Amiodarone-Induced Thyrotoxicosis Late After Amiodarone Withdrawal

Circulation Journal Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Advance Publication by-j-stage Amiodarone-Induced Thyrotoxicosis Late After Amiodarone Withdrawal Atsuhiko Yagishita, MD; Hitoshi Hachiya, MD; Mihoko Kawabata, MD; Tomofumi Nakamura, MD; Koji Sugiyama, MD; Yasuaki Tanaka, MD; Tetsuo Sasano, MD; Mitsuaki Isobe, MD; Kenzo Hirao, MD Background: Amiodarone-induced thyrotoxicosis (AIT) may develop long after amiodarone withdrawal. This study sought to determine the incidence and clinical characteristics of AIT after amiodarone withdrawal. Methods and Results: The incidence and clinical characteristics of AIT were examined retrospectively in 71 patients (51 males, mean age 65±13 years) whose amiodarone therapy had been discontinued after at least 1 month of administration. Five (7%) patients developed AIT late after amiodarone withdrawal (11±3 months): 2 patients exhibited exacerbation of heart failure by atrial fibrillation, 2 developed dyspnea on exertion, and 1 patient was asymptomatic. The patients who developed AIT had a high incidence of amiodarone-induced hypothyroidism during amiodarone therapy (100 vs. 24%, P=0.002), had received amiodarone therapy for longer (76±86 months vs. 16±22 months, P<0.001), with a larger cumulative dose (271.1±268.5 g vs. 63.4±86.5 g, P<0.001) compared with those who did not. In all 5 patients, AIT resolved spontaneously within 5 months without the use of steroids. Conclusions: Occurrence of amiodarone-induced hypothyroidism during amiodarone therapy and long duration of therapy may be cautionary markers of late AIT. Key Words: Amiodarone; Amiodarone-induced hypothyroidism; Amiodarone-induced thyrotoxicosis Amiodarone is an effective agent in maintaining sinus rhythm in patients with atrial fibrillation (AF) 1 3 and in reducing shock delivery in recipients of an implantable defibrillator. 4 On the other hand, the use of amiodarone can be associated with significant adverse effects, of which thyroid dysfunction is a common manifestation. Various published studies report an overall incidence of amiodarone-induced thyrotoxicosis (AIT) ranging from 1% to 23% and of amiodaroneinduced hypothyroidism ranging from 1% to 32%, 5 with higher doses of amiodarone conferring a higher risk of thyroid dysfunction. 6,7 AIT is a diagnostic and therapeutic challenge unlike amiodarone-induced hypothyroidism. The 2 main mechanisms leading to AIT are (1) iodine-induced hyperthyroidism (type 1 AIT), a form of Graves disease, and (2) destructive thyroiditis (type 2 AIT). 8 Type 2 AIT is the more frequent form 9 and is distinguished from type 1 AIT by low thyroidal radioactive iodine uptake values, 10,11 absence of increased thyroidal vascularity on color-flow Doppler sonography, and absence of circulating thyroid-directed autoantibody. 12 Several studies have shown that patients with AIT have high morbidity and mortality during long-term follow-up. 13,14 Because of tissue accumulation of amiodarone and its metabolites and their slow release, the sys- temic effects of amiodarone may persist for a long period of time. It has been reported that AIT can occur even after withdrawal of amiodarone. 15 17 However, the clinical features of AIT that occurs after amiodarone withdrawal have never been carefully examined. Therefore, the goal of this study was to investigate the incidence and clinical characteristics of such AIT. Editorial p???? Methods Study Subjects We performed a retrospective analysis of 71 patients (73% male, mean age 65±13 years, range 17 82 years) who discontinued amiodarone after taking the drug for at least 1 month between 2002 and 2011. The reasons for amiodarone withdrawal included change of rhythm control strategy to rate control strategy for AF (n=30), reduction