儿童甲亢治疗指南

Clin Pediatr Endocrinol 2017; 26(2), 29–62Copyright© 2017 by The Japanese Society for Pediatric Endocrinology Original Article Guidelines for the treatment of childhood-onset Graves’ disease in Japan, 2016 The Committee on Pharmaceutical Affairs, Japanese Society for Pediatric Endocrinology, and the Pediatric Thyroid Disease Committee, Japan Thyroid Association (Taskforce for the Revision of the Guidelines for the Treatment of Childhood-Onset Graves’ Disease), Kanshi Minamitani1, Hirokazu Sato2, Hidemi Ohye3, Shohei Harada4, and Osamu Arisaka5 1 Department of Pediatrics, Teikyo University Chiba Medical Center, Chiba, Japan 2 Sunrise Children’s Clinic, Chiba, Japan 3 Department of Internal Medicine, Ito Hospital, Tokyo, Japan 4 Division of Neonatal Screening, National Center for Child Health and Development, Tokyo, Japan 5 Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan. Abstract. Purpose behind developing these guidelines: Over one decade ago, the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2006” (Japan Thyroid Association (JTA)) were published as the standard drug therapy protocol for Graves’ disease. The “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” were published to provide guidance on the treatment of pediatric patients. Based on new evidence, a revised version of the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2006” (JTA) was published in 2011, combined with the “Handbook of Radioiodine Therapy for Graves’ Disease 2007” (JTA). Subsequently, newer findings on pediatric Graves’ disease have been reported. Propylthiouracil (PTU)-induced serious hepatopathy is an important problem in pediatric patients. The American Thyroid Association’s guidelines suggest that, in principle, physicians must not administer PTU to children. On the other hand, the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2011” (JTA) state that radioiodine therapy is no longer considered a “fundamental contraindication” in children. Therefore, the “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” required revision. Key words: Graves’ disease, guidelines, treatment Received: October 3, 2016Accepted: December 2, 2016Corresponding author: Dr. Kanshi Minamitani, Depart-ment of Pediatrics, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara-shi, Chiba 299-0111, JapanE-mail: kminami@med.teikyo-u.ac.jp This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License .IntroductionGraves’ disease is defined as acquired autoimmune hyperthyroidism with a diffuse goiter. Graves’ disease is a common disorder in adults, with a prevalence of approximately 0.5–1% (1, 2). It is often diagnosed and treated by general practitioners. The evidence-based “Guidelines for the Treatment of Graves’ Disease 30Juvenile Graves’ disease guidelinesVol.26 / No.2with Antithyroid Drug in Japan, 2006” (Japan Thyroid Association: JTA) (3) were prepared as the standard therapeutic protocol for Graves’ disease for general physicians. cases are attributable to Graves’ disease. The majority of childhood hyperthyroidism Pediatric patients account for less than 5% of the total number of patients with Graves’ disease and the prevalence in children is 0.02% (4, 5). Therefore, very few large cohort clinical studies have been conducted, and scientific evidence on childhood Graves’ disease is scarce. Physicians must make diagnoses based on the “Guidelines for the Diagnosis of Graves’ Disease” (6). However, these guidelines include very little information on pediatric treatment for Graves’ disease. However, the guidelines do state that, “the remission rate with antithyroid drugs is lower in children with Graves’ Disease, and the drug therapy is not always easy. Insufficient treatment of pediatric Graves’ disease may result in major problems, and pediatric patients with Graves’ disease should generally be treated by specialists” (3). Consequently, both the Committee on Pharmaceutical Affairs of the Japanese Society for Pediatric Endocrinology (JSPE) and the Pediatric Thyroid Diseases Committee of the JTA took action. These two groups conducted questionnaire surveys (7) and retrospective clinical studies, as well as comprehensive literature searches for preparation of the “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” (JSPE, JTA) (8). for the Treatment of Graves’ Disease with Based on newer evidence, the “Guidelines Antithyroid Drug in Japan, 2006” were also revised and combined with the “Handbook of Radioiodine (131 in Japan, 2007” (JTA) (9); subsequently, the I) Therapy for Graves’ Disease “Guidelines for the Treatment of Graves’ Disease in Japan, 2011” (JTA) (10) was published. Graves’ disease have been reported. One major Since then, even newer findings on pediatric problem faced by pediatric patients is the occurrence of serious hepatopathy associated with PTU administration (11–18). According to other causes of thyrotoxicosis: management the US guidelines, “Hyperthyroidism and guidelines of American Thyroid Association (ATA) and American Association of Clinical Endocrinologists” (19), it is suggested in principle that children. In addition, according to the “Guidelines physicians refrain from using PTU in for the Treatment of Graves’ Disease in Japan, 2011” (10), radioiodine (131considered a “fundamental contraindication.” I) therapy is no longer In other words, 131in children and is instead subject to “careful I is not contraindicated administration” (i.e., 131to children with care). This change has provided I should be administered physicians with more therapeutic options (10). The current ATA guidelines recommend a lower initial dose of methimazole (MMI) (or thiamazole in Japan) than older guidelines (19). Newly reported findings in Japan include the efficacy of MMI and PTU in pediatric patients, as well as adverse reactions (20), the relationship between the initial MMI dose and effectiveness (21), the initial MMI dose and adverse reactions (22), and a higher remission rate with long-term MMI treatment (23).reports, we revised the “Guidelines for the Given these new findings and overseas Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008”. These guidelines include statements of recommendation. For each recommendation, a “grade” and “level of the quality of the evidence” are provided. The “grade” indicates the strength of a recommendation, and the “level of the quality of the evidence” defines the level of the study used as the rationale for the recommendation. Recommendation grading was primarily based on published research findings. However, opinions from experts were provided if appropriate or in the absence of sufficient published findings.Grade levels1. Strong recommendation: “The recommendation April 2017 Juvenile Graves’ disease guidelines31 2. is beneficial for most patients.” Weak recommendation: “In many cases, the recommendation is beneficial for patients; therefore, using the recommendation should be considered. Always make the most beneficial choice for the patient depending Level of the quality of the evidenceon circumstances”. ●○○ Low: Uncontrolled case collection●●○ Moderate: Uncontrolled cohort study ●●● randomized controlled trial High: Controlled cohort study, non-Evidence that has not been investigated, but is widely acknowledged is labeled “consensus.” 1. Definition and Diagnosis of Graves’ Disease Recommendation 1-1. Graves’ disease is an autoimmune disease. Thyroid stimulating hormone (TSH; thyrotropin) receptor antibodies (i.e., thyrotropin receptor antibodies [TRAb]) stimulate the TSH receptor, leading to increased thyroid hormone production and secretion, causing diffuse toxic goiter. 1 1-2. (Consensus) Hyperthyroidism, defined as the increased production and secretion of thyroid hormone, and an excess of thyroid hormone in the absence of increased thyroid hormone production are collectively called thyrotoxicosis. 1 (Consensus)Explanation state that results from increased metabolism and The term thyrotoxicosis refers to “a clinical activity due to an excess of thyroid hormone”. Therefore, thyrotoxicosis is not a synonym for hyperthyroidism. Hyperthyroidism, defined as the increased production and secretion of thyroid hormone, and an excess of thyroid hormone (i.e., excess intake of thyroid hormone and destructive thyroiditis, defined as a leakage of thyroid hormone caused by inflammatory destruction of thyroid follicles) in the absence of increased thyroid hormone production are collectively called thyrotoxicosis (1, 2). by excessive thyroid hormone secretion. In Hyperthyroidism is a disorder characterized addition to Graves’ disease, hyperthyroidism has multiple causes, including a TSH-producing tumor, choriocarcinoma, struma ovarii, toxic multinodular goiter (TMNG), toxic adenoma (TA), congenital hyperthyroidism (gain-of-function mutation of the TSH receptor or G protein), and excessive iodine. include painless thyroiditis, subacute thyroiditis, Common causes of destructive thyroiditis acute suppurative thyroiditis, radiation thyroiditis, and drug-induced thyrotoxicosis. Amiodarone, gonadotropin releasing hormone derivatives, lithium carbonate, or interferon-alpha may cause Graves’ disease or destructive thyroiditis. cases involve hyperthyroidism, and most of The majority of pediatric thyrotoxicosis these patients develop Graves’ disease (4, 5). In contrast, subacute thyroiditis is extremely rare in children. physician Robert Graves, who studied and Graves’ disease was named after the Irish reported this disease. This term is usually used in English-speaking countries. In non-English-speaking countries, the term Basedow’s disease, named after a German physician, Karl Adolph von Basedow, is more commonly used. 2. Diagnosis of Graves’ Disease Recommendation 2-1. A diagnosis of Graves’ disease should be based on the “Guideline for the Diagnosis of Graves’ Disease (revised on June 24, 2013)” (Table 1), which was prepared by the JTA and is available on their website. a) Clinical findings 1 (Consensus)1. Signs of thyrotoxicosis such as tachycardia, weight loss, finger tremor, and sweating. 32Juvenile Graves’ disease guidelinesVol.26 / No.2Table 1. Guidelines for the diagnosis of Graves’ disease (Japan Thyroid Association) a) Clinical findings1. Signs of thyrotoxicosis such as tachycardia, weight loss, finger tremor, and sweating.2. Diffuse enlargement of the thyroid gland.3. Exophthalmos and/or specific ophthalmopathy. b) Laboratory findings1. Elevation in serum free thyroxine (FT4) and/or free triiodothyronine (FT3) level.2. Suppression of serum thyroid stimulating hormone (TSH): less than 0.1 μU/ml.3. Positive for anti-TSH receptor antibody (TRAb or TBII) or thyroid stimulating antibody (TSAb).4. Elevated radioactive iodine (or 99mTcO4–) uptake to the thyroid gland. 1) A patient is diagnosed with Graves’ disease if he/she has satisfied at least 1 of the clinical findings and all 4 laboratory findings.2) A patient is suspected of having Graves’ disease if he/she has satisfied at least 1 of the clinical findings and laboratory findings 1–3.3) A patient is suspected of having Graves’ disease if he/she has satisfied at least 1 of the clinical findings and both of laboratory findings 1–2. Elevation in serum FT4 has usually been present for at least 3 months. 【Notes】1. Decrease of serum cholesterol and increase of serum alkaline phosphatase are often observed.2. There are rare cases with free triiodothyronine (FT3) elevation alone and normal FT4.3. A patient is diagnosed with “euthyroid Graves’ disease”or “euthyroid ophthalmopathy” if he/she has ophthalmopathy and is positive for TRAb or TSAb, but shows normal FT4 and TSH.4. In an elderly patient, clinical symptoms and signs including an enlargement of the thyroid gland, may not be clear.5. In children, decreased scholastic ability, accelerated growth, restlessness, and other symptoms may be observed.6. The FT3/FT4 ratio is helpful to exclude painless thyroiditis.7. Measurements of thyroid blood flow and urinary iodine levels are useful for differentiation of painless thyroiditis.Revised on June 24, 2013. 2. Diffuse enlargement of the thyroid gland.1 through 3.3. Exophthalmos and/or specific 3) A patient is suspected of having Graves’ ophthalmopathy.disease if he/she has satisfied at least 1 of b) Laboratory findingsthe clinical findings and both of laboratory 1. Elevation in serum free thyroxine (FT4) and/findings 1 and 2. Elevation in serum FT4 has or free triiodothyronine (FT3) level.usually been present for at least 3 months.2. Suppression of serum thyroid stimulating 2-2. A Graves’ disease severity assessment hormone (TSH): less than 0.1 μU/mL.should be based on the following criteria:3. Positive for anti-TSH receptor antibody (1) Clinical assessment of the symptoms of (TRAb or TSH binding inhibitory thyrotoxicosis (goiter size).immunoglobulin (TBII)) or thyroid (2) Pre-treatment serum FT4 level analysis stimulating antibody (TSAb). (e.g. Severe: ≥ 7 ng/dL, Moderate: < 5–7 ng/–99m4. Elevated radioactive iodine (or TcO4) dL, Mild: < 5 ng/dL) (FT4 levels may vary uptake to the thyroid gland.depending on the measurement kit. The 1) A patient is diagnosed with Graves’ disease above values are merely references).if he/she has satisfied at least 1 of the clinical (3) Ultrasonography findings.findings and all 4 laboratory findings.The assessment of criteria (1) through (3) 2) A patient is suspected of having Graves’ should be performed in a comprehensive disease if he/she has satisfied at least 1 of manner. 1 (●○○)the clinical findings and laboratory findings April 2017Juvenile Graves’ disease guidelines33Explanation 1. Diagnosis Disease, 2013” (6) were prepared for adult patients The “Guidelines for the Diagnosis of Graves’ primarily; however, these guidelines should also be used to diagnose pediatric patients. Diagnosis of Graves’ disease can be confirmed in a patient who has, according to clinical observations, the following: (1) symptoms of thyrotoxicosis, including tachycardia, (2) diffuse goiter, and (3) distinctive ocular manifestations. Additionally, laboratory findings will show the following: (1) high FT4 or FT3 level, (2) suppressed TSH, (3) causative positive TSH receptor antibodies (TRAb, TBII, TSAb), and (4) nuclear medicine findings of a high uptake rate in the thyroid gland. However, few medical institutions can perform thyroid uptake and scintigraphy tests. These tests are not always performed, even on adults. Therefore, treatment can be initiated with a diagnosis of “probable Graves’ disease”. In pediatric patients, radiation exposure should be kept to a minimum. Such tests should be performed only in cases involving difficult diagnoses. In recent years, measurement of thyroid blood flow by ultrasonic pulse Doppler has been widely used for the diagnosis of Graves’ disease. 