Annette Grüters, Heiko Krude
Detection and treatment of congenital hypothyroidism.
Nat Rev Endocrinol. 2011 Oct 18;8(2):104-13. doi: 10.1038/nrendo.2011.160. Epub 2011 Oct 18.
Abstract/Text
Congenital hypothyroidism is the most frequent endocrine disorder in neonates. Controversy exists regarding the necessity to adjust current screening programs to also diagnose patients with central hypothyroidism or those with mild forms of congenital hypothyroidism, who have high TSH levels but normal T(4) and normal T(3) levels (also known as 'subclinical hypothyroidism'). Thyroid hormone replacement should start as soon as the diagnosis is confirmed by measurement of elevated TSH and low serum thyroid hormone levels. Further diagnostic approaches, such as ultrasonography, scintigraphy and measurement of thyroglobulin levels, to determine the subtype of congenital hypothyroidism, should not delay initiation of treatment. Recommendations regarding the initial dosage of levothyroxine vary considerably, and no general accepted guideline exists with regards to initial dosage or optimal time point for dose adjustment according to biochemical parameters. More than 30 years after the introduction of the first neonatal screening programs, mental retardation can be prevented in the majority of children (>90%) with congenital hypothyroidism if therapy is commenced within the first 2 weeks of life, making neonate screening for this disorder the most successful population-based screening test in pediatrics.
C M Dayan, G H Daniels
Chronic autoimmune thyroiditis.
N Engl J Med. 1996 Jul 11;335(2):99-107. doi: 10.1056/NEJM199607113350206.
Abstract/Text
Richard S Olney, Scott D Grosse, Robert F Vogt
Prevalence of congenital hypothyroidism--current trends and future directions: workshop summary.
Pediatrics. 2010 May;125 Suppl 2:S31-6. doi: 10.1542/peds.2009-1975C.
Abstract/Text
In response to published newborn-screening data that have shown an increase in the incidence (birth prevalence) rate of primary congenital hypothyroidism (CH) in the United States, a workshop was held in Atlanta, Georgia, on February 27 and 28, 2008, to examine this issue. Topics of the meeting included pathophysiology, medical management, and follow-up of CH; transient hypothyroidism (etiology, clinical implications, management, and changes in prevalence); risk factors for CH; laboratory approaches to newborn screening for CH; state-specific evaluations of trends in incidence rates of CH; and concluding discussions on future directions to resolve outstanding issues. Through presentations and discussion, gaps in knowledge were identified, such as the lack of consistent definitions for CH and transient hypothyroidism and the effects of preventable risk factors on incidence rates of CH. One outcome of the meeting was a series of accompanying articles that examined (1) trends in the incidence rates of CH in individual states and nationally, (2) effects of newborn-screening practices on CH-incidence rates, (3) the contribution of transient hypothyroidism to CH-incidence rates, and (4) future research directions. In this summary, we briefly touch on the topics of these articles and examine highlights of other presentations from the workshop that illuminated the secular trends in reported CH-incidence rates in the United States.
Stephen H LaFranchi
Approach to the diagnosis and treatment of neonatal hypothyroidism.
J Clin Endocrinol Metab. 2011 Oct;96(10):2959-67. doi: 10.1210/jc.2011-1175.
Abstract/Text
Congenital hypothyroidism, occurring in 1:3000 newborns, is one of the most common preventable causes of mental retardation. Neurodevelopmental outcome is inversely related to the age of diagnosis and treatment. Infants detected through newborn screening programs and started on l-T(4) in the first few weeks of life have a normal or near-normal neurodevelopmental outcome. The recommended starting dose of l-T(4) (10-15 μg/kg · d) is higher on a weight basis than the dose for children and adults. Tailoring the starting l-T(4) dose to the severity of the hypothyroidism will normalize serum T(4) and TSH as rapidly as possible. It is important to obtain confirmatory serum thyroid function tests before treatment is started. Further diagnostic studies, such as radionuclide uptake and scan and ultrasonography, may be performed to determine the underlying cause of hypothyroidism. Because results from these tests generally do not alter the initial treatment decision, however, these diagnostic studies are rarely indicated. The developing brain has a critical dependence on thyroid hormone for the first 2-3 yr of life; thus, monitoring occurs at more frequent intervals than in older children and adults. Serum free T(4) and TSH should be checked at intervals frequent enough to ensure timely adjustment of l-T(4) dosing and to keep serum free T(4) and TSH levels in target ranges. Given the success of early detection and treatment of neonates with congenital hypothyroidism, a public health mandate should be to develop similar programs for the 75% of babies worldwide who are born in areas without newborn screening programs.
