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European Journal of Endocrinology -19-0212 Abstract Rheumatology, ShanghaiUniversityofMedicine&HealthSciencesAffiliatedZhoupuHospital,Shanghai,China of Endocrinology,AffiliatedHospitalYananUniversity,Shanxi,China,and 1 Jin-an Zhang Bin Wang and thyroidautoimmunityriskinadults U-shaped relationshipbetweeniodinestatus the mostcommonautoimmune disease.TAI canresult and themaincauseofhypothyroidism, whichisalso most populations( autoimmunity (TAI) anditsprevalenceisover 10%in positivity areusuallyconsideredtosufferfromthyroid disease (GD)( include Hashimoto’s thyroiditis(HT)andGraves’ diseases occurring in theendocrinesystemandmainly Autoimmune thyroiddiseases(AITDs)areautoimmune Introduction future studies. deficiency andiodineexcessareriskfactorsofTAIinadults.Theunderlyingmechanismsneedtobeelucidated Conclusion: findings. iodine deficiencyorexcess.Stratifiedanalysisofstudieswithlowriskconfoundingbiasalsoidentifiedsimilar iodine intakeandTAIinadults,whichprovedthesignificantlyincreasedriskofamongindividualswitheither epidemiological studieswithatotalof69,987participantsandfurthervalidatedtheU-shapedrelationshipbetween 1.09–2.07, iodine excessallhadhigherriskofTAI,andtheadjustedORswere1.50(95%CI1.03–2.17, with thosemorethanadequateiodinestatus,individualswithdeficiency,statusand Results: dose–response meta-analysisofeligibleepidemiologicalstudieswasalsocarriedout. adults. Oddsratio(OR)with95%confidenceinterval(95%CI)wascalculatedthroughlogisticregressionanalysis.A Methods: epidemiological studies. between iodinestatusandTAIthroughbothapopulation-basedstudydose–responsemeta-analysisofeligible its relationshipwiththyroidautoimmunity(TAI)isstillcontroversial.Ourstudyaimedtoelucidatethe Background: Department ofEndocrinology&Rheumatology,JinshanHospitalFudanUniversity, Shanghai,China, https://doi.org/ https://eje.bioscientifica.com Clinical Study Thecross-sectionalstudyshowedanU-shapedrelationshipbetweeniodineintakeandTAIinadults.Compared Apopulation-based,cross-sectionalstudywasfirstlycarriedout,whichenrolledatotalof2808Chinese 1 P ThestudysuggestsanU-shapedrelationshipbetweeniodineintakeandTAIinadults,both , Weiwei He 10.1530/EJE Iodinestatushaslongbeenregardedasanenvironmentaldeterminantforthyroiddysfunction,but = 0.013) and1.68(95%CI1.11–2.53, 3 1 ). Individualswiththyroidantibodies -19-0212 2 , 3 , 2 , Qian Li 4 ). HTisthemajortypeof TAI 3 © 2019EuropeanSociety ofEndocrinology B Wangandothers 1 , Xi Jia 1 , Qiuming Yao Printed inGreatBritain P = 0.014), respectively.Thedose–responsemeta-analysisincluded22 1 , Ronghua Song 3 Department ofEndocrinology& multiple factorsincludingsusceptibility geneticvariants been wellacceptedthatTAI resultsfromthe interplayof numerous studiesonTAI inthepasttwodecades, ithas ( as miscarriageandpremature delivery rates ofcomplicationsduringandafterpregnancy, such 8 thyroid cancerandotherautoimmunediseases( other commondiseases,suchascardiovascular in thyroiddysfunction,anditalsoincreasestherisks of Iodine statusandTAI , Published byBioscientifica Ltd. 9 , 10 ). Additionally, TAI isalsoassociatedwithhigher 3 , Qiu Qin 2 Department 3 and Downloaded fromBioscientifica.com at10/02/202102:53:21AM P = 0.032), 1.50(95%CI (2019) Endocrinology European Journalof [email protected] Email Zhang J to should be addressed Correspondence 181 181 :3 3 , 255–266 , ,

11 ). Through 255 5 –266 , 6 , via freeaccess 7 , European Journal of Endocrinology https://eje.bioscientifica.com Fudan University. by theEthicsCommittee ofJinshanHospital the DeclarationofHelsinki. Thestudywasapproved provided written informed consent in accordance with were fromtheChineseHanpopulation.Allparticipants thyroidectomy. Finally, 2808adults were enrolled,andall in 2016,and16wereexcludedfromthisanalysisfor recruited fromresidentsofJinshanDistrictShanghai cross-sectional study, 2824individualswere randomly Studies inEpidemiology(STROBE)statement( to theStrengtheningReportingofObservational study. We reportedthecross-sectional studyaccording We firstperformedapopulation-basedcross-sectional Participants Methods cross-sectional studyandadose–responsemeta-analysis. between iodinestatusand TAI risk,weconducted both a ( for theassociationofiodinestatuswithTAI isstilllacking iodine statusandTAI iscomplex,andconvincingevidence between iodine status and TAI. Therefore, the link between However, otherstudiesreportednoobviousrelationship could induceTAI inpatientswithendemicgoiter( controlled trial by Kahaly iodine intakecouldincreasetheriskofTAI. Arandomized TAI. Severalepidemiological studies found that excessive limited studiesassessingtheimpactofiodineintakeon impact of iodine intake on thyroid dysfunction, there are ( risk factor for both hypothyroidism and thyroid goiter have established that iodine deficiency is an important the prevalenceofthyroiddiseases( of iodineintakeinthepopulationiscriticaltoreduce determinant ofthyroiddysfunction( hormone andiodinestatushaslongbeenregardedasakey vitamin Ddeficiency( the developmentofTAI, suchasseleniumdeficiencyand been identifiedasriskfactorsfor TAI andareimplicatedin factorshave those modifiableriskfactors.Somedietary identify thoseimportantriskfactorsforTAI, especiallyfor adverse impact on health. Therefore, it is essential to most patientsareasymptomatic,TAI canstillcausemuch 14 factors havebeenidentifiedasriskfor TAI ( and environmentalfactors( 18 17 Clinical Study ), butitsetiologyisstilllargelynotelucidated.Though ). Therefore,toadequatelyelucidatetherelationship ). Despite numerous epidemiological studies on the Iodine isessentialforthesynthesisofthyroid 15 , 16 et al ). . also supported that iodine 12 B Wangandothers ). Additionally, some 17 ). Previousstudies 17 ). Optimization 20 ). Inthe 19 13 ). ,