5 years or younger. The occurrence of Graves’ Graves’ disease is extremely rare in children disease increases from age 11 to 15 yr, with a peak at high-school age (2, 4). A hospital-based study of 132 children with Graves’ disease 15 yr or younger in Japan, found that only 4 patients were under 5 yr-of-age (24). However, a few cases of Graves’ disease development in very young children (1–2 yr) have been reported. Therefore, careful observation is necessary, regardless of age. Graves’ disease is more common in girls, with reported boy to girl ratios of around 1:3 to 1:6 (2, 4). Graves’ disease are goiter (68.4%), excessive The major clinical symptoms of pediatric sweating (53.4%), fatigue (50.4%), restlessness (47.4%), and finger tremors (45.1%). Table 2. Clinical symptoms and their frequencies in pediatric Basedow’s diseaseExcessive sweatingFatigue53.40%Restlessness50.40%Hand tremor47.40%Exophthalmos45.10%Weight loss38.30%Increased appetite36.10%Tachycardia35.30%Palpitation33.80%Decreased academic performance24.80%Decreased athletic performance24.10%Sensitivity to heat15.00%Increased bowel movement12.00%Slight fever11.30%Others: insomnia, thirst, bed-wetting, amenorrhea10.50%(24).Exophthalmos (38.3%), weight loss (36.1%), and tachycardia (33.8%) are also common (24) (Table 2). In adults, frequent clinical symptoms include goiter (69%), ocular manifestations (63%), weight loss (61%), sensitivity to heat (55%), finger tremors (54%), and palpitations (51%) (25). Weight loss is less common in children. Weight gain is a common physiologic change in puberty. Therefore, a lack of weight gain in an adolescent is a significant clinical observation. It is difficult to recognize finger tremors in schoolchildren, whereas hyperactivity, typified by restlessness, and excessive growth promotion tend to be easily recognized. Occasionally, the drawing of a pediatric growth curve might help to detect the onset of the disease. Fatigue is a common symptom among patients who are junior high-school students. Other nonspecific symptoms, although less frequent, have been reported; these include a decline in academic performance, slight fever, nocturnal enuresis, menstrual irregularities, and diarrhea. In addition, thyrotoxic myopathy (muscle weakness), caused by increased catabolism of muscle fibers, has been reported to precede thyrotoxicosis in 34Juvenile Graves’ disease guidelinesVol.26 / No.2two-thirds of studied patients (26). Thyrotoxic myopathy is occasionally accompanied by thyrotoxic hypokalemic periodic paralysis or encephalopathy associated with thyroid storm.to tachycardia, palpitations, dyspnea, cardiac Patients may complain of discomfort due dilatation, or cardiac failure. However, atrial fibrillation is rare in children. An apical systolic regurgitant murmur may be present because of mitral valve insufficiency resulting from papillary muscle dysfunction (4). exhibit nonspecific physical symptoms, and may Prepubertal patients with Graves’ disease manifest various mental symptoms. Accordingly, the disease tends to be overlooked and 6 to 12 mo may easily pass between onset of the disease and the final diagnosis. Therefore, when a school-age patient visits a hospital, clinical data tend to indicate a severe condition and accelerated growth and an increased bone age may be observed. However, this rapid growth will not affect the final height of the patient (27–29).in children are almost similar to those in adults; The reported frequencies of exophthalmos however, this symptom is minor, and highly active ophthalmopathies such as ocular motility disorder or optic nerve disturbances are fairly uncommon (30, 31). of the index case is 11.6-fold higher than that The incidence of Graves’ disease in a sibling in the general population (32). The incidence of Graves’ disease in identical twins is significantly higher (35%) than in dizygotic twins (3%). As reported, 79% of the pathogenic mechanisms of Graves’ disease can be explained by genetic factors (33). In Japan, 40% of children with Graves’ disease have a familial history of the disease (24), and the frequency of familial Graves’ disease is 2–3% (4). In addition to multiple genetic factors, environmental factors are involved; when a patient’s immune tolerance to thyroid antigens is broken, they will develop Graves’ disease. Several candidate gene analyses and comprehensive genome-wide association studies have identified the following disease-susceptibility genes: (HLA)-DR3(Tg)associated , TSH , receptorHLA-DRβ1-Arg74human leukocyte antigen , , thyroglobulin tyrosine phosphatase-22protein 4 (cytotoxic CTLA4), T-lymphocyte-CD40, protein gene in AITD susceptibility region (PTPN22), receptor-like 3interferon-induced helicase 1 (FCRL3), interleukin-23 (zinc-finger ZAFT (IL-23R), Fc ), box P3( ( (IFIH1), Forkhead HLA regions are attributed to 20% of the genetic IL-2RA; FOXP3CD25), among others (34, 35). Notably, ), and interleukin-2 receptor-α factors associated with Graves’ disease, and only SNPs in the odds ratios greater than 2 (36, 37). The following CTLA4 and TSH receptor genes have environmental factors have been reported to cause Graves’ disease: infectious diseases, iodine, smoking, alcohol, stress, pregnancy/childbirth, selenium, drugs, dioxins such as polychlorinated biphenyls (PCBs), and radiation exposure (38).according to the patient’s age, sex, and secondary The function of the thyroid gland changes sexual characteristics. Therefore, it is not appropriate to apply adult standards to children. Previously, the reference values for children were based on solid-phase radioimmunoassay (RIA) standards that were established by the Research Group on Reference Values for Children and presented in the “Reference Values for Laboratory Tests on Japanese Children” (published in 1996 by the Japan Public Health Association). Several non-RIA methods have been developed since these standards were established. Presently, an enzyme immunoassay (EIA), that does not use radioactive substances, and a more sensitive luminescent immunoassay (LIA) are commonly used. In particular, fully automatic measuring devices have been developed for a chemiluminescent enzyme immunoassay (CLEIA) and chemiluminescent immunoassay (CLIA). Reference values of thyroid function in healthy children can be measured by a kit, ECLusys® (Roche Diagnostics GmbH, Mannheim, Germany) with an electrochemiluminescent immunoassay (ECLIA) (39) (Table 3). According to these standards, the maximum FT3 value is April 2017 Juvenile Graves’ disease guidelines35 Table 3. Reference levels of FT3, FT4, and TSH by age (ECLIA method)Age group(pg/mL)FT3 (ng/dL)FT4 (μU/mL)TSH 4–6 yr7–8 yr2.91–4.701.12–1.679–10 yr3.10–5.101.07–1.610.62–4.900.53–5.1611–12 yr3.10–4.8713–14 yr2.78–4.900.96–1.600.62–3.3615 yr2.77–4.591.02–1.520.67–4.520.54–2.78Adult 2.50–4.640.96–1.522.20–4.30 0.85–1.530.80–1.60 0.32–3.000.20–4.50 Iwaku K. Endocr J 2013; 60: 799-804 (38). 5.10 pg/mL (age 7–8 yr), and the maximum FT4 value is 1.67 ng/dL (age 4–6 yr). However, values may vary depending on the measurement kit. in patients with Graves’ disease are noted in Increased serum alkaline phosphatase levels the JTA’s diagnostic guidelines. However, age-dependent reference values in healthy children show a large range compared to the range of adult values. So, alkaline phosphatase levels have been deleted as a diagnostic reference note in these guidelines. measurements of “thyroid blood flow” and In the JTA’s diagnostic guidelines, “urinary iodine” are noted. A maximum blood flow rate of the superior thyroid artery on ultrasonic pulse Doppler that exceeds 45 cm/sec supports a diagnosis of Graves’ disease (40). Additionally, a ratio of 0.5 or more between blood flow pixels/total pixels as measured by a semi-quantitative method is a diagnostic indicator for Graves’ disease (41). In patients with Graves’ disease, iodine uptake of the thyroid gland increases and urinary iodine excretion decreases. On the contrary, in patients with painless thyroiditis, iodine uptake of the thyroid decreases and urinary iodine excretion increases as a result of thyroid gland destruction. A 100 × TRAb/total urinary iodine ratio of over 3:0 supports a diagnosis for Graves’ disease (42). 2. Severity Poor remission rates are reported in Graves’ disease patients with high levels of FT4 and FT3, with large goiter, with T3 pre-dominance, or with childhood onset (1, 2, 43). Disease, 2011” suggest that the starting dose of The “Guidelines for the Treatment of Graves’ antithyroid drug be modified according to the severity of the disease (10). According to the ATA guidelines, severe Graves’ disease is defined as a FT4 level 2–3 times greater than the upper limit of the reference value (19). According to a retrospective study of pediatric Graves’ disease in Japan, in which MMI was used as the initial treatment, the mean pre-treatment FT4 level of patients initially treated with a high dose of MMI was 6.1 ± 2.0 ng/dL. On the other hand, the pre-treatment FT4 level of patients initially treated with a low dose of MMI was 4.6 ± 2.6 ng/dL (21). It is recommended that the pre-treatment FT4 level be used as a reference guide for assessing the severity of the disease and predicting the therapeutic effect. TRAb, and the TRAb level is therefore useful Graves’ disease is directly induced by as a diagnostic or control index. However, the disease prognosis cannot be predicted from the pre-treatment TRAb value (10, 44). requirement at 1 year after starting treatment A previous report indicated that the MMI is greater if the maximum blood flow rate in the inferior thyroid artery exceeds 100 cm/sec at disease onset; ultrasonic measurement of the maximum blood flow rate might predict responsiveness to an antithyroid drug (45). 3. Initial Treatment of Graves’ DiseaseRecommendation 3-1. If a patient with Graves’ disease does not have a history of treatment, explain the various treatment options, including antithyroid drug therapy, surgical treatment, and radioiodine therapy (131initiating treatment. Thoroughly explain the I therapy) before benefits and drawbacks of each treatment option, as well as the indications and 36Juvenile Graves’ disease guidelinesVol.26 / No.2 contraindications, and obtain consent from the patient and their family before selecting 3-2. The benefits of antithyroid drugs include a treatment method. 1 (Consensus) no risk of radioactive iodine exposure, no bothersome hospitalization, and no surgical procedure. The drawbacks include a lower remission rate in children compared to adults, treatment-related suffering, longer duration of the treatment, and higher frequency of adverse drug reactions. 1 3-3. Surgical treatment is more reliable and (Consensus) associated with a shorter treatment duration. However, surgery requires invasive procedures, and thyroid hormone replacement therapy will be required after the surgery. To avoid recurrence, total or near total thyroidectomy to reduce the remaining thyroid tissue should be performed. Either surgery must be performed by a skillful 3-4. thyroid surgeon. 1 (Consensus) 131However, this treatment is associated I therapy is a safe and reliable treatment. with a high risk of future hypothyroidism development. In Japan, 131subject to “careful administration” for I therapy is children 18 yr or younger because of the risk of thyroid cancer development or gonadal damage consequent to radiation exposure. 3-5. 1 (Consensus) For children, antithyroid drug therapy is the primary treatment option. 1 (Consensus)Explanation for Graves’ disease, including antithyroid drug Multiple treatment options are available therapy, surgical treatment, and 13147). Drug therapy is available on an outpatient I therapy (46, basis, and can be used by most patients with Graves’ disease. In Japan, approximately 90% of patients without a treatment history are initially treated with antithyroid drugs. Similarly, long-term antithyroid drug treatment tends to be used in Europe (approximately 80%), Asia and Oceania, and South America (48). Previously, more than 70% of patients without a treatment history in the US received 131in recent years, 40% of patients without a I therapy. However, treatment history are initially treated with antithyroid drugs; thus, the use of 131is decreasing (48, 49). I therapy Graves’ disease are limited to patients who The indications for surgical treatment for wish to achieve remission sooner, have large goiters, have complicating thyroid cancer, do not wish to receive treatment with antithyroid drugs, or cannot use antithyroid drugs (1, 2, 10, 19). If a patient exhibits severe symptoms of thyrotoxicosis, antithyroid drugs should be used initially to normalize thyroid gland function before undergoing surgical treatment. subject to “careful administration” for children 18 As a general rule, in Japan, 131I therapy is yr or younger. However, there is no evidence to support this designation. 131for patients who do not wish to take antithyroid I therapy is only used drugs or receive surgical treatment or who cannot choose other treatment options (10). However, the ATA guidelines suggest that 131considered at an early stage for pediatric patients I therapy be 5 yr or older with severe Graves’ disease who do not achieve remission via drug therapies or fail to achieve remission with drug therapies after 1 or 2 yr (19). If the patient exhibits severe symptoms of thyrotoxicosis, antithyroid drug therapy should be combined with a β-blocker to improve the systemic condition and ensure that 131I therapy can be performed safely. therapy is the primary treatment option for For the above reasons, antithyroid drug pediatric patients (8, 10, 50–52). 4. Drug Therapies for Graves’ DiseaseRecommendation 4-1. As a general rule, use an antithyroid drug 4-2. therapy for Graves’ disease. 1 (Consensus)Two antithyroid drugs are available: Thiamazole [MMI, proprietary name: April 2017Juvenile Graves’ disease guidelines37 Mercazole Tablet 5 mg, Thiamazole Tablet 5 mg] and Propylthiouracil [PTU, proprietary name: Thiuragyl Tablet 50 mg, Propacil Tablet 50 mg]. Use MMI as the first-line therapy. If using PTU for pediatric Graves’ disease, thoroughly explain that the patient may develop severe hepatic dysfunction as an adverse effect and administer the drug 4-3. cautiously upon obtaining consent. 1 (●●○)The starting dose of MMI should be 0.2–0.5 mg/kg/d once daily (QD) or twice daily (BID); the starting dose of PTU should be 2–7.5 mg/kg/d three times daily (TID). When a dose for a pediatric patient (calculated based on his/her body weight) exceeds the dose for adults, use the adult dose as a general rule (15 mg/d for MMI, 300 mg/d for PTU). For severe cases, use twice the amount of the 4-4. For a patient with severe symptoms of maximum dose. 1 (●●○) thyrotoxicosis, use a β-blocker concurrently. 4-5. 