Research Article Response to Radioiodine Therapy for Thyrotoxicosis: Disparate Outcomes for an Indigenous Population

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1 Iteratioal Joural of Edocriology Volume 2016, Article ID , 6 pages Research Article Respose to Radioiodie Therapy for Thyrotoxicosis: Disparate Outcomes for a Idigeous Populatio Jade A. U. Tamatea, 1 Joh V. Coagle, 1 ad Mariae S. Elsto 1,2 1 UiversityofAucklad,WaikatoCliicalCampus,PrivateBag3200,Hamilto3240,NewZealad 2 Departmet of Edocriology, Waikato Hospital, Private Bag 3200, Hamilto 3240, New Zealad Correspodece should be addressed to Jade A. U. Tamatea; jade.tamatea@waikatodhb.health.z Received 3 February 2016; Accepted 22 May 2016 Academic Editor: Jack Wall Copyright 2016 Jade A. U. Tamatea et al. This is a ope access article distributed uder the Creative Commos Attributio Licese, which permits urestricted use, distributio, ad reproductio i ay medium, provided the origial work is properly cited. Despite 70 years of experiece treatig thyrotoxic patiets with radioiodie ot all patiets are successfully treated by a sigle dose. Multiple factors predictig radioiodie efficacy have bee reported. The aim of this study was to assess whether ethicity was associated with radioiodie respose. A retrospective review was performed of patiets who received radioiodie therapy for thyrotoxicosis from 1 Jauary 2008 to 31 December 2010 ad had follow-up available of a miimum of 12 moths. 224 patiets were icluded, 82.4% female, ad 63.7% had Graves s disease. Radioiodie failed i 21.5% of patiets overall, with a higher failure rate i the idigeous populatio (35.2%). Whe cotrollig for other ifluecig factors by logistic regressio, there cotiued to be a icreased risk for the idigeous group (OR 2.82) ad those treated with atithyroid drugs followig radioiodie (OR 2.04). Youger age was also associated with a icreased risk of failig radioiodie therapy (OR 0.97 for each year of age). Cure rates followig radioiodie were lower for idigees idepedet of factors kow to affect radioiodie outcome. This is the first report demostratig ethicity as a possible idepedet variable for radioiodie efficacy. Further work is eeded to ivestigate the cause of this differece. 1. Itroductio Thyrotoxicosis is a importat cause of morbidity ad whe treated iadequately may result i premature mortality [1]. Graves s disease (GD) ad toxic multiodular goitre (TMNG) are the most commo causes of thyrotoxicosis [2]. Despite hyperthyroidism beig commo, the therapeutic optios have remaied essetially uchaged for 50 years. It is recogised that further research i this area is eeded to improve cliical outcomes [3]. For patiets who require defiitive treatmet for GD or TMNG the treatmet optios remai either surgery or radioiodie (RAI). RAI has bee used as treatmet of thyrotoxicosis for over seve decades [4, 5]. I New Zealad, the most commo defiitive treatmet for GD is RAI [6]. RAI eters the thyrocyte via the sodium-iodie symporter with β radiatio resultig i cell death ad reduced thyroid fuctio. The aim of RAI is to achieve a euthyroid or hypothyroid state (with the latter corrected by thyroid hormoe replacemet); however ot all patiets become euthyroid or hypothyroid followig a sigle dose of RAI. Successful treatmet of hyperthyroidism rages from 66 to 93% i all-cause hyperthyroidism [7 12] ad from 66 to 90% i Graves s disease [13 24]. Factors reported to decrease the success of a sigle dose of RAI iclude male geder, youg age, use of atithyroid medicatio (ATD) either before orfollowigrai,alargeglad,severityofthyrotoxicosisat presetatio, severity of thyrotoxicosis at time of treatmet, uptake o scitigraphy scas prior to therapy, dose of RAI give,adpreseceofophthalmopathy[7 12,14,16 23]. Māori are the idigeous people of New Zealad ad comprised 14.6% of the populatio at the time of the study [25]. Our cliical impressio is that Māori are more likely to have a usuccessful respose to RAI treatmet tha most other patiets (Coagle JV, persoal commuicatio). To date, this observatio has ot bee formally studied. I additio, there have bee o published studies assessig whether there are differeces i respose of thyrotoxicosis to RAI i other specific ethic groups.

