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Influence of Iodine-131 Dose on the Outcome of Hyperthyroidism in Children

From the Departments of Pediatrics and Diagnostic Imaging, Yale University School of Medicine, New Haven, Connecticut

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	ABSTRACT

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Objectives. Iodine-131 is an effective treatment for Graves’ hyperthyroidism in children and adults. Yet the responses to treatment as related to iodine-131 dose in children are not well-defined. The objective of this study was to examine the relationship between the dose of iodine-131 in children with hyperthyroidism and thyroid status 1 year after treatment.

Methods. We examined the outcome of iodine-131 treatment in children and adolescents with Graves’ disease, as related to dose. Three iodine-131 doses were compared: 72 to 108 Gy (80–120 µCi/g), 180 to 225 Gy (200–250 µCi/g), and 270 to 364 Gy (300–405 µCi/g) in 31 patients ranging in age from 7 to 18 years old. Thyroid status was assessed >1 year after therapy.

Results. We found that doses of 100 Gy (110 µCi/g), 200 Gy (220 µCi/g), and 300 Gy (330 µCi/g) resulted in hypothyroidism in 50%, 70%, and 95% of treated individuals, respectively. These data show that to insure ablation of thyroid tissue doses, >270 Gy (300 µCi/g) is needed, especially when the thyroid is large.

Key Words: thyroid • hyperthyroidism • Graves’ disease • radioactive iodine

Abbreviations: CTTFS, Cooperative Thyrotoxicosis Therapy Follow-up Study • rem, roentgen-equivalent-man

	INTRODUCTION

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Graves’ disease is the most common cause of hyperthyroidism in children.^1–3 Treatments for Graves’ disease include the use of antithyroid medications, thyroidectomy, and radioactive iodine.^1–3 Although antithyroid medications are commonly used as first-line treatment, only 20% to 30% of pubertal and 15% of prepubertal individuals treated medically will experience long-term remission.^4–7 Thus, either surgery or radioactive iodine is needed to achieve long-term cure for most pediatric patients with Graves’ disease.

Radioactive iodine was introduced for the treatment of Graves’ disease in children >50 years ago.⁸ In the years since, the use of radioactive iodine to treat Graves’ disease has been reported for >1000 children, with administered iodine-131 doses ranging from 50 to 400 µCi/g.^4,9–16 Follow-up studies have not revealed increases in rates of thyroid cancer or genetic abnormalities in children or in the offspring of such children treated with moderate or high doses of radioactive iodine.¹⁷ These observations coupled with disappointing results associated with medical therapy for most patients have lead to the increased use of radioactive iodine for treating Graves’ disease in children.^7,15 However, there is still a paucity of long-term follow-up data from children who have been treated with radioactive iodine, and the responses to treatment as related to iodine-131 doses in children are not well-defined.

In adults with Graves’ disease, therapy outcome is related to the administered dose. A radiation-absorbed dose of 200 Gy, which is equivalent to an iodine-131 dose of 220 µCi/g of thyroid tissue, results in hypothyroidism in 44% of patients.¹⁸ A radiation-absorbed dose of 300 Gy (330 µCi/g) results in hypothyroidism in 66% of patients, and 400 Gy (440 µCi/g) results in hypothyroidism in 80% of patients.¹⁸

Although the use of iodine-131 for the treatment of childhood Graves’ disease has been widely reported,⁷ the doses used vary markedly among institutions.^{3,4,7,9,10,12,14–17,19} It is also not known if iodine-131 dose-response relationships are similar in children and adults. To provide insights into these issues, we have examined outcomes of iodine-131 treatment as related to dose.

	METHODS

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The medical records of all pediatric patients (<18 years old) at Yale New Haven Hospital who received a single treatment of radioactive iodine for Graves’ disease from 1991 to 2001 were examined. The Yale University Medical School Human Investigations Committee approved this review.

Standard criteria^1,3 were used to diagnose Graves’ disease including elevated thyroxine and/or triiodothyronine levels, suppressed thyrotropin concentrations, elevated levels of thyroid-stimulating antibodies, the presence of goiter, ophthalmopathy, and diffuse and elevated uptake of iodine-123 within the thyroid.

Iodine-131-absorbed radiation doses were based on the Quimby-Marinelli equation: dose (ß + radiation; in Gy) = 90 x [oral iodine-131 dose (µCi) x oral 24-hour uptake (%)/g x 100%], assuming a half-life of 6 days for iodine-131.²⁰ Thyroid size was determined by palpation and ultrasound (ultrasound volume = 0.48 x length x width x depth).²¹ Twenty-four-hour iodine uptake was determined from an oral dose of 100 µCi of iodine-123 that was administered 2 or 3 days before iodine-131 treatment. In general, the doses of radioactive iodine used at our institution increased over the past 10 years, providing a range of radioactive iodine doses for outcome analysis.

