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Treatment of Type II Amiodarone-Induced Thyrotoxicosis by Either Iopanoic Acid or Glucocorticoids: A Prospective, Randomized Study

Departments of Endocrinology and Metabolism, University of Pisa (F.B., C.C., S.B., E.D., L.G., F.A.-L., A.P., E.M.) and University of Insubria (L.B.), 21100 Varese, Italy; Department of Epidemiology and Biostatistics, Institute of Clinical Physiology (G.R.), National Research Council, 56124 Pisa, Italy; and Section of Endocrinology, Diabetes and Nutrition (L.E.B.), Boston Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Fausto Bogazzi, M.D., Dipartimento di Endocrinologia e Metabolismo, Università di Pisa, Ospedale Cisanello, Via Paradisa 2, 56124, Pisa, Italy. E-mail: fbogazzi{at}hotmail.com or f.bogazzi{at}endoc.med.unipi.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Amiodarone-induced thyrotoxicosis (AIT) may occur either in the presence of underlying thyroid disease (type I AIT) or in apparently normal thyroid glands (type II AIT). Type II AIT, a destructive thyroiditis, often favorably responds to glucocorticoids. Iopanoic acid (IopAc) is an iodinated cholecystographic agent that inhibits deiodinase activity and reduces the conversion of T₄ toT₃. It has recently been reported that cholecystographic agents restore euthyroidism in patients with type II AIT. We describe the results of a prospective randomized study conducted in 12 patients with type II AIT treated with either iopanoic acid (group A, n = 6) or glucocorticoids (group B, n = 6). Serum free T₃ levels normalized rapidly in both groups after 7 d, from 0.75 ± 0.20 ng/dl (11.5 ± 3.1 pmol/liter) to 0.46 ± 0.10 ng/d (7.1 ± 1.7 pmol/liter), P < 0.01, and from 0.58 ± 0.10 ng/dl (9.0 ± 1.2 pmol/liter) to 0.34 ± 0.03 ng/dl (5.2 ± 0.5 pmol/liter), P < 0.003, in groups A and B, respectively (P = NS). Serum free T₄ levels reduced at 6 months in group B [from 2.70 ± 0.32 ng/dl (35.1 ± 4.1 pmol/liter) to 1.0 ± 0.04 ng/dl (13.4 ± 0.6 pmol/liter), P < 0.0001] but not in group A (from 2.90 ± 0.6 ng/dl (38.0 ± 7.5 pmol/liter) to 2.30 ± 0.4 ng/dl (35.6 ± 6.1 pmol/liter, P = 0.39; P = 0.005 group B vs. group A). All patients in both groups became euthyroid and had their amiodarone-induced destructive thyroiditis cured as defined by normalization of both serum free T₄ and free T₃ levels, during both drugs therapy. However, patients in group B were cured more rapidly than patients in group A (43 ± 34 d vs. 221 ± 111 d, respectively, P < 0.002). This study shows that, albeit both drugs are effective, glucocorticoids are probably the drug of choice for more rapidly curing type II AIT.

	Introduction

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AMIODARONE, AN IODINE-RICH antiarrhythmic drug widely used for cardiac tachyarrhythmias (1, 2), shares some degree of structural homology with the thyroid hormones (3). Amiodarone invariably causes changes in thyroid function tests and, in about 15–20% of patients, overt thyroid dysfunction (4, 5). In contrast to amiodarone-induced hypothyroidism, management of amiodarone-induced thyrotoxicosis (AIT) represents a difficult challenge (6, 7) because this disorder is often resistant to thionamide treatment. Type I AIT is due to increased synthesis and secretion of excess amounts of thyroid hormone due to the iodine load in the presence of an underlying thyroid abnormality (autonomous goiter, Graves’ disease; Ref.4). In keeping with this pathogenic mechanism, type I AIT is usually treated with thionamides and often in combination with potassium perchlorate (KClO₄; Ref.4). In contrast, type II AIT is a destructive thyroiditis resulting in an increase in serum thyroid hormone concentrations due to leakage of stored hormones into the blood rather than to increased thyroid hormone synthesis (4). Glucocorticoids are the most effective treatment for this inflammatory process (7). Mixed forms may require both thionamides, KClO₄ and glucocorticoids. Restoration of euthyroidism by thionamides-KClO₄ in type I AIT may require several weeks to months, a continued risk for these patients, who have serious cardiac problems. However, patients with type II AIT may have a relapse of their thyrotoxicosis when glucocorticoids are tapered.

