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A 36-Year Retrospective Analysis of the Efficacy and Safety of Radioactive Iodine in Treating Young Graves’ Patients

Departments of Pediatrics and Radiology (Division of Nuclear Medicine), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Dr. Charles H. Read, 3 Glenview Knoll NE, Iowa City, Iowa 52240-9146. E-mail: charlesread{at}msn.com.

	Abstract

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This report details the 26- and 36-yr outcomes of 116 patients under the age of 20 yr with Graves’ disease who were treated with radioiodine between 1953 and 1973. Contacted by telephone and mail in 1991–1992, 107 of them supplied personal historical data, and their physicians furnished interval histories, physical examinations, and laboratory data. This was repeated in 2001–2002, with 98 of them being contacted. At the time of treatment, the patients’ ages ranged between 3 yr, 7 months and 19 yr, 9 months. Six were less than 6 yr of age, 11 were between 6 and 11 yr, 45 were between 11 and 15 yr, and 45 were between 16 and 19 yr. The average length of follow-up in 1991–1992 was 26.1 yr; that in 2001–2002 was 36.2 yr. None of the patients developed cancer of the thyroid or leukemia. Early on, when the objective of treatment was euthyroidism, the dose of radioiodine was low, and retreatment was frequently needed. Later, the doses used were increased. Over time, all but two patients became hypothyroid. Pregnancies did not result in an unusual number of congenital anomalies or spontaneous abortions. Treating young people with Graves’ disease with radioiodine is safe and effective over the long term.

	Introduction

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RADIOACTIVE IODINE HAS long been used to treat Graves’ disease in adults, but many physicians have been hesitant to use it as a therapy in hyperthyroid children and adolescents for fear these patients might later develop leukemia or cancer of the thyroid. Possible genetic damage to future generations was also a concern (1). The Chernobyl disaster, with the subsequent occurrence of thyroid cancer in children exposed to radiation as infants or young children, served to renew these worries (2). In 1998, Rivkees et al. (3) pointed out the need for long-term studies to define "the true risk of thyroid neoplasia in children treated with radioiodine."

The purpose of this study is to report the long-term outcomes of 116 Graves’ disease patients under the age of 20 yr who had been treated with radioiodine. Data included are the doses of ¹³¹I, including retreatments, thyroid or other malignancies, late recurrences of hyperthyroidism, the length of time to developing hypothyroidism, the number and outcomes of pregnancies, and the development of thyroid or other malignancies.

	Patients and Methods

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Cohort

In 1953 the Thyroid Group of University of Iowa Hospitals and Clinics, having become dissatisfied with antithyroid drugs and surgery as methods for treating Graves’ disease in young patients, decided to use radioactive iodine as their method of treating this group of patients. They had concluded that radioactive iodine would be the most effective and lowest risk therapy for treating Graves’ disease in the young and adopted it as their therapy of choice. The patients so treated in the years between 1953 and 1973 constitute the cohort herein reported.

Having obtained prior approval from the University of Iowa institutional review board in 1989 (renewed each year until 2003), the two original investigators, C.H.R. and R.C.P. (now incapacitated), searched the University of Iowa Hospital records for all patients under the age of 20 yr who, in the 20 yr between 1953 and 1974, had been treated for hyperthyroidism with ¹³¹I; 116 patients were identified, and their charts were reviewed to verify the diagnosis by history, physical examination, and elevated serum levels of protein-bound iodine before 1968, or T₄, serum protein-bound iodine, or T₄. Additionally, they made certain that the patients had elevated 24-h radioiodine uptakes.

In 1990–1991, C.H.R., the physician who had had the most contact with the patients and their families, used the last known telephone numbers to find and interview them. Virtually all had moved from where they had originally lived; 32 now lived in other states, and two lived in foreign countries. Of the original 116 patients, five could not be located, and two patients did not want to participate. The original number was further reduced by the early death of two of the female patients. A 17-yr-old died within 2 yr of treatment from necrosis of the liver. The other, an 18-yr-old with poorly controlled type 1 diabetes mellitus, died in another hospital 10 d after treatment, possibly from ketoacidosis or thyroid storm; the available data were insufficient to make a diagnosis. Data from these two patients are not included in this report, thus reducing the initial number of patients to 107 from whom follow-up data were obtained in 1991.

