陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 7熏晕燥援 2熏 Apr.18, 圆园14 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 窑Review窑 Selenium supplementation in thyroid associated ophthalmopathy:anupdate

DepartmentofOculoplastics,LacrimalandOrbitalSurgery, subjects who are hyperthyroid. Restoration of ManchesterRoyalEyeHospital,OxfordRoad,Manchester euthyroidism is one of the main goals in the M139WH,UK managementofTAOandwhenanti-thyroiddrugsare Correspondenceto: ArunaDharmasena.Departmentof combinedwithSe,thepatientswithGraves'disease(GD) Oculoplastics,LacrimalandOrbitalSurgery,Manchester andautoimmunethyroiditis(AIT)achievedeuthyroidism RoyalEyeHospital,OxfordRoad,ManchesterM139WH, fasterthanthosetreatedwithanti-thyroiddrugsalone. Sestatusofnormaladulthumanscanvarywidelyand [email protected] SesupplementationmayconferbenefitonlyifserumSe Received:2013-10-16Accepted:2013-12-12 levelsareinsufficient.Theauthorrecommendsthat serumSelevelsofpatientswithTAOtobeassessed Abstract prior toand duringSesupplementationat regular · Thetherapeuticeffectofselenium (Se)hasalready intervals to avoid potential iatrogenic chronic Se overdose. beenproveninthyroiddiseaseandthyroidassociated ophthalmopathy (TAO).Inspiteofclearscientificproof ·KEYWORDS: selenium;selenoproteins;thyroidassociated ofitsbenefitsinTAO,thereappearstobenoclear ophthalmopathy;Graves'orbitopathy agreementamongthecliniciansregardingitsoptimum DOI:10.3980/j.issn.2222-3959.2014.02.31 dose,durationofthetreatment,efficacyandsafetyto date.Inthisreview,theauthorsummarisesthefindings DharmasenaA.Seleniumsupplementationinthyroidassociated of135Englishlanguagearticlespublishedonthis ophthalmopathy:anupdate. 2014;7(2):365-375 subjectoverthepastfourdecadesfrom1973to2013. Theregulationandmetabolismofthyroidhormones INTRODUCTION requireasteadysupplyofSeandrecentstudieshave 34 elenium(Se 79)isametalloid(semi-metal)which revealedseveralpossiblemechanismsbywhichSe S possessesintermediatepropertiesbetweenametalanda improvestheseverityofthyroiddiseaseandTAO.These non-metalanditsnameisderivedfromSelene-goddessof mechanismsinclude1)inhibitoryeffectofHLA-DR molecule expression on thyrocytes; 2) profound themoon.Seisfoundinsoilandwaterandentersthefood [1] reductionsofthyroidstimulatinghormone(TSH)receptor chainthroughtherootsofplantsandaquaticorganisms .It antibodies(TSHR-Ab)andTPOantibodies(TPO-Ab);3) actsasanessentialcofactorrequiredtoactivateseveral preventionofdysregulationofcell-mediatedimmunity enzymesystemsinhumans [2].Seisintegratedintothe andBcellfunction;4)neutralisingreactiveoxygen polypeptidechainsasthe21st aminoacid,selenocysteineand species(ROS)andinhibitionofredoxcontrolprocesses theproteins which containselenocysteineare called requiredfortheactivation,differentiationandactionof selenoproteins(SPs).ThekeymetabolicfunctionofSehas lymphocytes,macrophages,neutrophils,naturalkiller thereforebeenattributedtoitsroleinthisenzymaticcofactor cells involved in both acute and chronic orbital selenocysteine(SeC) [3-7].AmajormilestoneofSe inflammationinTAO;5)inhibitionofexpressionofpro- biochemistryemergedin1973whenglutathioneperoxidise inflammatorycytokinesand6)inhibitionofprostaglandin (GPx),aSecontainingmammalianenzymeandtwosuch andleukotrienesynthesis.Anincreasedoxidativestress bacterialenzymeswerediscovered [8-12].Sofar,25SPs, hasbeenobservedinbothacuteandchronicphasesof encodedby25humangenes,havebeencharacterisedin thyroiddiseasewithraisedtissueconcentrationsofROS. humansalthoughthefunctionsofsomeoftheseSPshaveyet ThebenefitsofSesupplementationinindividualswith [13,14] TAOappear tobeproportionatetothedegreeof tobeelucidated .Themostpopularselenoenzymesbelong [15] systemicactivityofthethyroiddisease.Themaximal totheGPxfamilywhichconsistsof8isoforms . benefitofSesupplementationisthereforeseeninthe TheimportanceofSeandSPsinhealthanddiseaseis

