For Peer Review Journal: Clinical Endocrinology

A low incidence of io dine -induced hyperthyroidism following administration of iodinated contrast in an iodine deficient region

Manuscript ID: Draft

Manuscript Type: 3 Original Article - Australia, Japan, SE Asia

Date Submitted by the Author: n/a

Complete List of Authors: Jarvis, Carol; Waikato Hospital, Endocrinology Simcox, Kim; Waikato Hospital, Department of Radiology Tamatea, Jade; Waikato Hospital, Department of Endocrinology; University of Auckland, Waikato Clinical School McAnulty, Kim; Waikato Hospital, Department of Radiology Meyer-Rochow, Goswin; Waikato Hospital, Department of Surgery; University of Auckland, Waikato Clinical School Conaglen, John; Waikato Hospital, Endocrinology; University of Auckland, Waikato Clinical School Elston, Marianne; Waikato Clinical School, University of Auckland; Waikato Hospital, Department of Endocrinology

Goiter, nodular < Conditions: < Thyroid, Hyperthyroidism < Conditions: < Key Words: Thyroid, Iodine deficiency < Conditions: < Thyroid, Thyroid function tests < Investigations & Rx: < Thyroid

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1 2 3 A low incidence of iodine-induced hyperthyroidism following administration of 4 5 iodinated contrast in an iodine deficient region 6 7 8 9 10 Short title: Low incidence of hyperthyroidism following iodinated contrast. 11 12 13 14 Carol Jarvis 1, Kim Simcox 2, Jade AU Tamatea 1, Kim McAnulty 2, Goswin Y Meyer- 15 16 Rochow 3,4 , John V Conaglen 1, Marianne S Elston 1,4 17 18 Departments For of Endocrinology Peer1, Radiology Review2 and Surgery 3, Waikato Hospital, 19 20 4 21 Hamilton, New Zealand; Waikato Clinical School, Faculty of Medical and Health 22 23 Science, University of Auckland, Hamilton, New Zealand 24 25 26 27 Correspondence: 28 29 Dr Marianne S Elston 30 31 Department of Endocrinology, Waikato Hospital, Private Bag 3200, Hamilton 32 33 34 3240, New Zealand 35 36 Email: [email protected] 37 38 Phone: +64 7 839 8899 39 40 41 42 Keywords: contrast media; thyrotoxicosis; iodine; computed tomography; 43 44 hypothyroidism 45 46 47 Acknowledgements: Waikato Medical Research Foundation project grant 48 49 (WMRF grant number 208) awarded to Dr Kim Simcox; Auckland University 50 51 PBRF grant awarded to Dr Goswin Meyer-Rochow. 52 53 Conflicts of interest: None to declare 54 55 56 57 58 Word count: Abstract 249 Main manuscript: 3072 59 60 1 Clinical Endocrinology Page 2 of 21

1 2 3 Abstract 4 5 Objective: There is limited data on the incidence of iodinated contrast induced 6 7 8 thyrotoxicosis, particularly in iodine deficient regions. The aim of this study was 9 10 to determine the incidence of iodinated contrast-induced thyrotoxicosis and to 11 12 determine whether thyrotoxicosis was more common in patients ≥70 years 13 14 compared to those <70 years of age. 15 16 17 Design: A prospective study of adult patients undergoing an outpatient CT with 18 For Peer Review 19 iodinated contrast was performed. 20 21 Measurements: Thyroid function tests (TFTs) and urine iodine measurements 22 23 were performed prior to the scan. TFTs were repeated at 4- and 8-weeks post 24 25 26 scan. Changes in TFTs from baseline were analysed. 27 28 Results: A total of 102 patients were included in the final analysis. Overall, TSH 29

