RELATIONSHIP BETWEEN THE EFFECTIVENESS OF INORGANIC IODINE AND THE SEVERITY OF GRAVES THYROTOXICOSIS: A RETROSPECTIVE STUDY

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP RELATIONSHIP BETWEEN THE EFFECTIVENESS OF INORGANIC IODINE AND THE SEVERITY OF GRAVES THYROTOXICOSIS: A RETROSPECTIVE STUDY Akira Honda MD, Toyoyoshi Uchida MD, Koji Komiya MD, Hiromasa Goto MD, Kageumi Takeno MD, Junko Sato MD, Ruriko Suzuki MD, Miwa Himuro MD, Hirotaka Watada MD From: Department of Metabolism & Endocrinology, Juntendo University Graduate School, Tokyo, Japan Running title: Iodine and thyrotoxicosis severity Corresponding address: Toyoyoshi Uchida, MD, PhD Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo , Japan uchitoyo@juntendo.ac.jp

2 Word count: Abstract: 248, Text: 2,833 Number of figures: 2 Number of tables: 1 Number of supplemental figures: 2 Abstract Objective: Inorganic iodine is often used to treat patients with Graves thyrotoxicosis who do not tolerate thionamides due to adverse effects. However, predictors of continued inorganic iodine efficacy have not been fully elucidated yet. This study aimed to investigate the factors affecting the continued efficacy of potassium iodide (KI) in patients with Graves thyrotoxicosis. Methods: In this study, among 1197 patients with Graves disease who were initially treated with thionamides, we retrospectively studied 24 consecutive Japanese patients whose treatment were changed to KI alone due to the adverse effects of thionamides. We divided these patients into two groups: patients who had maintained euthyroid function for at least 180 days (non-recurrence group, n=11), and patients who had not maintained euthyroid function for 180 days (recurrence group, n=13). Results: Free triiodothyronine (FT3) and free thyroxine (FT4) levels on the day of changing from thionamides to KI were statistically higher in the recurrence group than

3 in the non-recurrence group [FT3, 9.3 (range, ) vs. 3.7 ( ) pg/ml, p = 0.02 and FT4, 3.6 ( ) vs. 1.4 ( ) ng/dl, p = 0.02]. FT4 levels on the day of drug change were significantly higher in the recurrence group, even after adjusting for thionamide or KI dose. In the recurrence group, the duration of KI effect was inversed correlated with FT3 and FT4 levels on the day of drug change. Conclusions: Continued efficacy of KI after thionamides might be inversely correlated with thyrotoxicosis severity on the day of drug change. Keywords: Graves disease, inorganic iodine, recurrence, thionamides Abbreviations etv = estimated thyroid volume; FT3 = free triiodothyronine; FT4 = free thyroxine; IQR = interquartile range; KI = potassium iodide; MMI = thiamazole; PTU = propylthiouracil; RAIT = radioactive iodine therapy; TRAb = thyrotropin receptor antibody; TSH = thyrotropin.

4 Introduction Inorganic iodine has been used to treat patients with Graves disease for 100 years. It induces remission in 30% of patients, mostly those with mild Graves thyrotoxicosis (1,2). After thionamides such as thiamazole (MMI) and propylthiouracil (PTU) became available, inorganic iodine became an alternative treatment, as a transient treatment option for Graves thyrotoxicosis planning for thyroid surgery or with thyroid crisis (3,4). Thus, in the clinical setting, it has been difficult to elucidate the long-term therapeutic effects of inorganic iodine on Graves thyrotoxicosis in a prospective study. Instead, a retrospective cohort study was conducted to investigate the long-term therapeutic effects of inorganic iodine on Graves thyrotoxicosis (5). This study showed that two-thirds of patients with Graves disease treated with potassium iodide (KI) alone instead of thionamides due to their adverse effects had improved thyrotoxicosis. Except for this study, there have been almost no studies reporting the long-term therapeutic effects of inorganic iodine on Graves thyrotoxicosis. Thus, in the current study, we retrospectively recruited patients with Graves thyrotoxicosis treated with KI instead of thionamides due to their adverse effects and investigated the factors associated the efficacy of KI.

