Effects of short-term potassium iodide treatment for thyrotoxicosis due to Graves disease in children and adolescents

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Abstract

Introduction

Thyrotoxicosis is a disorder of excessive thyroid hormone production, while hyperthyroidism specifically refers to the increased synthesis and secretion of thyroid hormone. The most common cause of thyrotoxicosis is Graves disease (GD), in which autoantibodies bind to and stimulate thyroid-stimulating hormone (TSH) receptors on the surface of thyroid follicular cells, resulting in excessive production and release of triiodothyronine (T3) and thyroxine (T4)1). GD is the most common cause of hyperthyroidism in children2), accounting for approximately 10%-15% of childhood thyroid diseases3). The incidence of GD rises from 0.1 per 100,000 in young children to 3 per 100,000 in adolescence4) with higher annual global rates of 14.1 per 100,000 including Hong Kong5).

Although mortality is rare, thyrotoxicosis is associated with palpitations, weight loss, impaired skeletal mineralization, behavioral problems, poor academic performance, and detrimental effects on children and adolescents3,6). Prompt and aggressive treatment of hyperthyroidism is essential to avoid these associated mortality and morbidity. Antithyroid drugs (ATD), surgical resection, and radioactive iodine therapy are three major treatment options for Graves hyperthyroidism. Although most pediatric endocrinologists agree that ATDs should be the first line of treatment in children, the optimal treatment for hyperthyroidism remains controversial7).

Inorganic iodide has been used in combination with ATDs to achieve rapid normalization of thyroid hormone levels in severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy8). While previous studies have not shown treatment effectiveness using combined ATDs and potassium iodide (KI) to be superior to ATDs alone9,10), some recent studies reported improved short-term control of Graves hyperthyroidism in adults with combined methimazole (MMI) and KI treatment11). The purpose of the present study was to investigate clinical characteristics of childhood thyrotoxicosis and effectiveness of KI as an early phase treatment.

Materials and methods

Results

Of the 67 children, 53 were girls (79%) while 14 (21%) were boys. The average age at onset was 11.1±3.4 years. A positive family history was obtained in 32 patients (47.7%). A first-degree relative was involved in 20 patients (30%): 4 simple goiter, 11 hyperthyroidism, 3 hypothyroidism, 1 thyroiditis, and 1 thyroid cancer. The mean body weight and height were 40.2±13.9 kg and 146.9±21.6 cm, respectively (Table 1).

Table 1.

Characteristics in 67 children and adolescents at onset of thyrotoxicosis

Sixty children (89.6%) presented with goiter while ophthalmopathy was found in 34 children (50.7%) (Table 2). All patients had increased serum free T4 (mean, 3.89 ng/dL; range, 1.23-7.98 ng/dL), T3 (mean, 439 ng/dL; range 108-1748 ng/dL) and suppressed TSH levels (mean, 0.04 µIU/mL; range, 0.01-0.19 µIU/mL) at initial diagnosis.

Table 2.

Presenting features of children and adolescents with thyrotoxicosis

All patients (n=67) received ATDs (either PTU or MMI) while 18 patients (27%) were treated with a combination of ATD and KI. The levels of thyroid antibodies at initial presentation and eight weeks later demonstrated no significant differences between groups (Table 3). No significant differences were found between serum levels of free T4, T3, and TSH at initial diagnosis, but mean free T4 values were significantly lower (P<0.05) in the group receiving combined therapy of ATD+KI, after two weeks of treatment (Fig. 1A). Similarly, serum T3 levels rapidly decreased after two weeks of treatment and mean levels were significantly lower (P<0.05) in the group receiving combined therapy compared with those of the patients receiving ATD alone (Fig. 1B). Serum TSH levels after two weeks of treatment showed no significant differences between two groups (Fig. 1C). Serum levels of free T4, T3, and TSH showed no significant differences between two groups after eight weeks of treatment. No treatment-related adverse effects such as hypothyroidism were observed in both groups.

Table 3.

Serum levels of thyroid antibodies at onset and after 8 weeks of treatment

Fig. 1

Serial changes in serum free T4 (A), T3 (B), and TSH (C) in two groups. Open column indicates ATD alone group and shaded column indicates ATD+KI group. Significantly different at P<0.05 (^*) between groups receiving ATD alone and those receiving combined therapy. T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone; ATD, antithyroid drug; KI, potassium iodide.