30 levels dropped (p=0.01), and free T3 (FT 3) levels increased (p=0.04) between 31 32 33 baseline and week 4 with normalisation by week 8, however these changes were 34 35 not considered clinically significant. No significant differences in free T4 (FT 4) 36 37 occurred in the overall group (p=0.82). There were no differences in TFTs 38 39 between baseline and 4- or 8- weeks for those patients aged <70 compared to 40 41 42 >70 years. Two patients developed new subnormal TSH values. Of these, one had 43 44 a 90mm follicular variant papillary thyroid carcinoma diagnosed while the other 45 46 had a normal thyroid assessment and TSH spontaneously normalised by 12 47 48 weeks. 49 50 51 Conclusions: Only 2% of patients developed subclinical hyperthyroidism 52 53 following a standard dose of iodinated contrast for CT investigations. Given the 54 55 low incidence of iodine-induced thyrotoxicosis, there is no indication for routine 56 57 pre- and post-CT thyroid function testing in our region. 58 59 60 2 Page 3 of 21 Clinical Endocrinology

1 2 3 4 5 Introduction 6 7 8 9 10 Due to increasing use of contrast-enhanced computed tomography (CT) and 11 12 angiography, patients are frequently exposed to large amounts of iodinated 13 14 contrast. The current recommended daily intake of iodine for non-pregnant, non- 15 16 1 17 lactating adults is 150 mcg per day. This compares to the amount found in 18 For Peer Review 19 iodinated contrast media (ICM), which ranges from 270-350 mg iodine/mL. The 20 21 typical exposure from a CT scan is 35,000 mg iodine, which results in an acute 22 23 iodine load more than 200,000-fold higher than the recommended daily intake.2 24 25 26 While the normal thyroid gland can usually adapt to an excess iodine load, 27 28 individuals with an underlying thyroid abnormality, such as a multinodular 29 30 goitre, may develop hypo- or hyper-thyroidism. 31 32 33 34 35 Excess iodine inhibits thyroid hormone release (Wolff-Chaikoff effect), which is 36 37 usually transient and ‘escape’ occurs.3 Failure of escape results in iodine-induced 38 39 hypothyroidism which may be temporary or permanent. Patients thought to be 40 41 42 most at risk of iodine-induced hypothyroidism are those with underlying thyroid 43 44 disease such as autoimmune disease or type 2 amiodarone induced 45 46 thyrotoxicosis (reviewed in 4). 47 48 49 50 51 Iodine-induced thyrotoxicosis (IIT) (Jod-Basedow phenomenon) can also be 52 53 transient or permanent and is thought to be more common in those with 54 55 underlying thyroid autonomy, such as patients with a multinodular goitre. 4 The 56 57 elderly have also been proposed to be at increased risk of IIT.5 Not only is this 58 59 60 3 Clinical Endocrinology Page 4 of 21

1 2 3 population less tolerant to the effects of thyrotoxicosis, but IIT in the elderly is 4 5 more likely to be undiagnosed due to the non-specific nature of the symptoms. 6 7 8 Martin et al. reported 60 elderly patients with thyrotoxicosis in whom 23% had 9 10 received iodinated contrast in the preceding 6 months.5 Of particular relevance, 11 12 however, is that the diagnosis of thyrotoxicosis was not suspected in 62% of 13 14 those affected and five patients died with uncontrolled hyperthyroidism.5 15 16 17 18 For Peer Review 19 While many case reports or small case series have been published reporting 20 21 thyroid dysfunction following iodinated contrast, only a small number of 22 23 prospective studies have been performed. Conn et al. studied 73 patients from 24 25 26 an iodine sufficient area and identified two patients who became hyperthyroid 27 28 and an additional four others who developed either an elevated FT 4 or 29 30 suppressed TSH.6 Seven of 101 patients developed subclinical hyperthyroidism 31 32 7 33 after coronary angiography in a Turkish study, a region previously shown to be 34 35 iodine deficient. 8 A nested case-control study identified iodinated contrast as 36 37 being associated with the subsequent development of hyper- and 38 39 hypothyroidism in an iodine-sufficient area with the number needed to harm of 40 41 9 42 only 23. In contrast, Hintze et al identified only 2 new cases of iodine-induced 43 44 hyperthyroidism from 788 unselected patients undergoing coronary 45 46 angiography in an iodine-deficient area.10 No underlying thyroid disease was 47 48 identified in either of these patients. 49 50 51 52 53 New Zealand is an iodine-deficient area and also demonstrates borderline 54 55 selenium deficiency.11, 12 These two micronutrients are important in normal 56 57 thyroid physiology. Currently there is no New Zealand data available on the 58 59 60 4 Page 5 of 21 Clinical Endocrinology