After radioactive iodine treatment, thyroid function tests were obtained every 1 to 4 months. When thyroxine values fell below 5 µg/dL and/or thyrotropin levels increased above 20 µU/mL, replacement therapy with levothyroxine was initiated. The minimum follow-up period for each patient who became hypothyroid was 12 months. The minimum follow-up period for patients who remained hyperthyroid or euthyroid was 30 months.

Regression analysis and 95% confidence intervals were calculated using GraphPad Prism (GraphPad, San Diego, CA).

	RESULTS

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The age range of patients treated with iodine-131 for Graves’ disease was 7 to 18 years old. There were 9 males and 22 females. One patient received no medical therapy, and the other 30 patients were initially treated with antithyroid medication for 4 to 38 months (60% with propylthiouracil, 40% with methimazole). Treatment with radioactive iodine was performed due to the absence of remission after medical treatment for >9 to 38 months (71%) or the development of a presumed toxic reaction to antithyroid medication (29%; arthralgias, rash, hepatitis, myositis, granulocytopenia, mucositis). Antithyroid medication was discontinued 4 to 7 days before radioactive iodine uptake tests and treatment.

After administration of iodine-131, patients were treated with either propranolol or atenolol to control symptoms of hyperthyroidism until hyperthyroxinemia abated. Patients were not restarted on propylthiouracil or methimazole unless they had persistent hyperthyroidism. No individuals sought medical attention for tenderness over the thyroid after treatment and no individuals developed thyroid storm. Five days after treatment, 1 individual who could not be treated with ß-blockers developed palpitations that required medical attention.

Based on the doses of iodine-131 administered, patients were stratified into 3 groups: 72 to 108 Gy (80–120 µCi/g), 180 to 225 Gy (200–250 µCi/g), and 270 to 364 Gy (300–405 µCi/g) (Table 1). Seven patients received doses between 72 and 108 Gy. Following treatment, 2 patients remained hyperthyroid, 2 patients were euthyroid, and 3 patients were hypothyroid. Eight patients received doses between 180 and 225 Gy. Three patients remained hyperthyroid, no patient remained euthyroid, and 5 patients were hypothyroid. Sixteen patients received doses between 270 and 364 Gy. No patients remained hyperthyroid, 1 patient remained euthyroid, and 15 patients developed hypothyroidism. The relationship between iodine-131-absorbed radiation dose and the incidence of hypothyroidism was statistically significant (r = 0.98; P < .01; Fig 1).

View larger version (28K): [in this window] [in a new window]   Fig 1. Relationship between thyroid radiation dose and hypothyroidism rate in our patients who were <18 years old. The shaded area shows the 95% confidence interval; r = 0.98, P < .01.

View larger version (15K): [in this window] [in a new window]   Fig 2. Therapy outcome as related to dose and thyroid gland size. Each character represents an individual patient.

For those individuals who developed hypothyroidism, the time to hypothyroidism was 7 to 12 weeks for children treated with 72 to 108 Gy, 4 to 16 weeks for children treated with 180 to 225 Gy, and 4 to 16 weeks for the children treated with 270 to 364 Gy. No individual who became hypothyroid and was started on replacement therapy developed recurrent hyperthyroidism.

	DISCUSSION

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Increasing evidence suggests that hypothyroidism should be a goal of therapy when using iodine-131 to treat Graves’ disease in children. First, rates of relapse are lower in individuals rendered hypothyroid than euthyroid.^18,22 Second, the long-term risks of thyroid cancer appear to be lower when the thyroid gland is substantially ablated than when residual thyroid tissue remains.^23,24

Data from the Cooperative Thyrotoxicosis Therapy Follow-up Study (CTTFS) show that thyroid neoplasm risk is increased in children with Graves’ disease when the thyroid is irradiated, but not destroyed. When children were treated with low doses of radioactive iodine (<75 µCi/g) and rendered euthyroid, a high incidence of thyroid adenomas was observed (5 of 19 patients).^24,25 In contrast, when higher doses of radioactive iodine were used in children and patients received exogenous thyroid medication, only 1 in 303 individuals developed a thyroid adenoma.²⁴ We are also aware of malignancies of the thyroid gland described in case reports involving 4 children following iodine-131 treatment of childhood Graves’ disease.^10,25–29 In each of these circumstances, low doses of 131-iodine were given (5 years old, 50 µCi/g; 9 years old, 5.4 mCi; 11 years old, 1.25 mCi; 16 years old, 3.2 mCi).^10,25–29

CTFFS data also suggest that the amount of residual thyroid tissue after treatment of Graves’ disease plays an important role in determining the long-term risks of thyroid cancer in adults.²⁴ Thyroid cancer risks are 10- and 8-fold lower in patients treated with surgery or iodine-131 than in patients treated with antithyroid medications alone.²⁴ These favorable differences are believed to reflect less residual thyroid mass in surgically or iodine-131 treated than in medically treated patients,²⁴ and are not surprising as Graves’ disease itself may increase the risk of thyroid cancer.³⁰

