HYPERTHYROIDISMGRAVES‘ DISEASE

D HAKIMI S AKDr HAKIMI SpAK

Dr MELDA DELIANA SpAK

Dr SISKA MAYASARI LUBIS SpADr SISKA MAYASARI LUBIS SpA

PHYSIOLOGYPHYSIOLOGY

Backgroundg• Hyperthyroidism : overactivity of the

thyroid gland leading to excessive synthesis of thyroid hormones andsynthesis 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 inot the thyroid gland is the primary source

Causes of thyrotoxicosis in childhoody• Hyperthyroidism :

Diffuse toxic goiter (Graves' disease)Nodular toxic goiter (Plummer disease)

• TSH-induced hyperthyroidism:TSH producing pituitary tumorS l ti it it i t t th id hSelective pituitary resistance to thyroid hormone

• Thyrotoxicosis without hyperthyroidism:Chronic lymphocytic thyroiditis (CLT)Chronic lymphocytic thyroiditis (CLT)Subacute thyroiditisThyroid hormone ingestion

Pathogenesisg• 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

Frequencyq 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 hyperthyroidismhyperthyroidism

• 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 isantigen (CTLA) 4, an immunoregulatory molecule that is expressed on the surface of activated lymphocytes and inhibits T-lymphocyte activation

Frequencyq y• Associations between Graves' disease and other

autoimmune diseases are well described and include associations with DM Addison‘s diseaseinclude 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) dchildren with Down syndrome (trisomy 21) and

DiGeorge syndrome (22q11 deletion)

Mortality / Morbidityy y• Excellent prognosis

• Neonatal Graves' disease is self-limited, the prognosis is considerably worse than that in older children The patients are prone toworse 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

Ageg• 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-α therapyRare factors : Interferon α 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 nocturiaweakness, fatigue, urinary frequency, nocturia, thirst, anxiety, emotional lability, insomnia, restlessness, inability to concentrate, oligomenorrhea/amenorrhea errectileoligomenorrhea/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, Plummer‘s nails), palmar erythema, thinning of the hair, stare, lid retraction (and lag) bright shiny eyeslid 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) proptosischemosis (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 measuredshould 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 childhoodchildhood

• 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 icmeasurement 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 evaluationy• 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 itpatients who develop drug toxicity

Therapypy• 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 dadolescents, in children who are mentally retarded,

and in those about to leave home

Therapypy• PTU, MMI, and carbimazole (converted to MMI)

exert their antithyroid effect by inhibiting the organification of iodine and the coupling oforganification 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 thmore active isomer T3, a potential advantage if the

thyrotoxicosis is severe

Therapypy• 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 bestmg/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 tilbe added to control the CV overactivity until a euthyroid state is obtained

Therapypy• The serum concentrations of T4 and T3

normalize in 3-6 weeks, but TSH t ti t t t l tilconcentration may not return to normal until

several months later

• Approximately 50% of children will go into long-term remission within 4 years, with g ycontinuing remission rate of 25% every 2 years for up to 6 years of treatment

Therapypy• 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 ipermanent remission

P i t f TSH t Ab i di t• Persistance of TSH receptor Abs indicates a high likelihood of relaps

Therapypy• 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 tthese parameters

Therapypy• 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 thof the thyroid gland in the young to the proliferative effects of ionizing radiation

TherapyTherapy

• Although a dose of 50-200 uCi of 131 I / ti t d f th id ti h b destimated gram of thyroid tissue has been used,

the higher dosage is recommended, particularly in younger children, in order completely to ablatein 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 hgrams) x 50-200 uCi 131 I / fractional 131 I 24-h uptake)

Therapypy• One usually sees a therapeutic effect within

6 weeks to 3 months

• If significant ophthalmopathy is present, RAI g p p y ptherapy should be used with caution, and treatment with corticosteroid for 6-8 weeks

ft RAI d i i t ti b iafter RAI administration may be wise

TherapyTherapy

• Surgery is appropriate for patients who have failed di l t th h h k dlmedical 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 IodidesThe 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 the14 days before surgery in order to decrease the vascularity of the gland

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