Oral cholecystographic agents (OCAs) affect the peripheral metabolism of the thyroid hormones, mainly by inhibiting peripheral monodeiodination of T₄ to generate T₃ (8, 9, 10). In patients with spontaneous hyperthyroidism, a 70% reduction in serum T₃ levels was observed as soon as 48 h after ipodate administration, with little changes in serum T₄ levels (9). However, long-term treatment with OCAs may result in a high rate of recurrence of hyperthyroidsm due to the escape phenomenon (11, 12). The use of OCAs for a mixed form of AIT was previously reported in a case report in association with thionamides, KClO₄ and glucocorticoids (13). Recently, OCAs have been used in combination with thionamides in the treatment of type II AIT: this therapy was associated with normalization of both serum free T₄ (FT₄) and free T₃ (FT₃) levels or the occurrence of hypothyroidism after 15–31 wk of treatment (14). OCAs have also been used for a rapid control of thyrotoxicosis before thyrodectomy in patients with refractory type I AIT (15).

We now report the results of a prospective randomized study carried out on 12 patients with type II AIT treated with either iopanoic acid (IopAc) or prednisone.

	Patients and Methods

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Patients

Twelve consecutive patients with untreated type II AIT were enrolled in a prospective randomized study after referral to the Department of Endocrinology, University of Pisa, during the period 1999–2000. Diagnosis of type II AIT was based on the following criteria: biochemical hyperthyroidism, absence of goiter, absence of thyroidal hypervascularization on color flow Doppler sonography (CFDS), low (<4%) to undetectable 24-h thyroid radioiodine uptake (RAIU), absence of circulating antithyroglobulin (TgAb), antithyroperoxidase (TPOAb) and anti-TSH receptor (TRAb) antibodies. Patients were randomly assigned to either group A (IopAc) or group B (prednisone).

IopAc (Cistobil, Bracco, Milan, Italy) was given orally, 500 mg twice/daily, until normalization of both serum FT₄ and FT₃ levels (see study design). Prednisone was given orally with a starting daily dose of 30 mg for 2 wk, gradually tapered and withdrawn after 3 months. Amiodarone was discontinued in all patients at the time of enrollment.

The study was approved by the institutional review committee, and all patients gave their informed consent.

Study design

Baseline evaluation included evaluation of thyroid function, thyroid ¹³¹I scan and 3-h and 24-h thyroid ¹³¹I uptake (RAIU) and thyroid ultrasonography and CFDS.

Serum free T₄ (FT₄) and T₃ (FT₃) and TSH levels were measured on the day when amiodarone was discontinued, every 7 d for the first month and then every month for the entire follow-up period. Thyroid ultrasonography and CFDS were performed as previously reported (16, 17) by the same physician (F.B.).

The amiodarone-induced destructive thyroiditis was considered cured when both serum FT₃ and FT₄ levels normalized, sharing previously reported criteria (14).

Assays

Serum FT₄ and FT₃ (Lisophase kits, Laboratory Bouty, Sesto S. Giovanni, Italy) and TSH (Auto-Delfia Wallac, Inc., Gaithersburg, MD) were measured by commercial kits. Normal ranges were: FT₄, 0.60–1.80 ng/dl (8.4–23.2 pmol/liter); FT₃, 0.25–0.55 ng/dl (3.8–8.4 pmol/liter); TSH, 0.4–3.7 µU/ml (0.4–3.7 mU/liter). Serum TRAb was measured by a radioreceptor assay (TRAK assay, BRAHMS Diagnostica, Berlin, Germany; normal values, less than 1 U/liter). Serum TgAb (Sorin Biomedica, Saluggia, Italy; undetectable in normal controls), and TPOAb (Serodia, Tokio, Japan; undetectable in normal controls) were determined by commercial kits. Urinary iodine excretion was measured using an autoanalyzer (Technicon, Rome, Italy). The median urinary iodine excretion in the Pisa area is 110 µg/liter. Thyroid RAIU values were measured 3 and 24 h after the administration of a tracer dose (5 µCi) of ¹³¹-I. Normal 24-h RAIU values in the Pisa area are 30–45%. Thyroid volume was measured by ultrasound using a 7.5-MHz linear transducer and calculated by the ellipsoid model: width x length x thickness x 0.52 for each lobe (17); normal values range from 6–16 ml.

Statistics

Baseline values were expressed as mean ± SD (or SE, as specified) for quantitative variables. The baseline characteristics of the two groups were compared by ANOVA. Most analyses were performed after log transformation. The cure of the destructive thyroiditis in the two groups was analyzed using survival curves at 12 months by the Kaplan-Meier method. Comparisons between nonremission curves were performed by the Mantel-Cox and Breslow-Gehan-Wilcoxon test. The time trend of FT₄ and FT₃ within each treatment was evaluated by ANOVA with repeated measures.

