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0013-7227/01/$03.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 86(10):4707– 4710 Copyright © 2001 by The Endocrine Society Use of Oral Cholecystographic Agents in the Treatment of Amiodarone-Induced Hyperthyroidism INDER J. CHOPRA AND KHANSA BABER Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, University of California Center for Health Sciences, Los Angeles, California 90024 We describe here five cardiac patients with type II amiodarone-induced hyperthyroidism who were treated prospectively with a combination of an oral cholecystographic agent (sodium ipodate, Oragrafin, or sodium iopanoate, Telepaque) and a thionamide (propylthiouracil or methimazole); amiodarone was discontinued in all patients. All patients improved substantially clinically within a few days of treatment and became euthyroid or hypothyroid in 15–31 wk when treatment was discontinued. Four of the five became hypothyroid and required long-term treatment with L-T4; the remaining patient A MIODARONE IS AN effective, iodine-rich, antiarrhythmic agent that may cause both hyper- and hypothyroidism (1). It was approved by the FDA in 1985 for the treatment of serious ventricular arrhythmias; it reduces complex ventricular ectopy and cardiac-related mortality (2, 3). It is also effective in the treatment of paroxysmal supraventricular tachycardia and atrial fibrillation and flutter (2). Amiodarone is a benzofuron derivative with some structural similarities to thyroid hormone. It has two iodine atoms, and iodine accounts for 39.3% of its mol wt (4). Some 8 –17% of iodine in amiodarone is converted daily to inorganic iodine (5). Chronic treatment with amiodarone is associated with hyperthyroidism in up to 23% and with hypothyroidism in up to 32% of patients (6). Amiodarone-induced hyperthyroidism (AIH) is particularly common in regions with underlying iodine deficiency, e.g. Europe, where the incidence of hyperthyroidism approximates 20% of patients taking amiodarone (6). In iodine-rich regions, the incidence of AIH is generally less than 10% (7). Two types of AIH have been described. Type I AIH (AIH I) is associated with an underlying disorder of the thyroid gland, and hyperthyroidism is triggered by the large amount of iodine liberated from the metabolism of amiodarone. Both nodular goiter and autoimmune thyroid disease can be associated with this type of AIH (8). In contrast, type II AIH (AIH II) is characterized by thyroiditis, a form of toxic thyroiditis, wherein the inflammatory process of the thyroid and the associated derangement of its follicular parenchyma lead to the leakage of thyroid hormones into the circulation. This clinical picture is similar to that in subacute thyroiditis (8). Because of the fat solubility and long half-life (⬃20 –100 d) of amiodarone (7–9), the treatment of AIH is often more Abbreviations: AIH, Amiodarone-induced hyperthyroidism; AIH I, type I amiodarone-induced hyperthyroidism; AIH II, type II amiodarone-induced hyperthyroidism; FT3I, free T3 index; 5⬘-MD, 5⬘-monodeiodinases; OCA, oral cholecystographic agent. was euthyroid, but died from cardiomyopathy and congestive heart failure at 29 wk, when he had been off oral cholecystographic agent and thionamide for 6 wk. We did not find any clinical or biochemical adverse effects of the treatment. Our study suggests that a combination of oral cholecystographic agent and thionamide is a safe and effective treatment of type II amiodarone-induced hyperthyroidism. Data also suggest that hypothyroidism is a common end result of type II amiodarone-induced hyperthyroidism. (J Clin Endocrinol Metab 86: 4707– 4710, 2001) difficult and prolonged than that of the other forms of iodineinduced hyperthyroidism (10 –18). We describe in this report the combined use of oral cholecystography agents (OCAs) and antithyroid drugs (thionamides) in the management of AIH. OCAs are very potent inhibitors of iodothyronine 5⬘monodeiodinases (5⬘-MD) that catalyze the activation of the prohormone T4 to the more potent T3 (19). OCAs have previously been shown to be effective in the management of other forms of hyperthyroidism, e.g. Graves’ disease, thyroiditis, and thyrotoxicosis factitia (20 –24). Materials and Methods We studied prospectively five consecutive patients (42–71 yr old) with AIH II between 1995–2000. All patients were from clinical practice of I. J. Chopra. The diagnostic criteria for the AIH II included biochemical hyperthyroidism, normal-sized thyroid, no clinically discernible nodules, and undetectable antithyroid (anti-Tg and antithyroid peroxidase) autoantibodies. Patients were all males, who presented with clinical features of weight loss, muscle weakness, finger tremors, palpitation, and/or dyspnoea. The underlying cardiac diagnosis was cardiomyopathy in three cases and congenital heart disease in two cases with congestive heart failure and cardiac arrhythmias. Initial thyroid function test data are shown in Table 1. Patients had a history of long-term ingestion of amiodarone for 30 months or longer. Thyroid radioiodine uptake was