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Thyroid disorders in children

Pediatric Endocrine
Clinical Lecturer of School of Medicine Airlangga University
Dr. Soetomo Hospital - Surabaya
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Introduction

! Thyroid hormone:
! potent regulator of metabolic rate.
! essential to the function of most organ systems.

! Normal growth and neurodevelopment in

childhood needs the maintenance of normal
thyroid status.

! Failure to diagnose and treat promptly may lead to

irreversible neurologic damage.

! Early detection, appropriate therapy, careful

monitoring are needed for resulting best outcome.
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What does thyroid hormone do?
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Lecture outline

! Review of thyroid physiology and clinical

testing.
! Diagnostic approach to common pediatric
thyroid disorders:
! Hypothyroidism.
! Hyperthyroidism.
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Thyroid physiology and

clinical testing

Kuliah sem ester VI, FKUA 2012

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Embryonic development

! Under genetic control & the TFs of TTF1,TTF2 and

Pax8.

! 4 wks: as a thickening of the pharyngeal floor "

diverticulum " descends caudally " position of
mature thyroid gland.
! The track called thyroglossal duct " involutes by day 50.

! The diverticulum (thyroid primordium):

! Bi-lobed & fuses with the ventral aspect of the 4th
pharyngreal pouch.
! Differentiate into thyroid follicular cells " synthesize
thyroid hormone.
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Embryonic development

! Clinical standpoint: deviation from the

normal anatomic development of fetal
thyroid is the most common cause of
congenital hypothyroidism " Thyroid
dysgenesis.
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Normal and ectopic Thyroid sites
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Embryonic development

! 11 to 12 wks. Fetal thyroid is capable of

concentrating iodine and synthesizing thyroxine.
! Prior to this, the human fetus is dependent upon maternal
thyroid hormone.

! Even in later pregnancy, transplacental passage

remains an important source of fetal thyroid
hormone " thyroxine is detectable in the serum of
infants born with complete thyroid agenesis.

! TSH to T4 relationship matures throughout gestation.

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Fetal thyroid maturation

Rosalind S. Brown. The thyroid in: Brook’s Clinical Pediatric Endocrionology. 2009: 255.
Placental iodine and thyroid
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MOTHER PLACENTA FETUS
↑TBG
↑T4 Estrogens
↑T3

↑T4
↓TSH
hCG

Iodine I-
TRH TRH
metabolism

TBII TBII
TRH
TSH
T4 rT3
T4

T3 T2
T3

The placental role in thyroid metabolism during human pregnancy.

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Human nervous system and thyroid-
related developmental events.

http://www.thyroidmanager.org/chapter/thyroid-hormones-in-brain-development-and-function/
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Birth associated thyroid function

! Birth:
! Makes a transient and robust peak serum TSH & T4
" “neonatal surge”, followed by rapid changes in
the metabolism of thyroid hormone in peripheral
tissues.
! Normal neonatal thyroid surge typically lasts about
1 to 2 days.

This is the rationale for delaying newborn

screening until 2 days after birth.
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Postnatal TSH, T4, T3, and rT3 secretion in the full-term and premature
infant in the first week of life.
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Thyroid hormone synthesis

! Thyroid gland " synthesizes T4 and

T3.
! Dietary iodine " nutritional precursor
of thyroid hormones.
! Clinical consequence of dietary iodine
deficiency " “endemic cretinism”
! Thyroid enlargement.
! Neurodevelopmental retardation.
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Thyroid hormone synthesis

Follicle Colloid
TPO
T1 T2
Iodide (I-) NIS* I-
(20$40X)
Thyroglobulin

T4 T3 T4

TBG Thyroglobulin
T4 T3
T4
TBPA Thyroglobulin

T4 TSH
Alb

*Sodium/Iodide Symporter protein

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Thyroid hormone synthesis
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Circulating thyroid hormones

! 99.97% of T4 bound to plasma protein.

! TBG (60-75%).
! Transthyretrin/TPBA (15-30%).
! Albumin (10%).