UIC values,participantsweredividedintofourgroups: using theammoniumpersulfatemethod.Accordingto used UICtoevaluateiodinenutrition.wasquantified biochemical markerofiodinestatus.Inourstudy, wealso indicator ofiodineintakeandiscurrentlythemostuseful iodineconcentration(UIC)isawell-known Urinary Category criteriaforiodinestatus and 0–50 The referencevaluesforTPOAbandTGAbwere0–34 using immunochemiluminometric assay (ICMA)method. (TPOAb) andthyroglobulinantibody(TGAb)weretested Thyroid antibodiesincludingthyroidperoxidaseantibody testing. smokers. Fastingbloodwasusedforlaboratory study, smokingindividualsweredefinedasthosecurrent of medications were collected. In the cross-sectional Data onage,gender, anduse smoking,diseasehistory Clinical examinationandlaboratorytesting uncover possible sources of bias, the difference in clinical used tocomparethedifference betweentwogroups.To frequencies with percentages, and chi-square test was group difference.Categorical variablesarepresentedas U based ontheirtypesofdatadistribution.Mann–Whitney deviation ( Continuous variables are presented as mean with standard a total of 2632 individuals should be thus recruited. in eachgroup.Therewerefourgroupsourstudyand a sufficientpowerover80%needatleast658individuals and theproportionwithTAI inthepopulationwas15%, When theexpectedoddsratio(OR)wasdefinedas1.50 We calculatedsamplesizebeforethecross-sectional study. Statistical analysis TGAb as TPOAb of thesetwoantibodies.TPOAbpositivitywasdefined the presenceofpositiveTPOAborTGAbacombination individuals with specific iodine status. TAI was referred to The outcomeofinterestwastheprevalenceTAI in Diagnostic criterionforTAI ≥ status (UIC 200–299.9 status (UIC100–199.9 iodine deficiency (UIC Iodine statusandTAI 300 testor μ > g/L) ( 50 IU/L. IU/L, respectively. > s t . 21 testwereusedtocomparethebetween- 34 d . ) or median with interquartile range (IQR) ). IU/L, andTGAbpositivitywasdefinedas μ μ g/L) and iodine excess status (UIC g/L), morethanadequateiodine Downloaded fromBioscientifica.com at10/02/202102:53:21AM < 100 μ g/L), adequate iodine 181 :3 256 IU/L via freeaccess European Journal of Endocrinology risk (RR)orORwith95%CIs foratleastthreequantitative was TAI, TPOAb positivity or TGAb positivity; ( than adequateiodinestatus; ( such asiodinedeficiency, adequateiodinestatusormore ofiodinestatus was thoseindividualswithcertain category adolescents; ( sectional design;( the followinginclusioncriteria:( studies. Studieswereconsideredeligibleiftheysatisfied studies werealsoreviewedtoidentifyotherpossible following full-textevaluation.Thereferencesofeligible a by readingtitleorabstractandthenunderwent thyroid autoantibodies). Potential studies were screened OR thyroidautoimmunityautoantibody antibodies ORThyroglobulinantibodythyroiditis OR ThyroidperoxidaseantibodyThyroglobulin OR iodination)and(Thyroidperoxidaseantibodies was used: (iodization OR iodized OR iodised OR iodine limitation wasapplied.Thefollowingsearch strategy or cohortstudies(upto30November2018).Nolanguage database were searched toidentifyrelevant cross-sectional status andTAI risk.Pubmed,EMBASEandWanfang relationship existedintheassociationbetweeniodine The research question was whetheradose–response studies ofetiology (COSMOS-E) ( of observational on conductingsystematicreviewsandmeta-analyses analysis wasconductedinaccordancewiththeguidance of iodinestatusonTAI risk,adose–responsemeta- To getamorecomprehensiveevaluationoftheimpact Dose–response meta-analysis be statisticallysignificant. and two-sided gender. STATA (version12.0,StataCorp,USA)wasused, were performedbythetypesofthyroidantibodiesand were analyzedascategoricalvariables.Subgroupanalyses analyzed ascontinuousvariables,whiletheotherfactors factors in the logistic regression analysis. Age and BMI were hypertension werealsoregardedaspossibleconfounding logistic regressionanalysis.Smoking,diabetes,BMIand could causeriskofbias,whichwerethusadjustedinthe been regardedas important impact factors of UICand logistic regressionanalysis.Bothageandgenderhadlong (95%CI)wascalculatedthrough 95% confidenceinterval groups wasassessedusing‘nptrend’inSTATA. ORwith The trendforcontinuousvariablesacrossorderedUIC UIC groupswasassessed using Cochran–Armitage test. also analyzed.Thetrendinproportionsacrossordered characteristics acrossthosefourorderedUICgroupswas Clinical Study 3 P ) Exposurewasiodinestatus;( valueslessthan0.05wereconsideredto 2 ) Participantswereadults,childrenor 5 ) Theoutcomeofinterest B Wangandothers 1 ) Usingcohortorcross- 4 6 ) Control ) Relative 22 ). ‘low risk’,‘moderaterisk’and‘high( was assessedqualitativelyinthreecategoriesincluding of confoundingbias,selectionbiasandinformation assessed bythegeneralprinciplesofCOSMOS-E( the riskofbiasthoseincludedstudieswasfurther points weredeemedtohavesuboptimalquality. Moreover, Scale (NOS),andstudieswithscoresnomorethanfive according totheNewcastle–OttawaQualityAssessment another investigator. Qualityassessmentwasperformed the twoinvestigatorswassolvedbydiscussionwith extraction sheetswereusedandthediscrepancybetween ofiodinestatus.Standardizeddata 95% CIsineachcategory testing method,definitionsof TAI andriskestimateswith confounding variablesinthemultivariableanalysis,UIC study design,numberofcases,participants, independently, suchas the firstauthor, yearofpublication, studies withoutsufficientdatawereallexcluded. categories of iodine status were reported. Reviews or ie nSplmnayTbe 1(seesectionon Table given inSupplementary The characteristicsofthe 2808participantsare Characteristics ofparticipants Results considered tobestatisticallysignificant. version 12(StataCorpLP),and of bias.AllstatisticalanalyseswereperformedwithSTATA by excludingstudieswithsuboptimalqualityorhighrisk also performed. Sensitivity analysis was thenperformed ( risk estimateswerepooledusingarandom-effectmodel value forthedifference above wasalsocalculated ( between the spline model and the linear model and the linearitywasthustestedthroughthedifference the curve model wereusedinthedose–responsemeta-analysis,and was used( meta-analysis, generalized least-square regressionmodel distribution wereutilized( splines, andfourknotsat5,35,6595%ofthefull status andTAI riskwasassessedthroughrestrictedcubic nonlinear dose–responserelationshipbetweeniodine be samewiththatoftheadjacentcategory. Thepossible lengthwasassumedto theirinterval half-open interval, ofiodineintakewasa the lowestorhighestcategory corresponding iodineintakeforeachriskestimate.If the upperandlowerboundarieswasassignedas Iodine statusandTAI 25 ). Stratified analyses by risk of confounding bias were The median UIC, meanUICorthemidpoint of The following data were extracted by two investigator The followingdatawereextractedbytwoinvestigator 23 , 24 ). Boththesplinemodelandlinear Downloaded fromBioscientifica.com at10/02/202102:53:21AM 23 P ). Inthedose–response https://eje.bioscientifica.com valuelessthan0.05was 181 :3 22 ). 22 23 ). Risk ). Risk ). The 257 via freeaccess P