2 (Consensus)After initiating treatment, monitor adverse drug reactions every 2–3 wk for at least 2–3 mo. Perform blood and urine tests in addition to the thyroid function test. 1 (●●○)Explanation 1. Choosing an antithyroid drug propylthiouracil Two types of antithyroid drugs, available. Thiamazole comprises 2 subtypes of (PTU) and thiamazole, are drugs, MMI and carbimazole (CBZ). Methimazole is mainly used in Japan and the US, and CBZ is used in Europe. Carbimazole is promptly and completely metabolized to MMI in the liver. However, because the side chain is detached, 10 mg of CBZ is equivalent to 6 mg of MMI. Both PTU and MMI inhibit thyroid peroxidase and suppress iodination of tyrosyl residues on TG (inhibition of organification). In addition, PTU and MMI inhibit TG synthesis, coupling two iodotyrosines to form T3 or T4, and the secretion of thyroid hormone (53). PTU inhibits a Type-I deiodination enzyme in the liver and peripheral tissues and suppresses the conversion from T4 to T3. Therefore, PTU is considered for patients with thyroid storm. However, the clinical response is unsatisfactory unless a large quantity (approximately 1,000 mg of PTU) is used (54). The reported potency of MMI is 10- to 100-fold greater than that of PTU (55). The serum half-life of MMI is between 6 and 8 h, whereas that of PTU is 0.5 h. Therefore, MMI can be administered only once daily, whereas PTU must be administered 3 times daily (56). MMI and PTU do not differ with respect to placental transportability. MMI exhibits low protein-binding activity and a milk/plasma (m/p) concentration ratio of approximately 1. In contrast, PTU exhibits high serum protein-binding activity, and a relatively small amount of PTU is excreted into milk (m/p ratio: approximately 0.1) (10).in Japan and Europe because of its once-daily Compared with PTU, MMI is preferred dosing regimen. Such a regimen allows more rapid normalization of thyroid function with MMI than with PTU (57). In addition, MMI causes fewer adverse drug reactions. Accordingly, MMI is preferred in those areas (Japan: approximately 85% of cases, Europe: approximately 95% of cases) (7, 49). However, in the US, PTU was initially less expensive than MMI and was used predominantly in the 1980s (approximately: 85% of cases) (49). In the late 1990s, the first generic MMI formulations were released and use of MMI has increased (58).with a higher incidence of serious adverse drug In comparison with MMI, PTU is associated reactions (59–62). In particular, many cases of severe hepatopathy, liver failure (11–18), and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis syndrome (63–66) have been reported in children. In the US, many cases of serious PTU-associated hepatic dysfunction have been reported in children younger than 17 years. Regarding MMI, an association between use in early pregnancy and teratogenicity (i.e., MMI embryopathy) has been suggested (53, 67, 68). Based on these findings, the ATA guidelines 38Juvenile Graves’ disease guidelinesVol.26 / No.2principally suggest use of MMI for antithyroid drug therapy, whereas use of PTU is limited to the following exceptions: (1) during the first trimester of pregnancy, (2) patients with thyroid storm, and (3) patients with minor reactions to MMI who refuse 131 In Japan, the incidence of PTU-associated severe I therapy or surgery (10, 19). hepatopathy is extremely rare in children with Graves’ disease. However, given the reported situation in the US, these guidelines suggest that physicians provide a sufficient explanation to patients and families and obtain consent before administering PTU. developed Graves’ disease at 15 yr or younger A retrospective study of children who was conducted to evaluate the interval from treatment initiation to normalization of thyroid function, and the frequency of adverse drug reactions relative to the type and dosage of the initial medication. In this study, 133 children with Graves’ disease who had been monitored for more than 1 yr after the start of antithyroid drug therapy were divided into 4 groups: MMI Low-Dose Group (low MMI group: initial dose < 0.75 mg/kg, n = 34), MMI High-Dose Group (high MMI group: MMI ≥ 0.75 mg/kg, n = 30), PTU Low-Dose Group (low PTU group: PTU < 7.5 mg/kg, n = 24), and PTU High-Dose Group (high PTU group: PTU ≥ 7.5 mg/kg, n = 45). The mean intervals to normalization of thyroid function were 1.9 mo in the low MMI group, 1.4 mo in the high MMI group, 3.1 mo in the low PTU group, and 1.7 mo in the high PTU group. The low PTU group had a significantly longer treatment to normalization interval. However, a between-group comparison showed no significant relationships between the pre-treatment FT4 level and the interval to normalization of thyroid function (20). 2. Starting doses and dosage regimens of antithyroid drugs in adverse drug reactions as the highest priority, Since the recent designation of a reduction doses of antithyroid drugs have tended to decrease. As a textbook example, the stated starting doses are 0.25–1.0 mg/kg/d for MMI (2, 4) and 2–6 mg/kg/d for PTU (5). This amount is equivalent to 5–15 mg/d of MMI in adults.disease in Japan, 2011” suggest starting doses of The “Guidelines for the Treatment of Graves’ MMI of 15 mg/d for mild and moderate cases and 30 mg/d for severe cases. The suggested starting dose of PTU is 300 mg/d.suggested starting dose of MMI is 0.2–0.5 mg/According to the ATA guidelines (19), the kg/d, and MMI should be used within a range of 0.1–1.0 mg/kg/d (27, 44, 50, 69–72). Specifically, the suggested doses are 1.25 mg/d for infants, 2.5–5.0 mg/d for children aged 1–5 yr, 5–10 mg/d for children aged 5–10 yr, and 10–20 mg/d (i.e., the adult dose) for children and adolescents aged 10–18 yr. For severe cases, the dose can be increased to as high as twice the above-listed amounts. According to the guidelines used in Brazil (73), the suggested dose of MMI is 0.2–0.5 mg/kg/d, and MMI should be used within a range of 0.1–1.0 mg/kg/d. The upper limits are 30 mg/d for MMI. The suggested dose of PTU is 4.7–8.6 mg/kg/d. In a review article by Kaguelidou (74), the initial starting dose of MMI was 0.5–1.0 mg/kg/d with a maximum of 30 mg/d, whereas that of PTU was 5–10 mg/kg/d with a maximum of 300 mg/d. A retrospective study reported MMI starting doses of 0.7 mg/kg/d for children younger than 7 yr and 0.5 mg/kg/d for children older than 7 yr. In this study, an average of approximately 6 mo was required for patients younger than 7 yr to achieve normalization of thyroid function (75). In another study, low-dose MMI treatment was found to be successful for mild cases; however, for severe cases, dose increases only led to an increase in the incidence of adverse drug reactions, and the efficacy did not differ from that of low-dose treatment for mild cases. Based on these results, this study suggested a standard MMI dose of 0.5 mg/kg/d. This amount could be adjusted depending on disease severity. In particular, the suggested doses are 2.5–10 mg/d for children younger than 4 yr, 10–20 mg/d for April 2017Juvenile Graves’ disease guidelines39Fig. 1. Initial Methimazole (MMI) dose by age. The curve shows the doses per weight calculated from the average weights of Japanese female children. Low-dose group (Group A): Doses by age recommended in the US guidelines. High-dose group (Group B): Doses higher than but less than 2-fold that of Group A and lower than 30 mg/d (recommended for severe cases in the Japanese Guidelines for adults). Super high-dose group (Group C): Doses higher than that of Group B (Sato H. J Pediatr Endcr Met 2012; 25: 863-7) (21).children between 4–10 yr of age, and 15–30 mg/d for children 10 yr or older (Fig. 1) (21). opinions on whether to increase the doses for Specialists have expressed differing childhood-onset cases according to disease severity. Thyroidologists (internal medicine physicians) tend to use lower doses than do pediatric endocrinologists (pediatricians) (7). For adults, the highest priority is placed on reducing the incidence of adverse drug reactions, and physicians thus tend to initiate treatment with smaller doses of MMI than those used previously (19). In addition, the concurrent use of inorganic iodine is thought to reduce the required dose of MMI. treatment FT4 level, and persistently high TRAb A young age, large goiter, elevated pre-level at the initial visit have been reported as predictors of poor prognosis (i.e., decreased remission rate) (76–79). Using these findings as a reference and considering the impact of increased thyroid function on a patient’s growth, an initial dose of 1 mg/kg/d of MMI is considered reasonable for thyroid function normalization in severe cases with symptoms of heart failure. For mild and moderate cases, and particularly for older children, a starting dose of approximately 0.5 mg/kg/d of MMI is suggested. If the FT4 level does not decrease as expected with an initial low-dose treatment, the dose can be increased.weight may occasionally exceed the recommended Pediatric doses calculated based on body doses for adults. However, the use of a larger dose of MMI will only increase the incidence of adverse drug reactions; it will not affect the effectiveness of the therapy. Therefore, these guidelines suggest that the recommended pediatric dose must not exceed the adult dose. If symptoms cannot be controlled with the recommended dose of the antithyroid drug, the patient must be referred to a pediatric endocrinologist or thyroidologist.tend to emerge within 3 mo after treatment Most adverse reactions to antithyroid drugs initiation (59–61). As a general rule, the patient should be monitored for adverse reactions every 2–3 wk for at least the first 3 mo. In particular, monitoring should be performed every 2 wk during the first 2 mo. Adverse drug reactions may occur even during maintenance therapy; therefore, the patient must be monitored at prescribed intervals. For monitoring, the complete blood count, differential white blood count, and levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl bilirubin (T-Bil) should be checked. (80–82). transpeptidase (γ-GTP), and total The frequency of adverse reactions to MMI is associated with the delivered dose (21, 62, 83–85).3. Combination therapycatecholamines, thus causing the typical Thyroid hormone affects the actions of 40Juvenile Graves’ disease guidelinesVol.26 / No.2symptoms of thyrotoxicosis, which include tachycardia, excess sweating, and restlessness. Concomitant patients with severe symptoms of thyrotoxicosis. use of β-blockers is useful for The ATA guidelines strongly suggest concomitant use min of a β-blocker if administered orally: propranolol, 0.5–2.0 mg/(19). The following pulse β-blockers rate exceeds should 100/be kg/d TID; atenolol, 1–2 mg/kg/d QD; metoprolol, 1.0–2.0 mg/kg/d TID; nadolol; or esmolol. These β-blockers can be used carefully by patients with bronchial asthma (86). In Japan, however, the use of β1-nonselective β-blockers (e.g., propranolol, nadolol) is contraindicated in patients with bronchial asthma. 4. Other drug therapies and combination therapies are unable to use antithyroid drugs. For infants Inorganic iodine can be used by patients who or schoolchildren, the recommended starting doses are 10–20 mg /d QD of potassium iodide solution (adjusted dose of iodine: 12.5 mg/mL) or 3–4 drops/d of Lugol’s solution (1 drop of Lugol’s solution = 6.3 mg iodine). For junior high school students, 1–2 potassium iodide pills (inorganic iodine: 38.2 mg/pill) should be taken per day. A patient who intends to use potassium iodide must be referred to a thyroidologist as soon as possible.inhibit organification of iodine and suppress A large amount of inorganic iodine will the release of thyroid hormone, thus promptly controlling the thyroid function (Wolff–Chaikoff effect). Inorganic iodine therapy should be used to control thyroid function in the case of thyroid storm, as pre-operative Graves’ disease care, as pre- and post-131 developed an adverse reaction and cannot use I therapy, or in a patient who has any antithyroid drugs (87). In such cases, careful consideration must be given to the potential for escape phenomenon, or a rapid exacerbation of thyrotoxicosis after treatment discontinuation. A study of adult patients with relatively small goiters, FT4 levels ≤ 2.5 ng/dL, and relatively low TRAb levels, showed that approximately two-thirds of patients treated with inorganic iodine monotherapy did not develop escape phenomenon and maintained normal thyroid function for a long period; furthermore, approximately 60% of these patients achieved remission after an average of 7.4 yr of treatment (88, 89). In adults with Graves’ disease, combined treatment with MMI and inorganic iodine was used to reduce the MMI dose (83, 90, 91). In these studies, this combination therapy reduced blood flow in the thyroid gland and bleeding during surgery; however, exacerbated thyroid gland enlargement was also reported. Only a few reports have discussed the use of combination therapy in pediatric patients; therefore, this therapy should be administered to children with caution (87).sensitive to changes in MMI dose and experience For patients with thyroid function that is exacerbation of the condition, block and replace therapy is sometimes used to stabilize thyroid function. This therapy uses a sufficient amount of MMI (15 mg/d) to control thyroid function, combined with a minimum amount of L-thyroxine (LT4) to maintain normal thyroid function. Another type of block and replace therapy uses large fixed amounts of MMI and LT4. This therapy uses the immunosuppressive action of MMI to improve the remission rate. However, evidence that this type of long-term combination therapy improves the remission rate is not convincing, and this regimen was reported to significantly increase the incidence of adverse reactions. Therefore, the use of this therapy is not recommended (92–96).carbonate, perchlorate, corticosteroid, Other drug therapies include lithium cholestyramine, or immunoregulation therapy (rituximab).gland via active transport by the sodium/iodide Lithium carbonate is taken up by the thyroid symporter (NIS). This agent suppresses the synthesis and secretion of thyroid hormone, but causes escape phenomenon. Lithium carbonate is less effective than MMI and has been associated with many reported cases of adverse drug April 2017Juvenile Graves’ disease guidelines41reactions. This therapy is not covered by public health insurance. also taken up by the thyroid gland via NIS-Similarly, perchlorate (Perchloracap®) is mediated active transport. This drug releases iodine in the thyroid gland and inhibits the NIS, thus suppressing thyroid hormone synthesis. Perchlorate is used to diagnose the type of congenital hypothyroidism. However, this agent has not been approved by the Ministry of Health, Labor and Welfare. Adverse effects of perchlorate treatment, such as fever, rash, enlarged lymph nodes, renal disorders, agranulocytosis, and critical aplastic anemia, have been reported. Currently, perchlorate is not commonly used for long-term treatment of Graves’ disease. can suppress T4 secretion from the thyroid When used in large doses, corticosteroid gland or conversion of T4 to T3 in peripheral tissues. However, to avoid serious side effects related to long-term use, corticosteroid use should be limited to treatment of thyroid storm, Graves’ ophthalmopathy, or localized pretibial myxedema, or for pre-thyroidectomy control in patients with severe Graves’ disease. binds both T4 and T3 and inhibits enterohepatic Cholestyramine, an anion exchange resin, circulation. Cholestyramine may rapidly reduce the T3 and T4 levels when used concurrently with MMI for thyrotoxicosis (97). However, this treatment is not covered by health insurance.antibody, that specifically targets CD20-positive Rituximab is an anti-CD20 monoclonal B lymphocytes via antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis induction. Rituximab has been reported to be effective for non-Hodgkin’s lymphoma, granulomatosis with polyangiitis, rheumatoid arthritis, systemic lupus erythematosus, pediatric refractory nephrotic syndrome, idiopathic thrombocytopenic purpura, and type 1 diabetes mellitus. The ability of rituximab to reduce TRAb levels has been evaluated (98).5. Method for Reducing Antithyroid Drug Doses, Maintenance Therapy, and Duration of TreatmentRecommendation5-1. Once serum FT4 and FT3 levels have normalized, start reducing the antithyroid 5-2. Usually, the thyroid function will stabilize drug dose. 1 (Consensus)2–3 mo after starting the medication; the standard maintenance dose ranges from 5 5-3. At least once every 3–4 mo, perform a mg/every other day to 5 mg/d. 1 (●○○)thyroid function test and general blood test. annual myeloperoxidase-antineutrophil While using PTU, urinalysis and cytoplasmic antibody (MPO-ANCA) measurement are necessary to avoid overlooking signs of MPO-ANCA-associated 5-4. To achieve functional stabilization, small vasculitis syndrome. 1 (●●○)amounts of MMI and LT4 may be combined. 5-5. 2 (Consensus)For at least 18–24 mo, continue antithyroid 5-6. Long-term continuous antithyroid drug drug therapy to maintain remission. 2 (●○○)treatment (5–10 yr) may lead to remission. 