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.

Abstract/Text: Importance: Normal thyroid gland function is critical for early neurocognitive development, as well as for growth and development throughout childhood and adolescence. Thyroid disorders are common, and attention to physical examination findings, combined with selected laboratory and radiologic tools, aids in the early diagnosis and treatment.
Objective: To provide a practical review of the presentation, evaluation, and treatment of thyroid disorders commonly encountered in a primary care practice.
Evidence Review: We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2010, through December 31, 2015. Articles published earlier than 2010 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician, as well as consensus statements and guidelines. A total of 479 articles for critical review were selected based on their relevance to the incidence, pathophysiology, laboratory evaluation, radiological assessment, and treatment of hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer in children and adolescents. Eighty-three publications were selected for inclusion in this article based on their relevance to these topics.
Findings: The primary care physician is often the first health care professional responsible for initiating the evaluation of a thyroid disorder in children and adolescents. Patients may be referred secondary to an abnormal newborn screening, self-referred after a caregiver raises concern, or identified to be at risk of a thyroid disorder based on findings from a routine well-child visit. Irrespective of the path of referral, knowledge of the signs and symptoms of hypothyroidism, hyperthyroidism, and thyroid nodules, as well as the general approach to evaluation and management, will help the primary care physician complete an initial assessment and determine which patients would benefit from referral to a pediatric endocrinologist.
Conclusions and Relevance: Early identification and treatment of thyroid disease in children and adolescents is critical to optimize growth and development. The primary care physician plays a critical role in identifying patients at risk. An understanding of risk factors, clinical signs and symptoms, and interpretation of screening laboratories ensures an efficient and accurate diagnosis of these common disorders. Regular communication between the primary care physician and the subspecialist is critical to optimize outcome because the majority of patients with thyroid disorders will require long-term to lifelong medical therapy and/or surveillance.

Abstract/Text: Reference ranges for serum thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in children were set using the assay kits currently used in clinical settings. A total of 342 children (111 males and 231 females) who were negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonographic examination of the thyroid gland were divided into 6 age groups: 4-6 years (45 children), 7-8 years (40), 9-10 years (53), 11-12 years (65), 13-14 years (83), and 15 years (56) for the study. FT3, FT4 and TSH levels were determined by electrochemiluminescence immunoassay (ECLIA) (ECLusys FT3, FT4 and TSH).The reference range for FT3 (pg/mL) was 2.91-4.70 for the age group of 4-6 years, 3.10-5.10 for the age group of 7-8 years, 3.10-4.87 for the age group of 9-10 years, 2.78-4.90 for the age group of 11-12 years, 2.77-4.59 for the age group of 13-14 years, and 2.50-4.64 for the age group of 15 years . The reference range for FT4 (ng/dL) was 1.12-1.67, 1.07-1.61, 0.96-1.60, 1.02-1.52, 0.96-1.52, 0.95-1.53. The reference range for TSH (μU/mL) was 0.62-4.90, 0.53-5.16, 0.67-4.52, 0.62-3.36, 0.54-2.78, 0.32-3.00. Serum FT3, FT4 and TSH levels in children differ from those in adults. It is, therefore, of importance to perform evaluation of thyroid function in children using reference values appropriate for the chronological ages, because misdiagnosis of hypothyroidism or inappropriate secretion of TSH (SITSH) and oversight of mild subclinical hypothyroidism could occur if the diagnosis is made using reference values for adults.

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.