365 Seleniuminthyroidassociatedophthalmopathy gainingincreasingrecognition [16-19].Thepossibletherapeutic richinSeandvariesconsiderablyindifferentpartsofthe effectofSehasbeenstudiedinseveraldiseasessuchas world.Indrinkingtapwater,theSeconcentrationis1 g/L[32]. 滋 hemorrhagicpancreatitis,asthma,cardiovasculardisease, ROLEOFSELENOPROTEINSINTHEBODY stroke,severesepsis,rheumatoidarthritisandevenHIV [20-25]. Toxinsknownasreactiveoxygenspecies(ROS)areformed SeveralstudieshavealsoconfirmedSeinducedinhibitionof withinthecellsfromoxygenmetabolismundernormal thyroidcancercellgrowth [26-29].ImpairedexpressionofSPs physiologicalconditions.IftheseROStoxinsarenot observedtobeassociatedwithperturbedthyroidhormone neutralised;theydamagetoDNA,cellmembranes,anda levels,indicatingtheimportanceofSeforthyroidhormone varietyofothercellularstructures [1].Thismayresultincell homeostasisandSefoundtobebeneficialinthyroid deathandmayalsotriggeraviciouscycleoftissue associatedophthalmopathy (TAO)whichisthe most inflammation.SPs,whicharepowerfulantioxidantenzymes, commonextra-thyroidalmanifestationofthyroiddisease [30,31]. mitigatetheeffectsofoxidativestressbyeliminationof RecentstudiesonthebeneficialeffectsofSeandtheseSPsin ROS [1].GPxandthioredoxinreductase (TxR)arethetwo TAOhaveevokedexcitingdiscussion. mainseleno-enzymesystemsresponsibleforthereductionof NATURALSOURCESOFSELENIUM thesesuperoxideproduction [10,48,49].Sedeficiencyleadsto AlthoughSeisdistributedinsoilsworldwide,factorssuchas reducedproductionofSPs,includingGPx,resultinginthe soilcomposition,plantspeciesandthephysiological accumulationofH2O2causingtissueinflammationand conditionof theplant,environmentalconditionsand disease [50].Inaddition,SPsplayavitalroleintheregulation agriculturalpracticeshaveaprofoundinfluenceontheSe ofhumanimmunesystemandSedeficiencyisaccompanied contentof vegetables,fruit,meat,fishandwater [32]. bydysregulationofbothcell-mediatedimmunityandBcell [51] Therefore,theSecontentofnormaladulthumanscanvary function .H2O2isalsoaby-productofinflammatorycascade widelyand approximatelyfifteenpercentof world's alongwithotherperoxidasessuchaslipidhydroperoxideand populationisSedeficient [33].Somepartsoftheworld phospholipidhydroperoxide [52].Therefore,inSe-sufficient includingMiddle-East,India,ChinaandsomeEuropean environment,thesehydroperoxideintermediatesofthe countriessuchasFinlandareconsiderablylowinsoilSe cyclooxygenaseandlipoxygenasepathwaysareneutralised resultinginSedeficiencyinthelocalpopulation [34-38].In effectivelyresultingindiminishedgenerationof contrast,inseleniferousareas,asignificantproportionofthe proinflammatoryprostaglandins (PGs)andleukotrienes [53]. localpeopleconsuminglocallygrownfoodmaymanifest Thisminimisethesubsequenttissueinjury.Inadditionto signsofSetoxicity [38,39].Asanexample,thelentils,grownin theseintra-cellularSPs,theSelenoproteinP(SePP)whichis CanadiansoilsareextremelyrichinSe(425-673 g/kg)[33].A producedintheliveristhemajorcirculatingformofSein 滋 widegeographicalvariationmayalsobeobservedevenin plasmaandithasahighantioxidantpotential [54].Itisableto differentareasinthesamecountry.Forexample,inonesuch bindtotheendotheliumandbythismechanismSePPis study,SeintakeinadultsinSedeficientareasand recruitedtothesiteoftheinflammation [19,55-57].Alltheabove seleniferousareasinChinawerefoundtobe2.6-5.0and mechanismsofactionofSPsininflammatorydiseasemay 1338 g/drespectively [40,41].Vegetablessuchasonionsand explainthebeneficialeffectsofSeinTAO.Inadditiontothe 滋 asparagusgrownonseleniferoussoilmayaccumulateupto abovepropertiestheseenzymeshavenumerousother 17 g/gofSe.Garlicandbrassicas( cabbage,broccoli biologicalfunctionsinthyroidhormonemetabolism,tumour 滋 andmustard)arealsorichinSe.Othercommonlyconsumed prevention,immuneresponse,reproductionandmuscle vegetablesandfruitsgenerallycontainonlylowamounts, function [7,32]. rarelyexceeding10 g/kg.Brazilnutshavehighlevelsof EFFECTSOFSELENIUMDEFICIENCYONTHE 滋 proteinandalsoknowntohaveaveryhighconcentrationsof THYROIDGLANDANDTHYROIDASSOCIATED Se [42-44].Reyes [45] reportedthattheSecontentinfish OPHTHALMOPATHY differswidelyandrangedbetween0.1and5.0mg/kginthe Theregulationandmetabolismofendocrinesystemsrequire samplesoftheirstudy.TheSecontentofcodandsharkhas asteadysupplyofseveraltraceelementssuchasI,Se,Zn, beenfoundtobe1.5and2.0mg/kg,respectively [46].Some Cu,ironandvitaminA[58-62].EnvironmentalSelevelsstrongly marinefisharerelativelyhighinSe [46,47] andReyes [45] correlatewithserumSelevelswhichhavebeenshowntobe foundaparticularlyhighconcentrationof5.6mg/kgofSein significantlylowerinpatientswiththyroiddiseaseandTAO Tuna.Seconcentrationinwateroriginatesfromatmospheric andahigherincidenceofTAOisseenintheareasdeficient depositsorsoildrainageandsub-soilswhicharenaturally inSe.LowSelevelshavebeenobservedeveninthenew