1 (●●○)Explanation1. Management during treatmentin the hematopoietic system, immune system Graves’ disease may induce abnormalities (79), or hepatic function (80, 81).drugs tend to emerge within 3 mo of starting Most adverse reactions to antithyroid the medication. As a general rule, monitor the patient every 2–3 wk, at least during the first 3 mo, and check for any adverse reactions. In particular, monitoring should be performed every 2 wk in the first 2 mo. The risk of adverse reactions to antithyroid drugs is not negligible. The frequency of adverse reactions to MMI is dose-dependent (21, 62, 83–85). Because PTU and MMI may cross-react, adverse reactions 42Juvenile Graves’ disease guidelinesVol.26 / No.2may occur even with a change in the drug regimen (53). Adverse drug reactions tend to occur at the beginning of treatment, but may also occur during maintenance therapy. Therefore, the patient must be monitored at prescribed intervals. Regarding monitoring, tests should include a complete blood count, differential white blood count, analyses of AST, ALT, γ-GTP, T-Bil, and creatine kinase (CK), and urinalysis. 2. Method for reducing antithyroid drug doses and maintenance therapy mo after starting treatment. Normalization of Usually, thyroid function will stabilize 2–3 the FT3 level will occur after normalization of the FT4 level. Normalization of the TSH level will occur at a later time point. After the serum FT4 and FT3 levels are completely normalized, reduce the medication dose while monitoring the FT4 level. Once the TSH level becomes measurable, gradually reduce the antithyroid drug dose while maintaining the TSH level within the normal range (titration method). The usual maintenance dose of MMI ranges from 5 mg/every other day to 5 mg/d; the maintenance dose of PTU is 50 mg/d. Monitor the patient every 3–4 mo to confirm normal thyroid function. In the ATA guidelines, the maintenance dose of MMI is 5–10 mg/d and 100–150 mg/d for PTU. In the Brazilian guidelines, the maintenance dose of MMI is 5–10 mg/d and 50–100 mg/d for PTU. The maintenance dose for children should be approximately a quarter of the starting dose.MMI ranges from approximately 5 mg/every Although the usual maintenance dose of other day to 10 mg/d, this may vary among individual patients. Testing to confirm normal thyroid function should be performed every 3–4 mo. Sometimes, treatment may be combined with LT4 to achieve functional stabilization of the thyroid gland. treatment initiation and the thyroid function If more than 6 mo have passed since has not improved, or if a previously achieved therapeutic effect has weakened, consider drug discontinuation. TSH-stimulation blocking antibodies may cause sudden elevations of TRAb and TSH levels.3. Duration of treatmentexplain to the patient how long he/she will need Before starting treatment, it is important to to take the drug and obtain their commitment to continued treatment. Generally, as children are not aware of their disease, they tend to exhibit poorer medication adherence. Specifically, they tend to stop taking the drug once the subjective symptoms disappear. A positive TRAb result can be used as an indicator of the duration of treatment (99). A previous report suggested that in children, the TRAb level does not decrease during the course of treatment to the same extent as in adults (72). Some cases will require an extended duration of treatment before a negative TRAb result is achieved. Patients with Graves’ disease require long-term medication treatment. Accordingly, to support continued medication adherence, patients need to understand their illness and have a sense of participation in their treatment. Additionally, patients need social support.determining remission in Graves’ disease; There is no established method for accurately accordingly, there is no specific standard for treatment discontinuation. However, previous reports indicate that a longer duration of minimum dose treatment is associated with a higher remission rate (10, 71, 100, 101). Regarding the duration of antithyroid drug treatment, in “Endocrinology: Adult and Pediatric” by Jameson and De Groot (1), it is stated that children tend to exhibit poor medication compliance and require a longer treatment duration. If remission is not achieved after 3–4 yr of antithyroid drug treatment, another treatment method should be selected once the patient reaches 18–20 yr of age. In the ATA guidelines (19), the suggested duration of antithyroid drug treatment is 12–18 mo. The medication dose should be decreased or discontinued if the TSH level is normal. In such cases, the results of TRAb measurements can be April 2017Juvenile Graves’ disease guidelines43used to make such judgments. If remission cannot be achieved after 12–18 mo, either 131 surgical treatment should be considered unless I therapy or the patient wishes to continue antithyroid drug therapy (102, 103). In the Brazilian guidelines (44), the suggested duration of antithyroid drug therapy is 12–24 mo. In some studies, the remission rate did not improve after 18 mo of antithyroid drug therapy (43, 104). According to other studies, either 131 treatment should be considered if remission I therapy or surgical cannot be achieved after 2 yr of antithyroid drug therapy and if a child requires at least 2–4 yr to achieve remission (73, 105, 106). disease in a multicenter prospective study in Approximately 50% of children with Graves’ France achieved remission after 8–10 yr of long-term treatment with CBZ. This remission rate is higher than those in previous reports, but this rate did not improve after continued treatment beyond 10 yr (107). In the aforementioned study of Japanese children who developed Graves’ disease at ages 15 yr or younger, the remission, non-remission, and therapy change rates of children who received treatment for more than 10 yr were 50, 43, and 8%, respectively with PTU, and 35, 45, and 20%, respectively with MMI (20). Given the retrospective nature of the study, the data from cases treated with PTU were relatively old. Thus, drug therapy was continued for longer periods of time. In contrast, data for MMI were obtained from recent cases, and switching to other treatment methods appeared to occur at an earlier stage. After taking these factors into consideration, the non-remission rates achieved with MMI and PTU appear to be almost the same. This suggests that the continuous use of MMI might have led to remission. In another study of 1,138 children (age ≤ 18 yr) with Graves’ disease in Japan, the remission rate with antithyroid drug therapy was 46.2% after a median treatment period of 3.8 yr. As the remission rate usually improves for up to 5 yr after treatment initiation, this result suggests that the remission rate might be improved with long-term antithyroid drug therapy (23). Based on the above results, nearly half of all patients might achieve remission regardless of the type of antithyroid drug, as long as the drug is used for a long period of time. Because drug therapy must be continued for more than 10 yr in some cases, it is not always necessary to suggest other treatment methods even if remission cannot be achieved within 1 or 2 yr.if the patient is a junior or high-school student In particular, drug therapy may be continued and is preparing for an entrance examination in order to maintain stability in his/her school life, even if thyroid function has stabilized. Significant changes in a child’s environment, such as starting a new school term or advancing to the next stage of schooling, may lead to recurrence if treatment is interrupted. Thus, the timing of treatment discontinuation requires careful consideration.4. Lifestyle guidance for junior- or high-school studentsstudents, it is important to provide guidance For patients who are junior- or high-school regarding school activities, including physical education (PE) classes and sporting activities. No clinical reports have discussed exercise guidance during treatment. However, patients should refrain from PE classes and sporting activities until thyroid function normalizes. After this normalization, no particular restrictions are needed except for participating in vigorous sporting activities. If normal thyroid function is maintained for an extended period of time, no restrictions are necessary, even for vigorous sporting activities.seaweed, and the intake of iodine from food is In Japan, the traditional diet includes more common than in other countries. Because high amounts of iodide affect thyroid function, excess iodine intake has been reported to decrease the effects of antithyroid drugs in some countries with characteristically lower levels of iodine intake from food. However, in areas without iodine deficiency, iodine restrictions, during the initial 44Juvenile Graves’ disease guidelinesVol.26 / No.2treatment of Graves’ disease did not improve the treatment outcomes (108). In addition, iodine intake was not found to affect recurrence (109). Therefore, in Japan, it is not necessary to restrict dietary iodine intake as a component of Graves’ disease management. of pre-treatment, during treatment, or during The JTA guidelines state that, “regardless remission, patients with Graves’ disease should not smoke”. Smoking increases the risk of Graves’ disease, reduces the effects of antithyroid drugs, and increases the recurrence rate. Many adolescents begin smoking as junior or senior high-school students and this coincides with the age of disease onset. Therefore, it is strongly recommended both adolescents with Graves’ disease and their families refrain from smoking (8, 10). 6. Side Effects of Antithyroid Drugs Recommendation 6-1. If minor adverse drug reactions (rash, mild hepatopathy, fever, arthralgia, myalgia, etc.) appear, continue treatment while monitoring; if symptoms do not improve, 6-2. select a different drug. 2 (Consensus)If serious adverse drug reactions (agranulocytosis, severe hepatopathy, MPO-ANCA-associated vasculitis syndrome, etc.) appear, discontinue drug treatment immediately. Subsequently, administer an inorganic iodine preparation to prevent deterioration of thyroid function. Switch the treatment to surgical treatment or, if 6-3. A relationship between the use of MMI necessary, radioiodine therapy. 1 (●○○) during the first trimester of pregnancy and MMI embryopathy (scalp defect, the umbilical cord hernia, remnant of ductus omphaloentericus, tracheoesophageal fistula, esophageal atresia, choanal atresia, etc.) in newborns has been suggested. Use of MMI should be avoided during the first trimester of pregnancy. 1 (●●○)Explanationdrugs is certainly not negligible. The frequency The risk of adverse reactions to antithyroid of adverse reactions to MMI is known to be dose-dependent (60). Approximately 5–50% of MMI users experience minor adverse drug reactions such as rash or mild hepatic dysfunction (20, 23, 62); however, patients affected by these reactions tend to recover naturally. An antihistamine drug may be used concurrently in some cases. If the patient does not recover from these reactions, the other type of antithyroid drug should be used. Serious adverse drug reactions, including agranulocytosis, severe hepatopathy, polyarthritis, and MPO-ANCA-associated vasculitis syndrome occur in 0.1–1.0% of antithyroid drug users (59). If a patient develops such a severe reaction, the antithyroid drug should be discontinued immediately and the patient should be referred to a specialist. Because PTU and MMI exhibit cross-reactivity, adverse reactions may occur even if the drugs are switched (53). In such cases, an inorganic iodine preparation should be administered rather than the other type of antithyroid drug, and non-drug treatment options should be selected.developed Graves’ disease at age 15 yr or younger, In a study of Japanese children who the adverse reaction rates were 16.0% in the low MMI group, 29.2% in the high MMI group, 5.6% in the low PTU group, and 45.9% in the high PTU group; the difference between the low PTU and high PTU groups was significant (20).Graves’ disease at age 18 yr or younger, the In a study of Japanese children who developed frequencies of adverse drug reactions were 21.4% among all MMI users and 18.8% among all PTU users. Most patients developed adverse reactions within 3 mo of initiation of drug therapy, and PTU users more frequently experienced late-onset adverse reactions compared with MMI users (23).is a serious adverse drug reaction that tends to MPO-ANCA-associated vasculitis syndrome occur at or beyond 1 yr of treatment (63–66). Among PTU users, the MPO-ANCA positive April 2017Juvenile Graves’ disease guidelines45rate is higher in children (64%). In a study that included adult patients, PTU users were approximately 40 times more susceptible to MPO-ANCA-associated vasculitis syndrome compared to MMI users. However, there was no association between vasculitis severity and MPO-ANCA antibody levels (59, 64). Approximately 20% of MPO-ANCA-positive patients develop vasculitis. Patients who use PTU for extended periods of time should undergo an annual serum MPO-ANCA measurement and urinalysis should be performed for those with positive results. During the course of treatment, if the patient has fever, rash, arthralgia, myalgia, or common cold symptoms, MPO-ANCA-associated vasculitis should be suspected and the serum MPO-ANCA level should be measured. Urinalysis is necessary to avoid missing the signs of hematuria due to nephritis. A change in the drug regimen should be considered for patients with high MPO-ANCA antibody levels. If the antibody level is low and the patient is asymptomatic, it should be explained that the MPO-ANCA test was positive and the patient is at risk of developing MPO-ANCA-associated vasculitis syndrome. After obtaining consent, PTU use can then be continued. High dose adrenal corticosteroid therapy, immunosuppressants, or hemodialysis should be used for MPO-ANCA-associated vasculitis syndrome, with the treatment choice depending on disease severity. The prognosis of PTU-induced MPO-ANCA-associated vasculitis is reported to be better than that of other primary ANCA-associated vasculitis syndromes (66).as agranulocytosis, severe hepatopathy, or Serious adverse drug reactions, such polyarthritis, tend to appear within 3 mo after treatment initiation (59); however, these reactions may also occur several months later (110). If a patient develops such a reaction, discontinue use of the antithyroid drug immediately and switch to an inorganic iodine preparation including potassium iodide solution at 10–20 mg/d (QD) or 1–2 potassium iodide pills per day (inorganic iodine = 38.2 mg/pill). Treatment with an inorganic iodine preparation may induce the development of escape phenomenon, which could exacerbate hyperthyroidism. In such cases, the patient should be referred immediately and at an early stage to a medical institution with specialists in surgical treatment or 131antithyroid drug dose, reportedly occurs in 0.35% Agranulocytosis, which is dependent on the I therapy.of cases (85, 111, 112). Based on aggregated data from a study of Japanese children with agranulocytosis, the dose of MMI at the time of onset was 20–45 mg/d and the treatment period ranged from 15 to 1,344 d. Patients developed agranulocytosis after receiving more than 20 mg/d of MMI, regardless of the treatment period (22). To treat agranulocytosis, granulocyte colony stimulating factor (G-CSF) should be administered according to the severity (113, 114).hepatopathy was more common in patients A US study (115) reported that serious younger than 17 yr who were treated with PTU (23 of 76 patients with severe hepatopathy). In contrast, minor hepatopathy was more common in patients 61 yr or older who were treated with MMI (22 of 85 patients). Based on these results, use of PTU is not recommended for children in the US (11–18, 116). However, in Japan, aggregated data between 1995 and 2007 in patients aged 15 yr or younger who had serious hepatopathy failed to indicate PTU-induced liver failure in the “Study on Intractable Hepatobiliary Diseases” by the Health and Labour Sciences Research Grant. Based on information for adverse reactions submitted by two Japanese pharmaceutical companies that handle antithyroid drugs, no cases of PTU-induced liver failure have been reported since 1999 (117). However, according to the retrieved data, two Japanese children developed serious hepatitis and one died (118, 119). In comparison with the US, periodic hepatic function monitoring and earlier action may have led to a reduced number of patients with serious hepatitis (120). However, PTU should still be used for children with caution.The use of MMI during the first trimester of 46Juvenile Graves’ disease guidelinesVol.26 / No.2pregnancy has been suggested to be associated with MMI embryopathy (e.g., scalp defects, umbilical cord hernia, ductus omphaloentericus, tracheoesophageal fistula, esophageal atresia, and choanal atresia) in newborns (53, 68). All treatment guidelines suggest use of PTU, rather than MMI, during the first trimester of pregnancy. 