Abstract/Text: BACKGROUND AND OBJECTIVES: Many newborn screening (NBS) programs now perform repeat or serial NBS to detect congenital hypothyroidism. There is wide variation in thyroid-stimulating hormone (TSH) cutoffs used by NBS programs. Data on TSH reference ranges in preterm infants at increasing postnatal age are limited. Our study objective was to determine TSH reference ranges for preterm infants born at <32 weeks' gestation.
METHODS: We analyzed serial TSH levels on NBS performed on infants born between 22 and 31 weeks' gestation from 2012 to 2016 in Wisconsin. The study cohort was divided into 2 groups (22-27 and 28-31 weeks), and TSH percentiles were defined from birth to the term equivalent gestational age.
RESULTS: The study cohort consisted of 1022 and 2115 infants born at 22 to 27 and 28 to 31 weeks' gestation, respectively. The 95th percentile TSH level for the group born at 22 to 27 weeks' gestation gradually decreased and reached a nadir at ∼10 to 11 weeks. In contrast, for the group born at 28 to 31 weeks' gestation, the 95th percentile TSH level reached a nadir at ∼5 to 6 weeks. At 3 to 4 weeks after birth, the 95th percentile TSH level ranged from 11 to 11.8 μIU/mL for the group born at 22 to 27 weeks' gestation and ranged from 8.2 to 9 μIU/mL for the group born at 28 to 31 weeks' gestation.
CONCLUSIONS: Using a statewide cohort of preterm infants, we constructed TSH reference charts from birth to the term equivalent gestation for preterm infants born at <32 weeks' gestation. Use of a single cutoff for all preterm infants might lead to misdiagnosis. The differences in TSH levels according to gestational-age categories might explain the increased frequency in congenital hypothyroidism diagnoses among preterm infants. These data are useful for defining age-adjusted NBS TSH cutoffs for preterm infants.

Copyright © 2019 by the American Academy of Pediatrics.

Abstract/Text: Graves' disease is an autoimmune disorder. It is the leading cause of hyperthyroidism, but is rare in children. Patients are initially managed with antithyroid drugs (ATDs), such as methimazole/carbimazole. A major disadvantage of treatment with ATD is the high risk of relapse, exceeding 70% of children treated for duration of 2 years, and the potential major side effects of the drug reported in exceptional cases. The major advantage of ATD treatment is that normal homeostasis of the hypothalamus-pituitary-thyroid axis may be restored, with periods of drug treatment followed by freedom from medical intervention achieved in approximately 40-50% of cases after prolonged treatment with ATD, for several years, in recent studies. Alternative ablative treatments such as radioactive iodine and, less frequently and mostly in cases of very high volume goiters or in children under the age of 5 years, thyroidectomy, performed by pediatric surgeons with extensive experience should be proposed in cases of non-compliance, intolerance to medical treatment or relapse after prolonged medical treatment. Ablative treatments are effective against hyperthyroidism, but they require the subsequent administration of levothyroxine throughout the patient's life. This review considers data relating to the prognosis for Graves' disease remission in children and explores the limitations of study designs and results; and the emerging proposal for management through the prolonged use of ATD drugs.

© 2017 European Society of Endocrinology.

Abstract/Text: OBJECTIVES: To determine the incidence of congenital hypothyroidism in preterm infants and to identify associated risk factors.
STUDY DESIGN: A population-based cohort study was performed in preterm infants born at <32 weeks of gestational age between 2012 and 2016 in Wisconsin. Newborn screening (NBS) results and demographic data were obtained from the Wisconsin State Laboratory of Hygiene. Congenital hypothyroidism was subdivided to early TSH elevation (eTSH) and delayed TSH elevation (dTSH). Multivariate logistic regression analyses were performed to identify demographic factors associated with dTSH.
RESULTS: A total of 3137 preterm infants born at 22-31 weeks of gestational age were included in the study. Mean gestational age was 28.4 ± 2.4 weeks and mean birth weight was 1191 ± 399 g. Forty-nine infants were diagnosed with congenital hypothyroidism. The overall incidence of congenital hypothyroidism was 1.56%, including a 0.13% incidence of eTSH and a 1.43% incidence of dTSH. Birth weight <1000 g, multiple gestation, and initial TSH level were identified as independent predictors for dTSH.
CONCLUSION: Targeted serial NBS in Wisconsin led to a higher rate of diagnosis of congenital hypothyroidism in preterm infants than has been reported previously. The majority (92%) of congenital hypothyroidism cases were diagnosed with dTSH. Birth weight <1000 g, multiple gestation, and elevated initial TSH level were associated with increased risk for development of dTSH. We recommend obtaining targeted serial NBS in preterm infants (<32 weeks of gestational age) to improve the detection of congenital hypothyroidism.