1 2 3 incidence of iodine induced thyroid dysfunction and international data may not 4 5 be directly comparable due to both genetic variation and differences in 6 7 8 availability of these two micronutrients. 9 10 11 12 The aims of this study were to: 13 14 1. Assess the incidence of iodine-induced thyrotoxicosis following the 15 16 17 intravenous administration of iodinated contrast media used routinely in 18 For Peer Review 19 CT investigations 20 21 2. To determine whether IIT occurs more frequently in older patients (>70 22 23 years) as compared to younger patients (<70 years). 24 25 26 27 28 Methods 29 30 31 32 33 Adult patients undergoing an elective, outpatient intravenous (IV) contrast- 34 35 enhanced CT scan at Waikato Hospital, Hamilton, New Zealand, between 36 37 08/02/2013 – 08/07/2014 were invited to participate in the study. Exclusion 38 39 criteria included: pregnancy, age less than 16 years, inability to give informed 40 41 42 consent, use of thyroid replacement, anti-thyroid therapy or iodine-containing 43 44 medications in the past 6 months, use of kelp tablets or other over-the-counter 45 46 preparations containing iodine, or recent (within the past 6 months) iodinated 47 48 contrast investigations (including angiography). Ethical approval for the study 49 50 51 was granted by the Northern Y Regional Ethics Committee (NTY/12/02/019). 52 53 Written, informed consent was obtained from all patients. 54 55 56 57 58 59 60 5 Clinical Endocrinology Page 6 of 21

1 2 3 Following consent, baseline thyroid function tests (FT 4, FT 3, and TSH), thyroid 4 5 autoantibodies (anti-thyroid peroxidase [anti-TPO] and anti-thyroglobulin [anti- 6 7 8 TG]), and a fasting urine sample for urine iodine and creatinine values were 9 10 collected prior to contrast administration. Due to financial constraints only a 11 12 sample of 49 urine specimens underwent laboratory analysis. Follow up thyroid 13 14 function tests were requested at four and eight weeks after the scan for each 15 16 17 individual. The patient and/or their time point sample were excluded if further 18 For Peer Review 19 contrast was administered prior to the week eight blood test. FT 4, FT 3, and TSH 20 21 were measured using a Roche Modular Analytics E170 immunoassay (Roche 22 23 Diagnostics, Mannheim, Germany). 24 25 26 27 28 Omnipaque TM (iohexol) 300, Omnipaque TM 350 or Visipaque TM (iodixanol) 320 29 30 IV iodinated contrast media (ICM) was given depending on renal function and as 31 32 33 per the radiology department protocol. CT images were then obtained on either 34 35 the Siemens 256-slice dual-energy FLASH or Siemens 128-slice Edge scanner. In 36 37 those patients who had imaging of the thyroid available, the scans were 38 39 reviewed to assess thyroid size and the presence or absence of thyroid nodules. 40 41 42 Thyroid volume was assessed using the thyroid/trachea index, where the 43 44 maximum transverse diameter of each thyroid lobe were combined and 45 46 compared with the maximum trachea diameter at that level.13 47 48 49 50 51 Hypothyroidism was diagnosed if the TSH level was elevated above the upper 52 53 limit of the reference range. Hyperthyroidism was diagnosed if the TSH was 54 55 below the lower limit of the reference range. Hyperthyroidism was further 56 57 subdivided into subclinical if the free thyroid hormone levels were normal or 58 59 60 6 Page 7 of 21 Clinical Endocrinology

1 2 3 overt if they were elevated. Any patients who developed abnormal thyroid 4 5 function tests were referred to the endocrinology service for a detailed 6 7 8 assessment including bedside thyroid ultrasound and further management. 9 10 11 12 Statistical analysis was performed using STATA 13 (StataCorp. 2013. Stata 13 14 Statistical Software: Release 13. College Station, TX: StataCorp LP.) A p value of 15 16 17 <0.05 was considered significant. Differences in TSH, FT 3 and FT 4 in all 18 For Peer Review 19 participants over follow up were calculated using within-subjects repeated- 20 21 measures ANOVA. Comparisons between groups (age, gender and renal function) 22 23 over follow up were calculated using between-subjects within subjects repeated- 24 25 26 measure ANOVA. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 7 Clinical Endocrinology Page 8 of 21