7. Criteria for Antithyroid Drug Discontinuation Recommendation 7-1. During continued drug therapy, if normal thyroid function is maintained with the maintenance dose of an antithyroid drug (approximately 5 mg of MMI/every other day to 5 mg/d), consider discontinuation of 7-2. the drug. 2 (●○○)If the goiter decreases in size and negative TRAb results are maintained, the patient 7-3. may have achieved remission. 2 (●○○)Continue using an antithyroid drug (1 tablet every other day) for more than 6 mo. If thyroid function is normalized, it may be possible to discontinue drug therapy. 2 7-4. (Consensus)Drug therapy may be continued with consideration of the patient’s school life (e.g., preparation for entrance examinations). 2 7-5. (Consensus)Most recurrences occur within 1 yr of drug discontinuation. However, recurrences may also occur beyond 1 yr after discontinuation. Periodic check-up is required during remission. 1 (Consensus) Explanation the remission of Graves’ disease; therefore, there There are no accurate predicting factors for is currently no specific standard for treatment discontinuation. Patients with a younger age, larger goiters, higher serum T3/T4 ratios, severity of pre-treatment hyperthyroidism, and persistent positive TRAb results have a greater risk of recurrence (75–78, 121–127). In children, the reported remission rates vary (18–65%), but most studies suggest a rate of approximately 30% (29, 100, 122, 128–130). However, higher remission rates have been associated with longer minimum dose treatment durations (4.3 ± 1.5 yr) (131). In most cases, antithyroid drug therapy can be continued for an extended period if remission cannot be achieved after 18–24 mo of treatment. Once remission is achieved, therapy discontinuation can be considered if normal thyroid function, including the TSH level, is maintained for more than 6 mo with a treatment regimen involving one antithyroid drug tablet every other day (8, 10, 132).possibility of remission (133–136). According A negative TRAb result suggests the to the JTA guidelines, patients with negative TRAb results tend to have a significantly higher remission rate than those with positive results. However, even with negative results, approximately 30% of patients experienced a recurrence. In addition, approximately 30% of patients with positive results achieved remission. Therefore, accurate prediction of prognosis is very difficult (10).used to indicate the timing of antithyroid drug The T3 suppression test was previously discontinuation (99). T3 (Thyronamin Tablet® 5 μg, 25 μg) at 1.5 μg/kg/d (75 μg/d maximum) TID should be administered for 7 days while continuing antithyroid drug therapy. If using the thyroid radioactive iodine uptake (RAIU) as an indicator, the RAIU (24-h value) should be measured after administering T3. If the RAIU is 30% or lower, the T3 suppression test result is considered to be positive. If using the serum T4 level as an indicator, T4 levels should be measured before and after administration of T3. Next, the rate of decrease from before to after T3 administration is calculated; if the serum T4 level has decreased by more than 30%, the T3 suppression test result is considered to be positive. According to a study of pediatric Graves’ disease patients who were treated with PTU for more than 2 yr, the recurrence rate after April 2017Juvenile Graves’ disease guidelines47treatment discontinuation was 22.2% when the T3 suppression test was used as an indicator. In another study in adult patients with Graves’ disease who were treated with MMI for more than 2 yr, a T3 suppression test was performed and treatment was discontinued once 6 mo or more had passed since the normalization in TRAb levels. This study reported a recurrence rate of 22.0% (136). More recently, the T3 suppression test has been used less frequently to determine the timing of drug therapy discontinuation (7). 8. Surgical Treatment for Graves’ DiseaseRecommendation 8-1. Thyroidectomy is an effective treatment for 8-2. Graves’ disease. 2 (●●●)The following are surgical indications: 1) the patient’s condition is complicated by a thyroid cancer, 2) because of an adverse reaction, the patient cannot use any antithyroid drugs and does not wish to receive 131 the patient has a large goiter and has not I therapy, 3) achieved remission with antithyroid drug treatment, 4) the patient’s antithyroid drug compliance is poor, and the thyroid function is not stable, and 5) the patient wishes to achieve complete remission and regain his/8-3. Surgery must be performed by a skillful her social life more quickly. 1 (Consensus)8-4. thyroid surgeon. 1 (●●○)Total or near total thyroidectomy should be performed to reduce the remaining thyroid 8-5. Children tend to have a higher recurrence tissue as much as possible. 1 (●●○) rate and higher frequency of complications. 8-6. 1 (●○○)The patient requires life-long thyroid hormone replacement therapy because of decreased thyroid gland function after thyroidectomy. 1 (●●○) Explanation 1. IndicationsSurgical treatment is effective for Graves’ disease. It is a quick and reliable method; however, the necessity of hospitalization, surgical scarring, and post-operative complications preclude its selection as a primary treatment option (8, 10). This method is used to treat patients who are not responsive to drug therapy, cannot continue drug therapy because of adverse reactions, cannot achieve remission after long-term drug therapy, wish to achieve remission more quickly, are complicated by thyroid cancer, have a large goiter, and/or exhibit poor medication adherence (8, 10). This treatment is indicated for children of age 5 yr or younger who require complete remission. Most patients who select surgery tend to do so for personal reasons such as poor medication adherence.2. Complicationslaryngeal nerve paralysis, and hypoparathyroidism Hemorrhage, hoarseness due to recurrent are known complications of surgery. A larger goiter is associated with an increased amount of bleeding during surgery, and the risks of blood transfusion are increased in children. Because the recurrent laryngeal nerves are thinner in children than in adults, pediatric cases must be handled with caution. Post-operative hypoparathyroidism might be prolonged in children as a result of growth-related bone metabolism.the surgical outcomes of 3 age groups—(1) According to a Japanese study that compared 15 yr or younger (74 patients), (2) 16–20 yr (345 patients), and (3) 21 yr or older (1,478 patients)—, the respective recurrence rates at 5 yr after surgery in patients with less than 4 g of remaining thyroid tissue were 18, 10, and 8%, respectively. In Group (1), both recurrences and complications such as voice hoarseness occurred more frequently (137).thyroid surgeons, the incidence rates of When surgery was performed by skillful permanent hypoparathyroidism and permanent recurrent laryngeal nerve paralysis were less than 2% and less than 1%, respectively (138–141). 48Juvenile Graves’ disease guidelinesVol.26 / No.2 3. Operative procedures before surgery by MMI, an inorganic iodine Hyperthyroidism should be well controlled preparation, useful to improve uncontrolled hyperthyroidism or a β-blocker. Dexamethasone is also rapidly. disease activity and have a higher recurrence Children with Graves’ disease exhibit high rate. Therefore, total or near total thyroidectomy (i.e., < 3 g of remaining thyroid tissue) is recommended to reduce the remaining thyroid tissue as much as possible (142–144). In such cases, thyroid function will certainly decrease and thyroid hormone replacement therapy will be required (145, 146). According to the ATA guidelines (19), total or near total thyroidectomy is suggested for children younger than 5 yr, if a complete cure for hyperthyroidism is desired, or if the goiter is large (> 80 g). Other guidelines and reviews also suggest total or near total thyroidectomy in consideration of the risks of recurrence or bleeding during surgery. thyroid surgeon (147, 148). The surgery must be performed by a skillful 9. 131I Therapy for Graves’ DiseaseRecommendation 9-1. 1319-2. treatment for Graves’ disease. 2 (●●○) I therapy is a reliable, effective, and safe 131in children 18 yr or younger. In addition, I therapy should be performed thoughtfully 131I therapy is generally contraindicated in 9-3. children 5 yr or younger. 1 (●○○) A specialist with sufficient experience 9-4. Before performing should perform the procedure. 1 (●○○) 131a sufficient explanation of the treatment I therapy, provide and obtain consent from the patient. 1 9-5. (Consensus) Prior to 131or β-blocker to normalize thyroid function. I therapy, use an antithyroid drug 9-6. 1 (●○○) To reduce thyroid function with a single 131therapeutic procedure, a sufficient dose of I 1319-7. After I should be given. 1 (●○○) 131I therapy, thyrotoxicosis may be 9-8. temporally exacerbated. 2 (●○○) Patients who receive 131to develop hypothyroidism in the future. 1 I therapy are likely (●○○)Explanation 1. Indications 131treatment for Graves’ disease (149, 150). I therapy is a reliable, effective, and safe 131therapy had been generally contraindicated in I patients 18 yr or younger. However, according to the “Guidelines for the Treatment of Graves’ Disease in Japan, 2011”, 131performed with caution. This change was made I therapy can be to provide physicians with more options in cases that cannot tolerate other treatments (10). 131therapy should even be considered in children I who do not respond at all to drug therapy, cannot receive drug therapy because of an adverse reaction, and/or refuse to have surgical treatment. The usefulness of 131pediatric patients has also been reported in I therapy for several articles published overseas (151–154). are patients who experienced serious adverse The absolute indications for 131I therapy drug reactions during antithyroid drug therapy and do not wish to receive surgical treatment and patients who cannot use either of the antithyroid drugs and do not wish to receive surgical treatment (10). The relative indications are as follows: 1) patients who do not wish to use another treatment method, 2) those who can not achieve remission with an antithyroid drug and do not wish to continue drug therapy, 3) those with recurrent Graves’ disease after surgery, 4) those who wish to receive a complete cure for hyperthyroidism, 5) those who wish to decrease the size of their goiter, and 6) those with a chronic disease, such as heart disease or diabetes mellitus, that lead to difficulties achieving control with drug therapy. The relative contraindication for 131of severe thyroid-associated ophthalmopathy. I therapy is the presence April 2017 Juvenile Graves’ disease guidelines49 the patient: 1) does not have complicating thyroid As a general rule, it should be ensured that cancer, 2) is not pregnant or lactating and is not likely to become pregnant in the next 6 mo, 3) is 19 yr or older, and 4) does not have thyroid-associated ophthalmopathy. 131if other treatment options are not possible. In I therapy can only be used in children such cases, the physician must fully explain the therapy, consult with the patient and their family, and decide whether to select this treatment method (155). 2. Practical guidelines to 131Restrict iodine intake more than 1 week prior drug more than 3 days prior to I therapy, and discontinue the antithyroid 131Measure the RAIU (156) to confirm that iodine is I therapy. restricted. Methods have not yet been established to determine the dose of 131the thyroid function after this treatment. I required to normalize therapy should be avoided in children younger The ATA guidelines (19) state that 131I than 5 yr of age. 131children aged 5–10 yr if less than 10 mCi of I therapy is acceptable in 131is administered. In patients 10 yr or older, 131I therapy is acceptable if the dose exceeds 150 I μCi/g of thyroid tissue (157–160). therapy is acceptable in patients 10 yr or older The Brazilian guidelines state that 131I if the dose exceeds 160 μCi/g of thyroid tissue. For patients with a smaller goiter, 131is useful at a 131I therapy 131I dose between 10 and 15 mCi. induced hypothyroidism in 95% of patients (73, I dose exceeding 150 μCi/g of thyroid tissue 161, 162). Kaguelidou suggested that the 131should be between 220 and 275 μCi/g of thyroid I dose tissue (74). Rivkees recommended 131administered at a fixed activity dose of 15 mCi. If I should be calculating the dose according to thyroid weight, the activity should exceed 150 μCi/g of thyroid tissue. If the thyroid weight is between 30 and 80 g (163), the 131I dose should be as high as 200 to 300 μCi/g of thyroid tissue (106, 164). temporarily exacerbated. If necessary, use an After 131I therapy, thyrotoxicosis may be antithyroid drug, inorganic iodine preparation, or corticosteroids (165, 166). 6-mo period after The TRAb level will be elevated in the 131significantly affect the state of hyperthyroidism I therapy, which might (167). Thyroid function should be evaluated periodically and, if necessary, an antithyroid drug should be used. After 131that the patient may develop or experience I therapy, note exacerbated thyroid-associated ophthalmopathy. The second 131for early achievement of normo- or hypo-thyroid I therapy should be considered function if antithyroid drug therapy cannot be discontinued after 1 yr. normal thyroid function for a long period, and After 131I therapy, it is difficult to maintain hypothyroidism will eventually develop. Thyroid hormone replacement therapy will be required in most patients (168, 169). 3. Malignant tumors and teratogenic and genetic disorders cancer following external irradiation of the head The relative risk of developing thyroid and neck was evaluated in children aged 5 yr or younger, 5–10 yr, and 10–15 yr; the calculated risks were 9.0, 5.4, and 1.8, respectively (149). However, overseas studies of 131no increase in the risk of malignant diseases, I therapy showed including thyroid cancer (151–154, 160, 170–180). were administered more than 10 mCi of Excluding children younger than 10 yr who 131children 5 yr or younger, there is no evidence to I and suggest that 131malignant tumors, including thyroid cancer, or I therapy increases the risk of risk of teratogenic or genetic disorders (19, 73, 74, 106, 181). the number of children and adolescents aged 20 yr According to a nation-wide study in the UK, or younger, treated with 131slightly. This increase has been attributed to the I therapy, is increasing decreased hesitation surrounding the use of 131I 50Juvenile Graves’ disease guidelinesVol.26 / No.2therapy, as well as the lowered indication age (from 18 to 11 yr) (182). bombings. In addition, Japan recently Japan is the only nation to suffer atomic experienced an accident at the Tokyo Electric Power Company Fukushima Daiichi Nuclear Power Station after the Great East Japan Earthquake. Therefore, Japanese citizens are very sensitive about “radiation”. If 131 must be used, it is important that a detailed I therapy explanation is provided by physicians, and that consent is obtained from patients. Subsequently, therapy should be performed by experienced specialists (183–185). 