James D. West, Timothy D. Cheetham, Carole Dane and Anuja Natarajan* Should radioiodine be the first-line treatment for paediatric Graves disease?

Transcription

1 J Pediatr Endocr Met 2015; 28(7-8): Review article James D. West, Timothy D. Cheetham, Carole Dane and Anuja Natarajan* Should radioiodine be the first-line treatment for paediatric Graves disease? Abstract Background: Debate exists regarding the optimal treatment strategy for paediatric Graves disease with radioiodine (RAI), and surgery, usually reserved for failure of medical therapy. We present our own experience to introduce a review of the published literature focussing on the predictors of remission after antithyroid drug (ATD) therapy from diagnosis, and discuss whether RAI should be considered as a first-line therapy. Method: A retrospective analysis of all diagnosed cases of paediatric Graves disease presenting to a large District General Hospital. Results: Thirteen patients were diagnosed with Graves disease between February 2004 and May The median age at diagnosis was 13.7 years (range years) with a female:male ratio of 11:2. Some nine patients completed a 2-year course of carbimazole out of which 8 relapsed after a mean duration of 0.82 years (range years); the ninth currently remains in remission. Of the eight patients who relapsed, three have undergone RAI treatment. Two patients failed to tolerate carbimazole treatment, one of whom received RAI treatment because surgery was contraindicated and one patient with severe autism proceeded to RAI treatment due to poor compliance and persistent hyperthyroidism. Literature Review: Prognostic factors at presentation predicting a low likelihood of remission following ATD treatment include younger age, non-caucasian ethnicity, and severe clinical and/or biochemical markers of hyperthyroidism. Psycho-social factors including compliance also influence management decisions. Conclusion: In specifically selected patients presenting with paediatric Graves disease, the benefits and risks of *Corresponding author: Anuja Natarajan, Doncaster Royal Infirmary, Armthorpe Road, Doncaster DN2 5LT, UK, anuja.natarajan@dbh.nhs.uk James D. West and Carole Dane: Doncaster Royal Infirmary, Armthorpe Road, Doncaster DN2 5LT, UK Timothy D. Cheetham: Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK radioactive iodine as a potential first-line therapy should be communicated allowing families to make informed decisions. Keywords: anti-thyroid drugs (ATDs); children; Graves disease; hyperthyroidism; management; paediatrics; radioiodine (RAI); remission; surgery; treatment. DOI /jpem Received May 2, 2014; accepted January 6, 2015; previously published online February 18, 2015 Introduction Graves disease is a multisystem, autoimmune disorder causing hyperthyroidism, ophthalmopathy and dermatopathy. The incidence of acquired thyrotoxicosis in the United Kingdom and Ireland for children under 15 years of age is around 0.9 per 100,000; of which Graves disease is the most common type (1). Peak incidence occurs in 10- to 15-yearolds with a marked female predominance. Traditionally in Europe, children with Graves disease are treated with antithyroid medications either alone ( block therapy ) or in conjunction with thyroxine ( block and replace therapy ) as the first-line treatment. Radioiodine (RAI) or surgery is considered if antithyroid drugs (ATDs) are poorly tolerated or if there is a problem with compliance or if the patient relapses after 2 years of treatment. We present a case series along with a review of the published literature focussing on predictors of remission after ATD therapy from diagnosis, and a discussion on the use of RAI as the first-line of therapy in the treatment of Graves disease. Case series Thirteen patients presented to our District General Hospital with Graves disease between February 2004 and May 2013 giving a local incidence of 2.0 per 100,000 children under 18 years of age (Table 1). The median age