5 Patients and methods Patients Between November 1, 2008, and July 30, 2015, 1197 patients with Graves disease were treated with thionamides at the Diabetes and Endocrine Clinics of Juntendo University Hospital. Among them, we screened patients whose treatment was changed to KI alone due to adverse effects with thionamides and found 24 patients. In the Diabetes and Endocrine Clinics of Juntendo University Hospital, endocrinologists chose an initial KI dose of 50 or 100 mg/day, with subsequent adjustment to the range of mg/day based on blood test results. In this study, recurrence was defined as worsening of thyroid function compared to that on the day of drug changing from thionamides to KI. In this study, we divided patients into two groups according to presence of the recurrence within 180 days. The study protocol was approved by the ethics committee of Juntendo University. Measurement of serological markers Blood samples were collected from all patients at clinic visits. FT4, FT3, and TSH values were measured using a commercial electrochemiluminescence immunoassay (Roche Diagnostics, Tokyo; FT4 normal range, ng/dl; FT3 normal range,

6 pg/ml; TSH normal range, μiu/ml). Serum TSH receptor antibody (TRAb) levels were measured using the ECLusys TRAb two-step radioreceptor assay (Roche Diagnostics, Tokyo; normal range, <2.0 IU/L; detectable level, 0.3 IU/L). Ultrasonography The estimated thyroid volume (etv) was computed using the ellipsoid model [(width length thickness π/6) for each lobe + (width length thickness) for the isthmus] as described in detail previously (6). Data used in this study were obtained in all patients before drugs were changed. Statistical analysis Results are presented as means±standard deviation (SD) for normally distributed parameters and medians with interquartile range (IQR) for parameters with skewed distributions. Differences in physical signs, various thyroid parameters, dosage of thionamides and KI, and duration of KI effect between patients with and without recurrence were examined for statistical significance using Student s t-test or the Mann-Whitney U test, as appropriate. Categorical data are reported as frequencies and compared using the chi-square test or Fisher s exact test. As the potency of MMI is at

7 least 10 times higher than that of PTU (7), we considered a daily dosage of 150 mg of PTU as equal to 15 mg of MMI in this study only for statistical analysis. Patients in each group were initially treated with 50 or 100 mg of KI and the values of each variable with a statistically significantly difference were compared using both an appropriate comparison test and two-way analysis of variance (ANOVA) to consider potential differences in the latest dose of thionamides or initial dose of KI. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Sciences (Inc., Chicago, IL). Results Among the 1197 patients with Graves disease treated with thionamides, 24 patients (2.17%) had adverse effects (agranulocytosis, 0.08%; granulocytopenia or rapid decrease in white blood cell count, 0.84%; severe drug-induced eruptions, 0.42%; liver dysfunction, 0.58%; other, 0.25%). We retrospectively studied the 24 patients whose treatment was changed to KI monotherapy (Figure 1). The baseline characteristics of the patients are shown in Table 1. Gender, age, thionamide, duration of thionamide therapy, reasons for thionamide discontinuation, and initial KI dose are well balanced between the recurrence and non-recurrence groups. In addition, thyroid volume assessed by ultrasonography before the change in therapy and TRAb on the