366 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 7熏晕燥援 2熏 Apr.18, 圆园14 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 borninfantsborntomotherssufferingfromthyroiddisease [63]. secretionofTSH receptorantibodies(TSHR-Ab) by Sehasbeenfoundtobeanimportantco-factorforboth activatedBcells.TheseantibodiesbindtotheTSHRonthe physiologicalfunctionandinautoimmunediseaseofthe thyrocytesandfibroblastsoftheorbit,wheretheyinitiatethe thyroid. H2O2 isan essential co-substrate forthyroid ocularchanges.Thisantigen-antibodyreactiononthe peroxidase(TPO)enzymeduringtheoxidationofinorganic thyrocytesmimictheactionofTSHbutwitha'long-acting'

IodineforthyroidhormonesynthesisandthenumberofH2O2 effectresultinginanunregulatedgrowthandthefunctionof moleculesproducedisproportionatetotheintensityofTSH thyroidfollicularcellsleadingtotheexcessiveproductionof [68,71] receptorstimulation.However, eveninphysiological thyroidhormones .ThisalsostimulatesH2O2production conditionsamuchhigheramountsofH2O2areproducedthan andsubjectsthethyroidglandtoextremelyhighlevelsof consumedbytheiodinationprocess,potentiallyexposingthe H2O2 requiringaconstant,muchhighersupplyofSPsinorder thyroidglandtoexcessiveamountoffreeradicalsinaddition toneutralisetheexcessH2O2tominimisetissueinjury.Ina tothe'normal'shareofacell [64,65].SPssuchasGPxandTxR populationbasedstudyPedersen [72] demonstrated neutralisetheseexcessH2O2andtheyaretherefore significantlylowerconcentrationsofserumSeinGD consideredasessentialSPsinthethyroidhormonesynthesis. comparedtonormalsubjects.Xu [73] investigatedthe

Inpathologicalhyperactivity,alargevolumeofH2O2and effectofSeonthethyroidglandsofpatientssubjectedto ROSareproducedandproportionatelylargequantityofSe excessiveiodineintakeandfoundthatsupplementalSecould arerequiredtoprotectthethyroidglandfromsuperoxide alleviatetoxiceffectofexcessiveiodineonthyroidaswell. damage [14,66].Severalotheragentssuchassuperoxide Althoughthyroidhormonesynthesisiscompartmentalizedto [67] dismutase,vitaminsCandEalsoassistH2O2disposal . thelumenofthefolliclesandboththeDUOXenzymesand ThetwomainautoimmunethyroiddiseasesareGraves' TPOarelocalizedtotheapicalmembraneofthethyrocytes, disease(GD)whichisthemost commoncauseof H2O2 canfreelydiffuseintothecytoplasmandnucleus,where thyrotoxicosis,andHashimoto'sthyroiditis(HT)whichisthe itmayleadtoaberrantoxidationandiodinationofproteins mostcommoncauseofhypothyroidism.Ninetypercentof andlipidstriggerapoptosisandinduceDNAdamage. patientswithTAOhaveGrave'sdiseaseand10%sufferfrom Therefore,H2O2inducedtissuedamagemayliberatethyroid Hashimoto'sthyroiditisandinthelattertheeyesignsare hormonestoredinthecolloidinthefolliclelumenintothe oftenmild.Theseautoimmunethyroiddiseasesarecausedby circulationfurtherworseningtheseverityofhyperthyroidism. abnormalimmuneresponsetoself-thyroidantigensandthe InsevereSedeficiency,peroxidecleavagewithinthethyroid keyroleisplayedbyTlymphocytes whenantigen cellsisdiminished [51] andnutritionalSedeficiencytherefore recognitionismediatedbyreceptorsonthecellsurface(T leadstoanincreasedrateofthyroidcellnecrosisand cellreceptor,TC-R).Thisbreaksthetolerancebydeficitof invasionofmacrophagesandfurtherincreaseinthyroid suppressorTcellsandaberrantexpressionofDRregionof hormonelevelsinbloodduetoliberationofstoredthyroid HLA (HLA-DR),absentonnormalthyroidcells.The hormones [74-76].LikeIodine,Sealsoinfluenceonthesizeof contemporaryexpressionofHLA-DRonthyroidfollicular thethyroidgland.Rasmussen [77] showedaninverse cellsandauto-antigenstriggerstheautoimmunereactionby relationshipbetweentheSerumSeconcentrationandthe antibody-dependent,complement-mediated,directorindirect volumeofthethyroidgland.Sedeficiencycanalso cytotoxicity [68].Sehasadose-dependentinhibitoryeffecton