Ten years later (2001–2002), C.H.R. again attempted to contact the subjects from the previously identified patients. He could not find four of the original group of 107, and five had died, the causes of which are shown in Table 1. All but the first patient had autopsies, none of which showed any evidence of malignancy. The surviving 98 patients supplied data up-dated through 2001–2002.

The questions asked were the following. 1) Have you had a recurrence of hyperthyroidism; if so, when, where, how treated, and by whom? 2) Have you developed an underactive thyroid; if so, when, how treated, and what dose of T₄ are you using? 3) What other drugs are you taking regularly? 4) How many children have you borne or fathered, including the number of pregnancies, miscarriages, the number of normal children, and whether there were any problems present at birth? 5) Did or do your parents, brothers, or sisters have a goiter, under- or overactive thyroid, or other thyroid disease? 6) Do you or your parents, brothers, or sisters have diabetes mellitus, rheumatoid arthritis, lupus, or Addison’s disease? 7) Have you had any type of cancer? 8) What are the names and addresses of the physicians who are familiar with your health status and when were you last seen by that person or persons? 9) Would you like a written summary of this report?

Calculation of doses of ¹³¹I

The radiation dose to the thyroid was calculated using the Quimby-Marinelli formula (4): Radiation dose (cGy) = administered ¹³¹I activity (µCi) x % uptake (24 h) x 90/thyroid weight (g) x 100. This formula assumes a biological half-life of 24 d, which corresponds to an effective half-life of 6 d and provides reasonable estimates of radiation dose in the majority of hyperthyroid patients, but will significantly overestimate the dose in 10–15% of patients who have a rapid turnover of iodine (5). The ¹³¹I dose in the thyroid was calculated in microcuries per gram of thyroid tissue based on the 24-h uptake: ¹³¹I dose in thyroid (µCi/g) = administered activity (µCi) x % uptake at 24 h/thyroid weight (g) x 100.

	Results

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One hundred seven of the cohort were followed for an average of 26 yr; 98 of them were followed for an average of 36 yr. The data obtained are reported under separate headings: demographics, responses to various doses of radioiodine, malignancies, hypothyroidism, late recurrences, pregnancies, and hyperparathyroidism.

Demographics

At the time of their original diagnosis and treatment, the patients’ ages ranged from 3 yr, 7 months to 19 yr, 9 months. Six of the patients were younger than 6 yr, 11 others were under 11 yr, 45 were between 11 and 15 yr, and 45 were between 16 and 20 yr. The mean age of the 27 males was 15 yr, 8 months; that of the 82 females was 14 yr, 9 months. There were no statistically significant differences in the median or average ages of the two sexes. The range of ages of the 107 members of the cohort in 1991–1992 was 26–59 yr; the average was 40 yr. The interval between treatment and time of follow-up ranged from 17.0–37.1 yr; the average was 26.1 yr. The average age of the 98 patients in the 2001–2002 cohort was 48 yr; the range was 37–69 yr. The interval between treatment and time of follow-up was 27.8–48.7 yr; the average was 36.2 yr (Tables 2 and 3).

During most of the 1953–1973 treatment period, the therapeutic objective was to produce euthyroidism, so the doses of ¹³¹I were conservative. This resulted in 36% of the 107 patients who received 5.3 mCi or less still being hyperthyroid when they returned for a follow-up 3–5 months later and required one or more similar doses before they became euthyroid. Later, when the doses were increased to 6.0 mCi or larger, continuing hyperthyroidism was no longer seen (Fig. 1).

View larger version (19K): [in this window] [in a new window]   FIG. 1. 131I dose and retreatment.

These results are mirrored when the dose given was administered as microcuries per gram of thyroid tissue. Twenty-six patients who received an average of 47.3 µCi/g became euthyroid without further treatment, but 13 whose average dose was 30.7 µCi/g required one or more additional treatments. Three patients who received low doses (18.0, 18.0, and 16.4 µCi/g thyroid tissue, respectively) became euthyroid and eventually hypothyroid with no further treatment; they remain free of thyroid cancer.