10. Thyroid Storm Recommendation 10-1. Thyroid storm is a severe, life-threatening 10-2. A patient with thyroid storm must be form of thyrotoxicosis. 1 (Consensus) treated in an intensive care unit under whole-body management. The patient must promptly receive a large fluid infusion, body temperature management, large dose of an antithyroid drug, inorganic iodine preparation, β-blocker, and adrenal corticosteroid. If the patient’s clinical symptoms do not improve, plasmapheresis should be performed. 1 (Consensus) Explanation 1. Definition, epidemiology, and diagnosis of thyrotoxicosis. Thyrotoxicosis is caused by Thyroid storm is an acute exacerbation an untreated or poorly controlled underlying thyroid condition; when accompanied by a strong stressor, such as infection, trauma, or surgery, multiple organ dysfunction will occur consequent to a disturbance in the mechanism that compensates for excessive thyroid hormone action. This life-threatening clinical condition requires emergency treatment (186). Infection is the most common trigger of thyroid storm. In addition, a patient may develop thyroid storm after an emergency operation if the presence of Graves’ disease is overlooked. The reported frequency of thyroid storm among patients with thyrotoxicosis is 1.0% (187); additionally, 1–2% of patients with thyrotoxicosis require hospitalization, and the fatality rate associated with this condition is 10–75% (188). A taskforce committee of the JTA and the Japan Endocrine Society for the “Establishment of Diagnostic Criteria and Nationwide Surveys for Thyroid Storm” conducted an epidemiological study in Japan in 2009, in which the estimated number of patients with thyroid storm was approximately 150 per year, or 0.22% of all thyrotoxicosis patients. Thyroid storm is an extremely rare clinical condition with a fatality rate of 11.0% (186). The pathogenic mechanisms underlying thyroid storm are unknown, and the associated fatality rate is high (186–188). This disease requires emergency treatment.previous study reported that this disease occurs Regarding thyroid storm in children, a in 0.1–3 per 100,000 children (189); however, there are not enough epidemiological data (187). In Japan, according to the retrieved data, only around 10 pediatric cases have been reported; however, the actual situation regarding thyroid storm remains unknown. Although most children undergo physical check-ups at school and visit pediatric clinics because of common colds, Graves’ disease may be overlooked in this population. Many of these children develop thyroid storm and finally receive treatment at emergency medical facilities. Thyroid diseases are rarely included in a differential diagnosis, particularly in pediatric emergency medical facilities. Many children who see physicians for central nervous system manifestations accompanied by fever are diagnosed with acute encephalopathy; thyroid storm may be overlooked (190).be used to diagnose thyroid storm according The Thyroid Storm Scoring System can to symptoms and signs (191). The JTA also established and published diagnostic criteria for thyroid storm (186) (Table 4). A diagnosis April 2017Juvenile Graves’ disease guidelines51Table 4. Criteria for the diagnosis of thyroid storm (2nd Edition) (Japan Thyroid Association) [Definite Case]a. Thyrotoxicosis and at least one central nervous system (S) manifestation and one of the following: fever, tachycardia, congestive heart failure (CHF), or gastrointestinal (GI)/hepatic manifestations.b. Thyrotoxicosis and at least three of fever, tachycardia, CHF, or GI/hepatic manifestations.[Suspected case]a. Thyrotoxicosis and a combination of two of the following: fever or tachycardia or CHF or GI/hepatic manifestations.b. Patients who meet the diagnostic criteria for “Definite Case” except that serum FT3 or FT4 values are not available, but in whom data before or after the episode suggest that they are thyrotoxic at the time of thyroid storm. DefinitionsThyrotoxicosis: Elevated FT3 or FT4.S manifestations: Restlessness, delirium, mental aberration/psychosis, somnolence/lethargy, convulsion, coma including a score of 1 or higher on the Japan Coma Scale (JCS), or 14 or lower on the Glasgow Coma Scale (GCS).Fever: 38 degrees Celsius or higher.Tachycardia:130 beats/min or higher (arrhythmias such as atrial fibrillation are evaluated by measuring the heart rate).CHF: The patient presents with severe symptoms such as pulmonary edema, moist rales for more than half the lung field, or cardiogenic shock. The patient’s CHF is categorized as Class IV by the New York Heart Association classification or Class III or higher by the Killip classification.GI/hepatic manifestations: The patient presents with nausea, vomiting, diarrhea, or a bilirubin of > 3 mg/dL.Exclusions and ProvisosCases are excluded if other underlying diseases are clearly causing any of the following symptoms: fever (e.g., pneumonia and malignant hyperthermia), impaired consciousness (e.g., psychiatric disorders and cerebrovascular disorders), heart failure (e.g., acute myocardial infarction), and liver disorders (e.g., viral hepatitis and acute liver failure). However, some of these disorders trigger thyroid storm. Therefore, it is difficult to determine whether the symptom is caused by thyroid storm or is simply a symptom of an underlying disease that is possibly triggered by thyroid storm; therefore, the symptom should be regarded as being due to a thyroid storm that is caused by these precipitating factors. Clinical judgment in this matter is required.must be made based on these clinical symptoms and signs (189). 2. TreatmentA patient with thyroid storm must be treated in an intensive care unit. In addition to respiratory support, resuscitation, and whole-body monitoring, the following treatment approach should be promptly undertaken: a large initial fluid infusion (10–20 mL/kg/h), cooling blankets, body temperature management with antipyretics (acetaminophen at 10 mg/kg/dose, maximum of 500 mg TID to QID), a large dose of an antithyroid drug (PTU at 15–30 mg/kg/d, adult dose of 800–1,200 mg/d TID to QID; MMI at 1.0–2.0 mg/kg/d, adult dose of 60–80 mg/d TID to QID), inorganic iodine preparation (125–250 mg/d TID to QID, 3–6 potassium iodide pills 1 h after administration of the antithyroid drug), β-blocker (initial intravenous administration of propranolol at 10 μg/kg), and adrenal corticosteroids (dexamethasone at 0.6 mg/kg/d; hydrocortisone at 15 mg/kg/d, TID) (19, 186–188). An antibacterial drug should be administered concurrently if thyroid storm has been triggered by an infection. If clinical symptoms do not improve, plasmapheresis should be performed. PTU, adrenal corticosteroids, inorganic iodine 52Juvenile Graves’ disease guidelinesVol.26 / No.2 preparations, and β-blockers suppress the T4 to T3 conversion. Usually, PTU is considered more effective than MMI for thyroid storm; however, there is no clear evidence to support this view. Inorganic iodine preparations must be used 1 h after administration of the antithyroid drug.Conflict of Interest for Committee Members:Each committee member was asked to report potential conflicts of interest that arose during the preparation of these guidelines. We have no conflicts of interest to declare. In accordance with the rules of the Japanese Society for Pediatric Endocrinology, the Conflict of Interest Standards presented by the Japan Pediatric Society must be observed. Acknowledgments were provided by the Japanese Society for Funds for development of these guidelines Pediatric Endocrinology. of the Committee on Pharmaceutical Affairs, We are very grateful to the following members Japanese Society for Pediatric Endocrinology, and the Pediatric Thyroid Disease Committee, Japan Thyroid Association for their collaboration on this project: Toru Kikuchi, Tomohiro Kamoda, Saori Kinjyo, Jyunji Takaya, Hidenori Haruna, Ichiro Miyata, Naoko Arata, Fumito Akasu, Hiroaki Inomata, Kazumichi Onigata, Shigetaka Sugihara, Keisuke Nagasaki, Satoshi Narumi, Soroku Nishiyama, Yukihiro Hasegawa, Shuji Fukata, Mako Fujiwara, Takashi Misaki, Tetsuya Mizokami, Naoko Momotani, Susumu Yokoya, and Hiroshi Yoshimura. Appendix 1. Preparation Funds the Japanese Society for Pediatric Endocrinology and The preparation of these guidelines was funded by the Japan Thyroid Association.2. Preparation Process 2-1. Understanding the current situation On April 27, 2013, at the 14th Committee Meeting of Pediatric Thyroid Diseases of the Japan Thyroid Association, a revision of the guidelines was suggested. On November 16, 2013, at the 15th Committee Meeting of Pediatric Thyroid Diseases, opinions were sought regarding clinical questions on the current guidelines. On December 14, 2013, a preparation committee meeting was held to draft these clinical questions. On April 26, 2014 and November 15, 2014, at the 16th and 17th Committee Meetings for Pediatric Thyroid Diseases, respectively, opinions were sought on a draft modification of the guidelines. 2-2. External evaluation Guideline was posted on the website to allow members From January 1 to January 31, 2016, a draft of the of the Japanese Society for Pediatric Endocrinology, as well as the Japan Thyroid Association, to view the draft and to solicit their opinions. created on March 10, 2016. Based on these opinions, a draft of the revision was the Guidelines Committee of the Japanese Society for The prepared draft was reviewed by members of Pediatric Endocrinology (including external members) to evaluate its scientific integrity as medical guidelines, as well as the appropriateness of the contents. In response to suggestions from the Guideline Committee Members (dated on March 22, 2016), the draft was again modified. Prior to its release, the final version of the Guideline was approved on April 6, 2016 by the Executive Board Members of the Japanese Society for Pediatric Endocrinology, and on April 22, 2016 by the Executive Board Members of the Japan Thyroid Association.2-3. Coordination with other related academic societiesand an understanding of the guidelines was shared via Information on preparation-related tasks, progress, close communication maintained with the Japan Thyroid Association during preparation committee meetings.3. Revision Schedule years of their release. Preparation committee members These guidelines are scheduled to be revised within 5 who will engage in this revision will be appointed by the Executive Board Members of the Japanese Society for Pediatric Endocrinology, as well as the Japan Thyroid Association. In the occurrence of any situations that might have a significant impact on the contents of the guidelines, or if either the Executive Board Members of the Japanese Society for Pediatric Endocrinology or the Japan Thyroid Association consider that urgent changes are required, modifications to the guidelines can be made as “recommendations.” April 2017 Juvenile Graves’ disease guidelines53 References 1. Marino M, Vitti P, Chiovato L. Graves’ disease. In: Jameson Jr, De Groot LJ, editors. Endocrinology: adult and pediatric, 7th Ed. Philadelphia, PA: 2. Saunders and Elsevier; 2016. p. 1437-64. LaFranchi SH, Hanna CE. Hyperthyroidism in the neonatal period and childhood. In: Braverman LE, Cooper DS, editors. Werner and Ingbar’s The thyroid: A Fundamental and Clinical Text, 10th Ed. Philadelphia, PA: Lippincott Williams 3. & Wilkins; 2013. p. 803-14. Japan Thyroid Association. Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug in Japan, 2006. Tokyo: Nankodo Co., Ltd.; 4. 2006 (in Japanese). Huang SA, LaFranchi SH. Graves’ disease. In: Kliegman RM, Stanton BF, St. Geme III JW, Schor NF, Behrman RE, editors. Nelson textbook of pediatrics. 20th ed. Philadelphia: Elsevier, 5. Inc.; 2016. p. 2681-4. Fisher DA. Hyperthyroidism. In: Rudolph CD, Rudolph AM, Lister GE, First LR, Gershon AA, editors. Rudolph’s Pediatrics. 22nd ed. New York: McGraw-Hill Companies Inc.; 2011. p. 6. 2039-40.Japan Thyroid Association. Guidelines for the Diagnosis of Graves, 2013. http://www. 7. japanthyroid.jp/doctor/guideline/japanese.html.Sato H, Harada S, Yokoya S, Tanaka T, Asayama K, Mori M, onset Graves disease in Japan: results of a et al. Treatment for childhood-nationwide questionnaire survey of pediatric endocrinologists and thyroidologists. Thyroid 8. 2007;17: 67–72. Sato H, Sasaki N, Harada S, Tanaka T, Akasu F, [Medline] [CrossRef] Asayama K, of Childhood-Onset Graves’ Disease with et al. Guidelines for the Treatment Antithyroid Drug in Japan, 2008. J Jpn Pediatr 9. Soc 2008;112: 946–52 (in Japanese).Japan Thyroid Association. Handbook of Radioiodine (131I) Therapy for Graves’ Disease 1 0. in Japan, 2007. Kyoto; 2007 (in Japanese). Japan Thyroid Association. Guidelines for the Treatment of Graves’ Disease in Japan, 2011. 1 1. Tokyo: Nankodo Co., Ltd.; 2011 (in Japanese).Ruiz JK, Rossi GV, Vallejos HA, Brenet RW, Lopez IB, Escribano AA. Fulminant hepatic failure associated with propylthiouracil. Ann Pharmacother 2003;37: 224–8. [Medline]1 2. Bahn RS, Burch HS, Cooper DS, Garber [CrossRef] JR, Greenlee CM, Klein IL, propylthiouracil in the management of Graves et al. The role of disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 1 3. 2009;19: 673–4. FDA. information for healthcare professionals-U.S. Food [Medline]and Drug [CrossRef] Administration propylthiouracil-induced liver failure. 2009. www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationfor PInformationforHeathcareProfessionals/atientsandProviders/DrugSafety 1 4. ucm162701.htm. Up To Date patient information. antithyroid drugs. www.uptodate.com/patients/content/topic.do?topicKey=~K7dgOAIby0pAB7&sourc1 5. e=see_link. Eunice Kennedy Shriver National Institute of Child Health and Human Development 2008 Conference Proceeding. Hepatic Toxicity Following Treatment for Pediatric Graves’ Disease Meeting: October 28, 2008. http://bpca.1 6. nichd.nih.gov/outreach/index.cfm. Rivkees SA, Mattison DR. Propylthiouracil hepatoxicity in children and recommendations (PTU) for discontinuation of use. Int J Pediatr 17. Endocrinol 2009; 132041. Cooper DS, Rivkees SA. Putting propylthiouracil [Medline] [CrossRef]in perspective. J Clin Endocrinol Metab 2009;94: 1 8. 1881–2. Rivkees SA, Mattison DR. Ending [Medline] [CrossRef]propylthiouracil-induced liver failure in children. N Engl J Med 2009;360: 1574–5. 1 9. [CrossRef] [Medline]Bahn Chair RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Thyroid Association American Association of et al. American Clinical Endocrinologists. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid 2011;21: 593–646. [Medline] [CrossRef] 54Juvenile Graves’ disease guidelinesVol.26 / No.2 2 0. Sato H, Minagawa M, Sasaki N, Sugihara S, Kazukawa I, Minamitani K, of methimazole and propylthiouracil in the et al. Comparison management of children and adolescents with Graves disease: efficacy and adverse reactions during initial treatment and long-term outcome. J Pediatr Endocrinol Metab 2011;24: 257–63. 