exacerbatetheeffectsofiodinedeficiencyandthesameis theexpressionofHLA-DRmoleculesofthyrocytesinduced trueforvitaminAorirondeficiency[60,78]. byinterferon-γ andthismayexplainoneofthemechanisms TAOinGDiscausedbyinflammationofextra-ocular ofbeneficialeffectofSeinreducingtheseverityof musclesandorbitaladiposetissue.SerumTSHR-Abis autoimmunethyroiddisease [69,70]. presentin70%-100%patientswithGraves'diseaseandin InGD,thelossoftoleranceofTcellstothe 1%-2%ofnormalindividuals [79-81].Inadditiontothyrocytes, thyroid-stimulatinghormonereceptors(TSHR), yet TSHreceptorsarealsoexpressedintheorbitalfibroblasts unknownmechanisms,ignitesanautoimmuneprocess.This andpreadipocytesandwhenboundbyTSHR-Abtriggersa firststepofthediseaseprocessofGDisconsideredtobe chronicinflammatorycascaderesultinginswellingofthe precipitatedbyenvironmentalfactorsofanHLArelated orbitaltissuesinTAO.KloproggeandFrauman [82] reported organ-specificdefectinsuppressorT-lymphocytefunction. positiveTSHreceptorsevenwithinnormalhumanmuscle TheTSHRis internalizedandpresented by antigen- fibres,using3G4and3B12antibodies.Usingasimilar presentingcellstohelperTcells.Thisresultsinanexcessive techniqueBoschi [83] comparedorbitaltissuesfrom30

367 Seleniuminthyroidassociatedophthalmopathy patientswithTAOwith24patientswithnon-thyroidorbital group [51].Thesignificantlyhigherresponsetooralsodium inflammationorstrabismusanddemonstratedsignificantly selenitewasnotedinhyperthyroidpatientscomparedto highTSHreceptorexpressioninelongatedfibroblast-like euthyroidorhypothyroidpatientsinthisstudyaswell.Inthe cellslocatedbetweenthemusclecellsinallTAObiopsies. subgroupanalysisoftheirpatients,Bhuyan [74] noteda Therefore,theophthalmicmanifestationsofGDarethe reductionintheTPO-Abtitreupto64.42%intheir productofacloseinteractionbetweenorbitalfibroblastsand subclinicalhyperthyroidgroupofpatients.Thereductionin T-celllymphocytes[84].Variousclassesofimmunomodulators theTPO-Ab titreintheeuthyroid, hypothyroid,and ( HLAantigens,CTLA-4,cytokines)mediatethis subclinicalhypothyroidgroupswerestillsignificantandwere interaction[84].Polymorphismsinimmunomodulatorgenescan 41.13%,47.18%,and42.64%respectively [74].Inanother altertheinteractionbetweenT-cellsandorbitalfibroblasts prospectiveplacebo-controlledprospectivestudyincluding andimpactdiseasesusceptibilityandprogression[84].Growing 132patientswithautoimmune thyroiditis,Bal zsand 佗 evidencesupportsthattheSe-containingenzymesandtheir Feh r [91] demonstratedadecreasedinflammatoryactivity 佴 antioxidantcapacity somehowmodifytheautoimmune paralleltothereductionofTPO-AbtitresinresponsetoSe mechanism[52].TheseSPshavediverseeffectsontheimmune supplementation.Aninversecorrelationwasfoundbetween system,eitherstimulatingorinhibitingtheimmunological antioxidantcapacityandlevelofTPO-Ab.Thisobservation responseinordertoregulateinflammation.Similareffectsof raisesthesuspicionthatSedeficiencybyitselfmightbe Seonextraocularmusclesandotherinflamedorbitaltissue responsiblefortheprecipitationofthyroiddisease.In mayexplainthebeneficialeffectofSeinTAO [85].Although addition,severalstudieshaveseenanimprovementinmood anti-thyroidperoxidase(TPO-Ab)antibodiesaremost and/orgeneralwell-beinginthesepatients.Zagrodzkiand commonlyassociatedwithHashimoto'sthyroiditisand Ratajczak [58] observedasharpfallofSeandGPx3witha TSHR-AbaremostcommonlyassociatedwithGraves' markedincreaseinTPO-AbpromptlyafterwithdrawalofSe disease,thereisanoverlap[79,80].TPO-Absarespecificforthe supplementation.Incontrast,intwo similarstudies autoantigenTPOandpresentinapproximately90%of Anastasilakis [92] failedtodemonstrateasignificant Hashimoto'sthyroiditis,75%ofGraves'diseaseand10%-20% benefitofSeonserumthyroidauto-antibodylevelsor ofnodulargoitreorthyroidcarcinoma.Also,10%-15%of lymphocyteinfiltrationofthethyroidglandinHashimoto's normalindividualscanhavehighlevelTPO-Abtitres [79,86].In thyroiditis andBonfig [93] observedthat Se addition,thepatientswithHashimotodiseasehavealower supplementationdidnotdecreaseTPO-Abconcentrationin GPxactivitythanhealthysubjects[87]. childrenandadolescents. ThereisclearevidencethatthebenefitsofSe