in the number of ventricular tachycardia episodes after improvement in left ventricular systolic function (n=3), and drug intolerance (n=38). Drug intolerance included amiodarone-induced hypothyroidism (n=12), AIT during treatment (n=5) and other causes (n=21). Thyroid-stimulating Received February 12, 2013; revised manuscript received July 17, 2013; accepted August 12, 2013; released online September 14, 2013 Time for primary review: 22 days Department of Cardiovascular Medicine (A.Y., M.K., T.N., K.S., T.S., M.I.), Heart Rhythm Center (H.H., Y.T., K.H.), Tokyo Medical and Dental University, Tokyo, Japan Mailing address: Atsuhiko Yagishita, MD, Division of Cardiology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. E-mail: atsuhikoyagishita@nifty.ne.jp ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0220 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

YAGISHITA A et al. Table 1. Clinical Characteristics of 71 Patients Ceasing Amiodarone Therapy AIT (n=5) Non-AIT (n=66) P value Male (%) 4 (80) 46 (70) 1.000 Age (years) 59±6 65±13 0.158 Hypertension (%) 0 (0) 23 (35) 0.164 Diabetes (%) 0 (0) 12 (18) 0.581 History of MI (%) 0 (0) 12 (17) 0.580 DCM (%) 3 (80) 12 (18) 0.600 HCM (%) 0 (0) 7 (11) 1.000 HHD (%) 0 (0) 7 (11) 1.000 VHD (%) 0 (0) 12 (18) 0.581 ARVC (%) 1 (20) 1 (1.5) 0.137 ASD (%) 1 (20) 0 (0) 0.070 AF/VA 3/2 50/16 0.595 Dosage (mg/day) 120±44 146±52 0.139 Duration of amiodarone therapy (months) 76±86 16±22 <0.001 Cumulative amiodarone dose (g) 271.1±268.5 63.4±86.5 <0.001 Amiodarone-induced hypothyroidism during 5 (100) 16 (24) 0.002 amiodarone therapy (%) AIT during amiodarone therapy (%) 0 (0) 7 (11) 1.000 egfr (ml min 1 1.73 m 2 ) 55.7±15.1 57.8±24.9 0.427 BNP (pg/ml) 98.0±57.8 387.3±419.7 0.088 LVEF (%) 47.4±9.8 48.1±16.7 0.462 LVDd (mm) 57±8 56±12 0.612 Left atrial diameter (mm) 46±1 46±8 0.477 Data are mean ± SD. AF, atrial fibrillation; AIT, amiodarone-induced thyrotoxicosis; ARVC, arrhythmogenic right ventricular cardiomyopathy; ASD, atrial septal defect; BNP, brain natriuric peptide; DCM, dilated cardiomyopathy; egfr, estimated glomerular filtration rate; HCM, hypertrophic cardiomyopathy; HHD, hypertensive heart disease; LVDd, left ventricular diastolic diameter; LVEF, left ventricular ejection fraction; MI, myocardial infarction; VA, ventricular arrhythmia; VHD, valvular heart disease. Results AIT After Withdrawal of Amiodarone Among the 71 patients who discontinued amiodarone, 5 (7%) developed late AIT after withdrawal of amiodarone. The mean follow-up duration after discontinuation of amiodarone therahormone (TSH), serum free thyroxine (ft4) and serum free triiodothyronine (ft3) data prior to amiodarone therapy were available for all patients. None of the patients had thyroid dysfunction, including Graves disease and autoimmune thyroiditis (Hashimoto thyroiditis), before amiodarone initiation. Thyroid function was monitored every 1 3 months after discontinuation of amiodarone in patients with amiodarone-induced hypothyroidism during amiodarone therapy, and monitored in the remaining patients when there was a change in symptoms. The incidence of newly diagnosed AIT occurring after withdrawal of amiodarone (late AIT) and the clinical characteristics of such patients were examined. The present analysis was approved by the Institutional Review Board of Tokyo Medical and Dental University Hospital. All patients provided verbal and written informed consent. Definitions AIT was defined as suppression of TSH to <0.1 µiu/ml with elevated ft4 and/or ft3 level. Normal values in our laboratory were: ft3, 2.5 5.5 pg/ml; ft4, 0.85 1.80 ng/ml; TSH, 0.34 3.5 µiu/ml. Type 1 AIT Diagnosis of type 1 AIT was based on the following: normal or elevated radioactive iodine uptake values, presence of diffuse or nodular goiter on thyroidal ultrasonography, increased