethyroid Thyroid functiontests inclinical practice C ); and the use of , suchasdopamine(47)(C ); andtheuseofdrugs, Diagnosing thyroid dysfunction in a critically ill pa Diagnosing thyroid occursinsituations otherthan TSH suppression and theexceptionofcentralhyperthyroidism With thatisolatedabnormalities It isessentialtorecognize orexcludesthediagnosis ofall TSHconfirms Serum T4 (FT4) le TSH and free We discordant observe ), that suppress TSHsecretion. ), thatsuppress ); severe nonthyroidal illness illness nonthyroidal ); severe ) or ) or ). ------T4 and low total and free T3. Therefore, thyroid func thyroid T3.Therefore, T4 andlowtotalfree levelsofTSHandfree serum orreduced have normal butdoes disease norclinicalsignsofhypothyroidism ofpituitary history patient whohasneitheraprevious function thanTSH(B). ofthyroid measure reliable T4isamore this case,free ofTHlevels.In despitethenormalization abnormal TSHmayremain hyperthyroidism, severe or chronic, for hypothyroidism In thefirstmonthsoftreatment Recommendation suspected(1,2)(D,D). are whentheseconditions T3 testingshouldberequested cannot beidentifiedbytestingforTSHalone.T4and that hormone, tothyroid resistance selective pituitary adenomasand pituitary TSH-secreting thyroidism, (40)(B). plained bradycardia) dysfunction,goiter,thyroid ophthalmopathyorunex of history dysfunction(forexample,previous of thyroid suspicion isastrong cally illpatientsexceptwhenthere oncriti performed tion testsshouldnot be routinely acquired or inherited changes in transporter proteins orinheritedchanges intransporter acquired various Furthermore, ofthehormone. cally activeform isthe biologi hormone levels.Thefree total hormone (49)(D). form inthefree T4 and0.2%ofT3circulate andonly0.02%of bound toplasmaproteins, dstream inthebloo in varioustissues.NearlyallTHscirculate peripheral conversion of T4 via5’-mono-deiodination the from T3results 80%ofserum gland. Approximately by the thyroid secreted hormone T4 is the primary HOW TOASSESSiodothyronines (T4ANDT3) (D). lithium,dopamineandglucocorticoids) darone, illnessandmedicationuse(includingamio thyroidal gical changes associated with pregnancy, non severe physiolo abnormal: whenTSHlevelsare considered T4isessential(D). offree asurement T4) low free T4values(highTSH/ TSHandfree exhibit discordant because noncompliant patients should be monitored T4 compliance,TSHandfree treatment thyroxine with suspected hypothalamic-pituitary disease;theme with suspectedhypothalamic-pituitary In patients with hypothyroidism andpoorlevo In patientswithhypothyroidism typesofTSH-mediatedhyper tworare are There FT4 and free T3 (FT3) levels are more relevant than relevant more T3(FT3)levelsare FT4 andfree disease shouldbe Conditions otherthanthyroid TSH should not be measured inisolationpatients TSH shouldnotbemeasured

(B). Arq Bras Metab. Endocrinol 2013;57/3 ------Arq Bras Metab. Endocrinol 2013;57/3 age-dependent,simi and T3forpediatric patientsare method (58)(B). the goldstandard librium dialysis,whichisconsidered methodofequi 2.5 ng/dL using the absolute direct forFT4is (35-77 pmol/L).Theupperlimitofnormal dL (9-23pmol/L)andthatforFT3is2.3-5.0pg/mL methods is 0.7-1.8 ng/ FT4 using comparative direct rangeof antibodies (2,57)(D,B).Theadultreference oranti-T3andanti-T4 proteins) transport or abnormal affinity teins (changesinT4-bindingglobulin(TBG) pro illness,changesintransporter with nonthyroidal inpatients reliable not entirely thesemethodsare re, Therefo dependentonTH-bindingproteins. T4 are (1.2-2.7 nmol/L)(2,56)(D). (58-160 nmol/L),andthatforTT3is80-180ng/dL