European Journal of Endocrinology https://eje.bioscientifica.com BMI, bodymassindex;TGAb,thyroglobulin antibody;TPOAb,thyroidperoxidaseTSH,thyroid-stimulating hormone. ≥ number withpercentages(%).Urinary iodineconcentrations:low, Normally distributedvariableswere expressedasmean TGAb (U/mL) TPOAb (U/mL) TSH (mIU/L) Iodized saltintake( Hypertension ( Type 2diabetes( Smoking ( BMI (kg/m Age (years) Urinary iodineconcentration Number Characteristics Table 1 of TAI inparticipantswithiodinedeficiency(14.4%), iodine status(9.3%),therewasahigherprevalence ( shown in The prevalenceofTAI overthosefourorderedUICgroupsis UIC andTAI iodine excessgroup( the morethan adequate iodine group ( was not higher in the iodine deficiency group( using theadequateiodinegroupasreference,TGAblevel not higherintheiodinedeficiencygroup( adequate iodinegroupasreference,TPOAblevelwasalso iodine excessgroup( the morethan adequate iodine group ( was not higher in the iodine deficiency group( using the adequate iodine group as reference, TPOAb level ( both thelevelofTPOAb( ( was observed clinical characteristicsacrossthosefourorderedUICgroups UIC ( lower prevalenceofhypertensionthanthosewith had youngerage,lowerBMI,prevalenceofdiabetes, ( characteristics acrossthosefourorderedUICgroups participants. of clinical characteristics between men and women 1alsoshowsthecomparison Table Supplementary TPOAb positivityand308(11.0%)hadTGAbpositivity. 359 (12.8%) were found to have TAI, 266 (9.5%) had The median UIC was 164.5 data supplementary Table 2 P Table 1 300

Clinical Study = 0.19) acrossthosefourUICgroups( μ g/L. P

< ). Asshownin ). Compared with those with more than adequate ). Compared with thosemorethanadequate 0.05, n Comparison ofclinicalcharacteristicsadultswithdifferenturinaryiodineconcentration. 2 Table 2 ) (%)) Table 1 n Table 1 (%)) al 1 Table n (%)) , which suggested a clear U-shaped curve , whichsuggestedaclearU-shapedcurve n (%)) givenattheendofthisarticle). showsthedifferenceinclinical P P ). Therewasnoobviousdifferencein =0.17).

