Filippo De LucaFilippo De Luca

Pediatric UnitPediatric UnitDepartment of PediatricsDepartment of Pediatrics

University of MessinaUniversity of Messina, Italy, Italy

GRAVES’ DISEASE IN GRAVES’ DISEASE IN ADOLESCENTSADOLESCENTS

Graves’ Disease (GD) in pediatric Graves’ Disease (GD) in pediatric ageage

EpidemiologyEpidemiology GD accounts for more than 95% of GD accounts for more than 95% of

hyperthyroidism cases in childhoodhyperthyroidism cases in childhood Prevalence of GD is approximately 0.02 in Prevalence of GD is approximately 0.02 in

childhood, accounting for fewer than 5% of childhood, accounting for fewer than 5% of the total cases of GDthe total cases of GD

Female-to-male ratio of 3-6:1Female-to-male ratio of 3-6:1 Incidence rate: 0.8/100.000/yearIncidence rate: 0.8/100.000/year Peak Incidence in children aged 10-15 yearsPeak Incidence in children aged 10-15 years Monozygotic twins show 50% concordance Monozygotic twins show 50% concordance

for GDfor GD

GD in pediatric age: GD in pediatric age: Risk FactorsRisk Factors

Positive family historyPositive family history Association with HLA B8 and HLA DR3 Association with HLA B8 and HLA DR3

haplotypehaplotype Association with other autoimmune Association with other autoimmune

diseasesdiseases Autoimmune polyglandular syndromes Autoimmune polyglandular syndromes

(APS) (APS) type 3 type 3 and type 2and type 2 Down syndrome (relative prevalence 0.7%)Down syndrome (relative prevalence 0.7%) Turner syndrome (relative prevalence Turner syndrome (relative prevalence

1.7%)1.7%)

Pathogenetic Pathogenetic Peculiarities of GDPeculiarities of GD In contrast to other autoimmune diseases (HT, In contrast to other autoimmune diseases (HT,

celiac disease, type 1 diabetes), GD is celiac disease, type 1 diabetes), GD is traditionally considered an autoantibody-traditionally considered an autoantibody-mediated T-helper (TH2)mediated T-helper (TH2)

Recent studies cast doubt on this traditional Recent studies cast doubt on this traditional classification and the existence of a clear classification and the existence of a clear demarcation between HT and GDdemarcation between HT and GD

In hyperthyroid patients with GD in the active In hyperthyroid patients with GD in the active phase, TH1 rather than TH2 cells predominate phase, TH1 rather than TH2 cells predominate among peripheral blood lymphocytesamong peripheral blood lymphocytes

After initiation of methimazole, an ongoing After initiation of methimazole, an ongoing transition from TH1 to TH2 occurstransition from TH1 to TH2 occurs

Inukai et al Eur J Endocrinol 2007, Inukai et al Eur J Endocrinol 2007, 156:623156:623

Relationship between Relationship between Hashimoto (HT) and Hashimoto (HT) and GravesGraves In pairs of identical twins, one can In pairs of identical twins, one can

develop HT and the other GDdevelop HT and the other GD GD and HT frequently aggregate in GD and HT frequently aggregate in

the same familiesthe same families They can coexist in the same glandThey can coexist in the same gland They can occur in the same patientThey can occur in the same patient They have the same predisposing They have the same predisposing

HLA aplotype (DR3)HLA aplotype (DR3)

HT antecedents in the clinical HT antecedents in the clinical history of children and history of children and adolescents with GDadolescents with GD

In a study population of 106 children and In a study population of 106 children and adolescents with GD, we report a frequency adolescents with GD, we report a frequency of HT antecedents in 4% of casesof HT antecedents in 4% of cases

The prevalence of this sequence of events is The prevalence of this sequence of events is more frequent in Down syndrome (20%)more frequent in Down syndrome (20%)

Our reports confirm the existence of a Our reports confirm the existence of a continuum between HT and GD within the continuum between HT and GD within the spectrum of autoimmune thyroid diseasesspectrum of autoimmune thyroid diseases

De Luca et al, Horm Res Paed 2010, 73:473De Luca et al, Horm Res Paed 2010, 73:473

De Luca et al, EJE 2010,162:591De Luca et al, EJE 2010,162:591

GD in pediatric ageGD in pediatric ageMajor Clinical Features (%)Major Clinical Features (%)

GoiterGoiter 100%100% Nervousness and IrritabilityNervousness and Irritability 100%100% TachycardiaTachycardia 90% 90% Hyperreflexia and HypertensionHyperreflexia and Hypertension

80%80% TremorTremor 75% 75% Excessive sweatingExcessive sweating 70% 70% Weight loss without loss of appetite 65%Weight loss without loss of appetite 65% Hyperkinesia and behavioral disorders 60%Hyperkinesia and behavioral disorders 60%

GD in pediatric ageGD in pediatric ageMinor Clinical Features (%)Minor Clinical Features (%)