	Results

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The two groups of AIT patients did not differ in their clinical and biochemical features at baseline (Table 1). Reduction in serum FT₃ values occurred rapidly in both group A and group B, from 0.75 ± 0.20 ng/dl (11.5 ± 3.1 pmol/liter) to 0.46 ± 0.10 ng/dl (7.1 ± 1.7 pmol/liter; P < 0.01) and from 0.58 ± 0.10 ng/dl (9.0 ± 1.2 pmol/liter) to 0.34 ± 0.03 ng/dl (5.2 ± 0.5 pmol/liter; P < 0.003), respectively, after 7 d of therapy (Fig. 1). The time-trend of serum FT₃ levels evaluated at 6 months and at the end of the follow-up period showed a reduction in both groups (P < 0.004 in both groups). Serum FT₄ levels remained unchanged for several months in group A, whereas they normalized after 30 d in group B. The time trend of serum FT₄ evaluated at 6 months showed a significant reduction in group B patients [from 2.70 ± 0.32 ng/dl (35.1 ± 4.1 pmol/liter) to 1.0 ± 0.04 ng/dl (13.4 ± 0.6 pmol/liter), P < 0.0001] but not in group A patients [from 2.90 ± 0.6 ng/dl (38.0 ± 7.5 pmol/liter) to 2.30 ± 0.4 ng/dl (35.6 ± 6.1 pmol/liter), P = 0.39]; the difference between the two groups was statistically significant, P = 0.005). Serum TSH levels were in the normal range after 84 ± 43 d in group A and 40 ± 34 d in group B (P = 0.107). All patients in both groups had thyrotoxic symptoms at baseline, consisting mainly in worsening of their cardiac disease, which improved when they reached euthyroidism and had their amiodarone-induced destructive thyroiditis cured during either IopAc or glucocorticoid therapy. In particular, thyrotoxic symptoms of group A patients improved in association with fall in serum FT₃ levels. However, patients in group B were cured more rapidly than patients in group A (43 ± 34 d vs. 221 ± 111 d, respectively, P < 0.002 by the Mantel-Cox test; P < 0.004 by the Breslow-Gehan-Wilcoxon test; Fig. 2). In conclusion, all patients treated with prednisone achieved euthyroidism faster than any of the OCAs treated patients. Thyrotoxicosis recurred in two patients in group A after IopAc was discontinued; they became euthyroid after IopAc was reinstituted. All patients remained euthyroid after the drugs were discontinued in group B, and one patient in group A became hypothyroid. One patients in group B was treated with ¹³¹I after becoming euthyroid because it was necessary to begin amiodarone therapy again. IopAc did not cause any adverse side effects, whereas two patients treated with glucocorticoids had a slight increase in their blood pressure that did not require discontinuing therapy. Two patients in group A had worsening of their cardiac symptoms 6 and 8 months after starting IopAc.

View larger version (22K): [in this window] [in a new window]   Figure 1. Mean changes in serum FT3 (A) and FT4 (B) levels during iopanoic acid (closed circle) or glucocorticoids (open circles) treatment. Bars indicate SE. Serum FT3 levels decreased in both groups from 0.75 ± 0.20 to 0.46 ± 0.10 ng/dl, P < 0.01 and from 0.58 ± 0.10 to 0.34 ± 0.03 ng/dl, P < 0.003, in group A and group B, respectively, after 7 d; serum FT4 reduced significantly only in group B (P = 0.005 group B vs. group A). To convert values for serum FT4 to pmol/liter, multiply by 1.29. To convert values for serum FT3 to pmol/liter, multiply by 1.54.

View larger version (15K): [in this window] [in a new window]   Figure 2. Kaplan-Meier estimates the proportion of patients who remained hyperthyroid. The overall outcome of the two groups of patients was assessed by Mantel Cox test (P < 0.002). The rapidity of cure was assessed by the Breslow-Gehan-Wilcoxon test (P < 0.004). All patients in each group completed the 12-month period of observation. Open circles, group A; closed circles, group B.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