Marvin L Mitchell, Ho-Wen Hsu, Inderneel Sahai, Massachusetts Pediatric Endocrine Work Group
The increased incidence of congenital hypothyroidism: fact or fancy?
Clin Endocrinol (Oxf). 2011 Dec;75(6):806-10. doi: 10.1111/j.1365-2265.2011.04128.x.
Abstract/Text
OBJECTIVE: The incidence of congenital hypothyroidism (CH) detected by newborn screening in the US has increased significantly since the early 1990s. We defined the characteristics associated with the increased incidence.
PATIENTS: A cohort of children with CH born during an earlier period of low incidence (1991-94) was compared with a cohort born during a later period when the incidence of CH had doubled (2001-04).
MEASUREMENTS: Screening was performed with T4 as the primary marker and thyroid stimulating hormone (TSH) on selected specimens. Follow-up on hypothyroid children determined whether they had permanent or transient hypothyroidism. Cases were classified based on laboratory results: initial TSH ≥100 mU/l was 'severe,' initial TSH <100 mU/l but ≥20 mU/l was 'mild' and initial TSH <20 mU/l with subsequent abnormal TSH was 'delayed'.
RESULTS: The overall incidence of CH almost doubled between the two time periods, from 1:3010 to 1:1660. Excess cases were found in the mild and delayed categories, with no increase in severe cases. The proportion of transient cases was <5% in severe cases, 40% in mild cases and 70% among delayed cases. There was no difference in the proportion of transient case between the two time periods. Modifications to the T4/TSH testing protocol between the two time periods resulted in substantially increased numbers of specimens in the younger cohort being selected for TSH testing in both initial and repeat specimens.
CONCLUSION: The rising incidence of CH in Massachusetts is confined to mild and delayed cases. Our findings suggest that this rise is attributable to enhanced detection rather than an absolute increase in numbers.
© 2011 Blackwell Publishing Ltd.
Nicole S Glaser, Dennis M Styne, Organization of Pediatric 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 Mar;121(3):e481-8. doi: 10.1542/peds.2007-1535. Epub 2008 Feb 11.
Abstract/Text
OBJECTIVE: The optimal treatment for Graves' disease in children is controversial. Antithyroid medications are often used initially, but many children eventually require alternative therapies. We evaluated predictors of remission after 2 years of antithyroid medication use.
METHODS: We prospectively studied children who had Graves' disease and were treated with antithyroid medications. We compared children who achieved remission after 2 years with those who had persistent disease to determine which variables were associated with remission; multiple logistic regression and binary recursive partitioning analyses were used to evaluate interactions among predictive variables.
RESULTS: Of 51 children who completed the study, 15 (29%) achieved remission. Children who achieved remission had lower thyroid hormone concentrations at presentation than those with persistent disease (free thyroxine: 6.17 +/- 3.10 vs 9.86 +/- 7.54 ng/dL; total triiodothyronine: 431 +/- 175 vs 561 +/- 225 ng/dL). Children who achieved remission were also more likely to be euthyroid within 3 months of initiating propylthiouracil (82% vs 29%). Binary recursive partitioning analysis identified rapid achievement of euthyroid status after initiation of propylthiouracil, lower initial triiodothyronine, and older age as significant predictors of remission. CONCLUSIONS; Thyroid hormone concentrations at diagnosis, age, and initial response to propylthiouracil can be used to stratify patients according to the likelihood of remission after 2 years of antithyroid medication use. These data provide a useful guide for clinical decision-making regarding Graves' disease in children.
Florentia Kaguelidou, Corinne Alberti, Mireille Castanet, Marie-Aline Guitteny, Paul Czernichow, Juliane Léger, French Childhood Graves' Disease Study Group
Predictors of autoimmune hyperthyroidism relapse in children after discontinuation of antithyroid drug treatment.
J Clin Endocrinol Metab. 2008 Oct;93(10):3817-26. doi: 10.1210/jc.2008-0842. Epub 2008 Jul 15.
Abstract/Text
CONTEXT: There is debate about how Graves' disease (GD) should be treated in children.
OBJECTIVE: The aim of this study was to identify predictors of relapse after antithyroid drug (ATD) treatment in children with GD.
STUDY DESIGN AND SETTING: We conducted a prospective, multicenter cohort study of children (n = 154) with GD treated with carbimazole for an intended duration of 24 +/- 3 months. After the end of treatment, patients were followed up for at least 2 yr. The primary outcome was hyperthyroidism relapse. Cox's regression analysis was used and a prognostic score was constructed.