= Table 1 ). No obvious difference in other 0.32). Whenusingthemorethan P

= 0.15) andthelevelofTGAb , participantswithhighUIC 11.9 (10.0–15.4) 24.1 (3.7) 46.5 (14.4) 68.0 (52.7–88.0) 396 (69.7) 191 (33.6) 113 (19.9) 9.0 (6.3–13.8) 2.7 (1.8–3.2) μ 86 (15.1) Deficiency g/L (IQR: 111.1–235.6). B Wangandothers 568 P P al 1 Table .1 ad the and =0.61) the and =0.13) P 0.13). When =0.13). ±

s . d 148.8 (126.0–172.2) . , non-normallydistributedvariables asmedianwithIQRandcategoricalvariables 11.5 (10.0–15.2) 24.4 (3.8) 44.5 (15.6) 955 (76.2) 410 (32.7) 174 (13.9) 353 (28.2) 8.8 (6.5–12.6) 2.7 (1.7–3.2) P P ). When =0.53), =0.27), < Adequate 100 1253 μ g/L; adequate,100–199.9

iodine intakewithTPOAbpositivityandTGAb Table 3.was showninSupplementary Therelationshipof relationship between iodineintake and TGAbpositivity andthe Table 2, positivity wasshowninSupplementary outcomes werenotstatisticallysignificant( and TAI inwomenwasalsolikelytobeUshaped,butthe and TAI ( obvious U-shapedrelationshipbetweeniodineintake respectively. Subgroupanalysisinmenalsofoundan 1.09–2.07, were 1.50(95%CI1.03–2.17, status allhadhigherriskofTAI, andtheadjustedORs deficiency, adequateiodinestatusandexcessive than adequateiodinestatus,individualswith intake and TAI ( confirmed theU-shapedrelationshipbetweeniodine ( adequate iodinestatus(13.5%)andexcess(13.7%) finally included. Maincharacteristics of those studies is studies fromliteratureandourcross-sectionalstudy)were 41 ( 21 studiesfromliteraturewereeligibleintometa-analysis full texts.Another164studieswerefurtherexcludedand 185 candidatestudieswerefurtherevaluatedbyreading excluding studiesthatdidnotfulfilltheinclusioncriteria, abstracts wereidentifiedthroughliteraturesearch. After 1. A total of 5191 Fig. shown in the Supplementary Flow chart of study selection for the meta-analysis was Dose–response meta-analysis was bothUshapedinmenbutnotwomen. Iodine statusandTAI al 2 Table 26 , , 42 The relationshipbetweeniodineintakeandTPOAb 27 241.5 (218.7–261.9) , More thanadequate , 11.6 (10.0–14.7) 24.0 (3.8) 41.3 (16.1) 43 513 (83.3) 174 (28.2) 185 (30.0) 8.6 (6.3–12.2) 2.7 (1.7–3.3) 28 ). Multivariate logistic regression analysis also ). Multivariatelogisticregressionanalysisalso 70 (11.4) Table 2 , P , 44

= 29 0.013) and1.68(95%CI1.11–2.53, , 616 , μ 45 g/L; morethanadequate,200–299.9 Table 2 30 ). The relationship between iodine intake ). Therelationshipbetweeniodineintake , , 46 31 ). Therefore,atotalof22studies(21 , ). Compared with those with more ). Compared with those with more 32 Downloaded fromBioscientifica.com at10/02/202102:53:21AM , 652.1 (332.4–1971.6) 33 12.4 (10.0–15.4) 23.8 (3.8) 39.8 (17.1) 315 (84.9) 101 (27.2) 8.6 (6.5–12.0) 2.9 (1.7–3.6) 94 (25.3) 39 (10.5) , 34 Excessive P

, = 371 35 0.032), 1.50 (95% CI 0.032), 1.50(95%CI 181 , 36 :3 , Table 2 37 μ g/L; excessive, , 38 P 0.014), =0.014), , ). < < 39 0.19 0.15 0.05 0.09 0.005 0.01 0.12 0.02 0.001 0.001 258 P – , 40 via freeaccess ,

European Journal of Endocrinology (Supplementary Fig. 2). (Supplementary iodine status(UIC100–199.9 iodine intakeandTAI inadultswhenthe adequate increase TAI between risk in adults. The U-shaped curve both low iodine status and excessive iodine status could at theUICof300 iodine intake and TAI in adults with the lowest TAI risk adults revealedanobviousU-shapedassociationbetween Dose–response meta-analysisofthose17studies in response meta-analysisinadultsandchildrenseparately. TAI betweenchildrenandadults,weperformedthedose- obvious differenceintheassociationofiodineintakewith Table 4).have suboptimalquality(Supplementary but three studies scored five or less and wereconsidered to scored morethanfivepointsandthushadgoodquality, 4).AccordingtotheNOScriteria,moststudies Table studies hadlowriskofselectionbias(Supplementary All studieshadlowriskofinformationbias,andmost Table 4).higher riskofconfoundingbias(Supplementary factors suchasageandgender, whichwereconsideredat other studiesdidnotexcludetheimpactofconfounding estimates andhadlowriskofconfoundingbias,butthe adults ( and theotherstudiesmainlyassessedrelationshipin on the association of iodine intake with TAI in children, studies were fromEurope ( most wereconductedinAsians( of 69,987participants( and samplesizerangedfrom209to15,008,withatotal shown in OR, oddsratio. *Confounding factorsinthemultiplelogisticregressionanalysisincludedage,sex,BMI,smoking,diabetesandhypertension. Urinary iodine Table 2 Urinary iodineconcentrations:low, Excessive More thanadequate Adequate Deficiency Women Excessive More thanadequate Adequate Deficiency Men Excessive More thanadequate Adequate Deficiency Total Clinical Study Because our preliminary pooled results suggested an Because our preliminary Table 3 Risk ofthyroidautoimmunityinadultswithdifferenturinaryiodineconcentrations. Table 3 ). Onlythreestudiesreportedadjustedrisk . All22studiesusedcross-sectionaldesign, μ g/L ( Table 3 P 1253 Number Nonlinearity 158 300 620 351 213 316 633 217 371 616 568 < Table 3 100 μ ). Amongthese22articles, g/L) wasusedasreference μ n g/L; adequate,100–199.9 B Wangandothers