AIT is a major problem for patients with underlying cardiac disorders and, therefore, requires prompt restoration of euthyroidism. However, type II AIT associated with excess iodine is often refractory to conventional antithyroid drug treatment and usually cannot be treated with ¹³¹I because of the low thyroid RAIU (4). Thyroidectomy has a higher surgical risk, even though local anesthesia may be sufficient and safe in these patients (21) and treatment with IopAc rapidly restores serum FT₃ levels to normal before surgery (15). Patients with type II AIT usually do not require additional therapy once euthyroidism has been restored. Thus, effective medical therapy, to rapidly and permanently control the thyrotoxicosis is warranted in this subset of patients. OCAs inhibit type I 5'-deiodinase activity and thereby reduce peripheral T₃ production. Their action is rapid, and a 70% reduction in serum FT₃ concentration has been observed 48 h after initiation of treatment in patients with Graves’ disease (9). However, continued use of OCAs may be associated with a relapse of the thyrotoxicosis (12). Although OCAs may have other effects on thyroid hormone metabolism, such as a decrease in the proteolysis of thyroglobulin and thyroid hormone release (22), this is unlikely to play a role in type II AIT. Recently, Chopra and Baber (14) reported that five patients with type II AIT had normalization of both serum FT₄ and FT₃ after 15–31 wk of treatment with OCAs and thionamides. OCAs were also used in other form of destructive thyroiditis and their use was associated with improvement of thyrotoxic symptoms after restoration of euthyroidism in 6–10 wk (23).

The results of the present prospective, randomized study of 12 patients with type II AIT, demonstrate that both IopAc therapy and glucocorticoid therapy are associated with a rapid decrease in serum FT₃ levels. However, IopAc exerts its effect almost exclusively on the peripheral T₃ generation from T₄ but does not affect the underlying destructive thyroiditis; this may explain why IopAc-treated patients required a longer period of time than glucocorticoid-treated patients to achieve normal serum FT₄ values. Because type II AIT may spontaneously remit (24), IopAc controls thyrotoxicosis in the short-term due to its peripheral effect, whereas the long-term outcome of IopAc therapy rather reflects the natural history of the destructive process and perhaps the effect of excess iodine in inducing hypothyroidism after many forms of thyroiditis (25). The persistent elevation of serum FT₄ levels might reflect both the inhibition of type I 5'-deiodinase activity and the persistence of the ongoing, albeit declining, inflammatory process in the thyroid. In contrast, glucocorticoids, besides their inhibitory effect on type I 5'-deiodinase activity, exert their major effects on the inflammatory process itself, thus promptly reducing serum FT₄ levels. Thus, glucocorticoids act on the pathogenic mechanism causing type II AIT. The fact that two patients had a recurrence of thyrotoxicosis shortly after IopAc was discontinued favors of the suggested mechanisms of action of the drug. Thus, both serum FT₄ and FT₃ levels should be normal before considering patients with type II AIT cured. The fact that some patients in group A have normal serum TSH values in spite of sustained elevated serum FT₄ levels is consistent with the inhibitory effect of IopAc on pituitary deiodinase activity (26). Moreover, if in the short-term normalization of serum FT₃ levels but persistently elevated serum FT₄ values might permit safe thyroid surgery in type I AIT (15), it is possible that prolonged exposure to high levels of serum FT₄ might not be without adverse effects in patients with cardiac disorders; T₄, albeit weaker than T₃, interacts with thyroid hormone receptors and activates thyroid hormone-sensitive genes (3). It should be pointed out that two patients in group A had a worsening of their cardiac arrhythmias at 6 and 8 months of IopAc treatment and sustained high serum FT₄ levels. A longer follow-up period is required to ascertain whether the prolonged exposure to IopAc, an iodine-rich drug, may be associated with a higher incidence of spontaneous hypothyroidism. Roti et al. (27) reported that reexposure of AIT patients, when they were euthyroid, to an iodine load may be associated with a higher risk of developing hypothyroidism. The finding that one IopAc-treated patient developed permanent hypothyroidism supports the view that prolonged and uncontrolled destructive thyroiditis may cause a permanent damage of the thyroid. Whether a prompter control of the inflammatory process, as achieved by glucocorticoids, may prevent hypothyroidism should be confirmed in a large series of patients with type II AIT. Accordingly, glucocorticoids represent the treatment of choice for type II AIT (4, 6); IopAc is valid therapeutic option if glucocorticoid treatment is contraindicated or, as a short-term treatment, in the preparation to thyroid surgery (14, 15).

	Footnotes

 
This work was partially supported by grants from the University of Pisa (Fondi d’Ateneo) and Ministero dell’ Istruzione, dell’ Università, della Ricerca, Rome (to E.M.) and from the University of Insubria at Varese (to L.B.).

Abbreviations: AIT, Amiodarone-induced thyrotoxicosis; CFDS, color flow Doppler sonography; FT₃, free T₃; FT₄, free T₄; IopAc, iopanoic acid; KClO₄, potassium perchlorate; OCA, cholecystographic agent; RAIU, radioiodine uptake; TgAb, antithyroglobulin; TPOAb, antithyroperoxidase; TRAb, anti-TSH receptor.

Received November 27, 2002.

Accepted January 29, 2003.

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