RESULTS: The overall estimated relapse rate for hyperthyroidism was 59% (95% confidence interval 52-67%) at 1 yr and 68% (95% confidence interval 60-76%) at 2 yr after the end of treatment. Multivariate survival analysis showed that the risk of relapse was higher for patients of non-Caucasian origin [hazard ratio (HR) = 2.54, P < 0.001], with high serum thyroid-stimulating hormone receptor antibodies (HR = 1.21 by 10 U, P = 0.03) and free T(4) (HR = 1.18 by 10 pmol/liter, P = 0.001) levels at diagnosis. Conversely, relapse risk decreased with increasing age at onset (HR = 0.74 per 5 yr, P = 0.03) and duration of first course of ATD (HR = 0.57 per 12 months, P = 0.005). A prognostic score was constructed, allowing the identification of three different risk groups, with 2-yr relapse rates of 46, 77, and 98%.
CONCLUSIONS: A longer initial duration of euthyroid state with ATD seems to be the only variable related to the risk of hyperthyroidism relapse in children that can be manipulated. Ethnic origin, age, and severity of the disease at diagnosis may guide long-term disease management decisions.
佐藤浩一, 佐々木望, 原田正平, 田中敏章, 赤須文人, 朝山光太郎, 荒田尚子, 猪股弘明, 大江秀美, 鬼形和道, 神崎晋, 杉原茂孝, 田尻淳一, 田中弘之, 西山宗六, 長谷川奉延, 長谷川行洋, 深田修司, 百渓尚子, 横谷進, 吉村弘, 森昌朋, 藤枝憲二. 小児期発症バセドウ病薬物治療のガイドライン2008. 日児誌 2008; 112: 946-952.
Paulina E Aleksander, Michaela Brückner-Spieler, Anne-Marie Stoehr, Erwin Lankes, Peter Kühnen, Dirk Schnabel, Andrea Ernert, Walter Stäblein, Maria E Craig, Oliver Blankenstein, Annette Grüters, Heiko Krude
Mean High-Dose l-Thyroxine Treatment Is Efficient and Safe to Achieve a Normal IQ in Young Adult Patients With Congenital Hypothyroidism.
J Clin Endocrinol Metab. 2018 Apr 1;103(4):1459-1469. doi: 10.1210/jc.2017-01937.
Abstract/Text
Context: The optimal levothyroxine (LT4) dose to treat congenital hypothyroidism (CH) remains unclear, with debate over whether higher starting doses (>10 µg/kg) are necessary and safe for a normal intelligence quotient (IQ).
Objective: To examine psychomotor, metabolic, and quality of life (QoL) outcomes in patients with CH treated with a mean high initial LT4 dose.
Design, settings, participants: A cross-sectional cohort study of patients with CH identified in the Berlin newborn screening program from 1979 to 2003; 76 patients with CH (mean age, 18 years; mean initial LT4 dose, 13.5 µg/kg) and 40 siblings completed the study.
Main outcome measures: Psychomotor (Wechsler Intelligence Test, CNS Vital Signs), QoL (short form-36 Health Survey), anthropometric (body mass index, height), and metabolic (intima media thickness, laboratory parameters) outcomes were compared with those of healthy siblings. Mean values and percentage of episodes of elevated thyroxine (T4) and tri-jod-thyronin (T3) and suppressed thyrotropin (TSH) before age 2 years were analyzed. A meta-analysis of CH treatment studies was performed.
Results: There were no significant differences in IQ, QoL, or other outcome measures in patients with CH compared with controls. Most T4 levels were high before age 2 years and during subsequent testing, but mean T3 and TSH levels remained normal. The meta-analysis showed a significant IQ difference in severe vs mild CH cases only when treatment started with an LT4 dose <10 µg/kg.
Conclusions: High initial LT4 dosing was effective and safely achieved optimal cognitive development in patients with CH, including those severely affected. Supranormal T4 values during infancy were not associated with impaired IQ in adolescence.
Jacoba J Bongers-Schokking, Wilma C M Resing, Wilma Oostdijk, Yolanda B de Rijke, Sabine M P F de Muinck Keizer-Schrama
Relation between Early Over- and Undertreatment and Behavioural Problems in Preadolescent Children with Congenital Hypothyroidism.
Horm Res Paediatr. 2018;90(4):247-256. doi: 10.1159/000494056. Epub 2018 Nov 8.
Abstract/Text
OBJECTIVE: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems.
DESIGN AND METHODS: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher's Report Form at children's ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient's individual fT4 steady state concentration.
RESULTS: ADA scores at 6 and 11 years for patients overtreated in the period 1-3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3-6 months postnatally had higher WAST scores at 6 and 11 years than all other patients.
CONCLUSIONS: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.
© 2018 S. Karger AG, Basel.
