A Retrospective and Prospective Observational Study of Hyperthyroidism in Children
Conditions: Hyperthyroidism
Sponsor: Shengjing Hospital

Study Protocol
A Retrospective and Prospective Observational Study of
Hyperthyroidism in Children
NCT number: not yet assigned
Date of the document: July 18, 2023

Background
Hyperthyroidism is rare in children, with a frequency of 0.1-3.0 per 100,000[1]. Hyperthyroidism
in children is mainly caused by Graves' disease (GD). The girl-to-boy incidence rate ratio is
approximately 4:1[2]. At present, antithyroid drugs (ATDs) remains the primary choice for children
with GD[2-5]. The guidelines strongly recommend that methimazole(MMI) should be used in
children undergoing ATDs treatment[2-5]. The common side effects of MMI include cutaneous
reaction, neutropenia, leukopenia, high transaminase levels, arthritis, etc[2]. Few studies focus
intensively
on
the
large
subjects
of
adverse
reactions
following
ATDs
treatment
in
hyperthyroidism children, as most patients failed to follow up regularly, and the risk factors of
adverse reactions were not investigated in depth. There are significant differences in research
results[6-12].
In studies of adults, the incidence of leukopenia and agranulocytosis was approximately 1.3%
and 0.1-0.3% respectively[13-15]. There is a scarcity of research on pediatric cohorts regarding this
topic. A review summarized the occurrence of adverse reactions in children with hyperthyroidism
treated with MMI, 17.6% of the patients underwent at least one adverse event[16]. The incidence of
neutropenia/leukopenia and agranulocytosis was roughly 1.1% and 0.3% respectively. However,
the studies included in this review were not systematic in the exploration of adverse reactions, and
the diagnostic criteria and follow-up time of adverse reactions were not consistent, hence the
incidence rate obtained might not be accurate.
In an earlier study, Sato et al. closely monitored 64 children with GD who were treated with
MMI for 1 year and discovered that only 1 patient (1.6%) developed neutropenia[11]. Subsequently,
Korean scholars also carried out relevant studies on 99 GD children and concluded that the
incidence of neutropenia under MMI was approximately 9.1%. The incidence of neutropenia
significantly rose with the increase in the initial dose of MMI[8]. In a Chinese study conducted a
12-week follow-up was carried out on 161 GD children, revealing that the incidence of
neutropenia after MMI treatment was approximately 5.0%[12]. Recently, a study compared the
occurrence of neutropenia in GD children treated with MMI (110 cases) and carbimazole (CBZ,
40 cases), and found that the incidence of neutropenia after MMI treatment was 16.5%. However,