2 2 Iteratioal Joural of Edocriology The objective of this retrospective study was to assess whether the efficacy of RAI therapy admiistered for thyrotoxicosis differed for Māori whe comparedwith o-māori adtoivestigatepotetialcofoudigfactorsthatmay ifluece differeces i outcome. 2. Materials ad Methods A retrospective otes review was udertake of all adult patiets who received RAI ( 131 I) for thyrotoxicosis at a 600- bed tertiary hospital i New Zealad, betwee 1 Jauary 2008 ad 31 December Participats were idetified from the regioal edocrie uit s database. Those patiets with less tha oe year of follow-up data available or who had received additioal defiitive therapy (either RAI or thyroid surgery) prior to the start of the study period were excluded. Patiets who did ot receive a stadard 555 MBq dose were also excluded. The study was coducted i accordace with thenatioalhealthadvisorycommittee sethicalguidelies for Observatioal Studies ad with permissio of the local Edocrie Departmet. The aetiology of the thyrotoxicosis was based o cliical, radiological, ad laboratory results. Patiets were cosidered to have GD if they had oe or more of the followig: diffuse symmetrical icreased thyroid uptake o 99m techetium isotope sca, thyroid receptor atibody (TRAb) positivity, thyroid associated ophthalmopathy, or the presece of a thyroid thrill or bruit o cliical assessmet. TMNG was diagosed i those with a multiodular goitre o examiatio, TRAb egativity, ad/or 99m techetium sca fidigs cosistet with multiple odules demostratig icreased uptake. The remaiig patiets had a solitary toxic adeoma (STA), diagosed by the presece of a solitary odule with icreased uptake o 99m techetium sca ad decreased uptake throughout the rest of the thyroid glad. Ethicity was determied retrospectively from hospital records, documetig patiets self-idetified ethicity o first hospital presetatio, ad ordered usig a prioritisatio method. Data regardig pretreatmet with ATD, the date ATD was started, ad presece of ophthalmopathy were collected from hospital records icludig letters from referrig cliicias. Weight measuremets documeted i cliical records from the day RAI therapy was admiistered were collected, or if o weight was documeted o the day of RAI, a weight recorded withi oe moth of RAI admiistratio was used. Historical laboratoryrecordswerereviewedtocollectthehighestfreet 4 levelmeasuredithemothsurroudigdiagosis.ithose patiets with relapsig GD, the highest free T 4 level was take from the moth the relapse was diagosed. Treatmet was cosidered successful if patiets became either hypothyroid requirig L-thyroxie replacemet or euthyroid ad remaied so to the ed of follow-up. Patiets who remaied hyperthyroid followig therapy ad/or required either a subsequet dose of RAI, thyroid surgery, or logterm ATD to achieve a euthyroid state were cosidered failed treatmet outcomes. This iformatio was gathered from cliical records ad laboratory results. Table 1: Baselie demographic data. Total Age (51.8, 55.6) F 184 (82.5%) Geder 223 M 39 (17.5%) Ethicity 213 Graves s 142 (63.6%) Diagosis 223 TMNG 75 (33.6%) STA 6 (3.7%) Media weight (kg) (52.2, 118.8) Nil 103 (73.57%) Ophthalmopathy 140 Sev. 4 (2.86%) T 4 at presetatio (12, 65.4) Pretreatmet ATD (86.4%) Legth of ATD (wks) (13, 439) Posttreatmet ATD (38.54%) Legth of FU (wks) (432, 1466) ATD: atithyroid medicatio; F: female; M: male; NMāori: o-māori; GD: Graves s disease; TMNG: toxic multiodular goitre; STA: solitary toxic adeoma; Mod.: moderate eye disease; Sev.: severe eye disease. Cotiuous variables are expressed as mea (95% cofidece itervals) or media (5th, 95th percetile) accordig to their distributio. Categorical variables are expressed as umber (percetage). Māori Mild 71 (31.9%) 26 (18.57%) NMāori Mod. 142 (63.6%) 7 (5.00%) All aalyses were carried out usig STATA 13 (StataCorp, 2013, Stata Statistical Software: Release 13, College Statio, TX, StataCorp LP). A p value of < 0.05wasusedtoreject the ull hypothesis. Results are preseted as mea with 95% cofidece itervals or media with 5th ad 95th percetiles depedig o the distributio of the data. Differeces betwee groups were aalysed usig chi-square, Ma- Whitey U, or idepedet t-tests as appropriate. Logistic regressio aalysis was used to determie idepedet factors impactig outcome with effect size preseted as odds ratios ad 95% cofidece itervals. Variables were idetified for the model usig stepwise aalysis with a variable cutoff of p < 0.05 for iclusio i the model. 