Beate Oerbeck, Kjetil Sundet, Bengt F Kase, Sonja Heyerdahl
Congenital hypothyroidism: influence of disease severity and L-thyroxine treatment on intellectual, motor, and school-associated outcomes in young adults.
Pediatrics. 2003 Oct;112(4):923-30.
Abstract/Text
OBJECTIVE: To describe intellectual, motor, and school-associated outcome in young adults with early treated congenital hypothyroidism (CH) and to study the association between long-term outcome and CH variables acting at different points in time during early development (CH severity and early L-thyroxine treatment levels [0-6 years]).
METHODS: Neuropsychological tests were administered to all 49 subjects with CH identified during the first 3 years of the Norwegian neonatal screening program (1979-1981) at a mean age of 20 years and to 41 sibling control subjects (mean age: 21 years).
RESULTS: The CH group attained significantly lower scores than control subjects on intellectual, motor, and school-associated tests (total IQ: 102.4 [standard deviation: 13] vs 111.4 [standard deviation: 13]). Twelve (24%) of the 49 CH subjects had not completed senior high school, in contrast to 6% of the control subjects. CH severity (pretreatment serum thyroxine [T4]) correlated primarily with motor tests, whereas early L-thyroxine treatment levels were related to verbal IQ and school-associated tests. In multiple regression analysis, initial L-thyroxine dose (beta = 0.32) and mean serum T4 level during the second year (beta = 0.48) predicted Verbal IQ, whereas mean serum T4 level during the second year (beta = 0.44) predicted Arithmetic.
CONCLUSIONS: Long-term outcome revealed enduring cognitive and motor deficits in young adults with CH relative to control subjects. Verbal functions and Arithmetic were associated with L-thyroxine treatment variables, suggesting that more optimal treatment might be possible. Motor outcome was associated with CH severity, indicating a prenatal effect.
Scott D Grosse, Guy Van Vliet
Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level?
Arch Dis Child. 2011 Apr;96(4):374-9. doi: 10.1136/adc.2010.190280. Epub 2011 Jan 17.
Abstract/Text
OBJECTIVE: Congenital hypothyroidism (CHT) is a common cause of preventable mental retardation, and the quantification of intellectual disability due to CHT is needed to assess the public health benefit of newborn screening.
DESIGN: Review of published studies conducted among children born prior to the introduction of newborn screening for CHT and reporting cognitive test scores.
SETTING: Population-based studies.
PATIENTS: Children with clinically diagnosed CHT.
INTERVENTIONS: Thyroid hormone substitution.
MAIN OUTCOME MEASURES: Intelligence quotient (IQ) (mean and distribution).
RESULTS: The prevalence of recognised CHT rose from one in 6500 prior to screening to approximately one in 3000 with screening. In four population-based studies in high-income countries, among children with clinically diagnosed CHT 8-28% were classified as having intellectual disability (defined as an IQ <70) and the mean IQ was 85 (a leftward shift of 1 SD). Among children with subclinical CHT, the risk of overt intellectual disability was lower (zero in one study), but decreased intellectual potential and increased behavioural abnormalities were documented.
CONCLUSIONS: Although the prevalence of overt disability among children with CHT in the absence of screening may be less than previously estimated, the preventable burden of intellectual disability due to CHT is substantial and justifies newborn screening. However, changes in existing newborn screening protocols to capture more cases are unlikely to prevent overt cases of disability and should therefore be justified instead by the documentation of other benefits of early detection.
Johan Svensson, Ulla-Britt Ericsson, Paul Nilsson, Catherine Olsson, Björn Jonsson, Bengt Lindberg, Sten-A Ivarsson
Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis.
J Clin Endocrinol Metab. 2006 May;91(5):1729-34. doi: 10.1210/jc.2005-2400. Epub 2006 Feb 28.
Abstract/Text
CONTEXT: The use of levothyroxine to reduce thyroid size in pediatric patients with goiter due to chronic autoimmune thyroiditis (AIT) remains controversial. In overtly hypothyroid patients, reductions in thyroid volume have been reported, whereas the effect in subclinically hypothyroid and euthyroid patients is less clear.
OBJECTIVE: The objective of the study was to evaluate the effect of levothyroxine treatment on thyroid size (determined with thyroid ultrasonography) in children and adolescents with AIT.
DESIGN AND SETTING: This study included patients with AIT treated at a university hospital outpatient clinic between 1987 and 2004.
PATIENTS: Ninety children with AIT (73 girls and 17 boys, aged 6.1-17.7 yr) were included in the study.
INTERVENTION: Intervention was treatment with levothyroxine for a median 2.8 yr (range 0.5-10.2).