=

). Five studies focused < 17), andtheotherfive 0.0001, 117 (18.9) 169 (13.5) 32 (20.3) 44 (14.7) 61 (17.4) 19 (8.9) 13 (4.1) 52 (8.2) 21 (9.7) 51 (13.7) 57 (9.3) 82 (14.4) TAI (%) i. 1 Fig. ), and μ g/L; morethanadequate,200–299.9 1.48 (0.89–2.44) 1.35 (0.93–1.97) 1.22 (0.80–1.87) 2.28 (1.10–4.73) 2.09 (1.12–3.89) 2.50 (1.22–5.10) 1.56 (1.05–2.34) 1.53 (1.11–2.10) 1.65 (1.16–2.37) OR (95%CI) o bevd(upeetr i. 6).Whenthe UIC Fig. (Supplementary not observed ( children with the lowest TAI risk at the UIC of 50 nonlinear associationbetween iodineintakeandTAI in response meta-analysisofthose fivestudiessuggesteda between iodineintakeandTAI inchildren.Dose– positivity inadults( U-shaped associationbetweeniodineintakeandTGAb studies onTGAbpositivityfurtherprovedanobvious ( between iodineintakeandTPOAbpositivityinadults positivity in adults also suggested an U-shaped association adults ( U-shaped associationbetweeniodineintakeandTAI in good qualityaccordingtoNOScriteriaalsorevealedan Moreover, dose–response meta-analysis of 14studieswith still existed( association betweeniodineintakeandTAI riskinadults moderate riskorhighofselectionbias,theU-shaped 3).Afterexcludingstudieswith Fig. Supplementary iodine intake and TAI risk in adults ( bias furtheridentifiedanU-shapedassociationbetween adjusted risk estimates and high risk of confounding Dose–response meta-analysisof14studieswithout risk attheUICof250 iodine intakeandTAI inadultswiththelowestTAI bias alsoidentifiedanU-shapedassociationbetween adjusted riskestimatesandlowofconfounding Iodine statusandTAI 1 1 1 P P Nonlinearity Nonlinearity Crude OR There wereonlyfivestudiesassessingtheassociation Dose–response meta-analysis of 13studiesonTPOAb Dose–response meta-analysisofthreestudieswith P Nonlinearity

= = 0.022), buttheU-shaped association was 0.007). Dose–responsemeta-analysisof12 P Nonlinearity 0.128 0.117 0.349 0.026 0.021 0.012 0.029 0.009 0.006

< – – – P

0.0001, Supplementary Fig. 5). 0.0001, Supplementary P μ g/L; excessive, Nonlinearity

< μ Downloaded fromBioscientifica.com at10/02/202102:53:21AM

g/L ( .01 upeetr i. 4). Fig. 0.0001, Supplementary 1.43 (0.86–2.38) 1.34 (0.92–1.96) 1.19 (0.77–1.82) 2.31 (1.11–4.83) 1.98 (1.06–3.71) 2.83 (1.34–5.99) 1.68 (1.11–2.53) 1.50 (1.09–2.07) 1.50 (1.03–2.17)

< P OR (95%CI) 0.0001). Nonlinearity https://eje.bioscientifica.com ≥ 300 1 1 1 Adjusted OR* 181 μ g/L. P

Nonlinearity < :3 0.0001,

< 0.0001, 0.166 0.129 0.433 0.026 0.033 0.006 0.014 0.013 0.032 i. 2 Fig. 259 – – – P μ g/L via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com

Table 3 Summary of published studies on the associations of iodine intake with thyroid autoimmunity. Clinical Study

Participants (mean or median Mean or median UIC determination Adjustment or matching Study (Ref.) Country Design age; female, %) UIC (μg/L) method factors Outcomes Wang 2004 (46) China Cross-sectional 3606 participants NA Ammonium persulfate None TAI (aged 7–74 years; 53.4%) method Dogan 2011 (43) Turkey Cross-sectional 1000 participants NA Ammonium persulfate None TAI (14.6 years; 50.0%) method Zhang 2011 (45) China Cross-sectional 1093 participants 236.4 (IQR: NA) Ammonium persulfate None TMAb; TGAb (52.3 yearss; 47.9%) method Zhang 2011 (44) China Cross-sectional 1683 participants 254.9 (s.d.: 44.6) Ammonium persulfate None TPOAb; TGAb (41.1 years; 48.9%) method Garcia-Garcia Spain Cross-sectional 1387 participants 199.5 (s.d.: 101.4) Ammonium persulfate None TAI 2012 (42) (8.4 years; 48.8%) method B Wangandothers Zimmermann 12 countries Cross-sectional 2,512 participants 151 (Range: 1–1883) Ammonium persulfate None TPOAb; TGAb 2013 (41) (9.4 years; 49.8%) method Habimana 2014 (40) Belgium Cross-sectional 209 participants 138 (IQR: 57–321) Ammonium persulfate None TPOAb (27.0 years; 100.0%) method Johner 2014 (39) Germany Cross-sectional 6101 participants 120.5 (IQR: NA) Ammonium persulfate None TPOAb (aged 6–17 years; 45.0%) method Shi 2015 (38) China Cross-sectional 7190 participants 152.6 (IQR: NA) Ammonium persulfate Age, weeks of gestation, TPOAb; TGAb (aged 19–40 years; 100.0%) method and BMI Qin 2016 (37) China Cross-sectional 1492 participants 238.9 (s.d.: 162.0) Ammonium persulfate None TAI; TPOAb; TGAb (45.2 years; 60.0%) method Guo 2016 (36) China Cross-sectional 1591 participants 130.7 (IQR: 77.4–198.9) Ammonium persulfate None TPOAb; TGAb (aged over 18 years; NA) method

