JOURNAL OF ENDOCRINE DIVISION

Sun Mi Hwang, MD1, Min Sun Kim, MD1,2, Dae-Yeol Lee, MD1,2
Purpose

 We aimed to investigate the predictive factors

for early response to methimazole (MMI) in
pediatric patients with Graves disease (GD).
Subjects and Methods
 Our study included 44 pediatric patients who were diagnosed
with GD between January 1, 1993, and December 31, 2013, and
were available for followup, achieving a normalization of
thyroid functions (TFs) at the Chonbuk National University
Hospital Pediatric Department. We retrospectively analyzed
TFs such as tri-iodothyronine (T3), free thyroxine (fT4),
thyroid-stimulating hormone (TSH), and thyroid antibody
levels at diagnosis. We also examined their family history of
thyroid disease, symptoms at presentation, and normalization
time for TF after treatment. We divided our clinical series of
patients into the following 4 age groups: <7 years old, 7–12
years old, 13–15 years old, and 16–18 years old.
Results
 At diagnosis, the time of normalization of T3 was
significantly shorter in the higher antimicrosomal
antibody (AMA) group compared with the lower
AMA group (2.53 months vs. 6.18 months) (P<0.05).
However, the time of normalization of T3/fT4/TSH
had no significant correlations with other variables
such as age, sex, a family history of thyroid
diseases, thyroglobulin, thyroid-stimulating
immunoglobulin, or antithyroglobulin antibody
(ATA).
Conclusions

Higher serological titers of AMA at diagnosis

may have prognostic value in the response
to initial MMI treatment in pediatric
hyperthyroid GD patients.
INTRODUCTION

Hyperthyroidism is characterized by the overproduction of thyroid

hormone.

More than 95% of pediatric hyperthyroidism evolves from Graves disease

(GD), also known as diffuse toxic goiter.

Children with GD should receive long-term antithyroid medications, such

as methimazole (MMI), which are essential for achieving complete
remission.

It would therefore be mandatory to predict the response to initial

treatment with MMI in such children.

We conducted this study to identify factors associated with

response to initial treatment with MMI in children with GD.
MATERIALS AND METHODS
100 patients who had been diagnosed with
hyperthyroidism during a 20-year period ranging from
1993 - 2013

Exclusion criteria: (1) loss

Inclusion criteria : (1) age was below 18 of follow-up before
years, (2) symptoms of GD, (3) past history normalized state of TSH,
fT4, T3, (2) other thyroid
of taking MMI, and (4) available follow-up
diseases (e.g., Hashimoto’s
data to normalized state of thyroid- thyroiditis or papillary
stimulating hormone (TSH), free thyroxine carcinoma), (3) past
(fT4), triiodothyronine (T3). history of taking
propylthiouracil (PTU).

enrolled a total of 44 children with GD (n=44)

MATERIALS AND METHODS
Diagnosis of GD  hyperthyroidism, such as tachycardia, excessive sweating,
weight loss or no weight gain, and elevated serum T3/ fT4 levels accompanied
by a decreased serum TSH.

We treated our clinical series of patients with MMI twice or three times
a day, at a dose of 0.5±0.2 mg/kg/day.

We analyzed baseline characteristics and the correlation of

normalization time of TF with such as age, sex, family history of
thyroid diseases and comorbidities.

We also evaluated changes in serum levels of TSH, T3, fT4,

antimicrosomal antibody (AMA), thyroglobulin, thyroid stimulating
immunoglobulin (TSI), and antithyroglobulin antibody (ATA).

We divided our clinical series of patients into the following 2 groups: the
lower AMA group (serum AMA levels≤100 U/mL) and the higher AMA group
(serum AMA levels>100 U/mL).
MATERIALS AND METHODS
Serum levels of fT4 (normal range, 11.5–23 pmol/ L),
TSH (normal range, 0.17–4.05 mIU/mL), TSI (normal range, 0–10 U/L)
and T3 (normal range, 0.78–1.82 ng/mL)

AMA (normal range, 0–0.3 U/mL), ATA (normal range, 0–0.3 U/mL)

We divided our clinical series of patients into 4 age groups:

<7 years old, 7–12 years old, 13–15 years old, and 16–18 years old.