thyroidal vascularity on color-flow Doppler sonography, and circulating-thyroid-directed antibody. Type 2 AIT Diagnosis of type 2 AIT was based on the findings of low thyroidal radioactive iodine uptake values and absence of (1) goiter on thyroidal ultrasonography, (2) increased thyroidal vascularity on color-flow Doppler sonography, and (3) circulating thyroid-directed autoantibody. Amiodarone-Induced Hypothyroidism Patients with TSH equal to or higher than upper limits of normal in combination with low serum levels of ft4 were considered to have hypothyroidism. There is a report of TSH concentrations >20 µu/ml in the majority of patients with amiodarone-induced hypothyroidism. 18 In the present study, we compared the incidence of amiodarone-induced hypothyroidism with raised TSH concentration >20 µu/ml between patients with and without late AIT. Because increases in serum TSH concentration are seen in euthyroid patients for the first 3 6 months after amiodarone therapy is initiated, amiodarone-induced hypothyroidism was diagnosed in this study when the TSH elevation persisted after 6 months of therapy. Statistical Analysis Continuous variables are expressed as mean ± standard deviation. Comparisons between groups were performed with Student s t test or the Wilcoxon rank-sum test, as appropriate. For categorical data, Fisher s exact test was applied. Kaplan-Meier curves were constructed, and the outcome in patients with or without amiodarone-induced hypothyroidism was compared using the log-rank test. A 2-tailed P-value <0.05 was considered to indicate statistical significance. All statistical analyses were performed with SPSS 20.0 (Chicago, IL, USA).

Late Amiodarone-Induced Thyrotoxicosis Table 2. Clinical Characteristics of Patients With Late AIT Case Age Sex Indication Duration of amiodarone Cumulative therapy dose (g) (months) Amiodaroneinduced hypothyriodism Time to AIT after withdrawal (months) Clinical manifestation Time to normalization of thyroid hormone values (months) Steroids Hypothyroidism after late AIT 1 64 F DCM, VT 228 693.8 + 7 Dyspnaea 2 2 66 M AF 49 148.5 + 11 Dyspnea 5 3 61 M AF 50 303.6 + 11 AF, CHF 5 + 4 63 M DCM, AF 30 89.7 + 10 AF, CHF 5 5 49 M ARVC, VT 15 46.2 + 16 None 1 + Thyroid Function in Patients With Late AIT Case Before amiodarone administration At time of amiodarone withdrawal At time of late AIT TSH (μiu/ml) ft3 (pg/ml) ft4 (ng/ml) TSH (μiu/ml) ft3 (pg/ml) ft4 (ng/ml) TSH (μiu/ml) ft3 (pg/ml) ft4 (ng/ml) 1 3.61 2.86 1.29 8.25 2.48 1.02 0.01 11.16 4.10 2 4.50 2.36 1.29 38.03 2.43 1.11 0.02 5.80 2.16 3 1.77 3.16 1.34 8.21 3.22 1.38 0.01 7.00 4.32 4 3.67 2.65 1.13 5.58 2.32 1.45 0.03 5.14 2.06 5 2.27 3.05 1.53 8.13 3.30 1.49 0.01 5.77 2.60 Normal values in our laboratory: TSH, 0.34 3.5 μiu/ml; ft4, 0.85 1.80 ng/ml; ft3, 2.5 5.5 pg/ml. CHF, congestive heart failure; VT, ventricular tachycardia; ft3, serum free triiodothyronine; ft4, serum free thyroxine; TSH, thyroid-stimulating hormone. Other abbreviation as in Table 1. try was as follows: TSH, 0.01 µu/ml. ft3, 11.16 pg/ml. and ft4, 4.10 ng/ml. Type 2 AIT was diagnosed and it resolved within 2 months without the use of steroids. Case 2 A 66-year-old man started taking amiodarone for rhythm control of lone AF. He developed asymptomatic amiodarone-induced hypothyroidism 49 months after initiation of amiodarone and discontinued treatment, at which time the cumulative dose was 148.5 g. Although amiodarone-induced hypothyroidism improved gradually during follow-up, the patient suffered from dyspnea 11 months after discontinuing amiodarone, at which time his serum biochemistry was as follows: TSH, 0.02 µu/ml. ft3, 5.80 pg/ml. and ft4, 2.16 ng/ml. Type 2 AIT was diagnosed and it resolved within 5 months without the use of steroids. Case 3 A 61-year-old man with a history of