Department of Pediatrics Yale University New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Scott Rivkees, M.D., Department of Pediatrics, Yale Child Health Research Center, 464 Congress Avenue, Room 237, New Haven, Connecticut 06520.
More than 50 yr have passed since radioactive iodine therapy was introduced for treating hyperthyroidism caused by Graves disease (1). Although few untoward effects have become manifest, concerns remain about potential long-term side effects of radioactive iodine use in the pediatric population. Thus, many physicians avoid this highly effective therapeutic option in favor of prolonged treatment with antithyroid medication or surgery. The report by Read et al. (2) detailing favorable outcomes nearly four decades after children and adolescents received radioactive iodine treatment suggests that fears of radioactive iodine use in children do not stand on strong legs.
Radioactive iodine therapy of Graves disease grew out of collaborative efforts in the 1930s and 1940s of physicists at the Massachusetts Institute of Technology (MIT) and clinicians at the Massachusetts General Hospital (Drs. J. Howard Means, Earle M. Chapman, and others) (1). As best can be determined, the first pediatric patient with radioactive iodine was also treated at Massachusetts General Hospital by Dr. John D. Crawford and colleagues. In the 1960s and 1970s, several groups reported their experience using radioactive iodine to treat childhood Graves disease (3, 4, 5, 6, 7, 8, 9). These reports showed both safety and efficacy in children. Thus, radioiodine therapy use became more widespread and extended progressively to younger children.
The use of radioactive iodine has now been detailed for more than 1000 children (10). These studies have found gratifying remission rates that top 95% and very few complications (10). Whereas the potential of worsening eye disease has been reported in a small percentage of adults who have received I-131 (11), this does not appear to be a problem in children (9), who have less severe eye disease in Graves disease than adults. There is also no evidence of increased risk of birth defects in the offspring of individuals treated with I-131 as children (10).
There have been a few black marks associated with I-131 use in the pediatric age group. In the early days of I-131 therapy of Graves disease, the use by todays standards of relatively low doses of radioactive iodine (<75 mCi/g of thyroid tissue) was associated with an increased risk of benign thyroid neoplasms in children (12). Thyroid cancer has also been reported in a few children who have received I-131 treatment for thyrotoxicosis; these children had received low doses of I-131 as well (10).
These observations of tumor occurrence are consistent with the fact that low-level thyroid irradiation in children increases the risk of thyroid malignancy (13, 14), sorrowfully exemplified in the children exposed to radioactive iodine isotopes after the explosion of the Chernobyl nuclear reactor (15). On the other hand, the risk of thyroid cancer does not appear to be increased when radioactive iodine is given in doses in excess of 150 mCi/g. Thus, when using I-131 in children for Graves disease therapy, it is important to avoid low doses (16, 17).
When treating children with radioactive iodine, in addition to selecting a dose that will achieve thyroid tissue destruction, the age of the patient and the total I-131 dose need to be considered. Total-body radiation doses after I-131 vary with age, and the same absolute dose of I-131 will result in more radiation exposure to a young child than to an adolescent or adult (17, 18, 19). Yet, we do not have good dosimetry information regarding I-131 use in children with Graves disease to assess actual total body exposure and the long-term theoretical risks associated with this exposure, especially in young children.
The findings by Read et al. (2) thus provide important information about long-term outcome. When more than 100 patients were surveyed nearly four decades after receiving radioactive iodine at ages ranging from 3 to 19 yr, no adverse events or deaths could be attributed to I-131 therapy (2). Pregnancies did not result in children with an increased incidence of congenital anomalies. None of the patients developed thyroid cancer or leukemia. One individual developed breast cancer, and one individual developed colon cancer, numbers in keeping with the incidence of these malignancies in the population at large.
Even considering the findings of Read and colleagues, some clinicians will remain skeptical about using I-131 in children; however, these lingering worries need to be balanced against the known remission rates and adverse effects of medical therapy and surgery. Despite the widespread popularity of medical therapy in the pediatric population, drug therapy is associated with disappointing remission rates and a higher incidence of adverse side effects than observed in adults (10, 20, 21). When treated medically, even for extended periods, long-term remission rates are generally less than 20%, especially when the thyroid is enlarged and high levels of thyroid-stimulating Ig are present. If the thyroid is small and thyroid-stimulating Ig levels are normal, remission can occur in more than 30% of children, and a trial of antithyroid medical therapy is warranted (10).
It is important to emphasize that although widely prescribed, antithyroid medical therapy in children and adolescents should never be viewed as trivial. Minor side effects occur in up to 20% of treated children (10). Serious side effects, including hepatitis and bone marrow suppression leading to patient death, occur rarely, but they do happen (10, 17).
One argument used by proponents of prolonged drug therapy is the fear of thyroid cancer in children treated with I-131. Thus antithyroid drugs are preferred to radioactive iodine therapy by some, assuming that thyroid cancer risk is less after drug therapy than after radioactive iodine. However, data do not support this notion. The Cooperative Thyrotoxicosis Therapy Follow-up Study found that the incidence of thyroid carcinomas over 1020 yr of follow-up was 5-fold higher in adults with Graves disease treated with thionamide drugs than in patients treated with I-131, and 8-fold higher than in patients treated surgically (12). Rather than reflecting a causative role for medical therapy in the pathogenesis of thyroid neoplasia, these observations may reflect the persistence of more thyroid tissue in patients treated with drugs than in individuals treated with radioactive iodine or surgery.
Similar to I-131, surgery is associated with high remission rates, especially if total thyroidectomy is performed (22). Thyroidectomy is associated with a small risk of hypoparathyroidism and vocal nerve damage (22). Not typically highlighted when surgical side effects are discussed are the much more common postoperative complaints of neck pain and a lasting neck scar. Thyroid storm can also occur during surgery, even with adequate preoperative antithyroid drug treatment. There is also a small risk of operative death (23).
The findings of Read et al. (2) are reassuring, yet one can argue that the sample size is modest. Thus, additional large-scale studies of this issue will be extremely valuable, and there is a pressing need for multicenter studies addressing this issue. As the newly formed Lawson Wilkins Pediatric Endocrine Society Clinical Research Network evolves to take advantage of the members vast experience, such studies may be possible.
We are indebted to Read and colleagues for their persistence in obtaining these precious follow-up data. This report also nicely illustrates what can be learned from registries and retrospective studies of uncommon conditions that can be mined to yield important information. With currently available informatics technology, establishing such registries at a national level is clearly feasible and needed in pediatric endocrinology.
One has to ask whether the establishment of such registries or necessary multicenter retrospective studies will now be squashed by the unintended consequences of the new Health Insurance Portability and Accountability Act (HIPAA). It is becoming increasingly apparent that HIPAA is discouraging clinical research even for low-risk studies (24). One also has to wonder whether Dr. Read, who completed his studies before HIPAA took effect, would have abandoned his efforts in the HIPAA era due to the now common heaps of added paperwork and backlogged Institutional Review Boards that struggle with new regulations, often without added support.
We now have the data of Read et al. (2) that address the long-term outcome of radioactive iodine therapy in children in an unprecedented manner. As such, we need to ask ourselves again whether it is proper to avoid I-131 therapy in children because of unsubstantiated concerns.
Received July 16, 2004.
Accepted July 16, 2004.
References
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