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GRAVES’ DISEASE IN ADOLESCENTS. Filippo De Luca Pediatric Unit Department of Pediatrics University of Messina , Italy. Graves’ Disease (GD) in pediatric age Epidemiology. GD accounts for more than 95% of hyperthyroidism cases in childhood
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GRAVES’ DISEASE IN ADOLESCENTS Filippo De Luca Pediatric Unit Department of Pediatrics University of Messina, Italy
Graves’ Disease (GD) in pediatric age Epidemiology • GD accounts for more than 95% of hyperthyroidism cases in childhood • Prevalence of GD is approximately 0.02 in childhood, accounting for fewer than 5% of the total cases of GD • Female-to-male ratio of 3-6:1 • Incidence rate: 0.8/100.000/year • Peak Incidence in children aged 10-15 years • Monozygotic twins show 50% concordance for GD
GD in pediatric age: Risk Factors • Positive family history • Association with HLA B8 and HLA DR3 haplotype • Association with other autoimmune diseases • Autoimmune polyglandular syndromes (APS) type 3 and type 2 • Down syndrome (relative prevalence 0.7%) • Turner syndrome (relative prevalence 1.7%)
Pathogenetic Peculiarities of GD • In contrast to other autoimmune diseases (HT, celiac disease, type 1 diabetes), GD is traditionally considered an autoantibody-mediated T-helper (TH2) • Recent studies cast doubt on this traditional classification and the existence of a clear demarcation between HT and GD • In hyperthyroid patients with GD in the active phase, TH1 rather than TH2 cells predominate among peripheral blood lymphocytes • After initiation of methimazole, an ongoing transition from TH1 to TH2 occurs Inukaiet al Eur JEndocrinol 2007, 156:623
Relationship between Hashimoto (HT) and Graves • In pairs of identical twins, one can develop HT and the other GD • GD and HT frequently aggregate in the same families • They can coexist in the same gland • They can occur in the same patient • They have the same predisposing HLA aplotype (DR3)
HT antecedents in the clinical history of children and adolescents with GD • In a study population of 106 children and adolescents with GD, we report a frequency of HT antecedents in 4% of cases • The prevalence of this sequence of events is more frequent in Down syndrome (20%) • Our reports confirm the existence of a continuum between HT and GD within the spectrum of autoimmune thyroid diseases De Luca et al, Horm Res Paed 2010, 73:473 De Luca et al, EJE 2010,162:591
GD in pediatric ageMajor Clinical Features (%) • Goiter 100% • Nervousness and Irritability 100% • Tachycardia 90% • Hyperreflexia and Hypertension 80% • Tremor 75% • Excessive sweating 70% • Weight loss without loss of appetite 65% • Hyperkinesia and behavioral disorders 60%
GD in pediatric ageMinor Clinical Features (%) • Deteriorationofschoolperformances 45% • Intolerancetoheat 40% • Palpitations 40% • Disordersofdiuresis 25% • Diarrhea 20% • Headache 20%
Basedow Ophthalmopathy in pediatric age • Frequencyvarieswidely in differentseries (35-70%) • Quite rare and rarely severe in children • Especially rare disordersofocularmotility and function • More common in countrieswithhigherincidenceofyouth smoking habit Krassaset al, Eur JEndocrinol 2004, 150:407
Eye symptoms • Exophthalmos (sometimes unilateral) • Eye lid retraction and lid lag • Ophthalmoplegia • Fixed gaze • Conjunctival injection and chemosis • Periorbital edema • Optic atrophy • Diplopia Only some of these symptoms resolve with regression of hyperthyroidism!
