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Endocrine Care |
Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, University of California Center for Health Sciences, Los Angeles, California 90024
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: ichopra{at}mednet.ucla.edu
Abstract
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 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.
AMIODARONE 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, 8, 9), the treatment of AIH is often more
difficult and prolonged than that of the other forms of iodine-induced
hyperthyroidism (10, 11, 12, 13, 14, 15, 16, 17, 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, 21, 22, 23, 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.
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). 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 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.
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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.
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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, 21, 22, 23, 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, 20, 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% 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, 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
Footnotes
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.
Received February 22, 2001.
Accepted May 10, 2001.
References
This article has been cited by other articles:
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  F. Bogazzi, L. Bartalena, L. Tomisti, G. Rossi, M. L. Tanda, E. Dell'Unto, F. Aghini-Lombardi, and E. Martino Glucocorticoid Response in Amiodarone-Induced Thyrotoxicosis Resulting from Destructive Thyroiditis Is Predicted by Thyroid Volume and Serum Free Thyroid Hormone Concentrations J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 556 - 562. [Abstract] [Full Text] [PDF]
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 R. Porsche and Z. R. Brenner Amiodarone-induced thyroid dysfunction. Crit. Care Nurse, June 1, 2006; 26(3): 34 - 41. [Full Text] [PDF]
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K. S. Dhillon, P. Cohan, D. F. Kelly, C. H. Darwin, K. V. Iyer, and I. J. Chopra Treatment of Hyperthyroidism Associated with Thyrotropin-Secreting Pituitary Adenomas with Iopanoic Acid J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 708 - 711. [Abstract] [Full Text] [PDF]
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F. Bogazzi, L. Bartalena, C. Cosci, S. Brogioni, E. Dell'Unto, L. Grasso, F. Aghini-Lombardi, G. Rossi, A. Pinchera, L. E. Braverman, et al. Treatment of Type II Amiodarone-Induced Thyrotoxicosis by Either Iopanoic Acid or Glucocorticoids: A Prospective, Randomized Study J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1999 - 2002. [Abstract] [Full Text] [PDF]
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