1 2 3 Results 4 5 General 6 7 8 A total of 110 patients were initially identified as eligible for the study. Four 9 10 patients were excluded due to not having had any post scan thyroid tests 11 12 performed. An additional four patients received additional iodinated contrast 13 14 within the first four weeks after the scan and were also excluded. The remaining 15 16 17 102 patients were included in the final analysis, 52 female and 50 male, with a 18 For Peer Review 19 mean age of 64.4 years (range 16 - 89 years). CT of the neck, chest, abdomen 20 21 and/or pelvis was performed in 70 patients, kidney in 19, brain in 9, aorta in 6 22 23 and adrenal in 1. In 17 patients (17%) the scan request specifically included the 24 25 26 neck. Several patients had multiple areas scanned e.g. neck and chest. 27 28 Omnipaque 300 was given to 75 (76.5%) of patients, at a mean volume of 100 29 30 mL (range 75 – 135 mL). Overall, the mean total iodine load was 29,808 mg 31 32 33 (range 16,000 – 40,500 mg). 34 35 36 37 38 39 Baseline Results 40 41 42 Baseline results for the group are shown in Table 1. Prior to iodinated contrast, 43 44 three patients had abnormal TSH values: one with subclinical hyperthyroidism, 45 46 (TSH 0.24mU/L [reference range 0.3 – 5mU/L]), and two with subclinical 47 48 hypothyroidism (TSH values 5.78 and 8.11mU/L, respectively). All three patients 49 50 51 had normal free thyroid hormone levels. Thyroid antibodies were elevated in 27 52 53 patients (28%) at baseline: 14 had elevated anti-TPO titres; 13 raised anti-TG; 54 55 and both anti-TPO and anti-TG were elevated in 8 patients. Seventeen patients 56 57 58 59 60 8 Page 9 of 21 Clinical Endocrinology

1 2 3 (17%) patients had an eGFR <60mL/min, including one patient who developed 4 5 subclinical hyperthyroidism. 6 7 8 9 10 11 12 Urine iodine was measured on 49 patients. One patient had a markedly elevated 13 14 value (9104.8 umol/L) and on further enquiry was identified to have collected 15 16 17 the sample following iodinated contrast. His result was therefore excluded from 18 For Peer Review 19 further analysis. The median urine iodine concentration was 0.9umol/L (range 20 21 0.2-2.6umol/L) with 4 participants (8%) having levels below 0.4umol/L. The 22 23 World Health Organization defines a population as having no iodine deficiency if 24 25 26 the median urine iodine level is 100-299ug/L (0.79-2.4umol/L) with <20% of 27 28 the population having a level <50ug/L (0.4umol/L).14 29 30 31 32 33 Follow up results 34 35 Following the iodinated contrast scan, 90 patients completed both 4- and 8-week 36 37 blood tests, on average at 30 days and 59 days, respectively. Seven patients 38 39 completed only one blood test, at either week 4 or week 8. An additional five 40 41 42 patients received further iodinated contrast between the 4- and 8-week blood 43 44 tests. The 8-week results for these five patients were excluded from further 45 46 analysis. 47 48 49 50 51 In the overall group, mean TSH levels dropped between baseline (TSH 52 53 1.78mU/L) and 4-weeks (TSH 1.58mU/L) with recovery back to baseline levels 54 55 by 8-weeks (TSH 1.74 mU/L), p=0.01. Mean FT 3 levels increased between 56 57 baseline (4.42pmol/L) and 4-weeks (4.55pmol/L), with a return to baseline by 58 59 60 9 Clinical Endocrinology Page 10 of 21