2 798 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? Table 1: Patient characteristics, response to treatment and outcomes in 13 children diagnosed with Graves disease. Patient Sex Age at presentation, years Symptoms and signs Family history Anti- TSH rab Anti- TPO Abs, U/mL Imaging Initial treatment Outcome 1 F Increased appetite, diarrhoea, irregular menses, exophthalmos, goitre, moist skin, tremor 2 F Daytime somnolence, palpitations, exercise intolerance, sweating, weight loss, heat intolerance, anxiety, tremor 3 F Nocturnal insomnia, palpitations, heat intolerance, weakness, anxiety, tremor 4 F Hyperactive, sweating, weight loss, heat intolerance, irregular menses, tremor, anxiety, goitre 5 F Increased appetite, nocturnal insomnia, irritability, palpitations, heat intolerance, irregular menses, tremor 6 F Irritability, weight loss, heat intolerance, anxiety, goitre 7 M Increased appetite, hyperactive, irritability, palpitations, exercise intolerance, sweating, weight loss Paternal thyrotoxicosis B ve S+ve Nil +ve 1634 US thyroid, Maternal grandmother hypothyroidism, paternal aunt hypothyroidism 8 M 7.21 Hyperactivity, agitated Maternal goitre during pregnancy 9 F Mood swings, goitre, dry skin, weight loss 2018 US thyroid stopped after 1.94 years. Relapse after 0.08 years. +ve 1008 US thyroid, Nil +ve 376 US thyroid, Nil Both ve (after Tx started) 838 US thyroid, Nil +ve 499 US thyroid, Nil +ve 176 US thyroid, Maternal aunt hyperthyroidism, maternal grandmother hypothyroidism stopped after 2.09 years. Relapse after 0.79 years. stopped after 2.29 years. Relapse after 0.45 years. stopped after 2.05 years. Relapse after 1.24 years. stopped after 1.99 years. Relapse after 1.33 years. stopped after 2.2 years. Relapse after 0.24 years. Back on carbimazole following relapse. stopped after 2.02 years. Relapse after 1.03 years US thyroid No medication commenced, ongoing thyroid function test monitoring. +ve 302 US thyroid, Fluctuating TFT s, carbimazole treatment commenced. Total thyroidectomy 3.43 years after diagnosis. Thyroxine postop. RAI treatment 3.6 years after diagnosis. Thyroxine restarted and continued. Continuing medical therapy. Decided against surgery, considering RAI treatment. Noncompliant with medication after relapse. High T4 delayed surgery. Total thyroidectomy after 4.67 years. Lost to follow-up. RAI treatment 3.14 years after diagnosis. Carbimazole and thyroxine recommenced and being weaned. Awaiting RAI. Total thyroidectomy 0.85 years after diagnosis. Thyroxine postop.

3 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? 799 (Table 1: Continued) Imaging Initial treatment Outcome Anti- TPO Abs, U/mL Symptoms and signs Family history Anti- TSH rab Patient Sex Age at presentation, years Admitted for surgery 3.01 years after diagnosis but recurrent laryngeal nerve signals could not be detected. RAI treatment 3.18 years after diagnosis. Carbimazole restarted. Carbimazole stopped after 18 months of treatment due to recurrent sore throats. +ve 818 US thyroid, Maternal grandmother hypothyroid 10 F 17.1 Weight loss, goitre, lethargy, palpitations, tremor, gallop rhythm Carbimazole restarted. Deciding on definitive treatment. stopped after 2.01 years. Relapse after 1.42 years. Nil +ve 624 US thyroid, 11 F Palpitations, weight loss, increasing appetite, pallor, heat intolerance, anxiety stopped after 3.43 years. Currently in remission after 1.39 years. +ve 54 US thyroid, 12 F 14.0 Palpitations, anxiety, goitre Type 1 diabetes mellitus RAI treatment 0.49 years after diagnosis. Thyroxine commenced post-rai treatment. Carbimazole started but poor compliance due to autism. +ve 95 US thyroid, Paternal hyperthyroidism 13 F Increased appetite, weight loss, anxiety, tachycardia, sweating, goitre at diagnosis was 13.7 years (range years) with a female:male ratio of 11:2. The diagnosis was based on the presenting symptoms and signs, characteristic findings on imaging of the thyroid gland and positive thyroid stimulating hormone (TSH) receptor antibodies (TRAb) and/or thyroid peroxidase antibodies (TPOAb). Out of the 12 patients who commenced on carbimazole, eight completed a 2-year course of treatment and they have all relapsed after a mean duration of 0.82 years (range years). Two patients then proceeded to a total thyroidectomy although the surgery had to be delayed in one patient because of persistent thyrotoxicosis secondary to poor compliance with medication. Two patients have undergone RAI treatment without significant complications, one of whom is on a weaning dose of carbimazole. One patient is awaiting RAI treatment; two others are undecided as to definitive treatment and remain on carbimazole. One patient was lost to follow-up and the ninth patient received a prolonged carbimazole course (of over 3 years) and is currently in remission after 1.39 years. Of the three patients who did not complete the oral therapy course, one patient had to proceed to total thyroidectomy due to fluctuating control despite good compliance. Another patient stopped treatment after 18 months due to recurrent sore throats (without agranulocytosis) and a total thyroidectomy opted for, but the procedure was abandoned because pre-operative recurrent laryngeal nerve signals could not be detected. The RAI treatment was administered and small doses of carbimazole were restarted. The third patient with severe progressive psycho-social regression and autism was noncompliant with oral medications. Although carbimazole was initially commenced the patient refused medications (after the 1st week) to the extent of stopping all oral intake when she suspected the medication had been mixed with food and had to be admitted for enteral feeding. She underwent RAI treatment (intravenous radioactive iodine had to be given due to complete refusal of oral intake) with resolution of her thyrotoxic symptoms. The 13th patient did not require treatment and continues to have thyroid function test (TFT) monitoring. Discussion Current practice considerations and implications Antithyroid drugs are currently the mainstay of Graves disease therapy with considerable limitations regarding

4 800 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? their use and often unsatisfactory results. Although generally well tolerated there can be a high prevalence of mild side effects such as skin rash, itching and leucopenia. Agranulocytosis is rare but potentially life-threatening and other major adverse effects including aplastic anaemia, thrombocytopenia, systemic lupus erythematous and vasculitis have been reported (2). Propylthiouracil (PTU) may induce liver damage (3) and fatal hepatotoxicity (4). Patient stratification to treatment modality As shown in our case series remission rates with ATDs can be poor (20% 30%) (5 8). High relapse rates exist in certain patient groups and the only apparent modifiable factor appears to be duration of ATD therapy with a reduced relapse rate in those treated with prolonged oral therapy (9, 10). To optimise management, patients would ideally be stratified depending on their clinical and biochemical characteristics at presentation to either ATD therapy, if prognostic factors indicate a high likelihood of remission, or definitive treatment. Many studies investigating prognostic factors at presentation for remission following ATDs have been performed in adults (10 16); however, results are not transferable and sometimes appear to contrast those of the paediatric population. Retrospective studies in children and adolescents (6, 10, 17 26) have identified younger age, larger goitre size, lower initial body mass index (BMI), higher thyroid hormone concentrations, and higher TRAb levels at diagnosis as predictors of relapse after stopping ATD therapy. Only two studies have investigated prognostic factors in children prospectively (9, 27) (Table 2). Following a previous review, Glaser and Styne (27) performed a prospective multicentre study with remission defined as euthyroid status 12 months after completing a 2-year course of ATDs. Of the 70 children who enrolled, 12 dropped out before completing the 2-year ATD treatment period four due to adverse reactions (although 11 children in total developed adverse reactions) and eight due to patient preference. A univariate analysis was performed on the results from the 51 children who completed the study and showed significantly lower T4 and T3 concentrations at presentation in children who achieved remission. There was no significant difference in BMI standard deviation (SD) score but when the population was divided into groups based on ethnicity, patients who achieved remission in the Caucasian group had higher BMI SD scores whereas children of other ethnicities who achieved remission had lower BMI SD scores. Although a multivariate logistic regression analysis did not identify significant factors, binary recursive partitioning analysis (used to derive a highly sensitive clinical prediction rule) showed age and initial T3 concentration as significant variables with older age ( > years) (p = 0.06) and lower T3 level indicating a greater chance of remission. In this study goitre size was not a useful predictor of remission; however, it was measured manually by clinicians knowing the hyperthyroid status of the patients and consequently may have been prone to overestimating goitre size introducing bias. More precise ultrasound measurement at presentation may provide better prognostic information. Kaguelidou et