The charts contained no record of instances of vomiting or headache after ingestion of radioiodine. After 1968, propanolol was used to ameliorate the patients’ thyrotoxic symptoms.

Hypothyroidism

One year after radioiodine therapy, 34 (32%) of the patients were hypothyroid, as determined by low serum protein-bound iodine or T₄, low radioactive iodine uptake, and later, when the test became available, elevated sTSH values. This high percentage of hypothyroidism 1 yr after treatment was due in part to the cumulative effect of the two, three, or in one instance four relatively small doses of radioiodine. By 1968, it had become evident that hypothyroidism occurred even when the dose of radioiodine had been low, so the dose was increased to determine the amount of radiation that would rapidly ameliorate the hyperthyroidism. Subsequent to the first year, hypothyroidism occurred at the rate of 2.9%/yr. This is depicted in Fig. 2.

View larger version (20K): [in this window] [in a new window]   FIG. 2. Time to hypothyroidism.

Recurrences at least 8 yr after ¹³¹I treatment

Six of the patients, ranging in age from 4 yr, 6 months to 16 yr, had recurrences of their hyperthyroidism 8 yr or more after their original treatment. Two of the females who had been euthyroid for 10 and 18 yr needed retreatment. Another female had a recurrence after 10 yr of euthyroidism, was again treated, and, after another 10 yr, became hyperthyroid a third time. A fourth female, who had a recurrence after being euthyroid for 15 yr, was treated with subtotal thyroidectomy; microscopic examination of the tissue showed no evidence of cancer. A male of 12 yr was euthyroid for 21 yr before needing therapy, whereas a 14-yr, 6-month-old male was hypothyroid and treated with L-T₄ for 16 yr, when he again became hyperthyroid.

Pregnancies

Of the females, 62 had total of 179 pregnancies. There were 19 spontaneous abortions, five induced abortions, and two ectopic pregnancies. Three of the offspring were stillborn, two were premature babies who died within 12 h of birth, and six had congenital anomalies: one hare lip, one Shone syndrome, one club foot, one hydatidiform mole, one misplaced ureter, and one hydrocele.

One female was treated with radioiodine inadvertently 1 wk after missing her menstrual period; she delivered a normal child. Eighteen females had no pregnancies. Thirteen remained single. One had an aspermic husband, and four, who were married, remained childless.

Eighteen of the 27 males fathered 36 pregnancies, resulting in 33 normal children, three spontaneous abortions, and no congenital abnormalities. The remaining nine males fathered no pregnancies. Of these, five remained single, one married a postmenopausal woman, two had wives who were unfertile, and one was fertile, as was his wife, but no pregnancies resulted. The frequency of congenital anomalies in the offspring of this cohort treated with radioiodine was 3.2%, within the expected rate of 3–4% (6).

Occurrence of hyperparathyroidism

One of the patients treated with radioiodine at age 16 yr developed hyperparathyroidism 14 yr later and was treated surgically.

Malignancies

The subjects were asked if they had developed any malignancy at the time of the 1990–1991 and 2001–2002 surveys; their physicians confirmed their answers. After 36 yr, none of above patients has developed either cancer of the thyroid or leukemia. One patient has had cancer of the colon, and one has had cancer of the breast. Two developed a single thyroid nodule; biopsies of the thyroid nodules in these two patients were benign.

An unexpected result was that after receiving the questionnaire and visiting their physicians, 17 patients whose thyroid status had not been evaluated for some time discovered, on the basis of their physical examinations and especially their T₄’s and TSH results, that they were hypothyroid and began replacement therapy. This indicates that even patients who have been euthyroid for years after treatment with radioiodine should be monitored for the high possibility of becoming hypothyroid.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The Thyroid Group’s original plan was to achieve euthyroidism using minimal amounts of radioiodine. Over time it became evident that more than one small dose was frequently necessary to achieve that goal. Also recognized was the great variability from one patient to another in the amount of radioiodine needed to produce the euthyroid state. A dose of radioiodine that caused hypothyroidism in some patients had little effect in others. Finally, it was decided to use a dose that would ablate the thyroid, and the doses of radioiodine were increased to find that dose. An additional consideration was that by destroying more thyroid tissue, the risk of thyroid malignancies would be reduced. The ablating doses of radioiodine described herein are much lower than those now frequently used to ablate the thyroid (7, 8).