1 2 3 8-weeks (p=0.04). Mean FT4 levels did not alter between baseline and 4- or 8- 4 5 weeks (p=0.82). Comparison was also made between the two age groups: >70 6 7 8 years (n=51) and <70 years (n=51) at these time points with no significant 9 10 differences seen between the two age groups. These results are shown in Table 11 12 2. There was no difference in TSH, FT4 or FT3 levels in those who had an eGFR 13 14 <60mL/min and those who had an eGFR >90mL/min (p=0.18, p=0.16 and 15 16 17 p=0.93, respectively). 18 For Peer Review 19 20 21 Of the three patients with abnormal baseline TSH levels, the patient with a low 22 23 baseline TSH had a persisting subnormal TSH at 4 and 8 weeks (0.28 and 24 25 26 0.18mU/L, respectively). At review, this patient had a normal thyroid 27 28 assessment, including ultrasound, and TSH had normalised within 3 months of 29 30 receiving ICM. Both patients with subclinical hypothyroidism prior to ICM 31 32 33 administration remained subclinically hypothyroid at both week 4 and 8 weeks. 34 35 36 37 Following ICM two patients developed new onset subclinical hyperthyroidism 38 39 with their free thyroid hormone levels remaining normal. Demographic and 40 41 42 clinical details for these patients are given in Table 3. One of these patients 43 44 (Patient A) had elevated anti-TPO antibodies at baseline and was identified to 45 46 have an enlarged right thyroid lobe and underwent a diagnostic 47 48 hemithyroidectomy to alleviate compressive symptoms. Histological 49 50 51 examination demonstrated Hashimoto’s thyroiditis and a 90mm follicular 52 53 variant papillary thyroid carcinoma. The second patient (Patient B) had negative 54 55 thyroid antibodies and a normal thyroid assessment, and thyroid function tests 56 57 58 59 60 10 Page 11 of 21 Clinical Endocrinology

1 2 3 normalised by three months post contrast ICM. No patients developed new 4 5 onset hypothyroidism. 6 7 8 9 10 One patient had a low baseline FT 3 level, which had returned to normal on 4- and 11 12 8-week follow up bloods. Two patients developed a low FT 3 at 4 weeks and 13 14 eleven patients at week 8 but none had an elevated TSH level. No patients 15 16 17 developed abnormal FT 4 levels. 18 For Peer Review 19 20 21 Thyroid imaging 22 23 Of the 102 participants, 63 (62%) had their thyroid gland included on the CT 24 25 26 scan field, although in only 38 patients (37%) was the thyroid visualized in 27 28 entirety with the remainder partially visualized (usually missing the upper few 29 30 millimetres only). Of those 38 individuals, 13 (34%) demonstrated thyroid 31 32 33 nodularity, with retrosternal thyroid extension in 4 (10.5%). Of those 25 in 34 35 whom the thyroid was only partially visualized, imaging demonstrated 36 37 nodularity in 10 patients and retrosternal thyroid extension in 6. Overall, 23/63 38 39 patients (37%) showed nodular thyroid disease and 10/63 (16%) had 40 41 42 retrosternal thyroid extension. 43 44 The mean value for the transverse diameter of the thyroid glands visualised in 45 46 entirety was 26.95mm (95% CI 24.96-28.94). Including the patients with a 47 48 partially imaged thyroid gland the mean transverse diameter was 28.43 mm 49 50 51 (95% CI 26.70-30.15). Measurements for the trachea showed a mean of 52 53 17.71mm (95% CI 17.03-18.39) in the fully visualized participants, which 54 55 decreased to 17.41 mm (95% CI 16.73-18.10) when including the partially 56 57 visualized participants. The mean thyroid/trachea index was 1.54 (95% CI 1.41- 58 59 60 11 Clinical Endocrinology Page 12 of 21

1 2 3 1.67) in the 38 fully visualized thyroid individuals; this increased to 1.68 (95% 4 5 CI 1.55-1.81) when the partially visualized thyroid glands were included. Twelve 6 7 8 patients demonstrated an index greater than 1 standard deviation above the 9 10 mean, 10 of whom also demonstrated thyroid nodularity and 6 retrosternal 11 12 thyroid extension. Only four individuals demonstrated an index greater than 2 13 14 standard deviations above the mean. Of these three demonstrated a nodular 15 16 17 thyroid and all had retrosternal extension present. The thyroid measurements 18 For Peer Review 19 are comparable to those calculated by Prince and Stark, who reported a mean 20 21 thyroid gland diameter of 28.79mm, a mean trachea diameter of 19.97mm and a 22 23 thyroid/trachea index of 1.46.13 24 25 26 27 28 Discussion 29 30 31 We have identified a low rate of iodine-induced hyperthyroidism in a cohort of 32 33 34 patients undergoing CT scans with intravenous ICM. Of those with new onset 35 36 thyroid dysfunction, the abnormalities were transient. No differences were seen 37 38 in those aged <70 years compared to the 70 and over age group. Low FT 3 results 39 40 developed in 13/102 patients at either week 4 or 8. This was not associated with 41 42 43 an elevated TSH outside of the reference range and is unlikely to be clinically 44 45 significant. This lowering of FT 3 is most likely to be due to the effect of the 46 47 iodinated contrast on the Type 2 deiodinase, decreasing FT 4 to FT 3 conversion 15 . 48 49 50 Similarly, while there was a statistically significant lowering of TSH and rise of 51 52 FT 3 for the overall group, these changes were not clinically significant. As such, 53 54 this study does not support the routine use of thyroid function testing following 55 56 iodinated contrast in an unselected group of patients, even for those aged over 57 58 59 60 12 Page 13 of 21 Clinical Endocrinology