8 day of the drug change were also comparable. However, thyroid function on the day of the drug change was higher in the recurrence group than in the non-recurrence group (FT3, 9.3 (IQR, ) vs. 3.7 ( ) pg/ml, p=0.020, and FT4, 3.6 ( ) vs. 1.4 ( ) ng/dl, p=0.020, respectively), although the FT3/FT4 ratio was comparable between the groups. Furthermore, after adjusting for thionamide dose or KI dose, we compared FT3 and FT4 levels on the day of the drug change between the groups using two-way ANOVA (dependent variable: FT3 or FT4 values, permanent variable: group, thionamide dose or KI dose). We found that FT4 was significantly higher in the recurrence group than in the non-recurrence group (FT4, adjusted for thionamide dose p=0.027; adjusted for KI dose p=0.042; FT3 adjusted for thionamide dose p=0.126, adjusted for KI dose p=0.129, respectively). We investigated thyroid function one clinic-visit before the day of drug change. Similar to the data from the day of the drug change, the recurrence group had also higher FT3 and FT4 than the non-recurrence group (supplemental Figure 1). The change in FT3 and FT4 levels between once before the day of the drug change and the day of the drug change that may reflect the therapeutic effects of thionamides were not statistically different between the recurrence and non-recurrence groups. Regarding the changes in TRAb levels during the KI treatment, 7 of 13 patients in the recurrence group showed an elevation of TRAb levels when compared with the

9 previous value recorded on the day of the drug change. Conversely, compared with that observed in the recurrence group, a lesser elevation was observed in only 2 of the 11 patients in the non-recurrence group (supplemental Figure 2). Finally, in the recurrence group, we investigated the correlation between FT3 or FT4 level on the day of the drug change and the duration between the day of the drug change and recurrence. Intriguingly, we found a moderate inverse relationship between these factors (Figure 2). These data suggest that the severity of thyrotoxicosis is an important predictor of the efficacy of KI among study patients. Discussion The present study evaluated patients initially treated with thionamides that were later changed to KI alone due to adverse effects. The results showed that FT3 and FT4 levels on the day of the drug change were statistically higher in the recurrence group than in the non-recurrence group. Furthermore, continued efficacy of KI is inversely correlated with FT3 and FT4 levels on the day of the drug change in the recurrence group. Regarding the baseline clinical characteristics of the 24 patients, they were mostly

10 female, relatively young, had mild goiter, and had improved thyroid function on thionamides. In addition, the frequency of thionamide-related adverse effects was similar to that reported in a recent review (8). Therefore, the patients in the present study reflect the typical patient population treated for Graves thyrotoxicosis. The classical studies (1,9) described that KI does not sufficiently suppress thyrotoxicosis in patients with moderate to severe thyrotoxicosis in drug-naïve patients. However, these previous studies (1,9) only demonstrated a relationship between the effectiveness of inorganic iodine and the severity of thyrotoxicosis based on symptoms or protein-binding iodine, not serum thyroid hormone levels. After serum thyroid hormone levels became measurable, several studies (10-16) elucidated that inorganic iodine had continued efficacy in a small number of patients with drug-naïve Graves thyrotoxicosis. These studies investigated the effectiveness of KI treatment for 10 days (10,11), 14 days (12), 20 days (13), 35 days (14) and 60 days (15). Only Shen et al reported a longer observation period (175 days) (16) similar to our study. In the study by Shen et al, they treated patients with Graves thyrotoxicosis by sodium ipodate which is commonly used for cholecystographic contrast media. The sodium ipodate has unique characteristics compared to KI due to chemical structure of the X-ray contrast compounds. The sodium ipodate possess inhibitory effects on 5 -deiodinase which plays conversion of T4 to T3 and on influx of T4 from serum to