measured in one patient, and it was markedly decreased (⬍1%). Amiodarone was discontinued after the diagnosis of AIH in all cases. All patients were started on treatment of hyperthyroidism using OCAs [sodium ipodate (Oragrafin, Bracco Diagnostics, Princeton, NJ; 500 mg/d; three patients) or sodium tyropanoate (Telepaque, Nycomed, Princeton, NJ; 500 mg 1–2 times/d; two patients)] and an antithyroid drug [propylthiouracil (100 –150 mg, three times per d; four patients) or methimazole (Tapazole; 15 mg, twice daily; one patient)]. Case 3 was treated first with ipodate for about 10 wk and later with iopanoate for 5 wk because ipodate was no longer available. Glucocorticoids were not used to treat our patients. The serum concentration of free T3 and/or the free T3 index (FT3I) was decreased to normal or near normal in four of five patients when first measured after initiation of treatment; the response of serum free T3 or FT3I was slow in the remaining patient (Fig. 1). The dose of the drugs for treatment of hyperthyroidism was decreased gradually as the serum concentration of free T4 decreased to normal or near normal. Treatment 4707 4708 J Clin Endocrinol Metab, October 2001, 86(10):4707– 4710 Chopra and Baber • Oral Cholecystographic Agents in Treatment of AIH TABLE 1. Clinical data and initial serum levels of TSH, free T4 index (FT4I), free T3 index (FT3I), free T4 (FT4) by dialysis, free T3 (FT3) by dialysis, and/or antithyroid antibodies in patients with AIH under study Case no. 1 2 3 4 5 Reference range Age (yr, sex) 42, 64, 63, 59, 59, M M M M M Weight (lbs) TSH (mIU/liter) 237 244 179 250 180 0.1 ⬍0.02 ⬍0.02 0.07 0.02 0.3– 4.7 FT4I FT3I 19.3 25.0 45.6 12.3 181 301 716 216 5–11 80 –175 FT4a (ng/dl) 8.4 5.3 24.9 0.7–2.2 FT3a (pg/ dl) 620 754 210 – 440 Antithyroid antibodies Thyroid 123I uptake UD UD UD UD UD ⬍2 IU/ml ND ND ND very low ND M, Male; UD, undetectable; ND, not done. FT4 and FT3 by dialysis, measurements done by RIA after equilibrium dialysis (Ref. 25). a was needed for 15–31 wk before both serum free T4 and free T3 (or FT3I) decreased to normal and stayed normal or became subnormal after the drugs were discontinued. Serum levels of free T3 and free T4 by dialysis, FT4I, FT3I, TSH, and antithyroid antibodies were measured in the clinical laboratories of University of California-Los Angeles as described previously (25). The study was approved by the institutional review board at University of California-Los Angeles. Results Figure 1 shows the data from thyroid function tests performed during and after treatment with the drug combination studied. All patients studied reported marked improvement in symptoms at their first visit (8 –15 d) after initiation of treatment with OCA. We observed no side effects of treatment with OCA. Four of five patients became hypothyroid in 15–31 wk (Table 2) and have required treatment with T4 to maintain euthyroid status. The remaining patient became euthyroid with normal serum free T4 and TSH levels at 20 wk of treatment and remained euthyroid when treatment was gradually tapered off at 23 wk. However, he died 6 wk later from cardiomyopathy and congestive heart failure. Two of the four hypothyroid patients (cases 1 and 3) treated with T4 were, after about 1 yr of treatment, asked to discontinue T4 for 1 month, and their serum TSH levels were measured. Both demonstrated elevated serum TSH, suggesting prolonged, possibly permanent, hypothyroidism. All four patients who became hypothyroid are stable and/or feel improved on continued T4 treatment. Discussion Amiodarone is a very effective antiarrhythmic agent, but it has several adverse effects, including thyroid dysfunction. Chronic treatment with amiodarone is associated with hyperthyroidism (AIH) in up to 23% of patients and with hypothyroidism in up to 32% of patients (6). It can be difficult to manage hyperthyroidism, and thyroidectomy has been employed in some cases (26). We find that thyroidectomy is often a significant challenge in seriously ill AIH patients with compromised cardiac status. AIH I has been treated with a combination of a thionamide and potassium perchlorate (18), whereas AIH II has been responsive to treatment with corticosteroids (27). However, several patients continue to manifest prolonged hyperthyroidism and its adverse cardiac effects despite these treatments (18), whereas several patients treated with corticosteroids suffer from their side effects. Furthermore, potassium perchlorate is a potentially toxic agent with some side effects as serious as aplastic anemia and agranulocytosis (12, 28). Fortunately, however, these serious side effects of potassium perchlorate are uncommon (29). Our study demonstrated that OCAs are safe and effective agents to quickly lower serum free T3 levels to normal or near normal levels in AIH patients. OCAs act by strongly inhibiting iodothyronine 5⬘-MD (19, 30). Thus, on a molar or weight basis, sodium ipodate (Oragrafin) is among the most potent inhibitors of iodothyronine 5⬘-MD, followed by sodium tyropanoate (Telepaque) (19). Ipodate inhibits this deiodinase competitively with