rangeforadultsis4.5-12.6μg/dL The TT4reference using competitive immunoassays (IMAs) (55) (D). red treatment. drug ofanti-thyroid interruption earlyafter an relapse and T3candetectathyrotoxicosis GD; elevatedT3isacommon,earlysignofGDrelapse; in treatment tothyrotoxicosis ring theacuteresponse usefulformonito symptoms;T3levelsare thyroidism withouthyper toTHsyndrome those withresistance tumorsand pituitary in patientswithTSH-secreting highT3iscommon hyperthyroidism; darone-induced T3 may indicate amio normal high or inappropriately TSH(<0.01mIU/L); illnessandsuppressed thyroidal incriticalpatientswithnon dicate hyperthyroidism T3levels may in (GD); highorparadoxicallynormal high TT3/TT4 ratio (> 20) suggests Graves’ disease (2,54)(D,B):a forthefollowingreasons thyroidism levels, isusefulfordiagnosingandmonitoringhyper (52)(D). becomessevere til hypothyroidism rangeun levelswithinthenormal maintains T3serum conversionofT4toT3 becauseincreased thyroidism cited tests(53)(D). existinthepreviously whendiscrepancies be measured dividual variability(52)(D).Total T4(TT4)should andhas little intra-in ofTHtransporters expression FT4isnotsusceptibleto changes inthe treatment. function andtomonitorhyper- andhypothyroidism status(50,51)(B,B). thyroid of levels,regardless alter T4andtotalT3(T3T)serum The reference ranges for total T4 and T3 and free T4 T4 rangesfor totalT4andT3free The reference T3and methodsformeasuringfree The routine Total measu levelsare T3and T4serum andfree of FT4 T3 testing, combined with an interpretation fordiagnosinghypo notappropriate T3 levelsare usedtoassessthyroid routinely TSH andFT4are ------based onpatientageinthepediatricpopulation(D (D). ofhyperthyroidism presentations usefulfordiagnosingcomplexandunusual T4,are free (D). city fordiagnosinghypothyroidism T3testinghasalowsensitivity andspecifi (D). Serum levels hormone inthefree discrepancies are when there tion (D). func notthyroid proteins, changesintransport from (D). thyroidism atment andmayornotbeusedincasesofhypo tre functionandfollowinghyperthyroidism of thyroid assessmentanddiagnosis commended fortheroutine T4testing,combinedwithTSHisre Free Recommendations adultvalues(24-28)(B , whentheyreach until period thatcontinuouslyandgraduallydecrease levelsintheneonatal serum lar toTSH,withincreased inhibition of5’- type1and2(64) (B). the from inT4resulting in T3andamodestincrease dinated contrastagents,including amarkeddecrease withio similar tothoseobserved useare amiodarone (63)(C). normal FT3 andFT4willremain levelsofTSH, TT3andTT4,butserum or decrease inTBG,themainTHtransporter,willincrease crease orde totalT3andT4levels.Anincrease alter serum therapy(62)(C). the onsetofreplacement after highandT4T3decrease which TSHremains incases patients,shouldbeconsidered bowel surgery (61) (C). T3levels totalandfree serum consequently decreasing activityandinhibitsT3production, sed adrenocortical and totalT3(59,60)(C). andtotalT3.Conversely,free free increases overeating andfastingcausedecreased Malnutrition, starvation iodothyronine TESTING(T4ANDT3)? BE CONSIDEREDWHENPERFORMING WHAT SPECIALSITUATIONS SHOULD Total T4and T3valuesshouldbeevaluated andfree in combination with T3 tests, interpreted Serum Total testing shouldonlybeperformed hormone levelsoftotalT4and T3oftenresult Abnormal Most changes in thyroid functionassociated with Most changesinthyroid orinheritedvariationsinTHtransporters Acquired mostcommonin Changes inabsorption,whichare whetherphysicaloremotional,causes increa Stress, Thyroid functiontests inclinical practice ). 197 ). ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. exogenous hyperestrogenism increase serum TBGle serum increase exogenous hyperestrogenism ly 1% to 10% in patients with (73)(B). ly 1%to10%inpatientswiththyroid approximate to 2%inthegeneralpopulationandfrom 0.1% approximately of thesecomplicationsrangesfrom The prevalence bodies (autoantibodies or heterophils). -reactivity, of anti interactions and the presence drug 198 levelshave beenassessed(D). and T3serum whenT4 bination, evenunderspecial circumstances disease(B). ofthyroid 1% to10%inthepresence to 0.2% ofthepopulation,and thisnumberincreases functiontests(D). when analyzingthyroid turbances intheimmunoassaysshouldbeconsidered (D). Samplecollectionandstoragepossibledis levels T4andT3serum mayexhibitaltered andexogenous phenytoin, carbamazepine,furosemide thoseofTBG(B). particularly levels, plasmaprotein conditionsthataffect or acquired byhereditary levelsmaybealtered T4 andT3serum Recommendations Immunoassay disturbances can be attributed to cross TSHlevels(72)(B). serum ofnormal the presence and T3testscause​​ and FT4levels(71)(C). non-esterified fattyacids, consequently elevatingFT3 se activity. theconcentrationof Thisenzymeincreases lipa patients induces lipoprotein heparin-treated from phenomenon. Thestorageorincubationofsamples TSH (69,70)(C,C). levels withoutaffecting theserum decreasing T3 hepaticmetabolism,therefore accelerateT4and mazepine, rifampicinandsertraline 30% (67,68) (D,C). Phenytoin, phenobarbital, carba itbyapproximately increase mazepine andfurosemide the fraction of FT4 up to 100%, and carba increase Salicylates phenytoin, carbamazepineandfurosemide. salicylates, that competewithT4forTBGbindingare FT3 and FT4. The principal drugs ding to increased TSH(66)(B). levels withoutaffecting T3andT4 TBGlevelsandtherefore decreases drogen (65)(C).Incontrast,an observed mal TSHlevelsare vels. Consequently, higher T3andT4levelsnor Thyroid functiontests inclinical practice Endogenous (pregnancy or hydatidiform mole) or orhydatidiform Endogenous (pregnancy TSH and FT4 testing should be performed incom TSH andFT4testingshould beperformed 0.1%to These complicationsoccurin approximately medications,salicylates, Patients takingcertain T4 withtotalandfree Most factorsthatinterfere an in FT4 are Heparin-induced increases TBG,lea displaceT3andT4from Several drugs inappropriately abnormal valuesin abnormal inappropriately in vitro ------in 10% of cases (2% of all pregnancies) (75) (B). in 10%ofcases(2%allpregnancies) hyperthyroidism) symptoms(pregnancy thyrotoxicosis of canoccurthatleadto aspectrum siological increases inFT4,butsupraphy associated withamodestincrease is inTSHduringthefirsttrimesterofpregnancy drop 10-12weeksgestation(76)(B).The approximately hCG peakandtheTSHnadiroccursimultaneouslyat homologueofTSH.The (hCG), whichisastructural -stimulating activity of humanchorionicgonadotropin thethyroid from TSHresults (75) (B).Thisdecreased pregnancies 20%ofnormal inapproximately observed TSHvalues​​ serum subnormal nancy; therefore, T3andtotalT4levels(74,75)(B). serum creasing in levelsandtherefore elevatingTBGserum creases, During pregnancy, graduallyin production INTERPRETED DURINGPREGNANCY? HOW SHOULDTHYROIDFUNCTIONTESTSBE quently decline in the second and third trimesters (B quently declineinthesecondandthird duringthefirst trimesterbutwillsubse slightly increase T4levelsmay TBG,andfree high becauseofincreased mIU/L) (D). (TSH > 2.5 failure tests that can detect mild thyroid orinthefirsttrimesterwith TSH med pre-pregnancy (B). functionduring pregnancy ce ofevaluatingthyroid psychomotor