MAIN OUTCOME MEASURE: Change in thyroid volume sd score (SDS) during the study period was measured.
RESULTS: Median thyroid volume SDS was reduced in patients euthyroid (-0.4 SDS, P < 0.001), subclinically hypothyroid (-1.4 SDS, P < 0.001), and overtly hypothyroid (-1.8 SDS, P < 0.002) at diagnosis of AIT. Both hypothyroid and euthyroid patients with goiter (thyroid volume > 2.0 SDS) at baseline reduced their median thyroid volume SDS (-1.6 and -0.9, respectively, P < 0.001). Hypothyroid patients without goiter also reduced median thyroid volume SDS (-1.2, P < 0.004), whereas no change was noticed in euthyroid children without goiter.
CONCLUSIONS: Levothyroxine treatment is effective in reducing thyroid volume in pediatric patients and is suggested in treatment of goiter caused by AIT, especially in cases of hypothyroid, but also in euthyroid children.
V Scarpa, E Kousta, A Tertipi, M Vakaki, A Fotinou, V Petrou, C Hadjiathanasiou, A Papathanasiou
Treatment with thyroxine reduces thyroid volume in euthyroid children and adolescents with chronic autoimmune thyroiditis.
Horm Res Paediatr. 2010;73(1):61-7. doi: 10.1159/000271917. Epub 2010 Jan 15.
Abstract/Text
BACKGROUND/AIMS: Treatment with thyroxine in children with chronic autoimmune thyroiditis (AT) is controversial. The aim of this study is to investigate, by using thyroid ultrasonography, whether thyroxine influences thyroid volume in non-goitrous euthyroid children with AT.
METHODS: We studied 50 euthyroid non-goitrous children and adolescents with AT for 2 years by thyroid function tests and ultrasonography; 25 were randomized to receive thyroxine and 25 did not receive treatment. Median (IQR) age was 12.1 (11.1-13.2) years.
RESULTS: At baseline there was no difference in thyroid volume SDS between the two groups (treatment group 1.1 (0.7-1.5) and controls 0.9 (0.4-1.4), respectively). After 2 years the treatment group had lower thyroid volume SDS compared to the controls (0.6 (0.3-1.0) vs. 2.0 (1.1-2.3), p = 0.001). One child of the treatment group and 12 of the control group developed goiter. Two control children developed subclinical hypothyroidism. Within the treatment group, thyroid volume SDS was lower after 2 years of treatment (p = 0.002). Within the control group, thyroid volume SDS and TSH levels increased after 2 years of follow-up (p = 0.016, 1.9 (1.5-2.8) vs. 3.2 (2.4-4.4) mIU/ml, p = 0.006, respectively).
CONCLUSIONS: Treatment with thyroxine reduces thyroid volume in non-goitrous euthyroid children with AT and may prevent goiter development.
Scott A Rivkees, Ana Szarfman
Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children.
J Clin Endocrinol Metab. 2010 Jul;95(7):3260-7. doi: 10.1210/jc.2009-2546. Epub 2010 Apr 28.
Abstract/Text
BACKGROUND: The antithyroid drugs propylthiouracil and methimazole were introduced for clinical use about 60 yr ago and are estimated to be used in more than 6000 children and adolescents per year in the United States. Over the years that these medications have been used, reports of adverse events involving hepatotoxicity have appeared. To date, there has not been a systematic and comparative evaluation of the adverse events associated with antithyroid drug use.
OBJECTIVE: Our objective was to assess safety and hepatotoxicity profiles of propylthiouracil and methimazole by age in the U.S. Food and Drug Administration's Adverse Event Reporting System (AERS).
DESIGN: We used the multi-item gamma-Poisson shrinker (MGPS) data mining algorithm to analyze more than 40 yr of safety data in AERS. MGPS uses a Bayesian model to calculate adjusted observed to expected ratios [empiric Bayes geometric mean (EBGM) values] for every drug-adverse event combination in AERS, focusing on hepatotoxicity events.
RESULTS: MGPS identified higher-than-expected reporting of severe liver injury in pediatric patients treated with propylthiouracil but not with methimazole. Propylthiouracil had a high adjusted reporting ratio for severe liver injury (EBGM 17; 90% confidence interval = 11.5-24.1) in the group less than 17 yr old. The highest EBGM values for methimazole were with mild liver injury in the group 61 yr and older [EBGM 4.8 (3.3-6.8)], which consisted of cholestasis. Vasculitis was also observed for propylthiouracil in children and adolescents, reaching higher EBGM values than hepatotoxicity signals.
CONCLUSIONS: MGPS detects higher-than-expected reporting of severe hepatotoxicity and vasculitis in children and adolescents with propylthiouracil but not with methimazole.