Clinical examination of thyroid • Goiter is mandatory for the diagnosis of GD! • It is rarely detectable from the beginning of clinical picture (this justifies any delay in diagnosis) • It is widely diffused and symmetrical • A murmur can be detected in cases of major thyromegaly (thyroid enlargement)
Clinical picture onset • Often insidious , especially in children • Initially the most typical symptoms are rare (goiter and ophthalmopathy) • Atypical symptoms are more prevalent, especially behavioral disorders, deterioration of school performances and hyperactivity syndrome
Growth and pubertal development in GD • Acceleration of growth and bone maturation is commonly found • Even in pre-pubertal-onset cases, final height is not significantly impaired despite initial bone age advancement • Target heights do not differ between males and females Segni et al, Thyroid 1999,9:871 Lazar et al, JCEM 2000, 85:3678 Cassio et al, Clin Endocrinol 2006,64:53
GD peculiarities in Down syndrome • No typical female predominance • More prevalent than in the general population • HT may often precede GD • Prevalence of ophthalmopathy is low • Response to drug therapy is not poor Goday-Arno et al Clin Endocrinol 2009, 71:110 De Luca et al, EJE 2010,162:591
The detection of autoantibodies to thyrotropin-receptor antibody (TRAb) • Commonly used: - in clinical practice for the diagnostic assessment of GD - in differential diagnosis between toxic multinodular goiter and autonomous adenoma. • New TRAB assays have specificity and sensitivity > 90% • It could have a prognostic value, either at the onset of GD or during treatment Cardia et al, Thyroid 2004, 14: 295 Cappelli et al, Endocrin J 2007, 54:713
TrAb positivity Hashimoto’s Thyroiditis Graves’ Disease
Otherdiagnostictests in GD (1) • Thyroid function tests are crucial for diagnosis confirmation and in d.d. between GD and other cases of hyperthyroidism • Evaluation of anti-peroxidase antibody is not very specific, and anti-thyroglobulin even less so
Other diagnositic tests in GD (2) • Echographic picture is not different from that of HT • Scintigraphy has lost much of its traditional value but may be useful with suspected toxic adenoma
Neonatal GD • Incidence of < 1% of all pediatric cases • No gender predominance • Caused by transplacental passage of TSI • Clinical signs: tachycardia, hypertension, tremors and hyperphagia without weight gain • Goiter and exophthalmos may be absent • Complications: craniosynostosis and mental retardation • Spontaneous resolution after 3-4 months
Subclinical hyperthyroidism • More frequent in older patients • The only biochemical sign is the suppression of TSH with normal FT4 and FT3 values • Increased risk of osteopenia and atrial fibrillation • Spontaneous remission in 40% of cases • Antithyroid therapy is justified in only the patients aged > 65 yr and in those with cardiovascular and/or osteoporosis problems Ginsberg, Can Med Ass J 2003, 4:168
Hashitoxicosis • Not a disease in itself but is the hyperthyroid phase of HT • Detectable in 10-15% of all cases at onset of HT • Short duration (usually< 6 months) • Concurrent with an increase in TPOA and TGA and only rarely in TRAB • Generally auto-resolution occurs, developing into euthyroidism or hypothyroidism • Responds to antithyroid therapy
Toxic adenoma • Very rare in pediatric age • Mostly benign (not always!) • Hashitoxicosis can present in a biochemical fashion that is similar to Graves disease • Negative autoimmunity • Typical scintigraphic image
Other rare causes of hyperthyroidism • Exogenous hyperthyroidism • Hyperthyroidism in McCune Albright syndrome (MAS) • Jod-Basedow thyrotoxicosis • HCG producing tumors • TSH-secreting pituitary tumor
GD Therapy (1) • In our very recent multicenter experience methimazole treatment (initial and maintenance dosages 0.46±0.1 and 0.15±0.03 mg/kg/day, respectively) induced a significant remission rate even during the first therapeutical cycle • The prevalence of relapse rates after withdrawal of the 1° methimazole cycle was relatively high (31.2%) and further pharmacological cycles were needed in most cases De Luca et al, EJE 2010:162:591
GD Therapy (2) • Persistent remission rates after prolonged methimazole withdrawal were 26.7% • Non-pharmacological therapies were needed in 11% of cases • Definitive remission rates after at least 2 years from withdrawal or after non-pharmacological therapies were obtained in 37.7% of cases De Luca et al, EJE 2010:162:591
Conclusions • In young patients, methimazole therapy may be effective to induce transient GD remission but several and prolonged therapeutical cycles are often needed • The prevalence of side effects is very low (3.8%) De Luca et al, EJE 2010:162:591