1 2 3 70 years. It has been hypothesised that patients with significant renal 4 5 impairment may be exposed to a greater cumulative iodide exposure and 6 7 16 8 therefore a greater risk of thyroid dysfunction, however in this small study 9 10 there was no significant difference in those with an eGFR <60mL/min compared 11 12 to those with an eGFR >90mL/min. 13 14 15 16 17 No correlation was seen between thyroid volume and/or nodularity and 18 For Peer Review 19 abnormal TFTs, although only 62% of our study population had their thyroid 20 21 gland at least partially included on the scan field, with only 37% viewed in its 22 23 entirety. Similarly, no correlation was identified between age (>70 years of age) 24 25 26 and thyroid volume or nodularity in our study population. The thyroid/trachea 27 28 index however was demonstrated to be a fitting predictor of thyroid volume, 29 30 with a high correlation with thyroid nodularity and retrosternal extension. 31 32 33 34 35 There were a number of limitations of this study. One limitation was that only a 36 37 subset of participants had complete imaging of their thyroid available so we 38 39 were not able to accurately determine the prevalence of underlying structural 40 41 42 thyroid pathology in this cohort. In those 63 patients who did have their thyroid 43 44 at least partially imaged a high rate of thyroid nodularity (37%) was identified. It 45 46 is likely that this would be higher if thyroid ultrasonography were performed on 47 48 all patients. This study does however suggest that even in a population with a 49 50 51 high rate of background nodular thyroid disease, the rate of iodine-induced 52 53 thyroid dysfunction is low. A spot urine iodine sample was collected in all 54 55 patients and analysed in a subset. Apart from the patient who collected the urine 56 57 sample following the ICM, no patients had elevated urine iodine levels at 58 59 60 13 Clinical Endocrinology Page 14 of 21

1 2 3 baseline. A urine iodine level is the method recommended by the World Health 4 5 Organization for assessment of the iodine status of a population.14 Whilst New 6 7 8 Zealand has traditionally been considered to be an iodine-deficient region, the 9 10 urine iodine results in this subgroup were consistent with iodine sufficiency, 11 12 however to get a true reflection of whether the population is truly iodine 13 14 sufficient a larger group (>500 participants) is required. Recent assessment of 15 16 17 New Zealand school children did suggest that New Zealand still has mild iodine 18 For Peer Review 19 deficiency.17 A control group of patients who had not received iodinated contrast 20 21 was not included in this study but previous work from our region has identified a 22 23 low incidence of thyrotoxicosis at 0.2%.18 24 25 26 27 28 Whilst these unselected patients, including those with nodular thyroid disease, 29 30 had a low rate of thyroid dysfunction following ICM, these findings may not 31 32 33 apply to those with evidence of pre-existing thyroid autonomy i.e. TSH 34 35 suppression or partial suppression. This particular group would be important to 36 37 study as they may be at increased risk of IIT. One unforeseen difficulty in this 38 39 study was patient recruitment. Due to one of our exclusion criteria being 40 41 42 previous iodinated contrast in the preceding six months, most patients 43 44 undergoing contrast-enhanced CT in our centre were not eligible for recruitment 45 46 and this would need to be considered in the design of future studies. 47 48 49 50 51 Conclusion 52 53 In this relatively small prospective study from an iodine deficient region, 2% of 54 55 patients developed new onset subclinical hyperthyroidism following a standard 56 57 dose of iodinated contrast for CT investigations. Given the low incidence of 58 59 60 14 Page 15 of 21 Clinical Endocrinology

