HYPERTHYROIDISM

GRAVES DISEASE
Dr D HAKIMI SpAK S AK Dr MELDA DELIANA SpAK Dr SISKA MAYASARI LUBIS SpA

PHYSIOLOGY

Background g
Hyperthyroidism : overactivity of the thyroid gland leading to excessive synthesis of thyroid hormones and accelerated metabolism in the peripheral tissues Thyrotoxicosis : the clinical effects of an unbound thyroid hormone, whether or not the thyroid gland i th primary t th th id l d is the i 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 Selective it it S l ti pituitary resistance t thyroid h i t to th id hormone Thyrotoxicosis without hyperthyroidism: 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 receptor antibodies bi d t TSH receptors (Th id t tib di bind to t (Thyroid gland) T3 and T4 (Clinical presentation of hyperthyroidism) (Pituitary gland) TSH ? TSH receptor antibodies bind to TSH receptors in retroorbital connective tissue T cells produce inflammatory cytokines Glycosaminoglycans / Eye muscle antibodies? 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 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 (CTLA) 4, 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 DM, disease, vitiligo, SLE, RA, myasthenia gravis, periodic paralysis, ITP, and pernicious anemia There is an increased risk of Graves' disease in children with D hild ith Down syndrome (t i d (trisomy 21) and d 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 children. prematurity, airway obstruction and heart failure. The mortality rate : as high as 16% 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) Postpartum period Iodine (including amiodarone) Lithium Rare factors : Interferon- therapy Interferon 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) asthma), weight loss (with hyperphagia), weight gain (rarely), hyperdefecation, tremulousness and tremor, weakness, fatigue, weakness fatigue urinary frequency nocturia frequency, nocturia, thirst, anxiety, emotional lability, insomnia, restlessness, inability to concentrate, oligomenorrhea/amenorrhea, oligomenorrhea/amenorrhea errectile dysfunction/gynecomastia, dyspepsia, nausea, vomiting (rare)

Clinical features *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 lag), bright, eyes, tachycardia, atrial fibrilation, widened pulse pressure, hyperdynamic circulation, tremor (fingers), hyperactive reflexes, proximal (fi ) h ti fl i l myopathy

Clinical features *Signs*

O hth l Ophthalmopathy : th Periorbital edema, conjunctival erythema, chemosis (conjunctival edema) proptosis edema), proptosis, ophthalmoplegia, loss of colour vision (optic neuropathy), neuropathy) papilledema (optic neuropathy)

Laboratory evaluation
Patients with Graves disease have elevated levels of T4 T3 and Graves' T4, T3, T3RU and low or undetectable levels of TSH If the diagnosis of Graves disease is unclear, TSH receptor Abs 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 Radioactive iodine uptake and scan are necessary to confirm the diagnosis of Graves disease only in atypical cases (for example, if measurement meas rement of TSH receptor Abs is negati e and if the th roto ic negative 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 patients who d ti t h develop d l drug t i it toxicity

 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 adolescents, i children who are mentally retarded, d l t in hild h t ll t d d and in those about to leave home

Therapy py

Therapy py
PTU, MMI, and carbimazole (converted to MMI) exert their antithyroid effect by inhibiting the 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 more active isomer T3 a potential advantage if th ti i T3, t ti l d t 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 daily 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 be dd d to b added t control th CV overactivity until a t l the ti it til euthyroid state is obtained

Therapy py
The serum concentrations of T4 and T3 normalize in 3-6 weeks, but TSH concentration may not return to normal until t ti t t t l til 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 permanent remission t i i P i t Persistance of TSH receptor Abs indicates a f t Ab i di t 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 these parameters th t

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 of the thyroid gland i th young t th f th th id l d in the to the proliferative effects of ionizing radiation

Therapy
Although a dose of 50-200 uCi of 131 I / estimated gram of thyroid ti ti t d f th id tissue h b has been used, d the higher dosage is recommended, particularly 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 50-200 24-h uptake)

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

Therapy
Surgery is appropriate for patients who have failed medical management, th di l t those who h h have markedly k dl 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 surgery. (Lugols solution, 5-10 drops twice a day, or potassium iodide, 2-10 drops daily) are added for 714 days before surgery in order to decrease the vascularity of the gland

THANK YOU