surgical closure of atrial septal defect started amiodarone for paroxysmal AF. Because ambulatory visits were discontinued, amiodarone was discontinued 50 months after its initiation, at which time the patient had amiodarone-induced hypothyroidism and the cumulative dose was 303.6 g. Eleven months later, the patient developed heart failure because of AF with rapid ventricular rate (Figure 1). His serum biochemistry was as follows: TSH, 0.01 µu/ml. ft3, 7.00 pg/ml. and ft4, 4.32 ng/ml. Type 2 AIT was diagnosed and it resolved within 5 months without the use of steroids. AIT was followed by subclinical hypothyroidism, which improved without thyroid hormone replacement. Case 4 A 63-year-old man with a history of dilated cardiomyopathy started amiodarone for persistent AF. Sinus rhythm was restored and maintained after administration of amiodarone. Because of the occurrence of amiodarone-induced hypothyroidism, therapy was discontinued 30 months after its inipy and the mean duration from discontinuation of amiodarone to occurrence of AIT were 37±29 months and 11±3 months, respectively. Table 1 summarizes the characteristics of patients with and without late AIT after amiodarone withdrawal. The duration of amiodarone therapy (76±86 months vs. 16±22 months, P<0.001) and the cumulative dose of amiodarone (271.1±268.5 g vs. 63.4±86.5 g, P<0.001) were significantly greater in patients with late AIT than in those without. Prevalence of amiodarone-induced hypothyroidism during amiodarone therapy was higher in the patients with late AIT (100% vs. 24%, P=0.002). As the 100% indicates, all the patients with late AIT had exhibited amiodarone-induced hypothyroidism. Among the patients with amiodarone-induced hypothyroidism, patients with TSH concentration >20 µu/ml were 1 of 5 patients with late AIT and 6 of 16 patients without late AIT, respectively (P=0.624). None of the patients who developed AIT during amiodarone therapy continued to have AIT or developed late AIT after amiodarone was discontinued. Clinical Characteristics of the Patients With Late AIT The clinical characteristics of the 5 patients with late AIT are shown in Table 2. Case 1 A 64-year-old woman with a history of dilated cardiomyopathy started taking amiodarone for the treatment of sustained ventricular tachycardia. When her symptoms ceased, amiodarone therapy was discontinued 228 months after its initiation, at which time the cumulative dose was 693.8 g. She was in a state of subclinical hypothyroidism at the time of amiodarone withdrawal, but improved gradually without thyroid hormone replacement therapy. At 7 months after discontinuing amiodarone, she complained of dyspnea. Her serum biochemis-

YAGISHITA A et al. Figure 1. Case 3. During amiodarone therapy, ECG showed sinus rhythm at 76 beats/min (A) and chest X ray showed no pulmonary congestion (B). At admission for deterioration of congestive heart failure and late AIT, ECG showed atrial fibrillation with rapid ventricular rate (178 beats/min) (C) and chest X ray showed pulmonary congestion (D). tiation, at which time the cumulative dose was 89.7 g. AF with rapid ventricular rate recurred 10 months after amiodarone withdrawal at which time the patient had dyspnea and developed congestive heart failure. Thyroid function was as follows: TSH, 0.03 µu/ml. ft3, 5.14 pg/ml. and ft4, 2.06 ng/ml. Type 2 AIT was diagnosed and it resolved within 5 months without the use of steroids. Case 5 A 49-year-old man with a history of arrhythmogenic right ventricular cardiomyopathy started amiodarone for nonsustained ventricular tachycardia. Because of the occurrence of amiodarone-induced hypothyroidism, therapy was discontinued 15 months after its initiation, at which time the cumulative dose was 46.2 g. During periodic follow-up of thyroid function, hyperthyroidism was noted 16 