Juliane Léger, Georges Gelwane, Florentia Kaguelidou, Meriem Benmerad, Corinne Alberti, 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. 2012 Jan;97(1):110-9. doi: 10.1210/jc.2011-1944. Epub 2011 Oct 26.
Abstract/Text
CONTEXT: Drug-based therapy is usually the initial treatment for Graves' disease (GD) hyperthyroidism in children, but there is some debate about treatment duration.
OBJECTIVE: Our objective was to assess the effect of long-term carbimazole therapy on GD remission in children and its determinants.
DESIGN AND SETTING: This was an observational prospective multicenter follow-up cohort study.
PARTICIPANTS: Participants included 154 children newly diagnosed with GD between 1997 and 2002. The intention was to treat patients with three consecutive courses of carbimazole, each lasting 2 yr. Definitive treatment was performed in cases of poor compliance with antithyroid drug (ATD) treatment, thyrotoxicosis relapse, or major adverse effects of ATD treatment.
MAIN OUTCOME MEASURE: The main outcome measure was remission for at least 18 months after the completion of each course of ATD treatment.
RESULTS: The median duration of follow-up was 10.4 (9.0-12.1) yr. Overall estimated remission rates (95% confidence interval) 18 months after the withdrawal of ATD treatment increased with time and were 20 (13-26), 37 (29-45), 45 (35-54), and 49 (40-57)% after 4, 6, 8, and 10 yr follow-up, respectively. A multivariate competing risk model revealed an independent positive effect of less severe forms of hyperthyroidism at diagnosis [subhazard ratio of 1 for patients with free T(4) <35 pmol/liter vs. 0.4 (0.20-0.80) for free T(4) ≥ 35 pmol/liter; P = 0.01] and of the presence of other autoimmune conditions [subhazard ratio of 2.23 (1.19-4.18); P = 0.01] on remission rate after medical treatment.
CONCLUSION: About half the patients achieved remission after carbimazole discontinuation, and there seems to be a plateau in the incidence of remission achieved after 8-10 yr ATD therapy.
Scott A Rivkees
Pediatric Graves' disease: controversies in management.
Horm Res Paediatr. 2010;74(5):305-11. doi: 10.1159/000320028. Epub 2010 Oct 2.
Abstract/Text
BACKGROUND/AIMS: Graves' disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. Caused by immunologic stimulation of the thyroid-stimulating hormone receptor, lasting remission occurs in only a minority of pediatric patients with GD, including children treated with antithyroid drugs (ATDs) for many years. Thus the majority of pediatric patients with GD will need thyroidectomy or treatment with radioactive iodine (RAI; (131)I).
RESULTS: When ATDs are used in children, only methimazole should be used. Propylthiouracil is associated with an unacceptable risk of severe liver injury in children and should never be used as first-line therapy. If remission (defined as normal thyroid function off ATDs) is not achieved after 1 or 2 years of ATD therapy, (131)I or surgery may be considered, with the choice influenced by the age of the individual. When (131)I is used, administered doses should be >150 μCi/g of thyroid tissue. When surgery is performed, near total or total thyroidectomy is recommended.
CONCLUSION: Choosing a treatment approach for childhood GD is often a difficult and highly personal decision. Discussion of the advantages and risks of each therapeutic option is essential to help the patient and family select a treatment option.
Copyright © 2010 S. Karger AG, Basel.
Andrew J Bauer
Approach to the pediatric patient with Graves' disease: when is definitive therapy warranted?
J Clin Endocrinol Metab. 2011 Mar;96(3):580-8. doi: 10.1210/jc.2010-0898.
Abstract/Text
Pediatric Graves' disease accounts for 10-15% of thyroid disorders in patients less than 18 yr of age. The onset of symptoms may be insidious and subsequently associated with a delay in diagnosis. Decreased concentration and poor school performance are frequent complaints and can be quite frustrating for the patient and family. Severe ophthalmopathy is uncommon. The diagnosis is established by the findings of an increased heart rate and goiter in the setting of a suppressed TSH and elevated T(3) and/or T(4). The majority of pediatric patients are initially placed on antithyroid medications and maintained on these medications for prolonged periods of time in hopes of achieving remission. Unfortunately, for many children and adolescents remission is unattainable, ultimately occurring in only 15-30% of patients. Several recent studies have suggested that the age of the patient, the degree of thyrotoxicosis at diagnosis, the initial response to therapy, and the level of TSH receptor antibodies serve as reasonable predictors of remission and relapse. However, a consensus on the utility of these markers has not been reached. The present clinical case describes an adolescent with Graves' disease and highlights the negative impact that prolonged medical therapy can have on quality of life and school performance; it reviews pertinent data on the diagnosis, comorbidities, and treatment options; and it identifies gaps in knowledge for when definitive therapy should be pursued. The case serves as a reminder that earlier discussion and decision for definitive therapy should be more commonplace in caring for our pediatric patients with Graves' disease.
