Background/Aims: Graves’ disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid-stimulating hormone receptor, lasting remission occurs in only a minority of pediatric patients with GD, including children treated with antithyroid drugs (ATDs) for many years. Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine (RAI; 131I). Results: When ATDs are used in children, only methimazole should be used. Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy. If remission (defined as normal thyroid function off ATDs) is not achieved after 1 or 2 years of ATD therapy, 131I or surgery may be considered, with the choice influenced by the age of the individual. When 131I is used, administered doses should be >150 µCi/g of thyroid tissue. When surgery is performed, near total or total thyroidectomy is recommended. Conclusion: Choosing a treatment approach for childhood GD is often a difficult and highly personal decision. Discussion of the advantages and risks of each therapeutic option is essential to help the patient and family select a treatment option.

1.
LeFranchi S, Mandel SH: Graves’ Disease in the Neonatal Period and Childhood. Clinical Text. Philadelphia, Lippincott, 1995, pp 1237–1246.
2.
Rivkees SA: The treatment of Graves’ disease in children. J Pediatr Endocrinol Metab 2006;19:1095–1111.
3.
Conference Proceeding: Hepatic Toxicity following Treatment for Pediatric Graves’ Disease Meeting, October 28, 2008. Eunice Kennedy Shriver National Institute of Child Health and Human Development, 2009 (http://bpca.nichd.nih.gov/outreach/index.cfm).
4.
Nabhan ZM, Kreher NC, Eugster EA: Hashitoxicosis in children: clinical features and natural history. J Pediatr 2005;146:533–536.
5.
Weetman AP: Graves’ disease. N Engl J Med 2000;343:1236–1248.
6.
Chapman EM: History of the discovery and early use of radioactive iodine. JAMA 1983;250:2042–2044.
7.
Cooper DS: Antithyroid drugs. N Engl J Med 2005;352:905–917.
8.
Rivkees SA, Sklar C, Freemark M: Clinical review 99: the management of Graves’ disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 1998;83:3767–3776.
9.
Lee JA, Grumbach MM, Clark OH: The optimal treatment for pediatric Graves’ disease is surgery. J Clin Endocrinol Metab 2007;92:801–803.
10.
Cooper DS: Antithyroid drugs for the treatment of hyperthyroidism caused by Graves’ disease. Endocrinol Metab Clin North Am 1998;27:225–247.
11.
Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN, Montori VM: Hyperthyroidism: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2010 (in press).
12.
Rivkees SA, Mattison DR: Ending propylthiouracil-induced liver failure in children. N Engl J Med 2009;360:1574–1575.
13.
Cooper DS, Rivkees SA: Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009;94:1881–1882.
14.
Rivkees SA: 63 years and 715 days to the ‘boxed warning’: unmasking of the propylthiouracil problem. Int J Pediatr Endocrinol 2010 (in press).
15.
Rivkees SA, Szarfman A: Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 2010;95:3260–3267.
16.
Abalovich M, Amino N, Barbour LA, Cobin RH, De Groot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A: Management of thyroid dysfunction during pregnancy and postpartum: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2007;92:S1–S47.
17.
Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, Laurberg P, McDougall IR, Rivkees SA, Ross D, Sosa JA, Stan MN: The role of propylthiouracil in the management of Graves’ disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009;19:673–674.
18.
Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N: Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab 2007;92:2157–2162.
19.
Rivkees SA, Stephenson K, Dinauer C: Adverse events associated with methimazole therapy of Graves’ disease in children. Int J Pediatr Endocrinol 2010 (in press).
20.
Tajiri J, Noguchi S: Antithyroid drug-induced agranulocytosis: how has granulocyte colony-stimulating factor changed therapy? Thyroid 2005;15:292–297.
21.
Cooper DS, Goldminz D, Levin AA, Ladenson PW, Daniels GH, Molitch ME, Ridgway EC: Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose. Ann Intern Med 1983;98:26–29.
22.