3. Results Two hudred ad iety-three doses of RAI were admiistered to 256 treatmet aïve patiets betwee 1 Jauary 2008 ad 31 December A fixed dose of 555 MBq was give toallbutthreepatiets,whoreceived370mbq,adthese three patiets were excluded. After excludig the 30 patiets for whom 365-day or more follow-up was ot available, data were aalysed o 223 patiets Geeral. The baselie demographics are preseted i Table 1. The majority of patiets were female (82.5%), with a media age of 53.7 years. Thirty-two percet of patiets recorded Māori as their ethicity. Of the 63.7% classified as o-māori, 111 were recorded as New Zealad Europea with

3 Iteratioal Joural of Edocriology 3 Table 2: Baselie data by ethicity. No-Māori ( = 142) Māori ( =71) p Age (52.6, 57.6) (47.7, 53.1) Geder F 116 (81.7%) 61 (85.9%) M 26 (18.3%) 10 (14.1%) GD 98 (69.0%) 36 (50.7%) Diagosis TMNG (27.5%) (47.9%) STA 5 (3.5%) 1 (1.4%) Weight (kg) (52.2, 118.3) (55.1, 118.1) Nil 71 (74.0%) 25 (69.4%) Ophthalmopathy Mild 18 (18.8%) 7 (19.4%) Mod. 4 (4.2%) 3 (8.3%) Sev. 3 (3.0%) 1 (2.8%) T 4 at presetatio (12, 61) (11, 74) Pretreatmet ATD (83.1%) (93.0%) Legth of ATD (wks) (9, 374) (14, 504) Posttreatmet ATD (35.9%) (43.08%) 0.34 Follow-up legth (wks) (428, 1459) (432, 1481) ATD: atithyroid medicatio; F: female; M: male; GD: Graves s disease; TMNG: toxic multiodular goitre; STA: solitary toxic adeoma; Mod.: moderateeye disease; Sev.: severe eye disease. Cotiuous variables are expressed as mea (95% cofidece itervals) or media (5th, 95th percetile) accordigto their distributio. Categorical variables are expressed as umber (percetage). Table 3: Outcomes followig radioactive iodie. No-Māori Māori % % Overall Failure % % Success % % GD Success % % Failure % % TMNG/STA Success % % Failure % % GD: Graves s disease; TMNG: toxic multiodular goitre; STA: solitary toxic adeoma. p the remaider comprisig 14 Asias, 13 Other Europeas, 3 Pacific Isladers, ad 1 Africa. The 10 idividuals i whom ethicity was ot stated were excluded from aalyses where ethicity was a variable. GD was diagosed i 63.7% ad TMNG i 33.6%. The majority of patiets (87%) received ATD prior to RAI for a media legth of 49 weeks; most received carbimazole with oly 6 idividuals receivig propylthiouracil. All patiets stopped ATD therapy at least 5 days prior to RAI. The most commo reasos for ot receivig ATD were mild/subcliical disease (42.9%) or adverse reactios to ATD (39.3%). Patiets were followed up for a media duratio of 913 days Māori Ethicity. The demographics of Māori were differet whe compared to o-māori (Table 2). Māori participats were youger (p = ), more likely to have a TMNG (p = 0.011), ad more likely to receive ATDs prior to RAI therapy (p = 0.048) tha o-māori. There was o differece i geder distributio, body weight, free T 4 at presetatio, presece of ophthalmopathy (i GD patiets), media legth of follow-up, or use of ATD after RAI Outcomes. At the ed of follow-up 78.5% of patiets became either hypothyroid or euthyroid (Table 3). Factors ifluecig outcome are reported i Table 4. Patiets who had persistet thyrotoxicosis followig RAI were 5.9 years youger (p = 0.012) ad more likely to be Māori (54.4% versus 27.5%, p = 0.001) tha those who had achieved a successful outcome. Patiets i whom RAI therapy failed had at diagosis a FT 4 level that was pmol/l higher tha those who were successfully treated (p ) ad were more likely to be pretreated with ATDs (97.9% versus 84.0%, p = 0.011). I those patiets who received ATD therapy prior to RAI, there was o differece i the legth of treatmet i those who remaied thyrotoxic followig RAI as compared to those who became either euthyroid or hypothyroid (44 weeks