TheGDischaracterisedbythepresenceofincreased supplementationaregreaterwhenitiscommencedearlierin oxidativestressinbothacuteandchronicphaseofthe thediseaseprocessinpatientswithautoimmunethyroiditis disease [94,95].ThepathogenesisofTAOinGDsubstantially (AIT) [88].Karanikas [89] suggestedthatthevariable liesonthepresenceofaninflammatory-cellinfiltrate benefitofSesupplementationinindividualswithAITmaybe predominantlycomposedofactivatedTcellsproducing explainedbythediseaseactivityandthedegreeof cytokines(mainlyIL-1,TNF- ,IFN- )which,inturn, 琢 酌 inflmmation.Toulis [90] reportedasignificantlowering activateorbitalfibroblastsecretionofglycosaminoglycans, ofTPO-AbtitersinpatientswithHashimoto'sthyroiditisin furtherinducingorbitalfibrosisandoedema [96].Ina responsetoSesupplementationfor3mo.Inablinded retrospectivestudy investigating83patientswithGD, placebo-controlledprospectivestudyundertakenbyBhuyan Wertenbruch [97] demonstratedasignificantlow [74] themeananti-TPOantibodyconcentrationdropped concentrationsofTSHR-Ablevelsinpatientswhohadahigh by49.5%inthegrouptreatedwithadailydoseof200 g serumSelevelswithremissionofGD.Corroboratingthis 滋 (2.53 moL)oforalsodiumselenitefor3mocomparedto evidenceisthefindingthatpatientswithGD,whentreated 滋 10.1%reductioninthecontrolgroup.Inasimilarstudy withamixtureofantioxidants,includingSecombinedwith conductedinaSedepletedareaofBavariainsouthern anti-thyroiddrugs,achievedeuthyroidismfasterthanthose Germany,Grtner [51] showeda36%reductionin treatedwithanti-thyroiddrugsalone[98,99]. 覿 TPO-AbtitresintheSe-treatedgroup.Asubgroupanalysis EvidencesuggeststhatSedeficiencyaffectsboththe ofthosepatientswithTPO-Abgreaterthan1200IU/mL cell-mediatedandhumoralimmunity,whicharelinkedto revealedamean40%reductionintheSe-treatedpatients inflammatoryprocessesinvolvingtheproductionofROSand comparedwitha10%increaseinTPO-Abintheplacebo redoxcontrolprocesses [7].ROSproductionincreases

368 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 7熏晕燥援 2熏 Apr.18, 圆园14 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 expressionof proinflammatorycytokinesthrough currentlaboratoryfacilitiesSecanbemeasuredinplasma, up-regulationofnuclearfactor-kappaB(NF-κ B)activity [100]. serum,orevenintissuessuchaskidneyandliver [32].Itcan Lymphocytes,macrophages, andespeciallyneutrophils alsobemeasuredinurine,hairandnails [32].TheplasmaSe requireROSandproinflammatorymoleculesforactivation, levelrepresents theamountofcirculatingSPsand differentiation,andphagocytosis [7].Thismaybeanother selenoenzymes [105].AssessmentofGPxactivityin mechanismbywhichSeexertsitsbeneficialeffectsinTAO. erythrocytesisanothermeasureofSestatusofanindividual Inaddition,highSelevelsareassociatedwithfewernatural andthiscanbeassessedbyanindirecttechnique [32].Tiran killercells [100,101].ConfirmingtheabovehypothesisXue [106] describedaprocedurefordeterminationofSeby [102] demonstratedasignificantdifferencebetweenthe hydridegenerationatomicabsorptionspectroscopy(AAS)in severitiesoflymphocyticinfiltrationinthyroidsofSetreated wholeblood,serumandurine.Itemployssulfuricacid,H2O2 anduntreatedmicewithAIT. andvanadium(V)sulfuricacidreagentsolution.Thismethod GPxandTxRdecreasefreeradicalformationandreduce usesnoexplosivereagentsandcanbeperformedata

H2O2 andlipidandphospholipidhydroperoxides.Thekey constanttemperatureof100℃ anditgivesrapidreading. enzymesofprostaglandinandleukotrienesynthesisrequirea Therefore,itiseasilyapplicableinaroutineclinical certainperoxidetonetobecomeactive.Infact,theyare laboratoryforalargeamountofsamples.Selevelsinserum product-activated [10]. Accordingly,GPxplusreduced canbe assessedbyacommerciallyavailableatomic glutathionepreventanyarachidonateutilizationbycyclo- absorptionspectrophotometersuchasPerkin-Elmermodel oxygenase,5-lipoxygenase,and15-lipoxygenase [10].In 3100(Perkin-ElmerCorp.,Norwalk,CT,USA)incombination Se-sufficientenvironment,thehydroperoxideintermediates withanMHS-FIAS-200flowinjectionhydridegeneration ofthecyclooxygenaseandlipoxygenasepathwaysare systemandanAS-90auto-sampler [107].Jacobsonand thereforereducedandleadtodiminishedproductionof Lockitch [108] alsodescribedadevelopmentofadirectmethod proinflammatoryPGsandleukotrienes [53].Inaddition,both fordeterminationofSeinserumbygraphite-furnaceatomic GPxandTxRmodulatetherespiratoryburstandreduce absorptionspectrophotometrywithdeuteriumbackground superoxideproduction [10].Thismaybeconsideredasanother correction.ThereareseveralmethodstodeterminetheGPx beneficialeffectofSPsinTAOwhereSPsneutralisethe activityinplasmaandwholeblood.InonesuchmethodGPx ROSreleasedduringautoimmuneprocessandreducethe activitycanbedeterminedinplasmaandwholebloodusinga productionofproinflammatoryPGsandleukotrienes.In modificationofthemethodofdescribedbyPagliaDEand addition,thereisevidencetosupportthebeneficialeffectsof ValentineWNusingtertiarybutylhydroperoxide [109,110].An Seonthepsychologicalwell-beingofpatientswithTAO[90]. automatedanalysersuchas CobasFaraAutoanalyser CAUSESOFSELENIUMDEFICIENCY (Hoffman-LaRoche,Basle,Switzerland)canbeusedforthis TheSedeficiencyismostlycausedbylowdietaryintake(see purpose[107]. above)orpoorintestinalabsorption.RarelySeandSP SELENIUMSUPPLEMENTATION deficiencycanbegeneticallyinherited [103].Individualswith BloodSeconcentrationsinresidentsinaseveralEuropean inheriteddefectsinselenocysteineinsertionsequence locationsfoundtobebelowtheconcentrationrequiredfor (SECIS)bindingprotein 2displayasyndromeof optimalplasmaGPxactivityinhumans [111].Schrauzerand selenoprotein-relateddefectsincludingabnormalthyroid White [112] estimatedthattypicaldailyintakeofSeperperson hormone metabolism [103].Selenocysteine incorporation torangefrom90to168 g/dbasedona30dstudy.Seintake 滋 sequencebindingprotein2(SBP2)representsakey inEuropeislowerthanintheUnitedStatesandinmany trans-actingfactorfortheco-translationalinsertionof countriesitisbelowtheUKreferencenutrientintakeof selenocysteineintoSPs [104].InindividualswithSBP2 75mg/d[113].Thehighestintakeswereobservedinindividuals deficiencyduetomutationsintheSBP2genethedietarySe subsistingondietsrichinwholewheatgraincerealproducts intakeisobviouslynotthelimitingfactorintheindividuals andseafoodsuchascrab,othershellfishandfish [113].TheSe whenregulardailySeintakeisprovided [104].Thetotalserum concentrationsinwholebloodcorrelatewiththedietarySe Seconcentrationsinsuchindividualswithselenoprotein intakesdirectly [112].Toprovideasufficientlywidemarginof biosynthesisdefectsrespondto selenomethionine safety,thereferencedose(RfD)forSefromallnutritional supplementation [104]. sourcesfora70-kghumanhasbeensetat350mg/d [114], METHODSTOASSESSSELENIUMDEFICIENCY correspondingto5mgSe/kgbodyweight/day.TheRfDis ThereareseveralmethodsforevaluatingSeinhumans.With theamountofsafetotalintakeofSebyanadultwhosubsists

369 Seleniuminthyroidassociatedophthalmopathy onanormaldietandistakinganadditional200mgSeaday changesandalopecia [129,130].Nailchangesarethemost intheformofanutritionalsupplement [114].SPsareclassified commonsignofchronicSepoisoningandtheybecome asessentialandnonessentialandtheessentialSPsdecrease brittle,andwhitespotsandlongitudinalstreaksappearonthe moreslowlythannon-essentaialSPsinSedeficiencyand surface.Aschronicpoisoningbecomesmoresevere,breaks theirlevelsrecovermorerapidlyonSere-supplementation inthenailoccurandthenailcanbelost;nailsmaygrow thannonessentialSPs[115-117].Thomson [118,119] demonstrated backdeformedandbelostrepeatedly.Fragilenailsand asignificantincreaseinplasmaSeandwholebloodGPx similarchangesareobviouslynotspecificforselenosis,and activitywith adailysupplementationof 100 g othercausesincludefungalinfection,psoriasis,andarsenic 滋 L-selenomethioninefor12wk.Nochangeswerefoundinthe exposureandzincdeficiency.Whenexaminingapatientwith concentrationsofTSH,freeT3,freeT4,orthyroglobulin raisedserumSe,theabsenceofcharacteristicnailchanges concentrations,apartfromanonsignificantincreaseinfree suggeststhattheraisedbloodSeisduetorecentintakerather T3inthiscohortofpatientsinresponsetoSesupplements[118,120]. thanduetochronicpoisoning.Therefore,theexaminationof Severalotherstudiesdemonstratedtheabsenceofsignificant nailsshouldbeincludedintheexaminationofthepatientson influenceofSeonthefreeT3,FreeT4,TSHlevels [120-122].In