respect to T4. It inhibits iodothyronine 5⬘-MD in all tissues where it is present, including liver, kidney, and thyroid (19, 31). It has previously been shown to be effective in the management of hyperthyroidism in Graves’ disease, thyroiditis, and thyrotoxicosis factitia (20 –24). It reduces the serum T3 concentration markedly and to near-normal levels in hyperthyroid patients within 24 –36 h of initiation of treatment (19 –21). Thus, in hyperthyroid patients with Graves’ disease, ipodate treatment caused an average 70% reduction in the serum T3 concentration within 48 h (20). Additionally, OCAs improve hyperthyroidism by other mechanisms. Thus, ipodate has been shown to reduce tissue uptake of thyroid hormones (32). It is also a known inhibitor of the nuclear building of T3 (33). Its effects on the thyroid gland include reduced thyroid hormone synthesis, decreased proteolysis of Tg, decreased thyroidal response to TSH, and decreased release of thyroid hormone from the thyroid gland (34). Although the thyroidal effects of ipodate are of interest, they probably play a minor role in improving hyperthyroidism caused by leakage of thyroid hormones observed in thyroiditis or by ingestion of T4 in thyrotoxicosis factitia. The peripheral tissue effects of ipodate mentioned above are apparently mainly responsible for the systemic improvement observed after treatment with OCAs in these disorders (25). Another study of five hyperthyroid patients with severe heart failure treated with methimazole (45 mg/d) and a single dose of ipodate (3 g) demonstrated a marked improvement in cardiovascular parameters measured by the Swan-Ganz catheter (35). Thus, there was a significant decrease in systolic pressure and pulse pressure within 24 h after the administration of ipodate. Heart rate decreased from a mean of 132 to 110 beats/min, cardiac index fell 36.7% within 12 h after ipodate treatment, and there was a near normalization of the stroke volume and total systemic resistance. Additionally, left ventricular work improved progressively, while right ventricular work remained normal. T3 levels decreased in parallel with these improvements by 67% Chopra and Baber • Oral Cholecystographic Agents in Treatment of AIH J Clin Endocrinol Metab, October 2001, 86(10):4707– 4710 4709 TABLE 2. Duration of treatment with OCAs and thionamides and final outcome of AIH patients studied Case No. Duration of treatment with OCAs (wk)a Duration of treatment with thionamide (wk)b 1 2 3 4 22 26 15 23 31 26 15 23 5 17 17 Final outcome Hypothyroid Hypothyroid Hypothyroid Euthyroid at 23 wk, and then died at 29 wk Hypothyroid a The OCA used was sodium ipodate (Oragrafin) in cases 1, 2, and 4 and sodium tyropanoate (Telepaque) in cases 3 and 5. b The thionamide used was propylthionrocil in cases 1– 4 and carbimazole in case 5. however, because the iodine liberated from the metabolism of amiodarone may actually worsen hyperthyroidism. In a previous study several treatment modalities for hyperthyroidism, including ipodate, were tried without success in a patient with AIH (26). This case may have had type I or a combination of type I and type II AIH; he had to be treated with thyroidectomy (26). Interestingly, we observed no appreciable adverse effects of treatment with OCAs in our patients. Our study suggests that the combination of an OCA and a thionamide should be a useful treatment of AIH as in selected cases of other forms of hyperthyroidism. Curiously, we also discerned a high incidence of hypothyroidism in four of five cases of AIH II studied. Hypothyroidism was prolonged and persisted for over a year in two cases studied. Others have reported hypothyroidism after AIH even when patients were not treated with OCAs (36, 37). Acknowledgments Received February 22, 2001. Accepted May 10, 2001. Address all correspondence and requests for reprints to: Inder J. Chopra, M.D., Division of Endocrinology, Metabolism, Diabetes, and Metabolism, 900 Veteran Avenue, Suite 24-130, Warren Hall, Los Angeles, California 90095-7073. E-mail: [email protected]. References FIG. 1. Serum FT3I and free T4 determined by dialysis and of TSH in five patients with AIH II studied during treatment with a combination of an OCA (sodium ipodate, Oragrafin, or sodium tyropanoate, Telepaque) and a thionamide (propylthiouracil or methimazole). Treatment was discontinued when patients were euthyroid or hypothyroid. L-T4 treatment was added when serum TSH was elevated. after 24 h (35). These effects of OCAs may represent additional benefits for cardiac patients with AIH who are treated with OCAs. Our study suggested that OCAs are safe and effective in the treatment of AIH II. As noted above, this form of hyperthyroidism reflects a leakage of thyroid hormone into the circulation caused by amiodarone-induced toxic thyroiditis. It is not the type of hyperthyroidism that results from increased secretion and release of thyroid hormone, as would be expected to occur in AIH I. We have had no experience of using OCAs in AIH I. We would expect it not to work well, 1. 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