Wang 2016 (35) China Cross-sectional 1424 participants 222.6 (IQR: NA) Ammonium persulfate None TAI Iodine statusandTAI (aged no less than 18 years; method 60.6%) Chen 2017 (34) China Cross-sectional 1678 participants 106.4 (IQR: 71.5–158.5) Ammonium persulfate Age, sex, educational status, TAI (61.7 years; 63.5%) method current smoker, current drinker, BMI, and TSH Ye 2017 (33) China Cross-sectional 2794 participants 155.0 (NA) Ammonium persulfate None TPOAb; TGAb (27.4 years; 100.0%) method Xiao 2017 (31) China Cross-sectional 2282 participants 230.1 (IQR: 148.4–352.8) Ammonium persulfate None TAI; TPOAb; TGAb (40.6 years; 47.7%) method Liu 2017 (32) China Cross-sectional 2936 participants 146.1 (NA) Ammonium persulfate None TPOAb; TGAb Downloaded fromBioscientifica.com at10/02/202102:53:21AM (42.9 years; NA) method Hu 2018 (30) China Cross-sectional 2644 participants (aged no less 173.8 (IQR: 118.6–249.3) Ammonium persulfate None TPOAb; TGAb than 18 years; 48.9%) method Sha 2018 (29) China Cross-sectional 2827 participants (aged no less 258.7 (95% CI 76.6–1506.4) Ammonium persulfate None TPOAb; TGAb than 18 years; 49.8%) method

Kang 2018 (28) Korea Cross-sectional 1288 participants (aged 449 (range 15–21,905) Mass spectrometry None TPOAb 181

6–19 years; 44.8%) device :3 Kim 2018 (27) Korea Cross-sectional 6434 participants 291.7 (IQR: 157.4–666.9) Mass spectrometry None TPOAb (38.0 years; 41.1%) device Chen 2019 (26) China Cross-sectional 15,008 participants 205.2 (IQR: 65.7–537.7) Ammonium persulfate None TAI (45.5 years; 57.7%) method Present study China Cross-sectional 2,808 participants 164.5 (IQR: 111.1–235.6) Ammonium persulfate Age, sex, BMI, smoking, TAI; TPOAb; TGAb 260 (43.6 years; 50.9%) method diabetes and hypertension via freeaccess

NA, not available; RR, risk ratio. European Journal of Endocrinology linear model. in thepatternsbetweensplinemodeland curve forthelinearmodelwasshowntodisplaydifference trend. Thesplinemodelwastheoptimalmodel,while nonlinear trend.Theshortdashlinerepresentsthelinear dash linerepresents95%confidenceintervalsofthefitted black solidlinerepresentstheoddsratioandlong 17 studiesinadults.ThereferencelevelofUICis300 autoimmunity inadultsthedose-responsemeta-analysisof U-shaped associationbetweeniodineintakeandthyroid Figure 1 relationship betweeniodine intakeandTAI inadults. TAI risk.Thecross-sectionalstudyshowedan U-shaped meta-analysis investigatingthe impactofiodinestatuson epidemiological studies, which was thefirstdose–response we alsoperformedadose–responsemeta-analysisof22 independent roleofiodinestatusonTAI risk.Additionally, regression analysis,andthuswasabletoevaluatethe of confounding factors through multivariate logistic TAI risk.Ourcross-sectionalstudyadjustedtheinfluence to evaluatetheindependentimpactofiodinestatuson factors suchasgenderandage, thus, wereunable studies didnotadjusttheinfluenceofotherconfounding with TAI isstillcontroversial.Additionally, mostprevious determinant forthyroiddysfunction,butitsrelationship Iodine intakehaslongbeenregardedasanenvironmental Discussion Fig. 6). (Supplementary children nolongerincreasedwhenUICwasover250 children graduallyincreased.However, riskofTAI in increased from 50 Clinical Study μ g/L to 250 μ B Wangandothers g/L, the risk of TAI in