Hirotoshi Nakamura, Jaeduk Yoshimura Noh, Koichi Itoh, Shuji Fukata, Akira Miyauchi, Noboru Hamada
Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease.
J Clin Endocrinol Metab. 2007 Jun;92(6):2157-62. doi: 10.1210/jc.2006-2135. Epub 2007 Mar 27.
Abstract/Text
CONTEXT: Although methimazole (MMI) and propylthiouracil (PTU) have long been used to treat hyperthyroidism caused by Graves' disease (GD), there is still no clear conclusion about the choice of drug or appropriate initial doses.
OBJECTIVE: The aim of the study was to compare the MMI 30 mg/d treatment with the PTU 300 mg/d and MMI 15 mg/d treatment in terms of efficacy and adverse reactions.
DESIGN, SETTING, AND PARTICIPANTS: Patients newly diagnosed with GD were randomly assigned to one of the three treatment regimens in a prospective study at four Japanese hospitals.
MAIN OUTCOME MEASURES: Percentages of patients with normal serum free T(4) (FT4) or free T(3) (FT3) and frequency of adverse effects were measured at 4, 8, and 12 wk.
RESULTS: MMI 30 mg/d normalized FT4 in more patients than PTU 300 mg/d and MMI 15 mg/d for the whole group (240 patients) at 12 wk (96.5 vs. 78.3%; P = 0.001; and 86.2%, P = 0.023, respectively). When patients were divided into two groups by initial FT4, in the group of the patients with severe hyperthyroidism (FT4, 7 ng/dl or more, 64 patients) MMI 30 mg/d normalized FT4 more effectively than PTU 300 mg/d at 8 and 12 wk and MMI 15 mg/d at 8 wk, respectively (P < 0.05). No remarkable difference between the treatments was observed in patients with initial FT4 less than 7 ng/dl. Adverse effects, especially mild hepatotoxicity, were higher with PTU and significantly lower with MMI 15 mg/d compared with MMI 30 mg/d.
CONCLUSIONS: MMI 15 mg/d is suitable for mild and moderate GD, whereas MMI 30 mg/d is advisable for severe cases. PTU is not recommended for initial use.
Natsuko Watanabe, Hiroto Narimatsu, Jaeduk Yoshimura Noh, Takuhiro Yamaguchi, Kazuhiko Kobayashi, Masahiro Kami, Yo Kunii, Koji Mukasa, Kunihiko Ito, Koichi Ito
Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease.
J Clin Endocrinol Metab. 2012 Jan;97(1):E49-53. doi: 10.1210/jc.2011-2221. Epub 2011 Nov 2.
Abstract/Text
CONTEXT: Although antithyroid drug (ATD)-induced hematopoietic damage is a significant concern, it has not been comprehensively investigated.
OBJECTIVE: Our objective was to describe the clinical features of ATD-induced hematopoietic damage.
DESIGN AND SETTING: This was a retrospective cohort study in Tokyo, Japan.
PATIENTS: Between January 1983 and December 2002, 50,385 patients at Ito Hospital were diagnosed with Graves' disease. We retrospectively reviewed their medical, pathological, and laboratory records between January 1983 and December 2010.
MAIN OUTCOME: Incidence and clinical features of ATD-induced agranulocytosis and pancytopenia were evaluated.
RESULTS: Of 55 patients with documented hematopoietic damage, 50 had agranulocytosis and 5 had pancytopenia. All of them received ATD, either methimazole (n = 51) or propylthiouracil (n = 4). Median intervals between initiation of ATD therapy and the onset of agranulocytosis and pancytopenia were 69 d (range, 11-233 d) and 41 d (range, 32-97 d), respectively. Either anemia or thrombocytopenia was also documented in seven of the 50 patients with agranulocytosis. Agranulocytosis was the first manifestation of hematopoietic damage in four of the five patents with pancytopenia. Hematopoietic damage recovered with supportive measures including granulocyte colony-stimulating factor (n = 37), steroids (n = 10), and other supportive measures (n = 8) in 54 patients, whereas the remaining patient died of complications from infection. This study failed to identify the risk factors for ATD-induced hematopoietic damage.
CONCLUSIONS: This study showed that ATD cause hematopoietic changes, which are occasionally severe and potentially fatal. The pathogenesis of agranulocytosis and pancytopenia might overlap, and additional studies are warranted to clarify this and to establish an optimal treatment strategy.