Discussion

The current study assessed clinical characteristics of 67 pediatric patients diagnosed with thyrotoxicosis due to GD. Additionally, ATD monotherapy was compared with combined treatment of ATD and KI in terms of rapid normalization of thyroid hormones during the early phase. Most patients were female with an average age at presentation of 11.1 years, which was comparable to other studies12). The common clinical features observed in the patients at initial diagnosis were goiter (89.6%), exophthalmos (50.7%), weight loss (44.8%), tachycardia (44.8%), and palpitation (41.8%), which were similar to those noted in adults1). Although assessments of personality change or abnormal behavior were not included in our study, previous studies have reported behavioral problems such as lack of concentration, delayed advancement in school, perversity and enuresis13), as presenting features of thyrotoxicosis in children. When combined ATD and KI treatment was compared with ATD monotherapy, we clearly observed more effective reduction of free T4 and T3 by combined therapy than ATD monotherapy after 2 weeks of treatment. However, there was no significant difference in the serum free T4 and T3 values between two groups after 8 weeks of treatment. A previous study described that the beneficial effect of KI in hyperthyroidism was only temporary14). Moreover, another study reported that KI treatment alone in GD produced only short term control of severe symptoms in hyperthyroidism and that its use hindered the efficacy of following treatment with ATD15). In a recent Italian study, the combination of ATD with KI was not superior to ATD alone in the normalization of serum thyroid hormone concentrations. On the other hand, serum T3 levels as well as heart rates were more rapidly reduced when sodium ipodate was added to ATD10). A more recent study showed that combined treatment with ATD and KI enhanced the short-term control of Graves hyperthyroidism in adults11), but there have been few reports describing the effect of combination therapy of ATD with KI in childhood thyrotoxicosis.

A decreased secretion of thyroid hormones by inorganic iodine could have been brought about in several ways including an inhibition of thyroid hormone synthesis, a decrease in the fractional rate of hormone release, or both. The inhibition of organic binding of iodide in the thyroid gland by administration of a large amount of nonradioactive iodide, resulting in the reduction of thyroid hormone synthesis, is termed as the Wolff-Chaikoff effect (WCE). This effect can occur in patients with thyrotoxicosis16). Inorganic iodide is absorbed rapidly into the circulation and by the thyroid. In larger amounts, it immediately blocks further uptake of iodide by several means, particularly by saturating the iodide transport mechanisms of the thyroid, and by inhibiting the intrathyroidal organification of iodide. Although the exact mechanism of WCE remains speculative, elevated intrathyroidal iodide concentrations apparently induce decreased availability of hydrogen peroxide for iodination reactions17). Even if a decrease in synthesis occurs during iodide administration, several lines of evidence indicate that the major effect of iodide is to inhibit the release of thyroid hormones18). At the present time, iodide is primarily used in conjugation with ATDs to prepare patients for thyroidectomy19), rather than the use of iodide alone as definitive therapy for thyrotoxicosis.

In this study, more rapid reduction of thyroid hormones by combination therapy with ATDs and KI than with ATD monotherapy was observed in children and adolescents diagnosed as thyrotoxicosis due to GD. Although it is well known that use of KI as monotherapy may result in escape from control of thyrotoxicosis20), our study shows that this does not occur when KI is administered simultaneously with ATDs. We did not observe a reduction in the efficacy of ATDs by KI.

The study limitations include the retrospective use of clinical data, the relatively small number of patients and the use data at one institution. However, this is the first report on the effect of combination treatment of inorganic iodide and ATD in childhood thyrotoxicosis, and we expect that double-blinded randomized controlled studies would provide more compelling outcome in future.

In conclusion, more rapid normalization of thyroid hormones was achieved in the group with combined treatment of ATD and Lugol's solution, than the group treated with ATD alone in our 10-year retrospective study. Although no statistical difference was found between the two groups in later follow-up evaluations, we suggest that the use of Lugol's solution in combination with ATD during the initial phase of treatment is beneficial in alleviating the symptoms and signs by more effective normalization of thyroid hormones in childhood thyrotoxicosis. A larger study with adequate power should be undertaken to examine the effect of Lugol's solution in childhood thyrotoxicosis.

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