μ g/L. The μ g/L

effects onhumanhealth.Iodine deficiencycaninduce production ofthyroidhormones andthuscauseadverse been clearthatiodinedeficiency canresultinimpaired iodine deficiencyorexcessive iodine( above, therearealargepercentage ofpersonswitheither respectively ( than adequate intake and the presence of excessive iodine, the rangeof200–299 UIC shouldbebetween100and200 Health Organization(WHO)suggeststhatanadequate determinant ofthyroiddisordersinadults( and iodinestatushaslongbeenregardedasakey has gainedrapidlygrowingconcernsinthepastdecade, factors ofTAI. and both iodine deficiency and iodine excess are risk relationship betweeniodineintakeandTAI inadults, strong epidemiologicalevidencefortheU-shaped or excessiveiodinestatus.Therefore,thestudyprovides of TAI amongindividualswitheitheriodinedeficiency in adults,whichprovedthesignificantlyincreasedrisk U-shaped relationship between iodine intakeand TAI The dose–responsemeta-analysisfurthervalidatedthe reference levelofUICis250 three studiesinadultswithlowriskofconfoundingbias.The autoimmunity inadultsthedose-responsemeta-analysisof U-shaped associationbetweeniodineintakeandthyroid Figure 2 patterns betweenthesplinemodelandlinearmodel. linear modelwasshowntodisplaythedifferencein spline modelwastheoptimalmodel,whilecurvefor trend. Theshortdashlinerepresentsthelinear represents 95%confidenceintervalsofthefittednonlinear represents theoddsratioandlongblackdashline Iodine statusandTAI The consequenceofiodinestatusonhumanhealth 21 ). Accordingtothecriteriaofiodinestatus μ g/L and Downloaded fromBioscientifica.com at10/02/202102:53:21AM μ g/L. Theblacksolidline https://eje.bioscientifica.com > 300 181 μ μ g/L, andanUICin 28 g/L indicatemore :3 , 48 17 , , 47 49 ). World ). Ithas 261 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com revealed thatTAI riskwasnotincreasedbyeither iodine A largecross-sectionalstudy byZimmermann obviously higherUICthan Non-TAI controls ( by Tsatsoulis still controversial in children. An epidemiological study avoiding excessiveintake. supplementation andminimizeitsadverseinfluence by iodine statusisessentialtoimprovethebenefitsof iodine deficiencycanincrease TAI risk,themonitoringof risk. Additionally, becauseeitheriodineexcess statusor avoiding excessiveintakeisalsoessentialtoreduceTAI individuals withiodinedeficiencytoreduce TAI risk,but supplementation orsaltiodizationarerecommendedfor 400 while thosewithUICeitherlessthan200ormore UIC between200and300 with IDDs.Ourstudysuggestsanoptimaliodineintakeof obviously distinct pathogenic mechanism when compared an autoimmunedisease occurring in thyroid and has an prevention ofIDDsiswithin100–199.9 thyroid goiter, inwhichtherecommendedUICfor between UICandIDDssuchashypothyroidism nutrition fromWHOismainlybasedontherelationship of TAI prevalence.Theclassificationmethodforiodine iodine intakeisalsocriticalfortheeffectivereduction different typesofthyroiddiseases( inmonitoringiodinesupplementationacross thus vary is likelyinconsistent,andtheacceptableUICrangemay the impactofiodineondifferenttypesthyroiddiseases conclusion isavailable( as thyroidcancer, TAI andhypothyroidism,nodefinite impact ofiodineintakeonvariousthyroiddiseasessuch numerous studieshavebeenperformedtodefinethe risk ofthyroiddisorders( iodine statusisrequiredtooptimizeUSIanddecreasethe hyperthyroidism ( USI ontheprevalenceofotherthyroiddiseasessuchas Some studies also have shown an adverse impact of a medicalchallengetooptimizeiodineintake( intake hastobetakenintoaccount. Currently, itremains preventing IDDs,theadverseimpactofiodineexcess IDDs worldwide( improved iodinestatusandreducedtheprevalenceof have IDDs, and iodine prophylaxis interventions implemented universalsaltiodization(USI)toeliminate hypothyroidism andgoiter( a numberofiodinedeficiencydisorders(IDDs),suchas Clinical Study μ The association between iodine intake and TAI is Similar to other thyroid diseases, optimization of Though iodinesupplementationisessentialin g/L are at increased risk of TAI. Therefore, iodine t al et 51 54 . reportedthatchildrenwith TAI had , ). Therefore,acarefulmonitoringof 52 ). 17 μ ). Currentstudiessuggestthat 55 g/L forthepreventionofTAI, , 50 56 ). Manycountrieshave B Wangandothers ). Additionally, though 17 ). μ g/L ( 21 ). TAI is t al et 53 57 ). ). . However, mostincludedstudiesdidnotadjustforage and TAI, and they may cause the risk of confounding bias. been regardedasimportantimpactfactorsforbothUIC outcomes inourstudy. Bothageandgenderhavelong bias isamajorthreattothevalidityofpooled define theimpactofiodinestatuson TAI riskinchildren. status inchildren,futurestudiesarerecommendedto in children.Consideringthecriticalsignificanceofiodine definite relationshipbetweeniodineintakeand TAI risk in children,ourstudywasstillunabletoestablisha However, owing to the limited number of eligible studies was differentfromtheU-shapedrelationshipinadults. risk attheUICof50 iodine intake and TAI in children with the lowest TAI in children,andshowedanonlinearassociationbetween assessing theassociationbetweeniodineintakeandTAI dose–response meta-analysis included only five studies deficiency oriodineexcessinchildren( of hypertensionthanthosewithlowerUIC( BMI, lowerprevalenceofdiabetesand suggested thatparticipantswithhighUIChadlower for confoundingfactors.Besides,ourcross-sectionalstudy validated inmorefuturestudieswithadequateadjustment confounding risk,thefindingsinourstudystillneedtobe Considering thelimitednumberofstudieswithlowrisk and gender, whichincreasedtheriskofconfoundingbias. intake could increase thyroglobulin immunogenicity and possible explanationsbelow. Firstly, excessiveiodine been sufficientlyclarified. Somestudiesproposedseveral the underlyingmolecular mechanisms havenotyet has been identified as an important risk factor of TAI, balance amongimmunecells( attacks tothyroidantigensbybreakinguptheimmune of TAI, bothof which may initiate the autoimmune environmental riskfactorsareinvolvedintheetiology Previous studieshaveestablishedthatbothgeneticand immune cellssuchasTcells,Bandmacrophages( TAI isprecededbyanabsenceofimmunebalanceamong of TAI ( innate immunityisalsoanessentialpartintheetiology the developmentofTAI, butrecentstudiesindicatethat system whichareconsideredtoexertcriticalrolesin T cellsandBarethemainpartsofadaptiveimmune through multivariatelogisticregressionanalysis. studies needadjustingforallpossibleconfoundingfactors assess the relationship between iodine and TAI risk, future possible confoundingfactors.Therefore,toadequately suggesting thatdiabetes,BMIandhypertensionwere Iodine statusandTAI As shown in the Supplementary table4,confounding As shownintheSupplementary The mechanismofTAI isstilllargelyelusive. 1 , 58 , 59 ). Similartootherautoimmunediseases, μ g/L (Supplementary Fig. 6), which Fig. 6), g/L (Supplementary Downloaded fromBioscientifica.com at10/02/202102:53:21AM 58 ). Thoughhighiodine 181 :3 41 ). Thecurrent al 1 Table 262 58 via freeaccess ). ),