Treating adults, relatively high doses of radioactive iodine are needed to consistently achieve hypothyroidism. If Graves’ disease is not present and complete destruction of the thyroid is desired, 300 to 500 Gy are necessary.³¹ When Graves’ disease is present, >400 Gy are needed to achieve hypothyroidism in >80% of individuals.²¹

In comparison with adults,^21,22 our findings suggest that the thyroid gland of children and adolescents is more sensitive to the destructive effects of radioactive iodine. Whereas 200 Gy of absorbed radioactivity results in hypothyroidism in 44% of adults with Graves’ disease,²¹ 100 Gy achieves hypothyroidism in 50% of pediatric patients, 200 Gy results in hypothyroidism in 70%, and hypothyroidism is generally assured if doses >270 Gy are used. However, it is important to note that the outcome data reported for adults by Peters and coworkers¹⁸ is based on a German population, and may not be directly comparable to our findings. Yet, our findings generally agree with observations of others showing that 90 Gy results in hypothyroidism in <50% of children, and 200 Gy results in hypothyroidism in 70% to 80%.^{4,11,12,14,16}

As reported in adults,^21,22,32 we find that outcome of treatment is influenced by the size of the thyroid gland. When children with relatively large thyroid glands (61–80 g) were treated with 72 to 225 Gy, hypothyroidism is not seen in most patients. However, hypothyroidism occurred in children with large glands (61–80 g) treated with >270 Gy. We do not have data for children with thyroid glands larger than 80 g treated with iodine-131, as these patients are usually referred for surgery.

In addition to selecting a dose that will achieve the desired outcome, the age of the patient and the total iodine-131 dose needs to be considered when treating children with radioactive iodine. Total-body radiation doses following iodine-131 vary with age, and the same absolute dose of iodine-131 will result in more radiation exposure to a young child than to an adolescent or adult.^33,34 At 0, 1, 5, 10, 15 years of age, and in adulthood, respective total-body radiation doses are 11.1, 4.6, 2.4 1.45, 0.90, and 0.85 roentgen-equivalent-man (rem)/mCi of iodine-131.³³ Based on the Biological Effects of Ionizing Radiation Committee V analysis of external radiation exposure, the theoretical risk of cancer death following acute radiation exposure is 0.16% per rem for children and 0.08% per rem for adults,^35–37 although there is uncertainty associated with these projections.^35–37 Thus, if the same 10-mCi dose is given to a 10-year-old child and an adult, total body doses will be 14.5 and 8.5 rem, respectively, and the theoretical risks of cancer mortality will be 2.2% and 0.68%. These values can be compared with the natural lifetime risk for cancer death of 20%.^35,37

At present, data are not available to assess actual lifetime cancer risks in children treated with iodine-131 or medication for Graves’ disease. In adults with hyperthyroidism in the original CTTFS cohort, the total number of cancer deaths was close to that expected based on mortality rates in the general population (2950 vs 2857).²³ Yet, increased cancer mortality was seen among patients treated exclusively with antithyroid drugs.²³ Radioactive iodine was not linked to total cancer deaths or to any specific cancer with the exception of thyroid cancer, which in absolute numbers was very small.²³ In these cases the underlying thyroid disease, rather than iodine-131 therapy, was concluded to play a role in malignancy pathogenesis.²³ Although the CTTFS and other reports provide insights into therapy outcome in children and adolescents with Graves’ disease,^{9,10,12–14,24} large-scale studies involving individuals treated as children and adolescents have not been performed to assess long-term outcome as related to age, treatment modality, dose, and residual thyroid tissue.

	CONCLUSIONS

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We report that low doses of iodine-131 can induce hypothyroidism in some children, yet to insure ablation of thyroid tissue, doses >270 Gy (300 µCi/g) are needed, especially when the thyroid is large. Further studies are indicated to assess if the long-term risks of ablative iodine-131 therapy for childhood Graves’ disease are less than those associated with subablative doses of iodine-131 or exclusive medical therapy.

	ACKNOWLEDGMENTS

 
Special thanks goes to Drs Thomas Carpenter and Myron Genel (Yale University, New Haven, CT) for providing clinical data for analysis, and to Dr Richard Toohey (Radiation Internal Dose Information Center, Oak Ridge, TN) for providing valuable insights.

	FOOTNOTES

 
Received for publication Apr 15, 2002; Accepted Sep 11, 2002.

Address correspondence and reprint requests to Scott A. Rivkees, MD, Department of Pediatrics, Yale University School of Medicine, P.O. Box 208081, New Haven, CT 06520-8081. E-mail: scott.rivkees{at}yale.edu

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