Sesupplementsforoverdose.Otherfeaturesmayinclude themeantime,somerandomizedcontrolledtrialsinhealthy nausea,vomiting,diarrhoea,fatigue,andskinlesions. humanadultshaveshownastatistically-significantdecrease Musculoskeletaldisorderssuchasstiffgaitandlamenesscan inserumT4afterSesupplementation[123,124]. occurduetoalterationofthecartilages [9].Peripheral AccordingtoGrtner [51] ittook3motoachievea paresthesiascanbepresent,alongwithhyperreflexiaand 覿 significantreductionofthemeanTPO-Abconcentration painintheextremities.Asselenosisprogresses,decreased whensupplementedwith200 g(2.53 moL)oforalsodium cognitivefunction,weakness,paralysis,anddeathmayoccur. 滋 滋 selenite.Twentyfivepercentoftheirpatientsshoweda Preventionoffurtherexposureisthemostimportantaspectof completenormalizationofbothTPO-Abconcentrationsas thetreatmentandconservativemanagementisrecommended. wellasthyroidultrasoundechogenicitywithSe Chelationisnotrecommendedsinceanimalstudiessuggestit supplementation [51].Nacamulli [125] demonstratedthat mayincreasetoxicity[128,131]. dietarysupplementationwithphysiologicaldosesofSefor DISCUSSION 12motobeeffectiveinreducingbothTPO-Aband Seisanessentialmineralwithseveralimportantprotective thyroglobulinautoantibodies(Tg-Ab).Combs [120] functionsinTAO.Sedeficiencyhasshowntobeakey indicatedthat,aperiodof6moisrequiredtoreachanew environmentalfactorwhichtogetherwiththegeneticvariants steadystateplasmaSeconcentrationinhealthysubjectswhen thoughttoprecipitatesautoimmunethyroiddiseaseinseveral supplementedwith200 gSeperdayasSeMet.Se partsoftheworlddeficientinsoilSe [132].Itprotectsthe 滋 supplementationfoundtobesignificantlyassociatedwith thyrocytesfromsuperoxideinducedtissuedamageandhas thyroidvolumeregressioninautoimmunethyroiditis [77,126]. severalmodifyingeffectsonthethyroidautoantibodieswhich Marcocci [127] recommendsa6-mocourseofSein arethoughttotriggertheophthalmicmanifestations.In patientswithmildGraves'orbitopathy.Todate,thereisno addition,Selenoproteinshaveanti-inflammatoryproperties. robustscientificevidence recommendingtheoptimal Theylowerhydroperoxideswithintissuesandinhibitthe durationofSesupplementationinTAO. productionofinflammatoryprostaglandinsandleukotrienes. SELENIUMOVERDOSEANDTOXICITY Therefore,itispostulatedthatevenmildSedeficiencymay Sesupplementshavebecomeapopulartreatmentoption contributetothe developmentandmaintenanceof universallyinthemanagementofTAOandthyroiddiseasein autoimmunethyroiddiseasesandTAO [51].Dicksonand general.Intheabsenceofrobustevidencetosupportthe Tomlinson [133] discoveredthehighesttissueconcentrationof optimumdurationofSesupplementation,thecliniciansadopt Seinthehumanbodyintheglandulartissueofthethyroid drugregimensof personalpreferenceratherthana indicatingtheimportanceofSeinphysiologyofthyroid.In universallyagreedprotocol.TheSestatusoftheindividualis Graves'disease,Sesupplementationresultsineuthyroidism notofteninvestigatedpriortoorduringtheperiodofSe beingachievedmorerapidlywithabeneficialeffectonmild supplementation.AlthoughtheneedforSeinhuman inflammatoryorbitopathy[134].Marcocci [135] carriedouta nutritioniswellrecognized,likeothertraceelementsSehas randomized,double-blind, placebo-controlledtrialto longbeenrecognisedforitstoxicity [32,128].ChronicSe determinetheeffectofSeorpentoxifylline(ananti- overdose,orselenosis,oftenpresentswithnailandhair inflammatoryagent)in159patientswhohadmildsignsor

370 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 7熏晕燥援 2熏 Apr.18, 圆园14 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 symptomsofGOoflessthan18months'duration.Atthe TAO.TheseincludeinhibitoryeffectofHLA-DRmolecule 6-monthevaluation,treatmentwithSe,butnotwith expressiononthyrocytes,thereductionofserum pentoxifylline,wasassociatedwithanimprovedqualityof TPO-Ab/TSHR-Abconcentrations,influenceonthecell life ( <0.001)andlesseyeinvolvement( =0.01)and mediated/humoralimmunepathways,antiinflammatoryand slowedtheprogressionofGraves'orbitopathy( =0.01),as anti-oxidentpropertiesofSe.ThesebeneficialeffectsofSe comparedwithplacebo [135].BasedonthisliteraturereviewSe explainwhytheefficacyofSesubstitutionisproportionateto appearstohaveabeneficialinreducingtheextraocular