Abraham P, Avenell A, Park CM, Watson WA, Bevan JS: A systematic review of drug therapy for graves’ hyperthyroidism. Eur J Endocrinol 2005;153:489–498.
23.
Rivkees SA: Graves’ disease therapy in children: truth and inevitable consequences. J Pediatr Endocrinol Metab 2007;20:953–955.
24.
Weetman AP: Graves’ hyperthyroidism: How long should antithyroid drug therapy be continued to achieve remission? Nat Clin Pract Endocrinol Metab 2006;2:2–3.
25.
Glaser NS, Styne DM: Predicting the likelihood of remission in children with Graves’ disease: a prospective, multicenter study. Pediatrics 2008;121:e481–e488.
26.
Shulman DI, Muhar I, Jorgensen EV, Diamond FB, Bercu BB, Root AW: Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid 1997;7:755–760.
27.
Kaguelidou F, Alberti C, Castanet M, Guitteny MA, Czernichow P, Leger J: Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 2009;5:74–75.
28.
Glaser NS, Styne DM: Predictors of early remission of hyperthyroidism in children. J Clin Endocrinol Metab 1997;82:1719–1726.
29.
Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, Phillip M: Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab 2000;85:3678–3682.
30.
Hamburger JI: Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab 1985;60:1019–1024.
31.
Gruneiro-Papendieck L, Chiesa A, Finkielstain G, Heinrich JJ: Pediatric Graves’ disease: outcome and treatment. J Pediatr Endocrinol Metab 2003;16:1249–1255.
32.
Smith J, Brown RS: Persistence of thyrotropin receptor antibodies in children and adolescents with Graves’ disease treated using antithyroid medication. Thyroid 2007;17:1103–1107.
33.
Hertz S: Assurances as to the advantages and safety of radioactive iodine treatment of hyperthyroidism. New Orleans Med Surg J 1950;103:51–62.
34.
Read CH Jr, Tansey MJ, Menda Y: A thirty-six year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves’ patients. J Clin Endocrinol Metab 2004;89:4229–4233.
35.
Levy WJ, Schumacher OP, Gupta M: Treatment of childhood Graves’ disease. A review with emphasis on radioiodine treatment. Cleve Clin J Med 1988;55:373–382.
36.
Nebesio TD, Siddiqui AR, Pescovitz OH, Eugster EA: Time course to hypothyroidism after fixed-dose radioablation therapy of Graves’ disease in children. J Pediatr 2002;141:99–103.
37.
Rivkees SA, Cornelius EA: Influence of iodine-131 dose on the outcome of hyperthyroidism in children. Pediatrics 2003;111:745–749.
38.
Rivkees SA, Dinauer C: An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab 2007;92:797–800.
39.
Peters H, Fischer C, Bogner U, Reiners C, Schleusener H: Treatment of Graves’ hyperthyroidism with radioiodine: results of a prospective randomized study. Thyroid 1997;7:247–251.
40.
Kadmon PM, Noto RB, Boney CM, Goodwin G, Gruppuso PA: Thyroid storm in a child following radioactive iodine (RAI) therapy: a consequence of RAI versus withdrawal of antithyroid medication. J Clin Endocrinol Metab 2001;86:1865–1867.
41.
Sarkar SD, Beierwaltes WH, Gill SP, Cowley BJ: Subsequent fertility and birth histories of children and adolescents treated with 131I for thyroid cancer. J Nucl Med 1976;17:460–464.
42.
Boice JD Jr: Thyroid disease 60 years after Hiroshima and 20 years after Chernobyl. JAMA 2006;295:1060–1062.
43.
Boice JD Jr: Radiation-induced thyroid cancer – what’s new? J Natl Cancer Inst 2005;97:703–705.
44.
Dolphin GW: The risk of thyroid cancers following irradiation. Health Phys 1968;15:219–228.
45.
Sigurdson AJ, Ronckers CM, Mertens AC, Stovall M, Smith SA, Liu Y, Berkow RL, Hammond S, Neglia JP, Meadows AT, Sklar CA, Robison LL, Inskip PD: Primary thyroid cancer after a first tumour in childhood (the childhood cancer survivor study): A nested case-control study. Lancet 2005;365:2014–2023.