months after amiodarone withdrawal. The patient had no symptoms and thyroid function was as follows: TSH, 0.01 µu/ml. ft3, 5.7 pg/ml. and ft4, 2.60 ng/ml. Type 2 AIT was diagnosed and it resolved within 1 month without the use of steroids. AIT was followed by subclinical hypothyroidism, which improved without thyroid hormone replacement (Figure 2). Discussion The major findings of the present study were: (1) late AIT occurred in 7% of patients (5/71) after amiodarone withdrawal, most of whom were symptomatic, (2) all cases of late AIT were type 2, the destructive thyroiditis type, (3) the patients with late AIT had amiodarone-induced hypothyroidism during amiodarone therapy, and a longer treatment duration and larger cumulative dose of amiodarone compared with those without and (4) all patients with late AIT recovered spontaneously within 5 months without the use of steroids. Based on the finding that none of these 5 patients had underlying thyroid disease before initiation of amiodarone, and that hyperthyroidism occurred continuously after recovery from amiodarone-induced hypothyroidism, we considered that hyperthyroidism was unlikely to be caused by idiopathic painless thyroiditis, but was an adverse effect of amiodarone. Clinical Features of Late AIT There are 2 forms of AIT and the relative prevalence of each form depends on the underlying iodine intake. According to a

Late Amiodarone-Induced Thyrotoxicosis Figure 2. Case 5. Time course of thyroid function after amiodarone withdrawal. The patient developed hyperthyroidism 16 months after discontinuation and recovered within 1 month. Normal values in our laboratory: ft3, 2.5 5.5 pg/ml; ft4, 0.85 1.80 ng/ml; TSH, 0.34 3.5 µiu/ml. ft3, serum free triiodothyronine; ft4, serum free thyroxine; TSH, thyroidstimulating hormon. previous report, the destructive-type AIT was the major type of AIT in iodine-replete areas such as Japan, with a very low incidence of toxic multinodular goiter, 19 consistent with the findings of the present study. In our study, the absence of type 1 AIT was not surprising, because late AIT occurred at a time when the level of systemic amiodarone in the patients was not excessive. Histopathologic examination of the thyroid in patients with type 2 AIT reveals thyroid follicular damage and disruption, 20 swelling of follicular cells, vacuolization of the cytoplasm, and fibrosis, 21 24 indicative of destructive thyroiditis and consistent with in vitro studies demonstrating the cytotoxic effect of amiodarone and its metabolites, desethylamiodarone (DEA). 25 According to a previous study, average concentrations of amiodarone in the thyroid, adipose tissue and liver were 14, 316, and 391 mg/kg, respectively, in patients on long-term amiodarone and the corresponding concentrations of DEA were 64, 76, and 2,354 mg/kg. Terminal elimination half-lives in serum averaged 52.6±23.7 days for amiodarone and 61.2±31.2 days for DEA in 8 patients after cessation of long-term amiodarone therapy. 26 In our study, late AIT occurred after 7 11 months (range 210 330 days). The relatively low concentration of amiodarone and DEA in the thyroid tissue to begin with according to studies, and the delayed appearance of AIT after approximately 4 half-lives or more in our study, suggests that delayed injury from residual amiodarone in thyroid follicles can occur even after the serum concentration of amiodarone becomes undetectable. Several previous studies demonstrated a cumulative dose-dependent increase of both amiodarone-induced hypothyroidism and AIT. 27,28 Trip et al reported that the average length of amiodarone treatment before the occurrence of AIT during therapy was approximately 36 months, 29 which is shorter than the average length of amiodarone treatment (72 months) before drug withdrawal for patients in the present study. One mechanism of amiodaroneinduced hypothyroidism is a persistent Wolff-Chaikoff effect, which is a reduction in thyroid hormone synthesis caused by ingesting a large amount of iodine. 