4 4 Iteratioal Joural of Edocriology Table 4: Factors ifluecig radioactive iodie outcome. Success Failure p Age (52.8, 57.2) (45.3, 52.9) Geder F 148 (84.6%) 36 (75.0%) M 27 (15.4%) 12 (25.0%) GD 109 (62.3%) 33 (68.8%) Diagosis TMNG (34.3%) (31.2%) STA 6 (3.4%) 0 (0%) Ethicity NMāori 121 (72.5%) 21 (45.6%) Māori 46 (27.5%) 25 (54.4%) Weight (kg) (52.2, 118) (53.8, 118.1) Nil 81 (76.4%) 22 (64.7%) Ophthalmopathy Mild 18 (17.0%) 8 (23.5%) Mod. 5 (4.7%) 2 (5.9%) Sev. 2 (1.9%) 2 (5.9%) T 4 at presetatio (12.0, 60.1) (16.9, 68.0) Pretreatmet ATD (84.0%) (97.9%) Legth of pretreatmet (wks) (13, 335) (13, 556) Posttreatmet ATD (33.79%) (53.19%) Legth of follow-up (wks) (419, 1466) (456, 1483) ATD:atithyroid medicatio; F: female; M: male; GD:Graves s disease; TMNG: toxic multiodular goitre; STA: solitary toxic adeoma; NMāori: o-māori; Mod.: moderate eye disease; Sev.: severe eye disease. Cotiuous variables are expressed as mea (95% cofidece itervals) or media (5th, 95th percetile) accordigto their distributio. Categorical variables are expressed as umber (percetage). ad 57 weeks, resp., p = ). Treatmet with ATD therapy followig RAI was associated with a higher failure rate (53.2% ad 33.8%, p = 0.018). There was o effect of geder (p = 0.109), aetiology (GD versus TMNG) (p = 0.185), weight at treatmet (p = ), presece of ophthalmology (p = 0.461), or follow-up legth (p = 0.179)ooutcome Idepedet Variables. Usig stepwise regressio aalysis, variables with p value < 0.05 were idetified for the model. Thus age, ethicity, ad treatmet with ATD followig RAI were all idetified for iclusio i the model. ATD therapy priortoraiwasuabletobeicludedithemodelasitcorrectly predicted persistet thyrotoxicosis i all but two idividuals. Diagosis, weight, geder, FT 4 level at presetatio, ad legth of ATD therapy followig RAI were ot sigificat ad were ot icluded i the model. The logistic regressio aalysis is preseted i Table 5. Thisaalysisshowedthatevewhecotrolligforother ifluecig factors, there cotiued to be a icreased risk for Māori (OR 2.82) ad for those treated with ATD followig RAI (OR 2.04). There was also a associatio of icreased risk offailigraitherapywithyougerage(or0.97foreachyear of age). 4. Discussio Radioiodie has bee used for the treatmet of hyperthyroidismforover70yearswiththeaimofcurigthyrotoxicosis [4, 5]. The efficacy of RAI i curig thyrotoxicosis varies from Table 5: Logistic regressio aalysis of factors ifluecig radioactive iodie outcome. OR 95% CI p Age (per yr) , Māori ethicity , Posttreatmet ATD , ATD: atithyroid medicatio; OR: odds ratio; CI: cofidece iterval. Logistic regressio model of variables show to have p < 0.05 i stepwise aalysis. Variable of pretreatmet was omitted i aalysis due to estimability (ear-perfect predictio of failig therapy). 50 to 90% [26]; i this study 78.5% of patiets were cured by a sigle dose. Māori patiets experieced a icreased treatmet failure followig a sigle dose of RAI ad this disparity i outcome cotiued after cotrollig for other variables reported to affect outcome. Youg age ad severity at presetatio have bee reported previously as factors that ca egatively ifluece outcomes followig RAI ad were also idetified i this study [7 9, 11, 12, 22 24]. However, after stepwise regressio aalysis was performed, severity at presetatio was o loger foud to be associated with outcome. Pretreatmet with ATD, legth of ATD use, ad ATD followig RAI were also associated with therapy failure. Prior use of ATDhasbeeshowtoicreasefailureratesisomeobservatioal studies [7, 8, 17, 22]; however this was ot foud i radomised cotrolled trials ivestigatig the effect of ATD prior to RAI [27, 28]. Previous fidigs of male geder ad