46.
Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, Schneider AB, Tucker MA, Boice JD Jr: Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 1995;141:259–277.
47.
Boice JDJ: Radiation and thyroid cancer – what more can be learned? Acta Oncol 1998;34:321–324.
48.
Flynn RW, Macdonald TM, Jung RT, Morris AD, Leese GP: Mortality and vascular outcomes in patients treated for thyroid dysfunction. J Clin Endocrinol Metab 2006;91:2159–2164.
49.
Franklyn JA, Maisonneuve P, Sheppard MC, Betteridge J, Boyle P: Mortality after the treatment of hyperthyroidism with radioactive iodine. N Engl J Med 1998;338:712–718.
50.
Franklyn JA, Sheppard MC, Maisonneuve P: Thyroid function and mortality in patients treated for hyperthyroidism. JAMA 2005;294:71–80.
51.
Goldman MB, Monson RR, Maloof F: Cancer mortality in women with thyroid disease. Cancer Res 1990;50:2283–2289.
52.
Holm LE, Hall P, Wiklund K, Lundell G, Berg G, Bjelkengren G, Cederquist E, Ericsson UB, Hallquist A, Larsson LG, et al: Cancer risk after iodine-131 therapy for hyperthyroidism. J Natl Cancer Inst 1991;83:1072–1077.
53.
Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, Jaatinen P: Increased cancer incidence after radioiodine treatment for hyperthyroidism. Cancer 2007;109:1972–1979.
54.
Ron E, Doody BDV, Brill C, Goldman HB, Hoffman McConahey, Maxon PM, Warshauer W, Boice JDJ: Cooperative Thyrotoxicosis Therapy Follow-Up Study Group: cancer mortality following treatment for adult hyperthyroidism. JAMA 1998;280:347–355.
55.
Toohey RE, Stabin MG, Watson EE: The AAPM/RSNA physics tutorial for residents: internal radiation dosimetry: principles and applications. Radiographics 2000;20:533–546.
56.
Toohey RE, Stabin MG: Comparative analysis of dosimetry parameters for nuclear medicine. Orise Report 99–1064, 1999; in Proceedings of the Sixth International Radiopharmaceutical Dosimetry Symposium, Gatlinburg, Tenn., 1996, pp 532–551.
57.
Biological Effects of Ionizing Radiation Committee V (BEIR VII) – Phase 2: Health Risks from Exposure to Low Levels of Ionizing Radiation. Washington, National Academies Press, 2006.
58.
Miccoli P, Vitti P, Rago T, Iacconi P, Bartalena L, Bogazzi F, Fiore E, Valeriano R, Chiovato L, Rocchi R, Pinchera A: Surgical treatment of Graves’ disease: subtotal or total thyroidectomy? Surgery 1996;120:1020–1025.
59.
Peters H, Fischer C, Bogner U, Reiners C, Schleusener H: Reduction in thyroid volume after radioiodine therapy of graves’ hyperthyroidism: results of a prospective, randomized, multicentre study. Eur J Clin Invest 1996;26:59–63.
60.
Sosa JA, Tuggle CT, Wang TS, Thomas DC, Boudourakis L, Rivkees S, Roman SA: Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008;93:3058–3065.
61.
Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA, Udelsman R: The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998;228:320–330.
62.
Vitti P, Rago T, Chiovato L, Pallini S, Santini F, Fiore E, Rocchi R, Martino E, Pinchera A: Clinical features of patients with Graves’ disease undergoing remission after antithyroid drug treatment. Thyroid 1997;7:369–375.
63.
Davies T, Roti E, Braverman LE, De Groot LJ: Thyroid controversy – stimulating antibodies. J Clin Endocrinol Metab 1998;83:3777–3785.
64.
Wilkins L: The Diagnosis and Treatment of Endocrine Disorders in Children and Adolescence; in Hypothyroidism. Springfield, Thomas, 1965, pp 141–150.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.