11 liver (10,11). These inhibitory effects of the sodium ipodate cause faster decrease T3 level and less decrease T4 level than KI in 10 days period (10,11). However, these all studies did not focus on factors associated with the long-term therapeutic effects of inorganic iodine. Accordingly, the present study is the first to show that continued efficacy of KI is inversely correlated with thyrotoxicosis severity. In the study by Shen et al, although they treated patients by sodium ipodate, one of five patients with recurrent thyrotoxicosis after 35 days of treatment had severe thyrotoxicosis before treatment and two patients who had recurrent thyrotoxicosis after 140 days of treatment had moderate thyrotoxicosis. Two other patients in whom inorganic iodine had suppressive effects for 175 days had mild thyrotoxicosis (16). This data supports our results. The molecular mechanisms underlying the recurrence of thyrotoxicosis during inorganic iodine treatment in patients with Graves disease have not been fully elucidated. Nagataki et al demonstrated serial iodine kinetics in the thyroid using radioisotopes in six patients with Graves disease with thyrotoxicosis recurring during KI treatment (17). At the time of recurrence, the uptake of 131-iodine (I) and absolute thyroid iodine uptake, which were calculated based on the intra-thyroid attenuation of 131-I and the average serum concentration of 131-I, were similar to those during

12 treatment. Accordingly, the uptake of iodine and its organification did not change with the recurrence of thyrotoxicosis. Mechanisms after iodine organification may be related to the recurrence of thyrotoxicosis. In vivo studies demonstrated that acute iodine load is positively correlated with iodine organification in the thyroid of rodents until a certain threshold; however, a large amount of iodine over the threshold inhibits iodine organification in the rodent thyroid, known as the Wolff-Chaikoff effect (18,19). On the contrary, a chronic iodine load led to the resumption of iodine organification in the thyroid of rodents with elevated serum T3 and T4 levels, called escape (20) or adaptation (21). In attempts to elucidate the molecular mechanisms underlying escape or adaptation, several studies showed that the sodium/iodide symporter (NIS), which regulates the uptake of iodine on the apical side (7,22), thyroid peroxidase (TPO) with H2O2 generation, which regulates iodine organification (7,23,24), and monocarboxylate transporter 8 (MCT8), which regulates the secretion of T3 and T4 (25,26), were involved in this phenomenon. However, the precise mechanisms have not been elucidated. Investigating these mechanisms could be key to finding the mechanism behind the inverse relationship between continued efficacy of KI and thyrotoxicosis severity. The present study has several limitations. First, this study was a single-center,

13 retrospective, and small-scale study. Second, the patients were not randomly assigned to initial KI doses of 50 mg or 100 mg. Therefore, we conducted two-way ANOVA to adjust for initial KI dose to minimize this limitation. Third, the results of this study are limited to patients initially treated with thionamides and changed to KI alone due to adverse effects. If possible, it is important to conduct a prospective study to confirm the findings of the present study and to identify other clinical factors that predict the efficacy of KI treatment in patients with Graves disease. Finally, we propose the therapeutic strategy of inorganic iodine as an alternative treatment when thionamide couldn t be continued for Graves thyrotoxicosis. In our present study, the long-term efficacy is expected when the thyroid hormone levels are within normal range on the day of the drug change, but the efficacy is inversely correlated with the severity of thyrotoxicosis. Accordingly, patients with thyrotoxicosis should be subjected to radical treatment within the expected time as to present study (Figure 1). Additionally, during KI treatment, patients with the rapid elevation of TRAb also should be consider radical treatments as soon as possible (supplemental Figure 2). In conclusion, we demonstrated that KI has long-term efficacy in some patients with

14 Graves thyrotoxicosis and that continued efficacy of KI is inversely correlated with the severity of thyrotoxicosis. Acknowledgments The authors thank Emi Ito and Yoko Kawase for their excellent technical assistance. Disclosure The authors have no multiplicity of interest to disclose.