Ever since Chapman (9) introduced radioiodine as a method of treating hyperthyroidism over 60 yr ago, there has been concern about its potential for producing malignancies, especially in the thyroid. Having been used in more than 2 million adults, it is now regarded as safe to use in this age group (10). In children, this concern has lingered (1). In a comprehensive review of the use of radioiodine in young people, Rivkees et al. (3) pointed out that thyroid malignancies in children have occurred in only four cases, all of whom received small or moderate doses of radioiodine. In the present report, the three patients who received very low doses continue to be cancer free many years later, as are all of the other patients.

The lack of long-term studies of children with Graves’ disease who were treated with radioiodine has left unanswered many questions about potential complications. In this report, the 107 children, adolescents, and youth followed for an average of 26 yr have had no complications. The 98 patients who were followed for an average of 36 yr still have had no thyroid problems, other than hypothyroidism.

Initially, the recurrence of hyperthyroidism after several years of hypothyroidism was a surprise, especially in the patient who had recurrences after 10 and then 20 yr of euthyroidism. Noteworthy was the patient treated with T₄ for 16 yr, who then had a recurrence. Similar experiences have been reported previously by Abrams and Sander (11).

Being treated with radioiodine at a young age did not have a deleterious effect on the progeny of either the male or female subjects. Also, neither the number of miscarriages nor that of congenital anomalies was abnormal, a finding in accord with other studies (12, 13, 14, 15, 16, 17, 18).

One patient in this study who was treated with radioiodine at age 16 yr developed hyperparathyroidism 14 yr later. In 1975, Rosen et al. (19) was the first to note that after a long latency period hyperparathyroidism had developed in a patient treated with radioiodine for Graves’ disease and later added an additional case (20). In 1983, Esselstyn et al. (21) reported that four of 159 radioiodine-treated patients developed hyperparathyroidism after 6–25 yr, which was several times greater than expected. External radiation may also lead to hyperparathyroidism after 20 yr and is dose related (22), supporting the belief that this phenomenon is not a coincidence. Ito et al. (23, 24) reported that hyperparathyroidism is more likely to occur in hyperthyroid patients treated with radioiodine than in those treated with antithyroid drugs. Although hyperparathyroidismn is an uncommon complication, there may be an increased incidence after radioiodine therapy.

In conclusion, the data presented in this paper show that in a cohort of 107 people under the age of 20 yr, followed for 26 yr, 98 of whom were followed for 36 yr, there was not a single case of cancer of the thyroid or leukemia or any other deleterious effect. All but two of them are hypothyroid. The authors are unaware of any other study in which as large a group of young hyperthyroid patients was treated with radioiodine and subsequently followed for as many years.

Hamburger (17) once observed that treating young Graves’ disease patients with radioiodine is "safe, effective, and economic." Although we have no data to show that it is economic, we can add "over the long term."

	Acknowledgments

 
This study could not have been performed without the cooperation and interest shown by the patients, their parents, their friends, and their doctors. In 1953 the Thyroid Group consisted of Drs. E. Degowin (deceased) and H. Hamilton (deceased; Internal Medicine); and J. Buckwalter, Jr. (deceased), E. Mason, and R. Soper (Surgery), and T. Evans (deceased; Radiation Research). One of the authors (C.R.; Pediatrics) joined the group in 1954, agreed with their decision, and began keeping a record of the patients under the age of 20 yr, the purpose being to be able to conduct a long-term follow-up. Dr. R. Peterson (incapacitated; Nuclear Medicine) became a member in 1963 and was increasingly responsible for deciding the amount of radiation to be administered.

	Footnotes

 
C.H.R. underwrote the expenses involved in the study in 1991–1992. In 2001–2002, the major part of the expenses was paid for by the Department of Pediatrics, Dr. Frank Morriss, Head.

Abbreviation: sTSH, Serum TSH.

Received July 15, 2003.

Accepted April 14, 2004.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Read, C. H. Articles by Menda, Y. Search for Related Content PubMed PubMed Citation Articles by Read, C. H., Jr. Articles by Menda, Y.