21. [Medline]Sato H, Sasaki N, Minamitani K, Minagawa M, [CrossRef] Kazukawa I, Sugihara S, methimazole causes frequent adverse effects in et al. Higher dose of the management of Graves disease in children and adolescents. J Pediatr Endocrinol Metab 22. 2012;25: 863–7. Minamitani K, Oikawa J, Wataki K, Kashima K, [Medline] [CrossRef] Hoshi M, Inomata H, with antithyroid drug-induced agranulocytosis; et al. A report of three girls Retrospective analysis of 18 cases aged 15 years or younger reported between 1995 and 2009. Clin Pediatr Endocrinol 2011;20: 39–46. 2 3. [CrossRef] [Medline]Ohye Kunii Y, Watanabe N, H, Minagawa A, Noh JY, Mukasa K, treatment for graves disease in children: a long-et al. Antithyroid drug term retrospective study at a single institution. 24. Thyroid 2014;24: 200–7. Sato H, Minamitani K, Minagawa M, Kazukawa [Medline] [CrossRef]I, Sugihara S, Wataki K, diagnosis and responses to antithyroid drugs in et al. Clinical features at younger children with Graves disease compared with adolescent patients. J Pediatr Endocrinol 25. Metab 2014;27: 677–83. Burch HB. Overview of the clinical manifestations [Medline] [CrossRef]of thyrotoxicosis. In: Braverman LE, Cooper DS, editors. Werner and Ingbar’s The thyroid: A Fundamental and Clinical Text, 10th Ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2 6. 2013. p. 434-40. Nandi-Munshi D, Taplin CE. Thyroid-related neurological disorders and complications in children. Pediatr Neurol 2015;52: 373–82. 2 7. Cassio A, Corrias A, Gualandi S, Tato L, [Medline] [CrossRef] Cesaretti G, Volta C, and pubertal stage at diagnosis on growth et al. Influence of gender outcome in childhood thyrotoxicosis: results of a collaborative study. Clin Endocrinol (Oxf) 2006;64: 53–7. [Medline] [CrossRef]2 8. Takamatsu J, Kobe N, Ito M, Ohsawa N. Body height and weight of patients with childhood onset and adult onset thyrotoxicosis. Endocr J 2 9. 1999;46(Suppl): S101–3. Lazar L, Kalter-Leibovici O, Pertzelan [Medline] [CrossRef]A, Weintrob N, Josefsberg Z, Phillip M. Thyrotoxicosis in prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol Metab 2000;85: 3678–82. 30. [CrossRef] [Medline]Krassas GE, Segni M, Wiersinga WM. Childhood Graves ophthalmopathy: results of a European questionnaire study. Eur J Endocrinol 2005;153: 31. 515–21. Gogakos AI, Boboridis K, Krassas GE. Pediatric [Medline] [CrossRef] aspects in Graves orbitopathy. Pediatr Endocrinol 32. Rev 2010;7(Suppl 2): 234–44. Villanueva R, Greenberg DA, Davies TF, Tomer [Medline] Y. Sibling recurrence risk in autoimmune thyroid disease. Thyroid 2003;13: 761–4. [Medline] 33. [CrossRef] Brix TH, Kyvik KO, Christensen K, Hegedüs L. Evidence for a major role of heredity in Graves disease: a population-based study of two Danish twin cohorts. J Clin Endocrinol Metab 2001;86: 3 4. 930–4. Simmonds MJ. GWAS in autoimmune thyroid [Medline] disease: redefining our understanding of pathogenesis. Nat Rev Endocrinol 2013;9: 3 5. 277–87. Ban Y. Genetic factors of autoimmune thyroid [Medline] [CrossRef] diseases in Japanese. Autoimmune Dis. 2012;2012:236981. doi: 3 6. Epub 2011 Dec 27. 10.1155/2012/236981. Davies TF, Latif R, Yin X. New genetic insights from autoimmune thyroid disease. J Thyroid 3 7. Iwama S, Ikezaki A, Kikuoka N, Kim HS, Res 2012;623852. [Medline] [CrossRef] Matsuoka H, Yanagawa T, of HLA-DR, -DQ genotype and CTLA-4 gene et al. Association polymorphism with Graves disease in Japanese 3 8. Brent GA. Environmental exposures and children. Horm Res 2005;63: 55–60. [Medline]autoimmune thyroid disease. Thyroid 2010;20: 3 9. 755–61. Iwaku [Medline] [CrossRef] Suzuki M, Sekiya K, K, Noh JY, Minagawa A, Kosuga Y, pediatric reference levels of FT3, FT4 and TSH et al. Determination of April 2017 Juvenile Graves’ disease guidelines55 measured with ECLusys kits. Endocr J 2013;60: 4 0. 799–804. Uchida T, Takeno K, Goto M, Kanno R, Kubo [Medline] [CrossRef] S, Takahashi S, mean peak systolic velocity for the diagnosis of et al. Superior thyroid artery thyrotoxicosis in Japanese patients. Endocr J 4 1. 2010;57: 439–43. Kamijo K. Study on cutoff value setting for [Medline] [CrossRef] differential diagnosis between Graves disease and painless thyroiditis using the TRAb (Elecsys TRAb) measurement via the fully automated electrochemiluminescence immunoassay system. 4 2. Endocr J 2010;57: 895–902. Shishiba [Medline] [CrossRef]J, diagnosis of silent thyroiditis from Graves’ Ishikawa Y, Kamijyo N, Ozawa K, Y, Kurihara et al. Differential H, Sasaki disease in thyrotoxicosis by the measurement of the urinary iodine. Clin Endocrinol (Tokyo) 43. 2002;50: 629–40 (in Japanese). Franklyn JA, Boelaert K. Thyrotoxicosis. Lancet 4 4. 2012;379: 1155–66. Smith J, Brown RS. Persistence of thyrotropin [Medline] [CrossRef] (TSH) receptor antibodies in children and adolescents with Graves disease treated using antithyroid medication. Thyroid 2007;17: 4 5. 1103–7. Nagasaki T, Inaba M, Kumeda Y, Fujiwara-[Medline] [CrossRef] Ueda M, Hiura Y, Nishizawa Y. Significance of thyroid blood flow as a predictor of methimazole sensitivity in untreated hyperthyroid patients with Graves disease. Biomed Pharmacother 46. 2007;61: 472–6. Cooper DS. Antithyroid drugs in the management [Medline] [CrossRef] of patients with Graves disease: an evidence-based approach to therapeutic controversies. J Clin Endocrinol Metab 2003;88: 3474–81. 4 7. [Medline]Muldoon BT, Mai VQ, Burch HB. Management [CrossRef] of Graves disease: an overview and comparison of clinical practice guidelines with actual practice trends. Endocrinol Metab Clin North 4 8. Am 2014;43: 495–516. Burch HB, Burman KD, Cooper DSA. A 2011 [Medline] [CrossRef]survey of clinical practice patterns in the management of Graves disease. J Clin Endocrinol 49. Metab 2012;97: 4549–58. Wartofsky L, Glinoer D, Solomon B, Nagataki S, [Medline] [CrossRef]Lagasse R, Nagayama Y, et al. Differences and similarities in the diagnosis and treatment of Graves disease in Europe, Japan, and the United States. Thyroid 1991;1: 129–35. [Medline] 50. [CrossRef] Perrild H, Grüters-Kieslich A, Feldt-Rasmussen U, Grant D, Martino E, Kayser L, and treatment of thyrotoxicosis in childhood. A et al. Diagnosis European questionnaire study. Eur J Endocrinol 5 1. 1994;131: 467–73. Lee HS, Hwang JS. The treatment of Graves [Medline] [CrossRef] disease in children and adolescents. Ann Pediatr Endocrinol Metab 2014;19: 122–6. [Medline]5 2. [CrossRef] Léger J, Kaguelidou F, Alberti C, Carel JC. Graves disease in children. Best Pract Res Clin Endocrinol Metab 2014;28: 233–43. 5 3. [CrossRef] [Medline]Cooper DS. Antithyroid drugs. N Engl J Med 5 4. 2005;352: 905–17. Saberi M, Sterling FH, Utiger RD. Reduction in [Medline] [CrossRef] extrathyroidal triiodothyronine production by propylthiouracil in man. J Clin Invest 1975;55: 5 5. 218–23. Stanley MM, Astwood EB. 1-Methyl-2-[Medline] [CrossRef]mercaptoimidazole; an antithyroid compound highly active in man. Endocrinology 1949;44: 5 6. 588–9. Nicholas WC, Fischer RG, Stevenson RA, Bass [Medline] [CrossRef] JD. Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J 1995;88: 973–6. 5 7. [Medline]He [CrossRef] Yang CT, dose of methimazole and propylthiouracil in TC, Hsieh et alAT, . Comparison of single daily Pei D, Hung YJ, Wu LY, the treatment of Graves hyperthyroidism. Clin Endocrinol (Oxf) 2004;60: 676–81. [Medline]5 8. [CrossRef] Emiliano AB, Governale L, Parks M, Cooper DS. Shifts in propylthiouracil and methimazole prescribing practices: antithyroid drug use in the United States from 1991 to 2008. J Clin Endocrinol Metab 2010;95: 2227–33. [Medline] 59. [CrossRef] Cooper DS. The side effects of antithyoird drugs. 60. Endocrinologist 1999;9: 457–78. Rivkees SA, Stephenson K, Dinauer C. Adverse [CrossRef]events associated with methimazole therapy 56Juvenile Graves’ disease guidelinesVol.26 / No.2 of graves disease in children. Int J Pediatr 61. Endocrinol 2010;176970. Hamburger JI. Management of hyperthyroidism [Medline] [CrossRef]in children and adolescents. J Clin Endocrinol 6 2. Metab 1985;60: 1019–24. Nakamura [Medline] [CrossRef]Miyauchi A, Hamada N, Working Group of the H, Noh JY, Itoh K, Fukata S, Japan Thyroid Association for the Guideline of the Treatment of Graves Disease. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves disease. J Clin Endocrinol Metab 2007;92: 2157–62. 6 3. [Medline]Gunton JE, Stiel J, Caterson RJ, McElduff A. [CrossRef] Clinical case seminar: Anti-thyroid drugs and antineutrophil cytoplasmic antibody positive vasculitis. A case report and review of the literature. J Clin Endocrinol Metab 1999;84: 6 4. 13–6. Sato H, Hattori M, Fujieda M, Sugihara S, [Medline] [CrossRef] Inomata H, Hoshi M, antineutrophil cytoplasmic antibody positivity et al. High prevalence of in childhood onset Graves disease treated with propylthiouracil. J Clin Endocrinol Metab 6 5. 2000;85: 4270–3. Noh JY, Yasuda S, Sato S, Matsumoto M, Kunii [Medline] Y, Noguchi Y, myeloperoxidase antineutrophil cytoplasmic et al. Clinical characteristics of antibody-associated vasculitis caused by antithyroid drugs. J Clin Endocrinol Metab 6 6. 2009;94: 2806–11. Chen YX, Zhang W, Chen XN, Yu HJ, Ni LY, Xu [Medline] [CrossRef] J, cytoplasmic antibody (ANCA)-associated renal et al. Propylthiouracil-induced antineutrophil vasculitis versus primary ANCA-associated renal vasculitis: a comparative study. J Rheumatol 6 7. 2012;39: 558–63. Mandel SJ, Brent GA, Larsen PR. Review of [Medline] [CrossRef] antithyroid drug use during pregnancy and report of a case of aplasia cutis. Thyroid 1994;4: 6 8. 129–33. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato [Medline] [CrossRef] S, Sekiya K, with antithyroid et al. Treatment of graves disease of pregnancy and the prevalence of congenital drugs in the first trimester malformation. J Clin Endocrinol Metab 2012;97: 6 9. 2396–403. Dötsch J, Rascher W, Dörr HG. Graves disease [Medline] [CrossRef] in childhood: a review of the options for diagnosis and treatment. Paediatr Drugs 2003;5: 95–102. 7 0. [Medline]Dötsch J, Siebler T, Hauffa BP, Doeker B, [CrossRef] Andler W, Bettendorf M, management of juvenile hyperthyroidism in et al. Diagnosis and Germany: a retrospective multicenter study. J Pediatr Endocrinol Metab 2000;13: 879–85. 7 1. [Medline]Mussa GC, Corrias A, Silvestro L, Battan E, [CrossRef] Mostert M, Mussa F, predictive of lasting remission in pediatric et al. Factors at onset patients with Graves disease followed for at least three years. J Pediatr Endocrinol Metab 7 2. 1999;12: 537–41. Slyper AH, Wyatt D, Boudreau C. Effective [Medline] [CrossRef] methimazole dose for childhood Graves disease and use of free triiodothyronine combined with concurrent thyroid-stimulating hormone level to identify mild hyperthyroidism and delayed pituitary recovery. J Pediatr Endocrinol Metab 7 3. 2005;18: 597–602. Maia AL, Scheffel RS, Meyer EL, Mazeto GM, [Medline] [CrossRef] Carvalho GA, Graf H, Endocrinology and Metabolism. The Brazilian et al. Brazilian Society of consensus for the diagnosis and treatment of hyperthyroidism: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol 2013;57: 205–32. [Medline] 74. [CrossRef] Kaguelidou F, Carel JC, Léger J. Graves disease in childhood: advances in management with antithyroid drug therapy. Horm Res 2009;71: 7 5. Stafford D, Vaidyanathan P, Kaplowitz P. 310–7. [Medline] [CrossRef] Children with hyperthyroidism younger than age 7 require higher mg/kg doses of methimazole to normalize free T4 compared to older children. J Pediatr Endocrinol Metab 2015;28: 1339–42. 76. [Medline]Shulman DI, Muhar I, Jorgensen EV, Diamond [CrossRef] 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: 755–60. [Medline] [CrossRef] April 2017 Juvenile Graves’ disease guidelines57 7 7. Vitti P, Rago T, Chiovato L, Pallini S, Santini F, Fiore E, with Graves disease undergoing remission after et al. Clinical features of patients antithyroid drug treatment. Thyroid 1997;7: 7 8. 369–75. Benker G, Reinwein D, Kahaly G, Tegler L, [Medline] [CrossRef] Alexander WD, Fassbinder J, Multicentre Trial Group of the Treatment of et al. The European Hyperthyroidism with Antithyroid Drugs. Is there a methimazole dose effect on remission rate in Graves disease? Results from a long-term prospective study. Clin Endocrinol (Oxf) 1998;49: 7 9. 451–7. Michelangeli V, Poon C, Taft J, Newnham H, [Medline] [CrossRef] Topliss D, Colman P. The prognostic value of thyrotropin receptor antibody measurement in the early stages of treatment of Graves disease with antithyroid drugs. Thyroid 1998;8: 119–24. 8 0. [Medline]Jafarzadeh A, Poorgholami M, Izadi N, Nemati [CrossRef] M, Rezayati M. Immunological and hematological changes in patients with hyperthyroidism or hypothyroidism. Clin Invest Med 2010;33: 8 1. E271–9. Kubota S, Amino N, Matsumoto Y, Ikeda N, [Medline] Morita S, Kudo T, function tests in patients with thyrotoxicosis et al. Serial changes in liver induced by Graves disease and painless thyroiditis. Thyroid 2008;18: 283–7. [Medline]8 2. [CrossRef]Sarinnapakorn V, Noppavetchwich P, Sunthorntepwarakul T, Deerochanawong C, Ngongamrut S. Abnormal liver function test in Graves disease: a prospective study of comparison between the hyperthyroid state and the euthyroid state. J Med Assoc Thai 8 3. 2011;94(Suppl 2): S11–6. Sato S, Noh JY, Sato S, Suzuki M, Yasuda S, [Medline] Matsumoto M, and adverse effects between methimazole et al. Comparison of efficacy 15 mg+inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves disease patients with moderate to severe hyperthyroidism. Thyroid 2015;25: 43–50. 8 4. [Medline]Reinwein D, Benker G, Lazarus JH, Alexander [CrossRef] WD, European Multicenter Study Group on Antithyroid Drug Treatment. A prospective randomized trial of antithyroid drug dose in Graves disease therapy. J Clin Endocrinol Metab 8 5. Takata K, Kubota S, Fukata S, Kudo T, 1993;76: 1516–21. [Medline] Nishihara E, Ito M, agranulocytosis in patients with Graves disease et al. Methimazole-induced is more frequent with an initial dose of 30 mg daily than with 15 mg daily. Thyroid 2009;19: 8 6. Salpeter SR, Ormiston TM, Salpeter EE. 559–63. [Medline] [CrossRef] Cardioselective beta-blockers in patients with reactive airway disease: a meta-analysis. Ann Intern Med 2002;137: 715–25. [Medline]8 7. [CrossRef] Satoh M, Aso K, Nakayama T, Matsuura H, Ohara A, Tateno A. Three patients with Graves’ disease receiving long-term potassium iodide 8 8. Okamura K, Sato K, Fujikawa M, Bandai treatment. J Jpn Pediatr Soc 2010;114: 1713–7.S, Ikenoue H, Kitazono T. Remission after potassium iodide therapy in patients with Graves hyperthyroidism exhibiting thionamide-associated side effects. J Clin Endocrinol Metab 8 9. 2014;99: 3995–4002. Uchida T, Goto H, Kasai T, Komiya K, Takeno [Medline] [CrossRef] K, Abe H, potassium iodine in drug-naïve patients with et al. Therapeutic effectiveness of Graves disease: a single-center experience. 9 0. Takata K, Amino N, Kubota S, Sasaki I, Endocrine 2014;47: 506–11. [Medline] [CrossRef]Nishihara E, Kudo T, term iodide supplementation to antithyroid et al. Benefit of short-drug treatment of thyrotoxicosis due to Graves disease. Clin Endocrinol (Oxf) 2010;72: 845–50. 9 1. [Medline]Jeong short-term potassium iodide treatment for KU, [CrossRef] Lee HS, Hwang JS. Effects of thyrotoxicosis due to Graves disease in children and adolescents. Ann Pediatr Endocrinol Metab 92. 