1 2 3 iodine-induced thyrotoxicosis, there is no indication for routine pre- and post-CT 4 5 thyroid function testing in our region. 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 15 Clinical Endocrinology Page 16 of 21

1 2 3 References 4 5 1. Andersson M, de Benoist B, Delange F et al. (2007) Prevention and control 6 of iodine deficiency in pregnant and lactating women and in children less 7 8 than 2-years-old: conclusions and recommendations of the Technical 9 Consultation. Public Health Nutrition, 10 , 1606-1611. 10 2. Dunne P, Kaimal N, MacDonald J et al. (2013) Iodinated contrast-induced 11 thyrotoxicosis. Canadian Medical Association Journal , 185 , 144-147. 12 3. Wolff J & Chaikoff IL. (1948) Plasma inorganic iodide as a homeostatic 13 regulator of thyroid function. Journal of Biological Chemistry, 174 , 555- 14 564. 15 16 4. Leung AM & Braverman LE. (2014) Consequences of excess iodine. Nature 17 Reviews Endocrinology, 10 , 136-142. 18 5. Martin For FI & Deam Peer DR. (1996) HyperthyroidismReview in elderly hospitalised 19 patients. Clinical features and treatment outcomes. Medical Journal of 20 Australia, 164 , 200-203. 21 6. Conn JJ, Sebastian MJ, Deam D, et al. (1996) A prospective study of the 22 effect of nonionic contrast media on thyroid function. Thyroid, 6, 107- 23 110. 24 25 7. Ozkan S, Oysu AS, Kayatas K, et al. (2013) Thyroid functions after contrast 26 agent administration for coronary angiography: a prospective 27 observational study in euthyroid patients. Anatolian Journal of Cardiology, 28 13 , 363-369. 29 8. Yordam N, Ozon A, Alikasifoglu A, et al. (1999) Iodine deficiency in 30 Turkey. European Journal of Pediatrics, 158 , 501-505. 31 9. Rhee CM, Bhan I, Alexander EK et al. (2012) Association between 32 33 iodinated contrast media exposure and incident hyperthyroidism and 34 hypothyroidism. Archives of Internal Medicine, 172 , 153-159. 35 10. Hintze G, Blombach O, Fink H, et al. (1999) Risk of iodine-induced 36 thyrotoxicosis after coronary angiography: an investigation in 788 37 unselected subjects. European Journal of Endocrinology, 140 , 264-267. 38 11. Thomson CD, Woodruffe S, Colls AJ, et al. (2001). Urinary iodine and 39 thyroid status of New Zealand residents. European Journal of Clinical 40 Nutrition, 55, 387-392. 41 42 12. Thomson CD, Campbell JM, Miller J, et al. (2009) Selenium and iodine 43 supplementation: effect on thyroid function of older New Zealanders. 44 American Journal of Clinical Nutrition, 90, 1038-1046. 45 13. Prince JS & Stark P. (2002) Normal cross-sectional dimensions of the 46 thyroid gland on routine chest CT scans. Journal of Computer Assisted 47 Tomography, 26, 346-348. 48 14. World Health Organization. (2007) Assessment of iodine deficiency 49 50 disorders and monitoring their elimination: a guide for programme 51 managers. 3rd edition. 52 15. Bianco AC & Kim BW. (2006) Deiodinases: implications of the local 53 control of thyroid hormone action. Journal of Clinical Investigation, 116, 54 2571-2579. 55 16. Lee SY, Rhee CM, Leung AM, et al. (2014) A Review: Radiographic 56 Iodinated Contrast Media-Induced Thyroid Dysfunction. Journal of Clinical 57 Endocrinology and Metabolism, 100 , 376-383. 58 59 60 16 Page 17 of 21 Clinical Endocrinology