Statistical analysis was done using the IBM SPSS ver. 18.0.
A P-value of <0.05 was considered statistically significant.
 KERANGKA TEORI
HIPOTHALAMUS
TRH

PITUITARY GLAND

THYROID STIMULATING
IMMUNOGLOBULIN (TSI)
TSH RECEPTOR TSH

THYROID GLAND ATA

AGE
IODINE PEROKSIDASE THYROGLOBULIN

SEX
METHIMAZOLE /MMI AMA / TPO Ab
FAMILY
↑T3 ↑T4 HISTORY OF
THYROID
DISEASE

CARDIOVASKULAR GIT CNS METABOLIC OCULAR

Palpitation & Diarrhea & Irritability & Heat intolerance & Opthalmopathy
tachycardia malabrpsoption tremor excessive sweating

GRAVE’S DISEASE
 KERANGKA KONSEP
FAMILY
AGE SEX HISTORY OF T3
THYROID
DISEASE

IODINE

PITUITARY
MMI PEROKSIDASE TSH
GLAND

TIROGLOBULIN

AMA ATA

T4

: VARIABEL BEBAS : HUBUNGAN VARIABEL BEBAS

: VARIABEL TERGANTUNG : HUBUNGAN VARIABEL TERGANTUNG

: VARIABEL ANTARA : HUBUNGAN VARIABEL ANTARA

: VARIABEL KENDALI : HUBUNGAN VARIABEL KENDALI

: VARIABEL RANDOM : HUBUNGAN VARIABEL RANDOM

RESULTS
RESULTS
RESULTS
RESULTS
Hyperthyroidism is a disease involving
hyperactivity of the thyroid gland.

The major cause of hyperthyroidism is GD, and

other causes include neonatal thyrotoxicosis,
thyroiditis, or McCune- Albright syndrome.

The diagnosis is confirmed when TF shows a

decrease in TSH levels and an increase in T4 and T3
levels commensurate with the patient’s age.

Antithyroid drugs should remain the first-line

therapy for the treatment of thyrotoxicosis in
children.

PTU and MMI, interfere with the production of

thyroid hormones alleviating symptoms, rather than
actually treating the cause of the disease.
• The predictive factors of
remission with medical therapy
have been studied in children
with thyrotoxicosis.
• Benker et al. stated  ↑ thyroid
hormone levels, ↑ thyroid
autoantibody levels, and >> sized • AMA level before treatment
thyroid gland prior to treatment might correlate with the
had an unfavorable prognosis.
Pretreatment serum T3 levels degree of TF responsiveness.
were the main factor behind the • There was a relationship
therapeutic response to MMI in between the T3 recovery time
GD. and the AMA level at
• In other studies, the remission diagnosis. The higher AMA
rates are higher in those patients
with low AMA levels at diagnosis titer group developed a
than in those patients who have normalized T3 earlier than the
high serological titers. lower AMA titer group.
Kim et al. showed that
prepubertal patients had
more severe symptoms • We found a tendency for
and complications than fT4 and TSH normalization
times to be longer in those
pubertal ones at
more than 16 years old,
diagnosis.
although there was no
statistical correlation.
• The normalization time of
T3, fT4, and TSH were not
significantly different by
sex or family history of
thyroid disease.
Therefore, serum AMA titers at diagnosis could be used as a
predictive factor for the degree of response to initial treatment
with MMI in children with hyperthyroidism.

To confirm this observation, there is a requirement for further

large-scale and multi-institution studies in the future to evaluate
the treatment effects of antithyroid drugs in a larger number of
children and adolescent patients.
N HAL YANG CHECK LIST PENILAIAN YA TIDAK