2014;19: 197–201. Raza J, Hindmarsh PC, Brook CG. Thyrotoxicosis [Medline] [CrossRef] in children: thirty years experience. Acta 9 3. Paediatr 1999;88: 937–41. Abraham P, Avenell A, Park CM, Watson WA, [Medline] [CrossRef]Bevan JS. A systematic review of drug therapy for Graves hyperthyroidism. Eur J Endocrinol 9 4. Razvi S, Vaidya B, Perros P, Pearce SH. 2005;153: 489–98. [Medline] [CrossRef] 58Juvenile Graves’ disease guidelinesVol.26 / No.2 What is the evidence behind the evidence-base? The premature death of block-replace antithyroid drug regimens for Graves disease. Eur J Endocrinol 2006;154: 783–6. [Medline] 95. Abraham P, Avenell A, Watson WA, Park CM, [CrossRef] Bevan JS. Antithyroid drug regimen for treating Graves hyperthyroidism. Cochrane Database 96. Abraham P, Avenell A, McGeoch SC, Clark LF, Syst Rev 2004; CD003420. [Medline] Bevan JS. Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database 97. Syst Rev 2010; CD003420. Solomon BL, Wartofsky L, Burman KD. [Medline]Adjunctive cholestyramine therapy for thyrotoxicosis. Clin Endocrinol (Oxf) 1993;38: 98. Heemstra KA, Toes RE, Sepers J, Pereira AM, 39–43. [Medline] [CrossRef] Corssmit EP, Huizinga TW, in relapsing Graves disease, a phase II study. et al. Rituximab Eur J Endocrinol 2008;159: 609–15. [Medline] 99. Tsuyusaki T. Prognosis of children with Graves’ [CrossRef] disease treated with Antithyroid Drug. Chiba 100. Med J 1989;65: 227–34 (in Japanese).Lippe BM, Landaw EM, Kaplan SA. Hyperthyroidism in children treated with long term remission every two years. J Clin Endocrinol medical therapy: twenty-five percent 101. Konishi Metab 1987;64: 1241–5. Y, T, Okamoto Y, [Medline]Ueda M, [CrossRef]Fukuda discontinuation after treatment with minimum Harusato I, Tsukamoto Y, et al. Drug maintenance dose of an antithyroid drug in Graves disease: a retrospective study on effects of treatment duration with minimum maintenance dose on lasting remission. Endocr 102. Weetman AP. Graves hyperthyroidism: how long J 2011;58: 95–100. [Medline] [CrossRef] should antithyroid drug therapy be continued to achieve remission? Nat Clin Pract Endocrinol 103. Metab 2006;2: 2–3. Glaser NS, Styne DM. Predictors of early [Medline] [CrossRef]remission of hyperthyroidism in children. J Clin 104. Maugendre D, Gatel A, Campion L, Massart Endocrinol Metab 1997;82: 1719–26. [Medline]C, Guilhem I, Lorcy Y, and Graves diseaseprospective randomized et al. Antithyroid drugs assessment of long-term treatment. Clin Endocrinol (Oxf) 1999;50: 127–32. [Medline] 105. Bauer AJ. Approach to the pediatric patient [CrossRef]with Graves disease: when is definitive therapy warranted? J Clin Endocrinol Metab 2011;96: 106. 580–8. Rivkees SA. Pediatric Graves disease: [Medline] [CrossRef]management in the post-propylthiouracil Era. Int J Pediatr Endocrinol 2014;2014: 10 107. Léger J, Gelwane G, Kaguelidou F, Benmerad [CrossRef]. [Medline] M, Alberti C, French Childhood Graves Disease Study Group. 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 108. Hiraiwa T, Ito M, Imagawa A, Takamatsu J, 2012;97: 110–9. [Medline] [CrossRef]Kuma K, Miyauchi A, Iodine does not ameliorate the early effect of et al. Restriction of dietary anti-thyroid drug therapy for Graves disease in an area of excessive iodine intake. J Endocrinol 109. Park SM, Cho YY, Joung JY, Sohn SY, Kim SW, Invest 2006;29: 380–4. [Medline] [CrossRef]Chung JH. Excessive iodine intake does not increase the recurrence rate of graves disease after withdrawal of the antithyroid drug in an iodine-replete area. Eur Thyroid J 2015;4: 110. Tamai 36–42. [Medline]Matsubayashi S, Kuma K, H, Takaichi [CrossRef]Y, Morita T, Komaki G, induced agranulocytosis in Japanese patients et al. Methimazole-with Graves disease. Clin Endocrinol (Oxf) 111. 1989;30: 525–30. Cooper DS, Goldminz D, Levin AA, Ladenson PW, [Medline] [CrossRef] Daniels GH, Molitch ME, associated with antithyroid drugs. Effects of et al. Agranulocytosis patient age and drug dose. Ann Intern Med 112. 1983;98: 26–9. Hamerschlak N, Maluf E, Biasi Cavalcanti [Medline] [CrossRef]A, Avezum Júnior A, Eluf-Neto J, Passeto Falcão R, agranulocytosis in Latin American countries the et al. Incidence and risk factors for Latin Study: a multicenter study. Eur J Clin 113. Tajiri J, Noguchi S, Murakami N. Usefulness Pharmacol 2008;64: 921–9. [Medline] [CrossRef]of granulocyte count measurement four hours April 2017 Juvenile Graves’ disease guidelines59 after injection of granulocyte colony-stimulating factor for detecting recovery from antithyroid drug-induced granulocytopenia. Thyroid 1997;7: 114. Tajiri J, Noguchi S. Antithyroid drug-induced 575–8. [Medline] [CrossRef]agranulocytosis: how has granulocyte colony-stimulating factor changed therapy? Thyroid 115. 2005;15: 292–7. Rivkees SA, Szarfman A. Dissimilar [Medline] [CrossRef]hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol 116. Metab 2010;95: 3260–7. Williams KV, Nayak S, Becker D, Reyes J, [Medline] [CrossRef]Burmeister LA. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 117. Harada S, Arisaka O, Yokoya S, Amemiya S, 1997;82: 1727–33. [Medline]Tanaka T, Hasegawa T, Japan-U.S. correspondence about the serious et al. Difference in liver damage of childhood Graves’ disease with the antithyroid drug. The 43rdthe Japanese Society for Pediatric Endocrinology annual meeting of 118. 2009. p. 71(abstract) (in Japanese).Takano T, Okazaki M, Kagimoto S, Joh K, Ohishi T, Kohda N, with Graves’ disease that developed serious et al. The 10-year-old boy hepatitis by Propylthiouracil. J Saitama Med 119. Umemoto Soc 2000;35: 467–70.Higashigawa M, Sakurai M. Propylthiouracil-M, Sawada H, Sugiyama K, induced hepatic failure with fatal outcome. Clin 120. Otsuka F, Noh JY, Chino T, Shimizu T, Mukasa Pediatr Endocrinol 1997;6: 73–5. [CrossRef]K, Ito K, reactions after antithyroid drug administration. et al. Hepatotoxicity and cutaneous Clin Endocrinol (Oxf) 2012;77: 310–5. [Medline] 121. Glaser NS, Styne DM, Organization of Pediatric [CrossRef] Endocrinologists of Northern California Collaborative Graves Disease Study Group. Predicting the likelihood of remission in children with Graves disease: a prospective, multicenter study. Pediatrics 2008;121: e481–8. 122. Poyrazoğlu S, Saka N, Bas F, Isguven P, Dogu [CrossRef][Medline]A, Turan S, treatment results in children with Graves et al. Evaluation of diagnosis and disease with emphasis on the pubertal status of patients. J Pediatr Endocrinol Metab 2008;21: 123. Kaguelidou F, Alberti C, Castanet M, Guitteny 745–51. [Medline] [CrossRef] MA, Czernichow P, Léger J, French Childhood Graves Disease Study Group. Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment. J Clin Endocrinol Metab 124. Takasu 2008;93: 3817–26. Y, N, Yamashiro [Medline]K, Komiya [CrossRef]hyperthyroidism predicted by smooth decreases Sato Y, Nagata A. Remission of I, Graves Ochi of thyroid-stimulating antibody and thyrotropin-binding inhibitor immunoglobulin during antithyroid drug treatment. Thyroid 2000;10: 125. Quadbeck B, Hoermann R, Roggenbuck U, Hahn 891–6. [Medline] [CrossRef]S, Mann K, Janssen OE, Basedow Study Group. Sensitive thyrotropin and thyrotropin-receptor antibody determinations one month after discontinuation of antithyroid drug treatment as predictors of relapse in Graves disease. 126. Bhadada S, Bhansali A, Velayutham P, Masoodi Thyroid 2005;15: 1047–54. [Medline] [CrossRef]SR. Juvenile hyperthyroidism: an experience. 127. Indian Pediatr 2006;43: 301–7. Gastaldi R, Poggi E, Mussa A, Weber G, [Medline]Vigone MC, Salerno M, children: thyroid-stimulating hormone receptor et al. Graves disease in antibodies as remission markers. J Pediatr 128. Gruñeiro-Papendieck L, Chiesa A, Finkielstain 2014;164: 1189–94.e1. [Medline] [CrossRef]G, Heinrich JJ. Pediatric Graves disease: outcome and treatment. J Pediatr Endocrinol 129. Metab 2003;16: 1249–55. Somnuke PH, Pusuwan P, Likitmaskul S, [Medline]Santiprabhob J, Sawathiparnich P. Treatment outcome of Graves disease in Thai children. J 130. Brownlie BE, Hunt PJ, Turner JG. Juvenile Med Assoc Thai 2007;90: 1815–20. [Medline]thyrotoxicosisa South Island, New Zealand experience with long-term outcome. N Z Med J 131. Barrio R, López-Capapé M, Martinez-Badás I, 2010;123: 23–31. [Medline]Carrillo A, Moreno JC, Alonso M. Graves disease in children and adolescents: response to long-term treatment. Acta Paediatr 2005;94: 1583–9. 60Juvenile Graves’ disease guidelinesVol.26 / No.2 132. Kashiwai T, Hidaka Y, Takano T, Tatsumi KI, [Medline] [CrossRef]Izumi Y, Shimaoka Y, with minimum maintenance dose of anti-thyroid et al. Practical treatment drugs for prediction of remission in Graves disease. Endocr J 2003;50: 45–9. 133. Harada S. Studies on TSH receptor antibodies [CrossRef] [Medline](TRAb) in patients with juvenile Graves’ disease: clinical studies on usefulness of TRAb determinations. J Jpn Pediatr Soc 1991;95: 134. Laurberg P, Wallin G, Tallstedt L, Abraham-1751–7 (in Japanese).Nordling M, Lundell G, Tørring O. TSH-receptor autoimmunity in Graves disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol 2008;158: 69–75. [Medline] 135. Okamoto Y, Tanigawa S, Ishikawa K, Hamada [CrossRef]N. TSH receptor antibody measurements and prediction of remission in Graves disease patients treated with minimum maintenance doses of antithyroid drugs. Endocr J 2006;53: 136. Takasu 467–72. [Medline]T. Simple and reliable method for predicting N, Akamine [CrossRef]H, Komiya I, Yamada the remission of Graves disease: revised triiodothyronine-suppression test, indexed by serum thyroxine. J Endocrinol Invest 1995;18: 137. 288–94. Sugino K, Ito K, Mimura T, Fukunari N, [Medline] [CrossRef]Nagahama M, Ito K. Surgical treatment of Graves disease in children. Thyroid 2004;14: 138. Lee JA, Grumbach MM, Clark OH. The optimal 447–52. [Medline] [CrossRef] treatment for pediatric Graves disease is surgery. J Clin Endocrinol Metab 2007;92: 139. Sosa JA, Tuggle CT, Wang TS, Thomas DC, 801–3. [Medline] [CrossRef]Boudourakis L, Rivkees S, economic outcomes of thyroid and parathyroid et al. Clinical and surgery in children. J Clin Endocrinol Metab 140. Tuggle CT, Roman SA, Wang TS, Boudourakis 2008;93: 3058–65. [Medline] [CrossRef] L, Thomas DC, Udelsman R, endocrine surgery: who is operating on our et al. Pediatric children? Surgery 2008;144: 869–77, discussion 141. Sherman J, Thompson GB, Lteif A, Schwenk WF 877. [Medline] [CrossRef] 2nd, van Heerden J, Farley DR, management of Graves disease in childhood et al. Surgical and adolescence: an institutional experience. Surgery 2006;140: 1056–61, discussion 1061–2. 142. Bergman P, Auldist AW, Cameron F. Review of [Medline] [CrossRef] the outcome of management of Graves disease in children and adolescents. J Paediatr Child 143. Sugino K, Ito K, Nagahama M, Kitagawa W, Health 2001;37: 176–82. [Medline] [CrossRef]Shibuya H, Ito K. Surgical management of Graves disease -10-year prospective trial at a single institution. Endocr J 2008;55: 161–7. 144. Miccoli P, Vitti P, Rago T, Iacconi P, Bartalena [Medline] [CrossRef] L, Bogazzi F, disease: subtotal or total thyroidectomy? et al. Surgical treatment of Graves Surgery 1996;120: 1020–4, discussion 1024–5. 145. Rudberg C, Johansson H, Akerström G, Tuvemo [Medline] [CrossRef] T, Karlsson FA. Graves disease in children and adolescents. Late results of surgical treatment. Eur J Endocrinol 1996;134: 710–5. 146. [CrossRef][Medline]Feliciano DV, Lyons JD. Thyroidectomy is optimal treatment for Graves disease. J Am Coll Surg 2011;212: 714–20, discussion 720–1. 147. Liu J, Bargren A, Schaefer S, Chen H, Sippel [Medline] [CrossRef]RS. Total thyroidectomy: a safe and effective treatment for Graves disease. J Surg Res 148. Cheetham TD, Hughes IA, Barnes ND, Wraight 2011;168: 1–4. [Medline] [CrossRef] EP. Treatment of hyperthyroidism in young people. Arch Dis Child 1998;78: 207–9. [Medline] 149. Peters [CrossRef]C, Schleusener H. Reduction in thyroid H, Fischer C, Bogner U, Reiners volume after radioiodine therapy of Graves hyperthyroidism: results of a prospective, randomized, multicentre study. Eur J Clin 150. Peters Invest 1996;26: 59–63. [Medline]C, Schleusener H. Treatment of Graves H, Fischer C, Bogner [CrossRef]U, Reiners hyperthyroidism with radioiodine: results of a prospective randomized study. Thyroid 1997;7: April 2017 Juvenile Graves’ disease guidelines61 151. Rivkees SA, Sklar C, Freemark M. Clinical 247–51. [Medline] [CrossRef]review 99: The management of Graves disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab 1998;83: 152. Kraiem 3767–76. [Medline]childhood. J Pediatr Endocrinol Metab 2001;14: Z, Newfield RS. Graves disease in 153. Ma 229–43. [Medline] [CrossRef]treatment for pediatric Graves disease. C, Kuang A, Xie J, Liu G. Radioiodine Cochrane Database Syst Rev 2008; CD006294. 154. Rivkees SA, Dinauer C. An optimal treatment [Medline]for pediatric Graves disease is radioiodine. J Clin Endocrinol Metab 2007;92: 797–800. 155. Ogawa T, Goshi K, Tajiri J. Radioactive iodine [Medline] [CrossRef] therapy for patients with Graves’ disease aged 18 or younger. J Jpn Pediatr Soc 2008;112: 156. Okubo T. The determination of thyroid weight in 15–21 (in Japanese). vivo with the scintigram. Jpn J Radiol 1959;19: 157. Ma 120–8 (in Japanese).treatment for pediatric Graves’ disease. C, Kuang A, Xie J, Liu G. Radioiodine Cochrane Database Syst Rev 2008; CD006294. 158. Levy WJ, Schumacher OP, Gupta M. Treatment [Medline] of childhood Graves disease. A review with emphasis on radioiodine treatment. Cleve Clin 159. Freitas JE, Swanson DP, Gross MD, Sisson JC. J Med 1988;55: 373–82. [Medline] [CrossRef]Iodine-131: optimal therapy for hyperthyroidism in children and adolescents? J Nucl Med 160. Kalinyak JE, McDougall IR. How should the dose 1979;20: 847–50. [Medline] of iodine-131 be determined in the treatment of Graves hyperthyroidism? J Clin Endocrinol 161. Zantut-Wittmann DE, Ramos CD, Santos AO, Metab 2003;88: 975–7. [Medline] [CrossRef]Lima MM, Panzan AD, Facuri FV, pre-therapy [99mTc]pertechnetate thyroid et al. High uptake, thyroid size and thyrostatic drugs: predictive factors of failure in [131therapy in Graves disease. Nucl Med Commun I]iodide 162. Nebesio TD, Siddiqui AR, Pescovitz OH, Eugster 2005;26: 957–63. [Medline] [CrossRef] EA. Time course to hypothyroidism after fixed-dose radioablation therapy of Graves disease in children. J Pediatr 2002;141: 99–103. 163. Ueda D. Normal volume of the thyroid gland in [CrossRef][Medline]children. J Clin Ultrasound 1990;18: 455–62. 164. Rivkees SA. Graves disease therapy in children: [Medline] [CrossRef] truth and inevitable consequences. J Pediatr 165. Kadmon PM, Noto RB, Boney CM, Goodwin G, Endocrinol Metab 2007;20: 953–5. [Medline]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: 166. Bonnema SJ, Bennedbaek FN, Gram J, Veje 1865–7. [Medline] [CrossRef]A, Marving J, Hegedus L. Resumption of methimazole after 131diseases: effect on thyroid function and volume I therapy of hyperthyroid evaluated by a randomized clinical trial. Eur J Endocrinol 2003;149: 485–92. [Medline] 167. Nakajo M, Tsuchimochi S, Tanabe H, Nakabeppu [CrossRef] Y, Jinguji M. Three basic patterns of changes in serum thyroid hormone levels in Graves disease during the one-year period after radioiodine therapy. Ann Nucl Med 2005;19: 297–308. 168. Rivkees [Medline]dose on the outcome of hyperthyroidism in SA, [CrossRef]Cornelius EA. Influence of iodine-131 children. Pediatrics 2003;111: 745–9. [Medline] 169. Cury AN, Meira VT, Monte O, Marone M, Scalissi [CrossRef] NM, Kochi C, radioactive iodine in the treatment of childhood et al. Clinical experience with and adolescent Graves disease. Endocr Connect 170. 2012;2: 32–7. Sheline GE, Lindsay S, McCormack KR, [Medline] [CrossRef]Galante M. Thyroid nodules occurring late after treatment of thyrotoxicosis with radioiodine. J Clin Endocrinol Metab 1962;22: 8–18. 171. Boice JD Jr. Thyroid disease 60 years after [CrossRef][Medline]Hiroshima and 20 years after Chernobyl. JAMA 172. 2006;295: 1060–2. Boice JD Jr. Radiation-induced thyroid [Medline] [CrossRef]cancerwhats new? J Natl Cancer Inst 2005;97: