Hyperthyroidism is often caused by Graves' disease, which results from autoimmune production of thyroid stimulating hormone (TSH) receptor antibodies. This leads to excessive thyroid hormone production and symptoms of hyperthyroidism. Graves' disease is the most common cause of childhood hyperthyroidism. Treatment options include antithyroid medications, radioactive iodine therapy, or surgery, with the choice individualized for each patient.

1. HYPERTHYROIDISM
GRAVES‘ DISEASE
D HAKIMI S AK
Dr HAKIMI SpAK
Dr MELDA DELIANA SpAK
Dr SISKA MAYASARI LUBIS SpA
Dr SISKA MAYASARI LUBIS SpA

2. PHYSIOLOGY
PHYSIOLOGY

6. Background
g
• Hyperthyroidism : overactivity of the
thyroid gland leading to excessive
synthesis of thyroid hormones and
synthesis of thyroid hormones and
accelerated metabolism in the peripheral
tissues
• Thyrotoxicosis : the clinical effects of an
unbound thyroid hormone, whether or
t th th id l d i th i
not the thyroid gland is the primary
source

7. Causes of thyrotoxicosis in childhood
y
• Hyperthyroidism :
Diffuse toxic goiter (Graves' disease)
Nodular toxic goiter (Plummer disease)
• TSH-induced hyperthyroidism:
TSH producing pituitary tumor
S l ti it it i t t th id h
Selective pituitary resistance to thyroid hormone
• Thyrotoxicosis without hyperthyroidism:
Chronic lymphocytic thyroiditis (CLT)
Chronic lymphocytic thyroiditis (CLT)
Subacute thyroiditis
Thyroid hormone ingestion

8. Pathogenesis
g
• Genetic clonal lack of suppressor T cells → T helper cells
multiply → B cells produce TSH receptor antibodies:
TSH t tib di bi d t TSH t (Th id
→ TSH receptor antibodies bind to TSH receptors (Thyroid
gland) →  T3 and T4 (Clinical presentation of hyperthyroidism)
→ (Pituitary gland) ↓↓ TSH
→ ? TSH receptor antibodies bind to TSH receptors in retro-
orbital connective tissue → T cells produce inflammatory
cytokines →  Glycosaminoglycans / Eye muscle antibodies? →
Swelling in muscle and connective tissues behind eyes →
Swelling in muscle and connective tissues behind eyes →
Ophthalmopathy

9. Frequency
q y
• In the US : because Graves' disease accounts for more than
95% of childhood cases of hyperthyroidism, the frequency of
Graves' disease approximates the frequency of all cases of
hyperthyroidism
hyperthyroidism
• Prevalence : 0,02% in childhood, accounting for fewer than 5%
of the total cases of Graves' disease
• Associated with MHC locus (HLA-B8, HLA-DR-3, and possibly
HLA-DQA1*0501) and polymorphisms of cytotoxic lymphocyte
antigen (CTLA)-4 an immunoregulatory molecule that is
antigen (CTLA) 4, an immunoregulatory molecule that is
expressed on the surface of activated lymphocytes and inhibits
T-lymphocyte activation

10. Frequency
q y
• Associations between Graves' disease and other
autoimmune diseases are well described and
include associations with DM Addison‘s disease
include associations with DM, Addison‘s disease,
vitiligo, SLE, RA, myasthenia gravis, periodic
paralysis, ITP, and pernicious anemia
• There is an increased risk of Graves' disease in
hild ith D d (t i 21) d
children with Down syndrome (trisomy 21) and
DiGeorge syndrome (22q11 deletion)

11. Mortality / Morbidity
y y
• Excellent prognosis
• Neonatal Graves' disease is self-limited, the prognosis is considerably
worse than that in older children The patients are prone to
worse than that in older children. The patients are prone to
prematurity, airway obstruction and heart failure. The mortality rate :
as high as 16%
• Hypercalcemia is occasionally seen in patients with hyperthyroidism
• Hypercalcemia is occasionally seen in patients with hyperthyroidism
• Female to male ratio = 6 to 8 : 1
• Prepubertal children tend to have more severe disease, require longer
medical therapy and achieve a lower rate of remission compared with
pubertal children. This appears to be particularly true in children who
present at < 5 years of age

12. Age
g
• Incidence increases throughout childhood,
with a peak incidence in children aged 10 -
15 years

13. Predisposing factors
p g
• Genetic susceptibility (including HLA alleles)
• Stress
• Smoking (especially associated with ophthalmopathy)
• Female sex (sex steroid)
Female sex (sex steroid)
• Postpartum period
• Iodine (including amiodarone)
• Lithium
• Rare factors : Interferon-α therapy
Rare factors : Interferon α therapy
Highly active antiretroviral therapy
(HAART) for HIV infection
Campath 1-H monoclonal antibody (for multiple sclerosis)

14. Clinical features
*Symptoms*
Symptoms
• Hyperthyroidism :
Heat intolerance, sweating, palpitations, pruritus,
dyspnea on exertion (exacerbation of asthma)
dyspnea on exertion (exacerbation of asthma),
weight loss (with hyperphagia), weight gain (rarely),
hyperdefecation, tremulousness and tremor,
weakness fatigue urinary frequency nocturia
weakness, fatigue, urinary frequency, nocturia,
thirst, anxiety, emotional lability, insomnia,
restlessness, inability to concentrate,
oligomenorrhea/amenorrhea errectile
oligomenorrhea/amenorrhea, errectile
dysfunction/gynecomastia, dyspepsia, nausea,
vomiting (rare)

15. Clinical features
*Symptoms*
*Symptoms*
• Ophthalmopathy :
Eye irritation, dryness, excessive tearing,
visual blurring, diplopia, retro-orbital
discomfort, pain on eye movement, visual
loss

16. Clinical features
*Signs*
g
• Hyperthyroidism :
Warm, smooth, moist skin, onycholisis
(loosening of the nail bed, Plummer‘s nails),
palmar erythema, thinning of the hair, stare,
lid retraction (and lag) bright shiny eyes
lid retraction (and lag), bright, shiny eyes,
tachycardia, atrial fibrilation, widened pulse
pressure, hyperdynamic circulation, tremor
(fi ) h ti fl i l
(fingers), hyperactive reflexes, proximal
myopathy

17. Clinical features
*Signs*
*Signs*
O hth l th
• Ophthalmopathy :
Periorbital edema, conjunctival erythema,
chemosis (conjunctival edema) proptosis
chemosis (conjunctival edema), proptosis,
ophthalmoplegia, loss of colour vision (optic
neuropathy) papilledema (optic neuropathy)
neuropathy), papilledema (optic neuropathy)

18. Laboratory evaluation
• Patients with Graves' disease have elevated levels of T4 T3 and
• Patients with Graves disease have elevated levels of T4, T3, and
T3RU and low or undetectable levels of TSH
• If the diagnosis of Graves‘ disease is unclear, TSH receptor Abs
should be measured
should be measured
• Tg and / or TPO Abs are often present but are less sensitive and
specific than TSH receptor Abs in the diagnosis of Graves‘ disease in
childhood
childhood
• Radioactive iodine uptake and scan are necessary to confirm the
diagnosis of Graves‘ disease only in atypical cases (for example, if
meas rement of TSH receptor Abs is negati e and if the th roto ic
measurement of TSH receptor Abs is negative and if the thyrotoxic
phase of either CLT or subacute thyroiditis or functioning thyroid
nodule is suspected). In Graves‘ disease, the uptake is elevated and
diffuse

19. Laboratory evaluation
y
• Obtaining a CBC before the initiation of
antithyroid medications may be valuable for
separating patients with underlying
Leukopenia or thrombocytopenia from
ti t h d l d t i it
patients who develop drug toxicity

20. Therapy
py
• The choice of which of the three therapeutic options
(medical th/, radioactive iodine, or surgery) to use
should be individualized and discussed with the
patient and his/her family
• Medical therapy with one of the thiouracil derivates
py
(PTU or MMI) is the initial choice of most
pediatricians, although radioiodine is gaining
increasing acceptance, particularly in non-compliant
d l t i hild h t ll t d d
adolescents, in children who are mentally retarded,
and in those about to leave home

21. Therapy
py
• PTU, MMI, and carbimazole (converted to MMI)
exert their antithyroid effect by inhibiting the
organification of iodine and the coupling of
organification of iodine and the coupling of
iodotyrosine residues on the Tg molecule to
generate T3 and T4
• PTU but not MMI, inhibits the conversion of T4 to the
ti i T3 t ti l d t if th
more active isomer T3, a potential advantage if the
thyrotoxicosis is severe

22. Therapy
py
• The usual initial dosage of MMI is 0.5 mg/kg/day
given once or twice daily and that of PTU is 5
mg/kg/day given thrice daily Carbimazole is best
mg/kg/day given thrice daily. Carbimazole is best
given in a dose of 10-20 mg twice or thrice daily
depending on the concentration of free T4
• In severe cases, a beta-adrenergic blocker
(propranolol, 0.5-2.0 mg/kg/day given every 8 h) can
b dd d t t l th CV ti it til
be added to control the CV overactivity until a
euthyroid state is obtained

23. Therapy
py
• The serum concentrations of T4 and T3
normalize in 3-6 weeks, but TSH
t ti t t t l til
concentration may not return to normal until
several months later
• Approximately 50% of children will go into
long-term remission within 4 years, with
g y
continuing remission rate of 25% every 2
years for up to 6 years of treatment

24. Therapy
py
• Lower initial degree of hyperthyroxinemia
(T4 < 20 ug/dL or 257.4 nmol/L, T3/T4 ratio
< 20), BMI, and older age have been
associated with an increased likelihood of
t i i
permanent remission
P i t f TSH t Ab i di t
• Persistance of TSH receptor Abs indicates a
high likelihood of relaps

25. Therapy
py
• Many authors also recommend checking the
white blood cell count and liver function tests
before therapy because Graves‘ disease
itself can be associated with abnormalities in
th t
these parameters

26. Therapy
py
• Radioactive iodine therapy should be used
with caution in children < 10 years of age
and particularly in those 5 years of age or
less because of the increased susceptibility
f th th id l d i th t th
of the thyroid gland in the young to the
proliferative effects of ionizing radiation

27. Therapy
Therapy
• Although a dose of 50-200 uCi of 131 I /
ti t d f th id ti h b d
estimated gram of thyroid tissue has been used,
the higher dosage is recommended, particularly
in younger children, in order completely to ablate
in younger children, in order completely to ablate
the thyroid gland and thereby reduce the risk of
future neoplasia
• The formula used is: (estimated thyroid weight in
grams) x 50 200 uCi 131 I / fractional 131 I 24 h
grams) x 50-200 uCi 131 I / fractional 131 I 24-h
uptake)

28. Therapy
py
• One usually sees a therapeutic effect within
6 weeks to 3 months
• If significant ophthalmopathy is present, RAI
g p p y p
therapy should be used with caution, and
treatment with corticosteroid for 6-8 weeks
ft RAI d i i t ti b i
after RAI administration may be wise

29. Therapy
Therapy
• Surgery is appropriate for patients who have failed
di l t th h h k dl
medical management, those who have markedly
enlarged thyroid, those whom refuse RAI, and for
the rare patient with significant eye disease in whom
RAI is contraindicated
• The child must be euthyroid before surgery Iodides
The child must be euthyroid before surgery. Iodides
(Lugol‘s solution, 5-10 drops twice a day, or
potassium iodide, 2-10 drops daily) are added for 7-
14 days before surgery in order to decrease the
14 days before surgery in order to decrease the
vascularity of the gland

30. THANK YOU
THANK YOU