15 References 1. Thompson W, Thompson PK, Brailey AG, Cohen AC. Prolonged treatment of exophthalmic goiter by iodine alone. Archives of internal medicine. 1930;45: Uchida T, Goto H, Kasai T, et al. Therapeutic effectiveness of potassium iodine in drug-naive patients with Graves' disease: a single-center experience. Endocrine. 2014;47: Fraser FR. An Address ON IODINE IN EXOPHTHALMIC GOITRE: Delivered before the Norwich Medico-Chirurgical Society, October 14th, British medical journal. 1925;1: Feek CM, Sawers JS, Irvine WJ, et al. Combination of potassium iodide and propranolol in preparation of patients with Graves' disease for thyroid surgery. N Engl J Med. 1980;302: Okamura K, Sato K, Fujikawa M, et al. Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects. J Clin Endocrinol Metab. 2014;99: Uchida T, Suzuki R, Kasai T, et al. Cutoff value of thyroid uptake of (99m)Tc-pertechnetate to discriminate between Graves' disease and painless

16 thyroiditis: a single center retrospective study. Endocr J. 2016;63: Braverman LE, Utiger RD. Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text 9th ed., Lippincott Williams & Wilkins, Philadelphia, Burch HB, Cooper DS. Management of Graves Disease: A Review. JAMA. 2015;314: Volpe R, Johnston MW. The effect of small doses of stable iodine in patients with hyperthyroidism. Ann Intern Med. 1962;56: Roti E, Robuschi G, Manfredi A, et al. Comparative effects of sodium ipodate and iodide on serum thyroid hormone concentrations in patients with Graves' disease. Clin Endocrinol (Oxf). 1985;22: Robuschi G, Manfredi A, Salvi M, et al. Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves' disease. J Endocrinol Invest. 1986;9: Philippou G, Koutras DA, Piperingos G, Souvatzoglou A, Moulopoulos SD. The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement. Clin Endocrinol (Oxf). 1992;36: Tan TT, Morat P, Ng ML, Khalid BA. Effects of Lugol's solution on thyroid

17 function in normals and patients with untreated thyrotoxicosis. Clin Endocrinol (Oxf). 1989;30: Philippou G, Piperingos G, Souvatzoglou A, Koutras DA, Moulopoulos SD. Treatment of hyperthyroidism with potassium iodide. Exp Clin Endocrinol. 1991;97: Emerson CH, Anderson AJ, Howard WJ, Utiger RD. Serum thyroxine and triiodothyronine concentrations during iodide treatment of hyperthyroidism. J Clin Endocrinol Metab. 1975;40: Shen DC, Wu SY, Chopra IJ, et al. Long term treatment of Graves' hyperthyroidism with sodium ipodate. J Clin Endocrinol Metab. 1985;61: Nagataki S, Shizume K, Nakao K. Effect of iodide on thyroidal iodine turnover in hyperthyroid subjects. J Clin Endocrinol Metab. 1970;30: Wolff J, Chaikoff IL. The inhibitory action of excessive iodide upon the synthesis of diiodotyrosine and of thyroxine in the thyroid gland of the normal rat. Endocrinology. 1948;43: Nagataki S, Ingbar SH. Relation between Qualitative and Quantitative Alterations in Thyroid Hormone Synthesis Induced by Varying Doses of Iodide. Endocrinology. 1964;74:

18 20. Wolff J, Chaikoff IL, et al. The temporary nature of the inhibitory action of excess iodine on organic iodine synthesis in the normal thyroid. Endocrinology. 1949;45: Braverman LE, Ingbar SH. Changes in Thyroidal Function during Adaptation to Large Doses of Iodide. J Clin Invest. 1963;42: Eng PH, Cardona GR, Fang SL, et al. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology. 1999;140: Corvilain B, Van Sande J, Dumont JE. Inhibition by iodide of iodide binding to proteins: the "Wolff-Chaikoff" effect is caused by inhibition of H2O2 generation. Biochem Biophys Res Commun. 1988;154: Panneels V, Van den Bergen H, Jacoby C, et al. Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells. Mol Cell Endocrinol. 1994;102: Di Cosmo C, Liao XH, Dumitrescu AM, Philp NJ, Weiss RE, Refetoff S. Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion. J Clin Invest. 2010;120: de Souza EC, Dias GR, Cardoso RC, et al. MCT8 is Downregulated by Short Time Iodine Overload in the Thyroid Gland of Rats. Horm Metab Res.