development,highlightingthesignifican onfetal causesadverseeffects hypothyroidism Maternal Recommendations women(74,75)(B,B). inpregnant albumin decreases lower values (down to 50%) because serum ds produce value.Albumin-dependentmetho the averagenormal 30%below trimesterstoapproximately cond andthird or low T4 and normal or low TSH are typicalinthe orlowTSHare or lowT4and normal systemicdisease (78)(D). in patientswithsevere functiontests thyroid define theincidenceofabnormal usedto are and“lowT3syndrome” sick syndrome” illness”(NTI),“euthyroid “nonthyroidal The terms dysfunction(77)(B). function intheabsenceofthyroid thyroid Critically illpatientsoftenexhibitabnormal INTERPRETED INCRITICALL HOW SHOULDTHYROIDFUNCTIONTESTSBE Subsequently, in the se T3 and FT4 levels decrease TSH levels fall during the first trimester of preg During pregnancy, the total levels of T3 and T4 are dysfunctiontriageshould be perfor Thyroid Decreased T3, increased reverse T3 (rT3), normal T3(rT3),normal reverse T3,increased Decreased Arq Bras Metab. Endocrinol 2013;57/3 Y ILLPATIENTS? are are ). ------Arq Bras Metab. Endocrinol 2013;57/3 diseases(ATD)pathogenesis of autoimmunethyroid antigensinvolvedinthe thyroid primary The three ASSESSED? antithyroglobulin antibodies BE SHOULD antithyropero xidase and antibodies? INWHICHCLINICAL CONDITIONS WHAT ISTHESIGNIFICANCE OFantithyroid levels donotexcludethisdiagnosis(B). orlow inhospitalizedpatients,butnormal thyroidism TSHandT4)(B). typical ofNTI(discordant that are the transient abnormalities TSH andT4)from disease (concordant thyroid for distinguishingprimary cautiously,interpreted the most reliable but they are suspected(B diseaseisstrongly patients unlessthyroid inthese performed NTI, theyshouldnotberoutinely function testsin Given thepoorspecificityofthyroid Recommendations (81) (B). orelevatedTSHandlowT3FT4 exhibits normal patient orelevatedT3andFT4.Ahypothyroid normal TSHand typicallyhassuppressed and hyperthyroidism orlowT3andFT4.ApatientwithNTI and normal TSH withtransientlyreduced tient withNTIpresents pa TSHduetoNTI.Aeuthyroid those withreduced TSHfrom patientswithsuppressed tiate hyperthyroid sensitive assay(TSH<0.02mIU/L)thatcandifferen disease(80)(D). suspicionofthyroid strong isa incriticallyillpatientsunlessthere ly performed functiontestsshouldnotberoutine factors, thyroid rates(79)(D). survival ted withreduced associa of symptoms,andlowlevelsT3T4are withtheseverity with acutesystemicdiseasecorrelates (D). (79) salicylates, phenytoinandbeta-adrenergic furosemide, ,amiodarone, glucocorticoids, andtheuseofmedicationssuchas TH transporters of expression decreased sion, iodineuptakedisorders, axissuppres of 5’-deiodinase,hypothalamic-pituitary mechanisms:inhibition different occur inNTIthrough abnormalities se situations(78)(D).Theselaboratory High T3 (total or free) levels are indicativeofhyper levelsare High T3(totalorfree) levelsinNTIshouldbe TSH andT4(totalorfree) When necessary, usinga TSH shouldbemeasured confounding Considering alltheaforementioned function in patients thyroid of abnormal The degree ). ). ------(TPO) and TSH (TSH-R). (TPO) andTSHreceptor (Tg), thyroperoxidase the following: are AT hypo is suspected based on family history, primary (84)(B). thods andshouldbeusedpreferentially the most sensitive detection me­ disease. IRMAs are 10% to15%ofpatientswithnon-autoimmunethyroid of AT 80% of GD patients and patients, approximately (83)(D). Tg shouldbeconsidered with cancer patients,anditsabilitytointerfere thyroid should alwaysbetestedincombinationwithTg markerafterthyroidectomy.is akeylaboratory TgAb