al. (9) performed a prospective observational study including 147 children to identify risk factors for relapse within 2 years of completing a 2-year course of ATD therapy. Some 32% of patients found it difficult to comply with the treatment regimen while 6% of patients experienced adverse reactions to the ATDs. Four variables at presentation were found to be independent predictors of relapse: younger age; high FT4 levels; high TRAb levels and being non-caucasian in ethnicity. When these variables underwent internal validation, ethnicity and FT4 levels were particularly strong predictors of relapse. Table 2: Significant results from prospective studies investigating prognostic factors predicting remission after ATD therapy from diagnosis. Prognostic factor Glaser et al. (27) a, n = 51 OR (95% CI) Kaguelidou et al. (9) b, n = 147 HR (95% CI) Age 1.33 ( ), p = c ( ), p = 0.03 Non-Caucasian NR 2.54 ( ), p = Serum FT4 concentration NR 1.18 d ( ), p = Multiple of upper normal limit for TRAb concentration NR 1.21 e ( ), p = 0.03 a Multivariable logistic regression analysis of clinical and biochemical factors associated with remission; OR, odds ratio. b Multivariate hazard model for predictors of relapse within 2 years of ATD discontinuation; HR, hazard ratio. c HR related to a 5-year increase in age. d HR related to a 10-pmol/L increase in serum FT4 concentration. e HR related to a 10-unit increase in multiples of upper normal limit.

5 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? 801 A prognostic scoring system was developed to aid decision making on an individual patient basis. Hyperthyroidism can perpetuate itself by worsening the autoimmune process and autoimmunity results in the production of more TSH receptor antibodies (28). Therefore, noncompliance with ATDs can have a profound effect making remission less likely. Noncompliance or nonadherence with medication in children and adolescents is estimated to range from 25% to 60% (29, 30). Concordance is a particular problem in those with chronic conditions, especially in adolescents (31) (the age group with the highest incidence of Graves disease) who desire independence with less parental input (30), and in those with learning disabilities (32). Educational strategies are often implemented; however, evidence suggests that these result in only small to medium benefits (29). Adjusting dosing regimens can help and compliance has been proven to be better with once daily methimazole/carbimazole compared to thrice daily PTU (33). Failure to achieve permanent remission with ATDs leads to the consideration of other treatment modalities such as RAI or surgery. Surgery may be the optimal definitive treatment in certain patient groups including children under 5 years of age and children with a large goitre ( > 80 g) at diagnosis (34 36). Complication rates can vary from 15% when performed by paediatric surgeons compared to 4% (p < 0.01) for experienced thyroid surgeons ( > 30 thyroidectomies per year) (37). Furthermore, thyroidectomy scars, which may be hypertrophic requiring medical or surgical treatment may be considered cosmetically unacceptable and rule out this form of therapy for some adolescents. Radioiodine treatment Over 1200 cases of RAI treatment in childhood have been reported in the literature, achieving a 95% remission rate in Graves disease (38 41). Turner et al. (42) performed a survey of current RAI administration in patients with thyrotoxicosis over a 19-year period from 1990 to 2008 in the United Kingdom. Of 69,258 RAI treatments, 560 were in the group of patients under 21 years of age. There was a 7-fold rise in young people receiving RAI expressed as a percentage of the total from 0.2% in 1990 to 1.5% in 2008 with the youngest age receiving treatment falling from 19 to 11 years of age. This may be due to the superior efficacy of RAI treatment compared to ATDs, proven by many studies including a Cochrane Systematic review [relative risk already present (RR) 1.70, 95% confidence interval (CI) ] (43). The reluctance to use RAI in paediatric practice stems from concerns about short- and long-term complications. Nausea can occur immediately post-rai treatment and pain over the thyroid gland, which is self-limiting and can be managed with nonsteroidal anti-inflammatory drugs (38). Thyroid storm, more common after RAI treatment in those with severe thyrotoxicosis and large goitre, can be minimised by administering ATDs before RAI ablation. Symptoms of iatrogenic