Copyright © 2018 Elsevier Inc. All rights reserved.

Abstract/Text: Background: Congenital hypothyroidism (CH) is a common and preventable cause of mental retardation, which is detected in many neonatal screening programs. Upon suspicion of CH, plasma free thyroxine (fT4) and thyrotropin (TSH) concentrations are measured. CH can be of thyroidal or central origin (CH-T and CH-C, respectively). While CH-T diagnosis is based on an elevated TSH with a low fT4, CH-C diagnosis is based on a low fT4 without a clearly elevated TSH. Currently, reliable neonatal reference intervals (RIs) for plasma fT4 and TSH are lacking. Age-specific RIs would greatly improve the diagnostic process for CH, especially for CH-C. Our aim was to establish neonatal RIs for plasma fT4 and TSH in term neonates at day 3-7 (t = 1) and day 13-15 (t = 2). The study was particularly designed to provide a reliable fT4 lower limit of the RI to facilitate the diagnosis of CH-C. In the Netherlands, neonates are screened at day 3-7 of life. After a screening result suggestive for CH-C, pediatric consultation takes place on average at day 14. Thus, the time points were chosen accordingly. Methods: Venous blood was collected from 120 healthy neonates at each time point (94 participants provided blood samples at two time points; 52 participants provided a sample at t = 1 or t = 2). fT4 and TSH were measured using an immunoassay (Cobas; Roche Diagnostics). RIs were calculated using the 95% confidence interval for normally distributed data and the nonparametric percentile method if data were not normally distributed. Results: From 146 participants (49% female), ≥1 measurement was available. Ninety-five percent RIs for fT4 were 20.5-37.1 pmol/L (day 3-7) and 15.3-26.5 pmol/L (day 13-15). Ninety-five percent RIs for TSH were 1.0-8.4 mU/L (day 3-7) and 1.4-8.6 mU/L (day 13-15). Conclusions: Our results indicate an fT4 lower limit of the RI of 20.5 pmol/L at day 3-7 and 15.3 pmol/L at day 13-15. These lower limits are considerably higher than this assay's lower limit of the adult RI for fT4. In case CH is suspected, we recommend measuring fT4 and TSH using an assay with an established neonatal RI, taking into account the child's age in days.

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.

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.

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.

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.

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.

Abstract/Text: Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to estimate the global and regional prevalence of CH among births between 1969 and 2020. PubMed, Web of Sciences, and Embase databases were searched for relevant studies between January 1, 1975, and March 2, 2020. Pooled prevalence was calculated using a generalized linear mixed model, and expressed as a rate per 10,000 neonates. The meta-analysis involved 116 studies, which analyzed 330,210,785 neonates, among whom 174,543 were diagnosed with CH. The pooled global prevalence of CH from 1969 to 2020 was 4.25 (95% confidence interval (CI) 3.96-4.57). The geographic region with highest prevalence was the Eastern Mediterranean (7.91, 95% CI 6.09-10.26), where the prevalence was 2.48-fold (95% CI 2.04-3.01) that in Europe. The national income level with the highest prevalence was upper-middle (6.76, 95% CI 5.66-8.06), which was 1.91-fold (95% CI 1.65-2.22) that in high-income countries. Global prevalence of CH was 52% (95% CI 4-122%) higher in 2011-2020 than in 1969-1980, after adjusting for geographic region, national income level, and screening strategy.  Conclusion: The global prevalence of CH increased from 1969 to 2020, which may reflect the implementation of national neonatal screening, neonatal testing for thyroid-stimulating hormone, and a lowering of the diagnostic level of this hormone. Additional factors are likely to be driving the increase, which should be identified in future research. What is Known: • Cumulated evidence had suggested that the occurrences of congenital hypothyroidism (CH) among newborns were varied in different countries.. • Up-trends of the birth prevalence of CH were observed in many European and American countries. What is New: • This is the first meta-analysis to estimate global and regional prevalence of CH among newborns. • The global prevalence of CH has increased by 127% since 1969. The Eastern Mediterranean has the highest prevalence and stands out with the most pronounced escalation in the prevalence of CH.

© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Abstract/Text: Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.