cancer, thyroid Tg wherein patients with differentiated for is relevant even the ultra-sensitive ones. This effect withTgtests, detecting TgAb(82)(B).interferes for recommended immunosorbent assays (ELISAs) are munoradiometric assays(IRMAs)andenzyme-linked autoimmune diseases.Radioimmunoassays(RIAs),im with GDand10%to15%ofpatientsnon-thyroid (AT),autoimmune thyroiditis 30%to40%ofpatients healthy individuals(9%-25%)(15)(B). of inasignificantpercentage present dies (TPOAb)are ver, anti-Tgantibodies(TgAb)andanti-TPOantibo ofpatientswithATD.ally foundintheserum Howe thyroiditis, which is usually transient. Of the women whichisusually transient.Ofthewomen thyroiditis, women withpositiveTPOAb willdeveloppostpartum 50%ofpregnant 5% to10%ofwomen.Approximately whichoccursin thyroiditis, of postpartum probability specific(86)(B). more antibody(TRAb)is although theanti-TSHreceptor ofhyperthyroidism, theautoimmunenature may reveal whencostconstraintsexist. is preferable the mostsensitivewaytodetectATD. TPOAbtesting thanTgAb,andTPOAbtestingis prevalent more are disease,TPOAb of theunderlyingthyroid Regardless AT ultrasound (85) (B). diagnosis, such as a thyroid an toconfirm necessary otherclinicaltestsare refore, mal individuals have detectable antibody levels. The disease and afewnor with non-autoimmunethyroid todiagnose dies isinsufficient ATD becausepatients ofpatients.Conversely,group ofantibo thepresence undetectableinasmall because theseantibodiesare ce of TgAb andTPOAbdoesnot exclude thyroiditis goiter. and/ordiffuse thyroidism However, theabsen High thyroid autoantibody concentrations are usu autoantibodyconcentrationsare High thyroid TgAb and TPOAb testing can be performed when TgAb andTPOAbtestingcanbeperformed of90%to95% intheserum present TPOAbare in70%to80%ofpatientswith present TgAb are TPOAb testing in early pregnancy can predict the the canpredict TPOAb testing inearlypregnancy levelsinGD TgAbandTPOAbserum Determining Thyroid functiontests inclinical practice 199 ------

Copyright© ABE&M todos os direitos reservados. Copyright© ABE&M todos os direitos reservados. 200 of GDpatients, butitsdiagnosticutility islimited. theblocking antibody.the stimulatingantibodyfrom availablebutfailstodifferentiate bust andcommercially assay is ro activity of TSH (94) (B). The radioreceptor functionandinhibitsthebiological mulates thyroid sti antibody(TRAb)directly The anti-TSHreceptor BE DETERMINED? PRESENCE OFANTI-TSHRECEPTORANTIBODIES IN WHICHCLINICAL CONDITIONSSHOULDTHE (D). treatment antibodies duringhypothyroidism (false-negatives)(B). deceptively lowresults TgAb can cause of serum cancer because the presence thyroid while monitoringpatientswithdifferentiated vels) (B). aTPO (anti-TPO) antibodyle (increased thyroiditis therapy(D). productive orfailedassistedre ofinfertility tients withahistory andd)inpa lithiumoramiodarone; using interferon, dysfunction; c)inpatients in patientsatriskforthyroid the followingscenarios:a)whenATD issuspected;b) testing isthemostsensitivewaytodetectATD (B). bined withTSHandFT4testing(D). dysfunction(B)andshouldbecom ofthyroid nature theautoimmune TgAbandTPOAblevelsreveal Serum Recommendation nitor ATD (93)(B notrecommended are treatment (92) (C for GD and autoimmune hypothyroidism treatment (89-91) (B,B,C). function alterations in thyroid of treatment-induced therisk oftheseautoantibodiesincreases the presence andlithiumbecause interferon ment withamiodarone, unsuccessful and riskofmiscarriage been associatedwithanincreased ful toevaluateinfertility because highTPOAblevelshave (87)(B TSH isabnormal toms, and33%havesubclinicalsymptoms,evenwhen 67%haveclinicalsymp thyroiditis, with postpartum Thyroid functiontests inclinical practice TRAb is present in the serum of more than90% ofmore intheserum TRAb ispresent isnoindicationformonitoringantithyroid There TgAb andTgshouldbequantitatedincombination TPOAb testingcanassesstheriskofpostpartum in TgAb and TPOAb testing should be performed thanTgAb,andTPOAb prevalent TPOAb ismore antibodylevelsduring isevidence ofdecreased There TgAb andTPOAgtestingisindicatedduringtreat ), butinmostcases,autoantibodyteststomo fertilization therapy(88)(C in vitrofertilization ). TPOAbtestingmaybeuse ). ). ------

rable option in this group ofpatients(96,97) (D,D). rable optioninthisgroup favo useamore drug above 50%,makingantithyroid rate small goiters and negative TRAb havearemission femalepatientswithmilddisease, treatment; wing drug remission follo be identifiedwithahighorlowriskof ofpatientscan subgroups verity ofhyperthyroidism), clinical indicators(age,gender, volumeandse thyroid ment. However, bytitratingTRAbandassessingother treat drug toantithyroid dict theoddsofaresponse ophthalmopathy (96)(D). Graves’ goiterandeuthyroid withdiffuse thyroidism subclinicalhyper withthyrotoxicosis, sis gravidarum mayjustifyaTRAbtest: hypereme hyperthyroidism diagnosisof inwhichthedifferential cial circumstances spe are GD (95) (B). There to confirm unnecessary TRAb statusrender thyroid monly usedtodetermine In mostpatients,theclinicalanddiagnostictestscom sis of hyperthyroidism (B). sis ofhyperthyroidism diagno some instances,itmayfacilitate thedifferential but inmostcasesisnotessential forthediagnosis.In TRAb testinghasgoodspecificity fordiagnosingGD Recommendations (101)(B). pothyroidism the potential for neonatal hy predict dism to efficiently formothers with autoimmune hypothyroi pregnancy during TRAb testing is recommended hypothyroidism. withtransientneonatal inmothersofchildren served theriskforneo TRAb testingmaybeusedtoascertain (96,100) (D,D). the fetusatriskforhypothyroidism may nolongerbenecessary, anditscontinuitycanplace treatment drug of TRAbisanindicatorthatantithyroid dually diminishesduringpregnancy. Thedisappearance Persistently elevated TRAb levels following drug tre Persistently elevatedTRAblevelsfollowingdrug ). High titers are ob (102) (D). High titers are Hashimoto’s thyroiditis and in 0%to20%ofpatientswith thyroiditis atrophic GD orhashadinthepast(96,101)(D,B). orwhenthemotherhas of neonatalhyperthyroidism history isprevious dysfunctionwhenthere lar thyroid this particu trimester to predict in the third performed womenwithGD. TRAb testsshouldbe of pregnant 2% which occurs in approximately natal thyrotoxicosis, women.Inmanypatients, GDgra of GDinpregnant (98,99) (B,B). ofGD recurrence associatedwithincreased atment are By themselves,TRAbvaluesatdiagnosisfailtopre TRAb is present in10%to75%ofpatientswith TRAb ispresent theextent TRAb titrationisusefulfordetermining Arq Bras Metab. Endocrinol 2013;57/3 ------

to thyroid function testing, the primary recommenda functiontesting,theprimary to thyroid disease severityandmay, incombinationwithothercli Arq Bras Metab. Endocrinol 2013;57/3 tions includethefollowing: SUMMAR (B). sient neonatalthyrotoxicosis (between gestational weeks 20 pregnancy trimester of with GD at the beginning and in the third (D). levels indicatehigheroddsofremission TRAb who shouldinitiatemedicationcessation;normal mayidentifythosepatients treatment drug antithyroid decisions(D). nical indicators,contributetotreatment determine the risk for fetal hyperthyroidism andtran