hyperthyroidism after RAI treatment can be controlled with β-blockers or saturated potassium iodine (Lugol s solution). Whereas a small proportion of adult patients have worsening eye disease following RAI, this does not appear to be a problem in children (38). Long-term studies have shown RAI treatment to be safe. Although low-dose RAI exposure, from the environment or diagnostic procedures, is associated with an increase in thyroid carcinoma, high-dose RAI treatment which completely ablates the thyroid gland results in a much lower thyroid carcinoma incidence (44, 45). Read et al. (39) reported 26- and 36-year follow-up outcomes of 116 patients under the age of 20 who had been treated with RAI for Graves disease between 1953 and The age range at the time of initial treatment was 3 years 7 months 19 years 9 months. Initial doses of RAI were conservative and given to induce euthyroidism. Some patients needed repeat treatments leading to an increase in dose to ablate the thyroid. None of these patients developed leukaemia or cancer of the thyroid gland. Two patients developed single thyroid nodules which were found to be benign on biopsy. There were no other signs of genetic damage or thyroid problems, apart from iatrogenic hypothyroidism, associated with RAI treatment. Although these doses were much lower than doses used for ablation today ( cgy versus 10,000 20,000 cgy), higher doses destroying more thyroid tissue may reduce the risk of thyroid malignancies. Other studies have also reported the safe use of RAI in children with long-term follow-up data (46). However, a large retrospective study showed a positive association of radiation dose from CT s in children with leukaemia and brain tumours (47) and another study showed adult patients who received RAI treatment for hyperthyroidism (mean age 62 years) had an increased incidence of cancer overall (RR 1.25; 95% CI: ) and specifically kidney and breast cancers (48). The Cooperative Thyrotoxicosis Therapy Follow-up Study reported on 34,684 adult patients with hyperthyroidism treated between 1946 and 1968 with ATDs, surgery or RAI (49). At years of post-treatment follow-up there was a 5-fold higher incidence of thyroid carcinomas in patients with Graves disease treated with ATDs compared to RAI and an 8-fold higher incidence than in patients treated with surgery. Rates of thyroid adenomas were 10 and 20 times higher in adults treated with ATDs

6 802 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? than in patients treated with RAI and surgery, respectively. However, as younger children are at a greater risk of thyroid carcinoma after external exposure to RAI, there may be a small increase in the rate of thyroid cancer after RAI treatment in children, which declines progressively throughout childhood (38). In an unfortunate situation that a thyroid cancer develops, papillary carcinomas are the most common type which are slow growing and have an excellent prognosis. Long-term follow-up studies assessing nonthyroid cancer risks in children are yet to be performed. There is no evidence to support an increased risk of congenital anomalies in offspring of those treated with RAI as children (38). RAI as a first-line therapy in Graves disease There is a paucity of data on RAI as the first-line of therapy. A task force of expert clinicians commissioned by the American Thyroid Association in association with the American Association of Clinical Endocrinologists has produced thyrotoxicosis management guidelines (50). They suggest RAI can be considered at presentation if there is a low risk of remission using ATDs. The guidelines state that RAI should not be given to children under 5 years of age but is acceptable in children between 5 and 10 years of age depending on the dose. Pretreating with ATDs and β-blockers until T4 normalises before proceeding with RAI is recommended. Rivkees proposes that children approaching 10 years of age or older should be given ATDs if prognostic factors indicate a potential likelihood of remission, otherwise RAI should be considered as the first-line therapy whilst discussing the advantages and disadvantages of different treatment options with the patient and family (37). Therefore, it would seem appropriate for children above 5 years of age, especially those of non-caucasian ethnicity, with clinical and/or biochemical features of Figure 1: Flow diagram stratifying initial patient therapy based on clinical and biochemical features at presentation.

7 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? 803 severe hyperthyroidism at diagnosis to be considered for RAI as the first-line therapy. There may be other patient groups where initial oral therapy is deemed inappropriate such as those with poor engagement, noncompliance or behavioural difficulties and patients with contraindicators to surgery that may proceed directly to definitive RAI treatment. Figure 1 provides a possible treatment strategy based on the clinical, biochemical and psychosocial factors of individual patients on presentation. Conclusion Prolonged treatment of paediatric Graves disease with ATDs results in low remission and high relapse rates. Patients should be assessed at diagnosis for prognostic factors indicating a low likelihood of remission with ATDs. We, therefore, conclude from our own experience, which is supported by the literature review, that in children presenting with biochemical indicators of severe disease, contraindicators to surgery or learning disabilities, the benefits and risks of RAI as a first-line therapy should be discussed allowing the families to make an informed decision. Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Funding: This research did not receive any specific grant from any funding agency in the public, commercial or notfor-profit sector. References 1. Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol (Oxf) 2010;72: Bartalena L, Bogazzi F, Martino E. Adverse effects of thyroid hormone preparations and antithyroid drugs. Drug Saf 1996;15: Liaw Y-F. Hepatic injury during propylthiouracil therapy in patients with hyperthyroidism: a cohort study. Ann Intern Med. Am Coll Phys 1993;118: Levy M. Propylthiouracil hepatotoxicity. A review and case presentation. Clin Pediatr (Phila) 1993;32: Bergman P, Auldist A, Cameron F. Review of the outcome of management of Graves disease in children and adolescents. J Paediatr Child Health 2001;37: Collen RJ, Landaw EM, Kaplan SA, Lippe BM. Remission rates of children and adolescents with thyrotoxicosis treated with antithyroid drugs. Pediatrics 1980;65: Hamburger JI. Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab 1985;60: Gruñeiro-Papendieck L, Chiesa A, Finkielstain G, Heinrich JJ. Pediatric Graves disease: outcome and treatment. J Pediatr Endocrinol Metab 2003;16: Kaguelidou F, Alberti C, Castanet M, Guitteny M-A, Czernichow P, et al. Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 2008;93: Léger J, Gelwane G, Kaguelidou F, Benmerad M, Alberti C. Positive impact of long-term antithyroid drug treatment on the outcome of children with Graves disease: national long-term cohort study. J Clin Endocrinol Metab 2012;97: Witte J, Goretzki PE, Dotzenrath C, Simon D, Felis P, et al. Surgery for Graves disease: total versus subtotal thyroidectomy-results of a prospective randomized trial. World J Surg 2000;24: Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, et al. Age and gender predict the outcome of treatment for Graves hyperthyroidism. J Clin Endocrinol Metab 2000;85: Vitti P, Rago T, Chiovato L, Pallini S, Santini F, et al. Clinical features of patients with Graves disease undergoing remission after antithyroid drug treatment. Thyroid 1997;7: Nedrebo BG, Holm PI, Uhlving S, Sorheim JI, Skeie S, et al. Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves disease. Eur J Endocrinol 2002;147: Eckstein AK, Lax H, Lösch C, Glowacka D, Plicht M, et al. Patients with severe Graves ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission. Clin Endocrinol (Oxf) 2007;67: Rieu M, Raynaud A, Richard A, Laplanche S, Sambor B, et al. Evidence for the effect of antibodies to TSH receptors on the thyroid ultrasonographic volume in patients with Graves disease. Clin Endocrinol (Oxf) 1994;41: Glaser NS, Styne DM. Predictors of early remission of hyperthyroidism in children. J Clin Endocrinol Metab 1997;82: Lazar L, Kalter-Leibovici O, Pertzelan A, Weintrob N, Josefsberg Z, et al. Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab 2000;85: Lippe BM, Landaw EM, Kaplan SA. Hyperthyroidism in children treated with long term medical therapy: twenty-five percent remission every two years. J Clin Endocrinol Metab 1987;64: Mussa GC, Corrias A, Silvestro L, Battan E, Mostert M, et al. Factors at onset predictive of lasting remission in pediatric patients with Graves disease followed for at least three years. J Pediatr Endocrinol Metab 1999;12: Buckingham BA. Hyperthyroidism in children. Am J Dis Child. Am Med Assoc 1981;135: Gorton C, Sadeghi-Nejad A, Senior B. Remission in children with hyperthyroidism treated with propylthiouracil. Long-term results. Am J Dis Child 1987;141: Song SM, Youn J-S, Ko JM, Cheon CK, Choi J-H, et al. The natural history and prognostic factors of Graves disease in Korean children and adolescents. Korean J Pediatr 2010;53: Léger J, Carel JC. Hyperthyroidism in childhood: causes, when and how to treat. J Clin Res Pediatr Endocrinol 2013;5(Suppl 1):50 6.