theinflammatoryactivityofautoimmunethyroiddiseaseand muscleandorbitaladiposetissueinflammationandSemay TAO. exertthesebeneficialeffectsbyreducingtheTPO-Aband WhilstitseemsreasonabletorecommendSesubstitutionto TSHR-Abconcentrations,regulationofimmunemechanisms reducetheseverityofTAOandautoimmunethyroiddisease andinhibitingorbitalinflammation[74,91,97,98,102,135]. theSestatusoftheindividualpatientsshouldbetakeninto AlthoughSesupplementationappearstobebeneficialin accountpriortoprescribingSesupplementstoavoidchronic TAOitwillconferabenefitonlyifintakeofanutrientis iatrogenicoverdose.Incurrentpractice,thelaboratory inadequate.Supplementationofpeoplewhoalreadyhave measurementsofSearenotroutineinTAO,buttheauthor adequateintakewithadditionalSemightincreasetheirrisk proposethatearlyassessmentofSestatusshouldbecome oftype-2diabetes [111,134].Thereisawidegeographical mandatorypriortoSesupplementationtodeterminethedose variationofavailabilityofSeinfood.Thecrucialfactorthat anddurationofsupplementationofthisvitalmicronutrient. needstobeemphasisedwithregardtothehealtheffectsofSe ACKNOWLEDGEMENTS isthatwhereasadditionalSeintakemaybenefitpeoplewith ConflictsofInterest:DharmasenaA, None. lowstatus,thosewithadequate-to-highstatusmightbe REFERENCES affectedadverselyandshouldnottakeSesupplements [111]. 1WeeksBS,HannaMS,CoopersteinD.Dietaryseleniumand Therefore,itisimportanttoassesstheSestatusofthe selenoproteinfunction. 2012;18(8):RA127-132 individualpatientspriortoSesupplementationandatregular 2Przybylik-MazurekE,ZagrodzkiP,Kuzniarz-RymarzS, Hubalewska-DydejczykA.Thyroiddisorders-assessmentsoftrace intervalswhileontreatment. elements,clinical,andlaboratoryparameters. 2011; CONCLUSION 141(1-3):65-75. Seisauniquetraceelementinitsstructuralincorporation 3G nzlerWA,SteffensGJ,GrossmannA,KimSM, ttingF,WendelA, 俟 魻 intoproteinsanditisessentialforoptimalendocrineand Floh L.Theamino-acidsequenceofbovineglutathioneperoxidase. 伢 immunefunctionandmoderatingtheinflammatoryresponse. 1984;353:195-212 Ontheotherhand, thyroidautoimmunedisease,a 4ZinoniF,BirkmannA,StadtmanTC,B ckA.Nucleotidesequenceand 觟 multifactorial organ-specificautoimmunedisorder,is expressionoftheselenocysteine-containingpolypeptideofformate markingaconstantincreaseworldwideanditisthoughttobe dehydrogenase(formate-hydrogen-lyase-linked)fromEscherichiacoli. causedbymultiple environmentalfactorstriggering 1986;83(13):4650-4654 5B ckA,ForchhammerK,HeiderJ,BaronC.Selenoproteinsynthesis:an autoimmuneresponseingeneticallysusceptibleindividuals, 觟 expansionofthegeneticcode. 1991;16(12): thoughtheexactmechanismslinkingenvironmentalfactors 463-467 tothyroidautoimmunityarenotasyetwellunderstood. 6SchomburgL.Selenium,selenoproteinsandthethyroidgland: Nevertheless,thereisincreasingevidencethatnutritiveand interactionsinhealthanddisease. 2011;8(3):160-171 environmentalfactorsarethemaindeterminantsinthe 7HardyG,HardyI,ManzanaresW.Seleniumsupplementationinthe present-daydistributionofthisdiseaseanditsophthalmic criticallyill. 2012;27(1):21-33 manifestations.EvenmildSedeficiencythoughttocontribute 8Floh L,GunzlerEA,SchockHH.Glutathioneperoxidase:a 伢 tothedevelopmentandmaintenanceofautoimmunethyroid selenoenzyme. 1973;32(1):132-134 diseasesandTAO.Thepatientswiththyroiddiseasessuchas 9Rotruck,JT,PopeAL,GantherH,SwansonA,HafemanDG,Hoekstra WG.Selenium:biochemicalroleasacomponentofglutathioneperoxidase. GDandeventhyroidcancerappeartohavelowlevelsof 1973;179(4073):588-590 serumSelevelscomparedtotheagematchedcontrols. 10Floh L,AndreesenJR,Brigelius-Floh R,MaiorinoM,UrsiniF. 伢 伢 SeveralstudieshaveshownthattheSesubstitutioncould Selenium,theelementofthemoon,inlifeandearth. 2000;49 haveasignificantimpactoninflammatoryactivityin (5):411-420 thyroid-specificautoimmunediseaseandasignificant 11Andreesen,JR,LjungdahlL.FormatedehydrogenaseofClostridium improvementitsophthalmicmanifestations.Thereappearsto thermoaceticum:incorporationofselenium-75,andtheeffectofselenite, beseveralmechanismsbywhichSereducetheseverityof molybdateandtungstateontheenzyme. 1973;116(2):867-873

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