theriskforfetalhyperthyroidism determine • • • • • After reviewing and discussing the key topics related anddiscussingthekeytopicsrelated After reviewing An initialassessmentofTRAbisusefultoascertain • • women inpregnant TRAb testingisrecommended Quantitating TRAblevelspriortodiscontinuing during pregnancy becauseofthenegativeim during pregnancy function should be closely monitored Thyroid dism symptoms. with FT4,isusefulforevaluatinghyperthyroi incombination T3testing,interpreted Serum tients withhypothyroidism. testing forthediagnosisandmonitoringofpa T3 serum isnoindicationforroutine There circumstances. inparticular be performed testingshould totalhormone tion. Therefore, func notthyroid proteins, changes intransport Total from typicallyresult T3/T4abnormalities hypothyroidism. severe patientswithchronic, ths oftreating cases ofpoorcomplianceandinthefirstmon in tolevothyroxine for evaluatingtheresponse disease.Itisalsouseful hypothalamic-pituitary T4iscriticalforevaluatingpatients with Free dered. or in the first trimester; mild thyroid failure is failure or inthefirst trimester;mildthyroid prior to pregnancy tests should be performed obstetric outcome and fetal development. TSH canhaveon hypothyroidism pact thatmaternal disease, andotherconditionsshouldbeconsi TSHisnotsynonymouswiththyroid Abnormal dose oflevothyroxine. a goodmarkerformonitoringthereplacement TSHis also for hypothyroidism. being treated dysfunctionandformonitoring patients thyroid TSH testingisthebestmethodfortriaging Y OFRECOMMENDATIONS

and 24) to ------2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: context incombinationwithadditionaltests. each patient individually,treat considering the clinical available publisheddata,buttheclinicianshouldalways Guidelineshelptoschematicallyevaluatethe sidered. dications andtheindividualpeculiaritiesmustbecon in seen byendocrinologists.Foreachtest,theprecise frequently thatare ofdisorders dysfunction, agroup testinginthemanagementofthyroid te laboratory ofadequa This manuscriptillustratestherelevance FINAL CONSIDERATIONS

• • • • of thyroid disease. Thyroid. 2003;13:3-126. guidelines. Laboratorysupport for the diagnosisandmonitoring Academy ofClinicalBiochemistry, Laboratorymedicinepractice mussen U, HenryJF, etal.GuidelinesCommittee, National Baloch Z,CarayonP, LM,Feldt-Ras Conte-Devolx B,Demers ­ thyroid dysfunction. Arch InternMed.2000;160:1573-5. et al. American Thyroid Association guidelinesfor detectionof Ladenson PW, SingerPA, Ain KB,Bagchi N,BigosST, Levy EG, dysfunction. There isnoindicationformo dysfunction. There suggest theautoimmuneetiologyofthyroid The concentrationsofTPOAbandTgAb (NTI). illhospitalizedpatients inseverely performed function testsshouldnotberoutinely Thyroid first trimester. indicated byTSHvalues>2.5mIU/Linthe sis. AninitialevaluationofTRAblevelsena GD butisnotcommonlyessentialfordiagno andhasgoodspecificityfor of hyperthyroidism diagnosis TRAb testingenablesthedifferential cancer.tiated thyroid for monitoring patients with differen is crucial TgAb testing, in combination with Tg testing, thyroiditis. theriskofpostpartum determining common, isthemostsensitiveandusefulfor TPOAbtestingis treatment. hypothyroidism antibodylevelsduring nitoring antithyroid transient neonatalthyrotoxicosis. trimestertoassesstheriskof GD inthethird womenwith inpregnant should beperformed TRAbtesting timating theoddsofremission. decisions and es may contributetotreatment of disease severity and bles the determination Thyroid functiontests inclinical practice 201 ------

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