! 99.7% of T3 bound to plasma protein.

! TBG >>.

! fT4 (0.03%).
Only free hormone is
! fT3 (0.03%). active!
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Peripheral thyroxine metabolism

! T4 production is exclusively thyroidal.

! 70-90% of T3 is produced extrathyroidally.

! 95-98% of rT3 is produced extrathyroidally.

! Most peripheral de-iodination occurs in the liver.

! T3accounts for most of the thyroid hormone activity
in peripheral tissues.
! 3-4 times more potent than T4.
! Some researchers have questioned whether T4 has any
intrinsic biological activity.
! rT3 is biologically inactive.
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Thyroid hormones

NH3+ NH3+ NH3+

HC COO( HC COO( HC COO(

CH2 CH2 CH2

I I I I I

O O O

I I I I I

OH OH OH
Tetraiodothyronine 3,5,3´ Triiodothyronine 3,3´,5´ Triiodothyronine
(T4, Thyroxine) (T3) (reverse T3)
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Peripheral T4 metabolism

Huang SA. Thyroid. In: Pediatric Practice Endocrinology. 2010.

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Regulation of hypothalamic-pituitary
axis
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Regulation of hypothalamic-pituitary
axis

The inverse relationship between free T4 and TSH is log-linear.

Small changes in serum T4 produce large compensatory changes in serum TSH
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Age specific normal ranges for serum
thyroid tests in children
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Physical examination

Stephen A. Huang in Pediatric Practice Endocrinology, 2010

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Hypothyroidism in children
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Causes of hypothyroidism in pediatric

! Primary.
! CLT/Hashimotos thyroiditis.
! Congenital Abnormality.
! Iodine Deficiency.
! Drugs or Goitroges.
! Micellaneous.
! Secondary or Tertiary.
! Congenital abnormality.
! Acquired.
! Surgery.
! Radiation.
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Hypothyroidism

! Hypothyroidism is defined as thyroid insufficiency.

! Estimated population prevalence in childhood of
0.14%.
! Female : Male " 3 : 1.3.
! Distribution:
! Endemic.
! Sporadic.

! Onset:
! Congenital.
! Aquired.
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Case ilustration

Kuliah sem ester VI, FKUA 2012

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Dokumentasi div. PedEndo IKA FKUA/RSUD Dr. Soetomo Sby

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! ♀, 13
mo, referred by a pediatrician cause developmental
delay.
! Perinatalhistory: spontaneous delivery, term baby, BW:
3,200 g, BL: 50 cm, no asphyxia, no jaundice.
 Age : 13 mo
BL : 65 cm
BW : 6.7 kg

TSH > 100

FT4 0.1
FT3 0.938

Kuliah sem ester VI, FKUA 2012

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Congenital hypothyroidism

! Inadequate thyroid hormone production in

newborn infants.
! Anatomical defect.
! Inborn error of thyroid metabolism.
! Iodine deficiency.

! CH is one of the most common preventable

causes of mental retardation.
! Incidence: 1 : 3500-4000 infants.
!♀ : ♂ = 2 : 1.

Kuliah sem ester VI, FKUA 2012

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Etiology of congenital hypothyroidism

! Primary Hypothyroidism.
! Permanent 1 : 3800 – 4000.
! Transient 1 : 50,000 (North America).
1 : 200 - 8000 (Europe).
o
!2 and/or 3o Hypothyroidism (1 : 50,000 –
100,000).
! Permanent.
! Transient.

Kuliah sem ester VI, FKUA 2012

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Etiology of congenital hypothyroidism

! Thyroid dysgenesis (80-85%).

! Dyshormonogenesis (10-15%).

! Hypothalamic-pituitary dysfunction (<5%).

! Transient neonatal hypothyroidism:

! Maternal TSH receptor blocking Ab.
! ATD medication to the mother.
! Maternal Iodine intake.
! Prematurity.

