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For Peer Review Journal: Clinical Endocrinology Clinical Endocrinology A low incidence of io dine -induced hyperthyroidism following administration of iodinated contrast in an iodine deficient region For Peer Review Journal: Clinical Endocrinology 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 Page 1 of 21 Clinical Endocrinology 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 Forof 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.
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