30 This is an autoregulatory phenomenon that inhibits oxidation of iodide in the thyroid gland, the formation of thyroid hormones inside the thyroid follicle, and the release of thyroid hormones. Therefore, the exact pathogenetic relationship between amiodarone-induced hypothyroidism during treatment and late AIT remains unclear. In general, steroids are known to be effective in patients with type 2 AIT during amiodarone therapy. 8 Data supporting the utility of steroids for type 2 AIT occurring late after amiodarone withdrawal are scarce and other reports have demonstrated that steroids had no effect on the time to normalization of thyroxine levels and were associated with increased event rates. 13 Therefore, we did not use steroids in our patients, all of whom recovered spontaneously within 5 months; 2 of the 5 patients with late AIT developed hypothyroidism after recovery from late AIT, consistent with previous reports describing a subset of the patients with AIT developing hypothyroidism after recovery from AIT. 31 33 Clinical Implications In the present study, 4 of the 5 patients with late AIT were symptomatic. Moreover, 2 of the 4 symptomatic patients had exacerbations of heart failure because of AF with poor control of ventricular rate. Combined with previous studies describing the heralding of AIT by a worsening of the underlying cardiac disorder with tachyarrhythmias, 17 the occurrence or recurrence of tachyarrhythmia such as AF in patients with a history of amiodarone treatment should lead to an investigation of their thyroid function. 19 Because AIT leads to increased mortality, especially in older patients with impaired left ventricular function, 34 it is critical to treat tachyarrhythmias aggravated by AIT and to restore the euthyroid level as quickly as possible. Although the thyrotoxicosis itself resolved without treatment, we believe that early diagnosis of the condition could lead to preventive measures of its sequelae. For example, in the 2 symptomatic AIT patients whose thyrotoxicosis was diagnosed after AF and heart failure exacerbation, with prior knowledge, we may have been able to prevent clinical deterioration by expending extra effort in AF rhythm control and limiting heart failure exacerbation with judicious use of β-blockers and/or diuretics. Thus, thyroid status should be routinely followed even after amiodarone withdrawal. Study Limitations First, our study was retrospective with a small sample size. Prospective studies with a large number of patients are required to confirm our findings. Secondly, thyroid function was not fully

YAGISHITA A et al. evaluated at regular intervals in some of the patients. Therefore, there may have been patients with asymptomatic late AIT, which led to an underestimation of the incidence of late AIT. Although the results of the present study do not change the importance of routine evaluation of thyroid function after amiodarone withdrawal, prospective studies surveying thyroid function in all patients after amiodarone withdrawal should be conducted. Third, although all patients with late AIT recovered without the use of steroids in this study, it is premature to discuss the utility of steroids for late AIT based on the results of our study with its small number of patients with late AIT. Conclusions Both amiodarone-induced hypothyroidism during amiodarone therapy and long-term amiodarone therapy leading to a large cumulative dose of amiodarone may play an important role in inducing late AIT. Acknowledgments This work originated from Tokyo Medical and Dental University. 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