European Journal of Endocrinology nearly 3000participantsand didnotevaluatetheimpact status of TPOAb and TGAb by a cross-sectional study of with thyroidantibodies.Secondly, weonlyassessedthe the difference in thereported associations of iodine intake thyroid antibodiesinthose studies,whichmayresultin there wasobviousdifferenceintheassaysorcutoffs of unknown andneedtobeelucidatedinmorefuturestudies. among individuals with iodine deficiency are still largely the mechanismsunderlyingincreasedriskofTAI and furtherpromotethedevelopmentofTAI. However, iodine deficiencymayinduceaberrantimmuneresponse TSH level among hypothyroidism individuals caused by ( the function of the immune system and immune response found thatTSHhaveanimportantroleinregulatingboth can resultinincreasedTSHlevel( intensively related toiodine status, and iodine deficiency autoimmune attack( may furtherpromoteimmuneresponseandincrease deficiency increases the degree of oxidativestress which that iodine can contribute to redox balance and iodine 66 nodular goiterandcausingdamagestothyroidtissues( the TAI prevalence by increasingtheprevalenceofthyroid antibodies, iodine deficiency thus may indirectly increase with thyroidnodulargoiteroftenhaveconcurrent in individualswithiodinedeficiency. Firstly, sincepatients several possibleexplanations for theincreasedriskofTAI CD4 reactivity andincreasedintrathyroidaldendriticcells, iodine deficiencycouldinducethyroidautoimmune by onepreviousstudyMooij deficiency asariskfactorfor TAI. Thefindingwassupported future studies. largely notexplored,whichneedtobeelaboratedin effectofiodineonimmunecellsare for thestimulatory immune cells( indicated thatiodinemayenhanceantibodysynthesisby in humanperipheralbloodlymphocytesvitro,which of TAI. Forinstance,iodinecouldpromoteIgGsynthesis immune cellsmayalsobeinvolvedinthedevelopment 62 of TAI among individuals with excessive iodine intake ( which isanimportanteventunderlyingtheincreasedrisk of thyroidcellscausedbyiodinehasbeenwelldefined, development ( which couldinitiatetheautoimmuneprocessduringTAI TAI epitopeonthyroglobulin, riskbyunmaskingacryptic 74 Clinical Study , , , 63 There wereseverallimitationsinourstudy. Firstly, The findingsfromthecurrentstudyrevealiodine 67 + 75 TcellsandCD8 ). Finally, effectofiodineon thedirectstimulatory , , 68 76 , , 69 77 60 ). In addition, several studies have found ). Inaddition,severalstudieshavefound , 64 78 ). Additionally, thedirectcytotoxicinjury ). However, the molecular mechanisms , 79 + TcellsinWistar rats( 70 , 80 , 71 , 81 , ). Therefore, the increased ). Therefore,theincreased 72 et al B Wangandothers ). Finally, TSHlevelis 17 . which reported that . whichreportedthat , 73 ). Some studies ). Somestudies 65 ). There are ). Thereare 61 17 , , and Africans.MorestudiesfromCaucasiansAfricans be generalizedtootherpopulations,suchasCaucasians Asian populations,andthefindingsmaybeunableto them. Fifthly, mostincludedstudieswereperformedin poorly defined,andfuturestudiesareneededtouncover other riskfactorsinthedevelopmentofTAI aresofar and smoking.However, theinteractionsofiodinewith several otherfactorsaffecting TAI risk,suchasgender, age trials. Fourthly, apartfromiodinestatus,therearealso in moreprospectivecohortstudiesorclinicalcontrolled intake andTAI foundinthisstudystillneedstobevalidated between iodineandTAI. Therelationshipbetweeniodine thus had limited ability to assess the causality relationship included studiesusedcross-sectionalstudydesignand of iodineintakeonriskTRAbpositivity. Thirdly, most toadequatelyevaluatetheimpact participants isnecessary TRAb isrelativelylow, andastudywithlargernumberof receptor antibodies(TRAb)positivity. Theprevalenceof of iodineintakeonriskthyroid-stimulatinghormone The authors declare that there is no conflict of interest that could be could that interest of conflict perceived asprejudicingtheimpartiality ofthisstudy. no is there that declare authors The Declaration ofinterest EJE-19-0212 This islinkedtotheonline version ofthepaperat Supplementary data elucidate thosemechanisms. largely elusive,andmorestudiesarewarrantedtobetter mechanisms underlyingtherolesofiodineinTAI arestill from morelongitudinalstudies.Moreover, thepathogenic genetic factors or familyhistory, and it requires evidence populations suchaschildrenandthosewithpredisposing relationship betweeniodineintakeandTAI inspecific iodine status.However, uncertaintyremainsaboutthe monitoring iodinestatusisessentialforanoptimal and clinical implicationsforiodineinterventions, factors ofTAI amongadults.Thefindingshaveimportant iodine deficiencyandexcessivestatusarerisk between iodineintakeandTAI riskinadults,andboth convincing evidencefortheU-shapedrelationship lacking, andfurtherstudiesarewarranted. individuals withpredisposinggeneticfactorsarestill the relationshipbetweeniodinestatusandTAI riskamong of TAI issofarlargelyelusive.Forinstance,studieson However, theiodine–gene interaction in thedevelopment for iodine–geneinteractionsinthedevelopmentofTAI. intake andTAI risk.Finally, thereisahigh possibility are neededtovalidatetherelationshipbetweeniodine Iodine statusandTAI In conclusion, the findings in ourstudy provide . 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