1 2 3 17. Skeaff SA, Thomson CD, Wilson N et al. (2012) A comprehensive 4 assessment of urinary iodine concentration and thyroid hormones in New 5 Zealand schoolchildren: a cross-sectional study. Nutrition Journal, 11, 31. 6 18. Gibbons V, Conaglen JV, Lillis S, et al. (2008) Epidemiology of thyroid 7 8 disease in Hamilton (New Zealand) general practice. Australian and New 9 Zealand Journal of Public Health, 32, 421-423. 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 17 Clinical Endocrinology Page 18 of 21

1 2 3 Table 1. Baseline Laboratory Results 4 5 6 Mean 95% CI Reference range N 7 TSH 1.78 mU/L 1.55, 2.0 0.3 – 5.0 mU/L 102 8 9 Free T4 11.4 pM 11.0, 11.8 12 – 22 pM 102 10 Free T3 4.42 pM 4.32, 4.52 3.6 – 6.5 pM 102 11 eGFR 76mL/min 72, 79 >90mL/min 101 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 19 of 21 Clinical Endocrinology

1 2 3 4 5 6 7 Table 2. Subgroup comparisons 8 9 Baseline 4 weeks 8 weeks P-value 10 11 n Mean 95% CI n Mean change 95%CI n Mean change 95%CI 12 All 102 1.78 1.55, 2.00 99 -0.18 -0.28, -0.07 93 -0.04 -0.18, 0.10 p=0.0133 13 For Peer Review 14 15 <70yrs 51 1.33 1.30,1.82 50 -0.19 -0.35, -0.04 46 0.05 -0.18, 0.28 p=0.1021 16 TSH >70yrs 51 2.01 1.65, 2.36 49 -0.15 -0.29, -0.02 47 -0.13 -0.29, 0.03 17 18 Female 52 1.89 1.52, 2.26 51 -0.18 -0.33, -0.03 46 0.02 -0.22, 0.26 p=0.7520 19 20 Male 50 1.67 1.22, 1.67 48 -0.17 -0.31, -0.03 47 -0.10 -0.24, 0.04 21 All 102 11.4 11.0, 11.8 99 0.14 -0.21, 0.49 93 -0.12 -0.49, 0.25 p=0.8240 22 23 <70yrs 51 11.3 10.8, 11.9 50 0.01 -0.48, 0.57 46 -0.29 -0.92, 0.35 p=0.8150 24 FT4 25 >70yrs 51 11.5 10.9, 12.1 49 0.29 -0.10, 0.69 47 0.05 -0.35, 0.44 26 Female 52 11.2 10.6, 11.7 51 0.32 -0.14, 0.78 46 0.03 -0.46, 0.52 27 p=0.9721 28 Male 50 11.7 11.1, 12.3 48 -0.05 -0.58, 0.47 47 -0.26 -0.83, 0.30 29 30 All 102 4.42 4.32, 4.52 100 0.23 0.07, 0.40 93 0.002 -0.20, 0.20 p=0.0418 31 <70yrs 51 4.55 4.39, 4.70 51 0.30 0.07, 0.53 46 0.10 -0.22, 0.41 32 p=0.7622 33 FT3 >70yrs 51 4.29 4.17, 4.41 49 0.16 -0.08, 0.39 47 -0.09 -0.35, 0.17 34 35 Female 52 4.37 4.24, 4.50 52 0.31 0.09, 0.54 46 -0.04 -0.30, 0.22 p=0.1997 36 Male 50 4.46 4.31, 4.62 48 0.14 -0.10, 0.39 47 0.04 -0.27, 0.35 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Clinical Endocrinology Page 20 of 21

1 2 3 4 5 6 7 Table 3. Clinical details of patients with new onset thyroid dysfunction 8 9 Case Age preTSH AntiTg AntiTPO wk4TSH wk8TSH Scan Contrast Volume Iodine eGFR 10 yrs mU/L IU/mL IU/mL mU/L mU/L mL load 11 mg 12 A 45 1.63 5.5 352.3 0.03 0.83 Abdo/Pelvis Omn 300 95 28,500 >90 13 B 89 0.45 3.9 For 0.7 Peer 0.2 0.19 Review Kidney & Urogram Visi 320 100 32,000 53 14 15 Omn = Omnipaque; Visi = Visipaque 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 1 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 21 of 21 Clinical Endocrinology

1 2 3 4 5 6 7 8 9 10 11 12 13 For Peer Review 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 2 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60