19 2015;47: FIGURE LEGENDS Figure 1. Patient selection process KI: potassium iodide, RAIT: radioactive iodine therapy Figure 2. Inverse correlation between free triiodothyronine (FT3) or free thyroxine (FT4) levels and duration of potassium iodide (KI) effect In the recurrence group (n=13), levels of (a) FT3 and (b) FT4 showed a strong inverse correlation with the duration of KI effect.

20 Table 1. Characteristics of the study patients Total Recurrence Non-recurrence p group group Number of total patients Gender (Male/female) 4/20 1/12 3/ Age (years) 45 (32-56) 46 (30-52) 39 (35-68) Number of patients taking MMI / PTU 17/7 8/5 9/ Duration of thionamide therapy (days) 33 (18-72) 31 (15-61) 34 (21-81) Reason for thionamide discontinuation Agranulocytosis 1 (4.2%) 1 (9.1%) 0 (0.0%) Granulocytopenia 10 (41.7%) 4 (36.4%) 6 (46.2%) Severe eruptions 5 (20.8%) 4 (36.4%) 1 (7.7%) Liver dysfunction 7 (29.2%) 3 (27.3%) 4 (30.8%) Other 3 (12.5%) 1 (9.1%) 2 (15.4%) Initial KI dose (mg/day) 50 (50-100) 50 (50-100) 50 (50-100) Frequency of 100 mg/day as initial KI dose 8 (33.3%) 4 (30.8%) 4 (36.4%) etv (g) 29.2 ( ) 29.5 ( ) 24.6 ( ) TRAb (IU/L) 9.5 ( ) 9.8 ( ) 9.3 ( ) Thyroid function on the day of the drug change TSH (μu/ml) 0.01 ( ) 0.01 ( ) 0.01 ( ) N.A. FT3 (pg/ml) 5.2 ( ) 9.3 ( ) 3.7 ( ) 0.02 FT4 (ng/dl) 1.9 ( ) 3.6 ( ) 1.4 ( ) 0.02 FT3/FT4 ratio 2.84 ( ) 2.79 ( ) 2.95 ( ) Duration of KI effect (days) 149 (58-180) 59 (35-119) 180 <0.001 Data are medians (IQR) or number of patients. In the non-recurrence group, the data on the duration of KI effect was tentatively represented as 180 days for analysis.

21 Figure patients with Graves disease initially treated with thionamides Changed to KI because of adverse effects with thionamides n=24 Recurrence within 180 days n=13 No-recurrence in 180 days n=11

22 Duration of KI effect (days) Duration of KI effect (days) Figure 2 (a) FT3 (pg/ml) R=-0.644, p=0.018 (b) FT4 (ng/dl) R=-0.607, p=0.028

23 FT4 (ng/dl) FT3 (pg/ml) Supplemental Figure 1 (a) once before the day Difference (Δ) /week on the day of drug change of drug change recurrence 18.1 ( ) ( ) 9.3 ( ) non-recurrence 7.5 ( ) ( ) 3.7 ( ) p * 0.02 (b) once before the day 1.5 Difference (Δ) /week 2 on the day 2.5 of drug change of drug change recurrence 5.4 ( ) ( ) 3.6 ( ) non-recurrence 2.4 ( ) ( ) 1.4 ( ) p * 0.02 The change of FT3 and FT4 once before and on the day of drug changing from thionamides to KI. Each plot represents the levels of (a) FT3 and (b) FT4 of patients with recurrence of thyrotoxicosis (open circle; n=13) and patients without recurrence (filled circle; n=11) before and on the day of drug changing from thionamides to KI. Difference (Δ)/week = [(just prior to the day of the drug change) - (day of the drug change) as to FT3 or FT4 levels]/duration (weeks). The mean duration from pre-change measurements to the day of the drug change was 4.6 weeks. * Differences were calculated using AVCOVA.

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