8 804 West et al.: Should radioiodine be the first-line treatment for paediatric Graves disease? 25. Gastaldi R, Poggi E, Mussa A, Weber G, Vigone MC, et al. Graves disease in children: thyroid-stimulating hormone receptor antibodies as remission markers. J Pediatr 2014;164: e Shulman DI, Muhar I, Jorgensen EV, Diamond FB, Bercu BB, et al. Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. Thyroid 1997;7: Glaser NS, Styne DM. Predicting the likelihood of remission in children with Graves disease: a prospective, multicenter study. Pediatrics 2008;121:e Léger J, Kaguelidou F, Alberti C, Carel JC. Graves disease in children. Best Pract Res Clin Endocrinol Metab 2014;28: Hampson SE, Skinner TC, Hart J, Storey L, Gage H, et al. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review. Health Technol Assess 2001;5: Carter S, Taylor D, Levenson R, Britain MP. A question of choice: compliance in medicine taking: a preliminary review. Med Partnership 2003 [cited 2014 Nov 6]. Available at: books.google.co.uk/books/about/a_question_of_choice. html?id=wxixmweacaaj&pgis= Staples B, Bravender T. Drug compliance in adolescents: assessing and managing modifiable risk factors. Paediatr Drugs 2002;4: Costello I, Wong IC, Nunn AJ. A literature review to identify interventions to improve the use of medicines in children. Child Care Health Dev 2004;30: Nicholas WC, Fischer RG, Stevenson RA, Bass JD. Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J 1995;88: Lee JA, Grumbach MM, Clark OH. The optimal treatment for pediatric Graves disease is surgery. J Clin Endocrinol Metab 2007;92: 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: 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: Rivkees SA. Pediatric Graves disease: controversies in management. Horm Res Paediatr 2010;74: 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: Read CH, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves patients. J Clin Endocrinol Metab 2004;89: Levy WJ, Schumacher OP, Gupta M. Treatment of childhood Graves disease: a review with emphasis on radioiodine treatment. Cleve Clin J Med 1988;55: Moll GW, Patel BR. Pediatric Graves disease: therapeutic options and experience with radioiodine at the University of Mississippi Medical Center. South Med J 1997;90: Turner N, Driver I, Salotti JA, Pearce MS, Cheetham T. Increasing use of radioiodine in young people with thyrotoxicosis in Great Britain. Eur J Endocrinol 2012;167: Ma C, Kuang A, Xie J, Liu G. Radioiodine treatment for pediatric Graves disease. Cochrane Database Syst Rev 2008;3:CD Boice JD. Radiation and thyroid cancer: what more can be learned? Acta Oncol 1998;37: Tucker MA, Jones PH, Boice JD, Robison LL, Stone BJ, et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res 1991;51: Safa AM, Schumacher OP, Rodriguez-Antunez A. Long-term follow-up results in children and adolescents treated with radioactive iodine (131I) for hyperthyroidism. N Engl J Med 1975;292: Pearce MS, Salotti JA, Little MP, McHugh K, Lee C, et al. Radiation exposure from CT s in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 2012;380: Metso S, Auvinen A, Huhtala H, Salmi J, Oksala H, et al. Increased cancer incidence after radioiodine treatment for hyperthyroidism. Cancer 2007;109: Dobyns BM, Sheline GE, Workman JB, Tompkins EA, McConahey WM, et al. Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism: a report of the cooperative thyrotoxicosis therapy follow-up study. J Clin Endocrinol Metab. Endocr Soc 1974;38: Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011;21: