HYPERTHYROIDISM

GRAVES DISEASE
D HAKIMI S AK Dr HAKIMI SpAK
Dr MELDA DELIANA SpAK
Dr SISKA MAYASARI LUBIS SpA Dr SISKA MAYASARI LUBIS SpA
PHYSIOLOGY PHYSIOLOGY
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
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
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
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
Frequency q y
Associations between Graves' disease and other
autoimmune diseases are well described and
include associations with DM Addisons disease include associations with DM, Addisons 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)
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
Age g
Incidence increases throughout childhood,
with a peak incidence in children aged 10 -
15 years
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- therapy Rare factors : Interferon therapy
Highly active antiretroviral therapy
(HAART) for HIV infection
Campath 1-H monoclonal antibody (for multiple sclerosis)
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)
Clinical features
*Symptoms* *Symptoms*
Ophthalmopathy :
Eye irritation, dryness, excessive tearing,
visual blurring, diplopia, retro-orbital
discomfort, pain on eye movement, visual
loss
Clinical features
*Signs* g
Hyperthyroidism :
Warm, smooth, moist skin, onycholisis
(loosening of the nail bed, Plummers 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
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)
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
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
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
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
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
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
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
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
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
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)
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
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
(Lugols 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
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