O DINILAI
1 Judul a. Apakah judul tidak terlalu panjang atau terlalu √
makalah pendek?
b. Apakah judul menggambarkan isi utama √
penelitian? √
c. Apakah judul cukup menarik? √
d. Apakah judul menggunakan singkatan, selain
yang baku?
2 Abstrak
a. Apakah merupakan abstrak satu paragraf, atau
√
abstrak terstruktur?
b. Apakah sudah tercakup komponen
√
IMRAC(Introduction, Methods, Results,
√
Conclusion?)
c. Apakah secara keseluruhan abstrak informatif? √
d. Apakah abstrak lebih dari 200 atau 250 kata?
3 Pendahuluan a. Apakah mengemukakan alasan dilakukannya √
penelitian? √
b. Apakah menyatakan hipotesis atau tujuan penelitian ? √
c. Apakah Pendahuluan didukung oleh pustaka yang kuat
& relevan?
4 Metode a. Apakah disebutkan desain, tempat & waktu penelitian? √
b. Apakah disebutkan populasi sumber (populasi √
terjangkau)? √
c. Apakah kriteria pemilihan (inklusi & eksklusi) √
dijelaskan?
d. Apakah cara pemilihan subyek (teknik sampling) √
disebutkan?
e. Apakah perkiraan besar sampel disebutkan & disebut √
pula alasannya?
f. Apakah perkiraan besar sampel dihitung dengan rumus
√
yang sesuai?
g. Apakah observasi, pengukuran, serta intervensi dirinci √
sehingga orang lain dapat mengulanginya?
h. Bila teknik pengukuran tidak dirinci, apakah √
disebutkan rujukannya? √
i. Apakah definisi istilah & variabel penting -
dikemukakan? √
NO HAL YG YA TIDAK
DINILAI CHECK LIST PENILAIAN
5 Hasil a. Apakah disertakan tabel deskripsi subyek √
penelitian?
b. Apakah karakteristik subyek yang penting (data √
awal) dibandingkan kesetaraannya?
c. Apakah dilakukan uji hipotesis untuk kesetaraan √
ini?
d. Apakah disebutkan jumlah subyek yang diteliti? √
e. Apakah dijelaskan subyek yang drop out dengan √
alasannya?
f. Apakah semua hasil di dalam tabel disebutkan √
dalam naskah?
g. Apakah semua outcome yang penting disebutkan
√
dalam hasil?
h. Apakah subyek yang drop out diikutkan dalam
√
analisis?
i. Apakah disertakan hasil uji statistik (x2,t) derajat
kebebasan (degree of freedom), dan nilai p? √
j. Apakah dalam hasil disertakan komentar &
pendapat? √
NO HAL YA TIDA
K
YANG CHECK LIST PENILAIAN
DINILAI
6 Diskusi a. Apakah semua hal yang relevan dibahas? √
b. Apakah dibahas keterbatasan penelitian, dan
√
kemungkinan dampaknya terhadap hasil?
c. Apakah disebutkan kesulitan penelitian, penyimpangan √
dari protokol, dan kemungkinan dampaknya terhadap
hasil?
d. Apakah pembahasan dilakukan dengan
menghubungkannya dengan teori dan hasil penelitian √
terdahulu? √
e. Apakah dibahas hubungan hasil dengan praktek klinis? √
f. Apakah kesimpulan utama penelitian? √
√
g. Apakah kesimpulan didasarkan pada data penelitian?
√
h. Apakah efek samping dikemukakan & dibahas? √
i. Apakah disebutkan hasil tambahan selama diobservasi?
j. Apakah disebutkan generalisasi hasil penelitian? √
k. Apakah disertakan saran penelitian selanjutnya, dengan
anjuran metodologis yang tepat?
1. Apakah awal penelitian didefinisikan dengan jelas?(pertanyaan
penelitian / tujuan penelitian)
Ya, penelitian ini bertujuan untuk mengidentifikasi faktor prediktif
dari respon dini Methimazole (MMI) pada pasien anak dengan Graves
Disease.
2. Apakah dinyatakan desain penelitian dengan jelas ?
Ya, desain yang digunakan ialah retrospektif, dengan menggunakan
44 subjek penelitian yang sudah terdiagnosis menderita hipertiroid di
Chonbuk National University Hospital selama 20 tahun mulai 1 Januari 1993
sampai 31 Desember 2013.
3. Apakah pemantauan (follow up) pasien dilakukan cukup panjang dan
lengkap ?
Ya, follow-up dilakukan sampai didapatkan kadar T3, FT4, dan TSHs
pasien yang normal.
4. Apakah ada identifikasi dengan jelas kelompok dengan terapeutik yang
berbeda?
Ya, dibandingkan waktu yang diperlukan bagi kadar T3, FT4, dan TSHs
untuk menjadi normal antara kadar serum Antimicrosomal Antibody (AMA)
rendah dengan kadar serum Antimicrosomal Antibody (AMA) tinggi pada pasien
anak dengan Hipertiroid.

5. Apakah outcome dinilai dengan kriteria obyektif ?

Ya, kadar T3 dikatakan normal bila nilainya antara 0.78–1.82 ng/mL, kadar
FT4 dikatakan normal bila nilainya antara11.5–23 pmol/ L dan kadar TSHs
dikatakan normal bila nilainya antara 0.17–4.05 mIU/mL.
1. Apakah outcome/hasil dipaparkan secara jelas (hasil uji
statistik dengan hasil nilai P)
Ya, dikatakan waktu kadar T3 menjadi normal lebih singkat
secara bermakna pada grup dengan titer AMA yang tinggi
dibandingkan dengan grup dengan titer AMA yang rendah. (2.53
bulan vs 6.18 bulan) (p<0.05).
2. Seberapa besarkah ketepatan estimasi outcome yang didapat
dengan nilai korelasi 95% CI?
Tidak dijelaskan dalam jurnal ini.
1. Apakah pasien kita mirip dengan subyek yang diteliti?
Ya, terdapat pasien anak yang telah terdiagnosis dengan
hipertiroid yang rutin diperiksakan kadar FT4 dan TSHs setiap bulan,
namum pemeriksaan T3 dan AMA tidak lazim digunakan dan tidak
ditanggung BPJS.
2. Apakah bukti ini akan mempunyai pengaruh terhadap
kesembuhan pasien kita tentang apa yang telah
ditawarkan/diberikan kepada pasien kita?
Ya, karena didapatkan waktu yang diperlukan untuk kadar T3
menjadi normal lebih singkat secara bermakna pada grup dengan
titer AMA yang tinggi dibandingkan dengan grup dengan titer AMA
yang rendah.