5 Iteratioal Joural of Edocriology 5 ophthalmopathy ifluecig failure of treatmet [9, 12, 24] were ot associated with altered outcome i the curret study. I order to better uderstad the factors that ifluece this outcome differece for Māori other kow variables available were cotrolled for. I uivariate aalysis, Māori showed a higher risk of treatmet failure compared to o- Māori (OR 3.13, p = 0.001) ad whe other available cofoudig factors were cotrolled for, the icreased risk reduced but persisted for Māori (OR 2.61, p = 0.010). It is uclear why RAI was less successful i the treatmet of Māori. I this study, some of the effect ca be explaied by youg age ad use of ATD followig RAI. However, the elevated odds ratio followig cotrol of these factors idicates other, as yet, uexplaied factors at play. Ethic variatios i treatmet respose to other forms of therapy for hyperthyroidism have bee reported. Africa America patiets with GD were show to be less likely to have resolutio of thyrotoxicosis with ATD whe compared to o-hispaic Whites (72.7% versus 97.0%) [29]. However, this is the first report to demostrate a ethic disparity i the outcome of treatig thyrotoxicosis with RAI. Oe limitatio is that this is a retrospective study, so other factors potetially ifluecig RAI outcome such as percet 131 I uptake ad thyroid volume were ot available. Data o other variables, such as socioecoomic factors, barriers to care, ad dietary iodie exposure, were also uavailable ad these may playaroleidifferecesioutcome.traditioally,māori had a diet high i seafood which may have resulted i a higher iodie itake whe compared to o-māori; however icreased urbaizatio ad decreased socioecoomic status have altered access to such traditioal diets. Curretly we do ot have data o differeces i dietary iodie exposure betwee these two groups. Whether the observed differeces i outcome to RAI are cliical, social (icludig dietary), or a combiatio of both, these results emphasise the eed for further research to idetify why RAI outcome is poorer for Māori tha o-māori. Stadard practice i maagig patiets with thyrotoxicosis who fail iitial RAI therapy is to give additioal doses. This leads to a higher cumulative dose of RAI for these patiets. The higher doses of RAI used i maagemet of thyroid cacerarerecogisedtobeassociatedwithaicreasedrisk of a secod maligacy [30]. Data o the risk at the lower doses used for treatig thyrotoxicosis have bee coflictig. A Fiish study of 2793 patiets suggested that the lower doses of RAI used for thyrotoxicosis may be associated with a icreased risk of treatmet-associated maligacy, particularly breast, stomach, ad kidey cacer, ad that the risk of maligacy is associated with a icreased cumulative dose of RAI [31]. However, a more recet study by the same group suggested that cacer risk i thyrotoxicosis is ot affected by treatmet modality; rather ay icreased cacer risk may be related to thyrotoxicosis per se or other risk factors [32]. If the earlier Fiish fidigs were correct, the higher cumulative RAI doses for Māori may be of cliical sigificace. A potetial icrease i breast ad stomach cacer is of particular cocer give that these two maligacies are amog the five most commoly occurrig cacers for Māori as well as beig two of the most commo causes of cacer death for Māori [33]. 5. Coclusios RAI is the most commo defiitive treatmet for thyrotoxicosis i New Zealad. While RAI is successful therapy for the majority of patiets, approximately oe i five patiets still fail to respod to oe treatmet. May studies have ivestigated factors that ifluece the efficacy of RAI; however this study demostrates that for Māori, a specific idigeous ethic group, treatmet with RAI is ot as effective as whe admiistered to the rest of the populatio. More work is eeded to better uderstad the factors ifluecig this iequity to improve health outcomes for all. Competig Iterests The authors declare that they have o competig iterests. Ackowledgmets Jade A. U. Tamatea ackowledges fiacial support from the Royal Australasia College of Physicias ad the Health Research Coucil of New Zealad (14/074). The authors ackowledge Dr. Hele Coagle for her guidace with the iitial statistical aalysis. Refereces [1]F.Bradt,A.Gree,L.Hegedüs, ad T. H. Brix, A critical review ad meta-aalysis of the associatio betwee overt hyperthyroidism ad mortality, Europea Joural of Edocriology,vol.165,o.4,pp ,2011. [2] A. Carlé, I. B. Pederse, N. 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