the patients in this study were followed up at longer intervals, which might result in missed
diagnoses[17].
In summary, the current studies have several issues, including a small sample size, a short
follow-up period, and long follow-up intervals, which cannot accurately reflect the occurrence of
neutropenia after MMI treatment. Herein, we conducted a bidirectional cohort study with a large
sample size and regular follow-up to further investigate the clinical features and risk factors for
neutropenia after MMI treatment in hyperthyroidism children.
References
1.
Lazar L, Kalter-Leibovici O, Pertzelan A, et al．Graves’ disease in childrenThyrotoxicosis in
prepubertal children compared with pubertal and postpubertal patients. J Clin Endocrinol
Metab. 2000, 85(10): 3678-382. DOI: 10.1210/jcem.85.10.6922
2.
Mooij CF, Cheetham TD, Verburg FA, et al. 2022 European Thyroid Association Guideline
for the management of pediatric Graves' disease. Eur Thyroid J. 2022,11(1): 210073. Doi:
10.1530/ETJ-21-0073
3.
Chinese Society of Endocrinology, Chinese Endocrinologist Association, Chinese Society of
Nuclear Medicine, et al. Guidelines for Diagnosis and Management of Hyperthyroidism and
Other Causes of Thyrotoxicosis. CLin J Endocrinol Metab. 2022, 38(8): 700-748.
DOI:10.3760/cma.j.cn311282-20220624-00404
4.
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, et al. Guidelines for
the treatment of childhood-onset Graves' disease in Japan, 2016.Clin Pediatr Endocrinol.
2017, 26(2):29-62. DOI: 10.1297/cpe.26.29
5.
Ross DS, Burch HB, Cooper DS,et al. 2016 American Thyroid Association Guidelines for
Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis.Thyroid,
2016,26(10): 1343-1421. DOI: 10.1089/thy.2016.0229
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Ohye H, Minagawa A, Noh JY, et al. Antithyroid drug treatment for Graves’ disease in
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7.
Song A, Kim SJ, Kim MS, et al. Long-Term Antithyroid Drug Treatment of Graves’ Disease
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Lee HG, Yang EM, Kim CJ. Efficacy and adverse events related to the initial dose of
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9.
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adverse events in pediatric patients with Graves’ disease. Clin Pediatr Endocrinol. 2017,
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Sato H, Minagawa M, Sasaki N, et al. Comparison of methimazole and propylthiouracil in
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Sato H, Sasaki N, Minamitani K, et al. Higher dose of methimazole causes frequent adverse
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Objectives of Study
This study intends to conduct a retrospective and prospective study on children with
hyperthyroidism, and it is a non-intervention study to collect information on diagnosis and
treatment and long-term follow-up of children with hyperthyroidism. To investigate the clinical
characteristics, treatment effect, side effects and remission of hyperthyroidism in children, to
analyze the predictive factors for the effect of antithyroid drug treatment, remission and
recurrence after drug withdrawal, and to explore the risk factors related to the occurrence of
antithyroid drug-related adverse reactions.
Object of Study
1 . Inclusion criteria
(1) Age ≤14 years old
(2) Initial diagnosis of hyperthyroidism
2 . Exclusion criteria
(1) Hyperthyroidism had been treated with medication in other hospitals
(2) History of autoimmune hepatitis, viral hepatitis, hematological diseases, bone marrow or liver
transplantation
(3) Patients with incomplete clinical data
Research Method
Children with hyperthyroidism admitted to Shengjing Hospital Affiliated to China Medical
University from January 2013 to December 2022 were collected and followed up, and children
with hyperthyroidism diagnosed after January 1, 2023 were continued to be included in the

prospective follow-up study. The patients received MMI treatment. The initial dose of MMI was
0.2-0.8 mg/(kg▪d). This dose was subsequently reduced by 25% to 50% and adjusted to maintain
euthyroidism, based on the results of serum thyroid hormone testing during follow-up.
Investigate the clinical characteristics of children suffering from hyperthyroidism, and dissect
the effect of MMI treatment, remission as well as the prognostic factors of relapse subsequent to
the withdrawal of MMI. Summarize the occurrence of adverse reactions following MMI treatment
and delve into the factors that might influence the occurrence of adverse reactions.
Statistical analysis plan
Continuous variables were presented as median (25th–75th percentile) or mean±standard
deviation and compared using the Mann–Whitney U test or independent sample t-test. Categorical
variables were presented as frequency and percentage and compared using the chi-square or
Fisher’s exact tests. Univariate and multivariate Logistic regression analyses were used to estimate
the odds ratio and 95% confidence intervals for potential risk factors for recurrence of
hyperthyroidism and adverse reaction under MMI treatment. P<0.05 was considered statistically
significant.
The problem to be solved
1. At present, most clinical studies on hyperthyroidism in children are retrospective studies with a
small sample size, and this study has both retrospective and prospective studies, which is of
clinical significance. Besides, more children with hyperthyroidism are admitted to the pediatric
Endocrinology Department of Shengjing Hospital every year, and the sample size of this study is
expected to be large.
2. To explore the clinical characteristics of children with hyperthyroidism at the first diagnosis,
the effect of MMI treatment, remission and the occurrence of adverse reactions, so as to help
clinicians better predict the occurrence of remission and adverse reactions, and better realize
individualized treatment in the long course of treatment.
Risk and benefit
Risks: This study is non-interventional and does not pose physiological risks.
Benefits: Patients in this study can enjoy free height and weight assessment and growth and

development related consultation, and can enjoy free consultation for disease diagnosis and
treatment and health problems in the later stage. Children with hyperthyroidism can enjoy green
channel service in pediatric endocrine clinic.