Kuliah sem ester VI, FKUA 2012

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Clinical aspects

! Theappearance of sign and symptom

depends on: the age of onset, duration, and
severity of hypothyroidism.
! Often, the
findings may not be obvious to
the parents or the physician until the child’s
growth velocity declines or hypothyroidism
has progressed to a moderate or severe
stage.
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Clinical aspects

Kuliah sem ester VI, FKUA 2012

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Clinical aspects

Kuliah sem ester VI, FKUA 2012

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Dr. Soetomo Hospital’s data.

! Period : 2000 – 2005.

! New affected : 24 (♂: 9 and ♀: 15).
! Age : 4 – 76 mos (20.9 mos).
! Clinical signs & symptoms (%):
! Anemia : 100.
! Motoric delay : 75.
! Hypotonia : 75.
! Macroglossia : 70.8.
! Umbilical hernia : 41.7.
! Constipations : 41.7.
! Down syndrome : 29.2.

Kuliah sem ester VI, FKUA 2012

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Clinical appearance

Before and after treatment

Bourgeois MJ, et al: http://www.emedicine.com

+ Mortality / morbidity of untreated affected
children
! Profound mental retardation.
! Absolutearrest, of linear growth and bone
maturation.
! Neurologic problems: spasticity and gait
abnormalities, dysarthria or mutism, and
autistic behavior.

Early detection (neonatal screening) and

treatment is the most effective way to
reduce the morbidity.
+ Chronic lymphocytic thyroiditis (Acquired
hypothyroidism)

! An autoimmune disorder " destructive

effect on thyroid gland.
! Other names :
! Hashimoto thyroiditis.
! Chronic autoimmune thyroiditis.

! The incidence: 1.3% (US).

! Predilection:
! Mostly in girl (11-18 yo).
! 30-40% have family history of AID.
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Diagnosis.

! Clinical presentation.
! Goitrous: hypo, hyper, hyper-hypo, euthyroid.
! Primary myxedema.

! Lab study.
! TSH↑,#T4↓,#T3↓ :#overt#hypothyroidism.
! TSH↑,#T4#&T3#nl :#subclinical#/#compensated.
! TSH,#T4,#T3#nl :#euthyroid.
! TSH#↓,T4#&#T3#↑ :#hyperthyroidism.
! Anti TPO +, Anti Tg+.
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Clinical symptoms of hypothyroidism
! Goiter.
! Poor growth velocity.
! Decrease appetite.
! Weakness.
! Cold intolerance.
! Constipation.
! Dry skin.
! ↑BMI.
! Delayed bone age.
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Physical appearance of CLT

Rosalind B, et al. Pediatric endotext: 2001

Therapy

General levothyroxine dose by age.

Age Dose in µg/kg BW
0-3 mo 10-15
3-6 mo 8-10
6-12 mo 6-8
1-5 yr 5-6
6-12 yr 4-5
> 12 yr 2-3
Styne DM: 2004.
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Strategy of therapy

! Overt hypothyroidism:
! Increased doses gradually to avoid unwanted side effect "
full doses.

! Mild hypothyroidism:
! Full doses replacement.

! Compensated/subclinical:
! Treated with low doses (controversial).

! Euthyroid:
! Observed TFT every 6 mo.
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Strategy of therapy

! Monitoring:
! Clinically.
! TFT: every 6-8 wks during adjusting doses or
every 6-12 mo after euthyroid state achieved.
! Growth velocity.
! Bone age.
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Hyperthyroidism in children
Graves’"disease
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Causes of hyperthyroidism in pediatric

! Primary.
! Graves’"disease.
! Plummer disease.
! TSH-induced hyperthyroidism.
! TSH-induced pituitary tumor.
! Central thyroid hormone resistance.
! Thyrotoxicosis without hyperthyroidism.
! CLT.
! Subacute thyroiditis.
! Thyroid hormone ingestion.
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Graves’"disease

! Themost common cause hyperthyroidism in

children.

! An immune-mediated disorder " TSI "

stimulation effect on thyroid gland.
! Incidence: 0.2-0.4% (US).
! Female : male " 6 to 8 : 1.

! Predilection: AID affected.