Nicole R van Veenendaal, Scott A Rivkees
Treatment of pediatric Graves' disease is associated with excessive weight gain.
J Clin Endocrinol Metab. 2011 Oct;96(10):3257-63. doi: 10.1210/jc.2011-1601. Epub 2011 Aug 17.
Abstract/Text
CONTEXT: Little information is available about changes in body weight and body mass index in children before, during, and after treatment for Graves' disease (GD).
OBJECTIVE: Our objective was to examine changes in body weight after treatment for GD in children as related to clinical features.
DESIGN: The medical records of 43 pediatric patients with GD [35 girls and eight boys, aged 4.0-18.5 (mean 10.9) yr] were examined. Patients were included if clinical data were available for 1 yr before and after the diagnosis of GD.
MAIN OUTCOME MEASURES: Weight, height, body mass index (BMI) z-scores, and thyroid hormone levels were assessed.
RESULTS: Overall, patients presented with an average BMI z-score of -0.02 ± 1.05 that was not different from the normal population (P = 0.921) or their premorbid values (P = 0.07). However, in the subset of patients who were initially overweight or obese in the premorbid state, the BMI decreased significantly during the development of hyperthyroidism (P < 0.05). After initiation of treatment, patients gained significant amounts of weight over the first 6 months leading to elevated BMI z-scores (P < 0.0001), and elevations in BMI persisted in about 25% of the patients.
CONCLUSION: Excessive weight gain within 6 months of treatment is seen in children treated for GD, and the gain in weight can persist.
Sumihisa Kubota, Nobuyuki Amino, Yuka Matsumoto, Naoko Ikeda, Shinji Morita, Takumi Kudo, Hidemi Ohye, Eijun Nishihara, Mitsuru Ito, Shuji Fukata, Akira Miyauchi
Serial changes in liver function tests in patients with thyrotoxicosis induced by Graves' disease and painless thyroiditis.
Thyroid. 2008 Mar;18(3):283-7. doi: 10.1089/thy.2007.0189.
Abstract/Text
CONTEXT: When the liver function tests are aggravated after starting antithyroid drugs (ATDs) in Graves' hyperthyroidism, discontinuation of ATDs is generally considered. However, a question arises whether such aggravation constitutes an adverse effect of the drugs or not.
OBJECTIVE: The aim of this study was to clarify the influence of thyrotoxicosis on liver function tests, comparing the results with those in thyrotoxicosis induced by painless thyroiditis.
DESIGN: We prospectively studied liver biochemical tests in 30 patients with Graves' disease and in 27 patients with painless thyroiditis.
MAIN OUTCOMES: Twenty-three (76.7%) untreated Graves' disease patients and 14 (51.9%) untreated painless thyroiditis patients were found to have at least one liver function test abnormality. One month after starting ATD therapy in patients with Graves' disease, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations from initial values were observed in 16 (53.3%). Similar elevations of AST and ALT from initial values at 1 month were observed in 10 (37.0%) and 7 (25.9%) patients with painless thyroiditis, respectively. Alkaline phosphatase (ALP) increased gradually after starting ATD therapy and maintained an elevated value for 3-5 months in Graves' disease. In painless thyroiditis, ALP also increased gradually, similarly to that in Graves' disease, but changes were mild. Elevation of ALT after 1 month of ATD therapy in Graves' disease was significantly higher in patients whose estimated disease duration was 6 months or more compared to those with duration of less than 6 months. Elevated AST and ALT at 1 month after ATD therapy decreased to normal ranges, even though patients were receiving the same ATDs in Graves' disease.
CONCLUSION: Similar serial changes in liver function tests in both Graves' disease and painless thyroiditis strongly suggest that increases of AST and ALT after starting ATD therapy may not be due to ATD side effects but may be induced by changes in thyroid function.
日本小児内分泌学会 編集:小児内分泌疾患の治療 初版.診断と治療社.2022年.
Christiaan F Mooij, Timothy D Cheetham, Frederik A Verburg, Anja Eckstein, Simon H Pearce, Juliane Léger, A S Paul van Trotsenburg
2022 European Thyroid Association Guideline for the management of pediatric Graves' disease.
Eur Thyroid J. 2022 Jan 1;11(1). doi: 10.1530/ETJ-21-0073. Epub 2022 Jan 1.
Abstract/Text
Hyperthyroidism caused by Graves' disease (GD) is a relatively rare disease in children. Treatment options are the same as in adults - antithyroid drugs (ATD), radioactive iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. The European Thyroid Association guideline provides new recommendations for the management of pediatric GD with and without orbitopathy. Clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases.