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Physical appearance

Jeremy, et al.Pediatric endocrinology and growth, 2003

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Common signs and symptoms.

Signs and symptoms % affected*

Goiter 98
Tachycardia 82
Nervousness 82
Increase pulse pressure 80
Proptosis 65
Increase appetite 60
Tremor 52
Weigh loss 50
Heat intolerance 30
*In 290 children and adolescent. Clayton,1982 in: Lifshitz, 1996.
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Diagnosis.

!Clinical presentation.
! Goiter (diffused).

!Lab study.
! TSH$↓,T4$&$T3$↑.
! Anti TPO +, Anti Tg+.
! TSI.
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Therapy

! Medical therapy: ATD.

! Radioiodine ablation.
! Surgical thyroidectomy.
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Medical therapy

PTU and MMI.

! Synthesis thyroid hormone inhibition.
! (-) iodide organification.
! (-) iodotyrosine coupling (- of TPO).

! PTU " inhibits peripheral conversion of T4 to T3.

! Initial doses.
! PTU : 5-7 mg/kg/day tid.
! MMI : 5-10% of PTU doses bid or once.
! Maintenance doses.
! 30-50% initial doses (as T4 & T3 normalize).
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Medical therapy

Propanolol.
! Indication: in severe cases to control
cardiovascular overactivity.
! Dosage : 0.5-2.0 mg/kg/day given every 8
hours.
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Medical therapy

Monitoring.

! Clinically.

! TFT.
! Every 4 to 6 weeks during adjusting doses " T4 and T3
normalizes.
! Every 4-6 mo once TFT normalized.

! Side effects.
! Erytematous rash, urticaria, arthralgias, granulocytopenia,
hepatitis, lupus like syndrome, thrombocytopenia.
+ Radioiodine ablation and surgical
thyroidectomy

! Should be consider:
! Failure to medical therapy or relaps.
! Lack of compliance.
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CASE 1

! 1. An S, 2 tahun dikonsulkan oleh

karena didapatkan perkembangan
terlambat. Pasien baru bisa duduk
sendiri. Riwayat lahir spontan,
langsung menangis, AS 8-9, ketuban
jernih.

! Dari pemeriksaan fisik didapatkan

kondisi umum stabil, didapatkan
makroglossia (+), hernia umbilikalis
(+),

! PDx:PTx? Pmx?
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! Untuk mencegah kondisi pada soal 1 maka dapat dilakukan

program apa? Pada usia berapa?
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CASE 2
! Anak D,'12'tahun,'perempuan,'dikonsulkan
oleh karena berdebar7debar.'Pasien juga
mengeluh mata menonjol dan pembesaran
di'leher.'

! Dari'pemeriksaan fisik didapatkan PR:'

142x/mnt,'TD:'150/100'mm'Hg ,'rr:'20x/mnt

! K/L:'struma difusa(+)

! Th:'Simetris(+),'C/P'dbn

! Abd:'supel(+)

! Extr:'CRT<2detik
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! Dd/?

! Pemeriksaan Dx yg diusulkan?

! Pemeriksaan penunjang ( lab+radiologis)?

! Planning terapi?

! Planning monitoring?
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CASE 3

! Anak S, 12 tahun, dikonsukan

dengan pembesaran leher

! Dirasakan sejak 3 bulan terakhir

! Tidak ada tremor, penurunan BB,

demam
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Pemeriksaan fisik

! TD: 110/70

! Rr: 24x /menit

! K/L: diffuse struma (+)

! TANNER A1M3P2
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Laboratorium

! Hb: 11.6 g/dl

! ,WBC: 10500 cells/mm3,

! Plt: 411000 cells/mm3,

! T3: 0.44 μg/dL

! T4 3.05 μg/dL

! TSHs 7.65 mU/mL.

! anti TPO and anti TG was positive with a titer of 481.83 and
1:10, respectively.
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Dd/ struma

Source: Kehar M. Approach to goiter in children. 2012. [accessed March 7th 2017]. Available at:
https://www.researchgate.net/publication/274071419
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