Deterioration of school performances 45%Deterioration of school performances 45% Intolerance to heat 40%Intolerance to heat 40% Palpitations 40%Palpitations 40% Disorders of diuresis Disorders of diuresis 25% 25% Diarrhea 20%Diarrhea 20% HeadacheHeadache 20% 20%

Basedow Basedow Ophthalmopathy in Ophthalmopathy in pediatric age pediatric age

Frequency varies widely in different Frequency varies widely in different series (35-70%)series (35-70%)

Quite rare and rarely severe in Quite rare and rarely severe in children children

Especially rare disorders of ocular Especially rare disorders of ocular motility and functionmotility and function

More common in countries with higher More common in countries with higher incidence of youth smoking habit incidence of youth smoking habit

Krassas et al, Eur J Endocrinol 2004, Krassas et al, Eur J Endocrinol 2004, 150:407150:407

Eye symptomsEye symptoms

Exophthalmos (sometimes unilateral)Exophthalmos (sometimes unilateral) Eye lid retraction and lid lagEye lid retraction and lid lag OphthalmoplegiaOphthalmoplegia Fixed gazeFixed gaze Conjunctival injection and chemosisConjunctival injection and chemosis Periorbital edemaPeriorbital edema Optic atrophyOptic atrophy DiplopiaDiplopia

Only some of these symptoms resolve with regression of Only some of these symptoms resolve with regression of hyperthyroidism!hyperthyroidism!

Clinical examination of Clinical examination of thyroidthyroid Goiter is mandatory for the Goiter is mandatory for the

diagnosis of GD!diagnosis of GD! It is rarely detectable from the It is rarely detectable from the

beginning of clinical picture (this beginning of clinical picture (this justifies any delay in diagnosis)justifies any delay in diagnosis)

It is widely diffused and symmetricalIt is widely diffused and symmetrical A murmur can be detected in cases A murmur can be detected in cases

of major thyromegaly (thyroid of major thyromegaly (thyroid enlargement)enlargement)

Clinical picture onsetClinical picture onset

Often insidious , especially in childrenOften insidious , especially in children Initially the most typical symptoms Initially the most typical symptoms

are rare (goiter and ophthalmopathy)are rare (goiter and ophthalmopathy) Atypical symptoms are more Atypical symptoms are more

prevalent, especially behavioral prevalent, especially behavioral disorders, deterioration of school disorders, deterioration of school performances and hyperactivity performances and hyperactivity syndromesyndrome

Growth and pubertal Growth and pubertal development in GDdevelopment in GD Acceleration of growth and bone Acceleration of growth and bone

maturation is commonly foundmaturation is commonly found Even in pre-pubertal-onset cases, Even in pre-pubertal-onset cases,

final height is not significantly final height is not significantly impaired despite initial bone age impaired despite initial bone age advancementadvancement

Target heights do not differ Target heights do not differ between males and femalesbetween males and females

Segni et al, Thyroid 1999,9:871Segni et al, Thyroid 1999,9:871

Lazar et al, JCEM 2000, 85:3678Lazar et al, JCEM 2000, 85:3678

Cassio et al, Clin Endocrinol 2006,64:53Cassio et al, Clin Endocrinol 2006,64:53

GD peculiarities in GD peculiarities in Down syndromeDown syndrome No typical female predominanceNo typical female predominance More prevalent than in the general More prevalent than in the general

populationpopulation HT may often precede GDHT may often precede GD Prevalence of ophthalmopathy is lowPrevalence of ophthalmopathy is low Response to drug therapy is not poorResponse to drug therapy is not poor

Goday-Arno et al Clin Endocrinol 2009, 71:110Goday-Arno et al Clin Endocrinol 2009, 71:110

De Luca et al, EJE 2010,162:591De Luca et al, EJE 2010,162:591

The detection of The detection of autoantibodies to thyrotropin-autoantibodies to thyrotropin-receptor antibody (TRAb)receptor antibody (TRAb)

Commonly used:Commonly used:- in clinical practice for the diagnostic - in clinical practice for the diagnostic assessment of GDassessment of GD- in differential diagnosis between toxic - in differential diagnosis between toxic multinodular goiter and autonomous multinodular goiter and autonomous adenoma.adenoma.

New TRAB assays have specificity and New TRAB assays have specificity and sensitivity > 90%sensitivity > 90%

It could have a prognostic value, either It could have a prognostic value, either at the onset of GD or during treatment at the onset of GD or during treatment Cardia et al, Thyroid 2004, 14: 295Cardia et al, Thyroid 2004, 14: 295

Cappelli et al, Endocrin J 2007, 54:713Cappelli et al, Endocrin J 2007, 54:713

TrAb positivity

Hashimoto’s ThyroiditisGraves’ Disease

Other diagnostic tests in Other diagnostic tests in GD (1)GD (1) Thyroid function tests are crucial Thyroid function tests are crucial

for diagnosis confirmation and in for diagnosis confirmation and in d.d. between GD and other cases d.d. between GD and other cases of hyperthyroidismof hyperthyroidism

Evaluation of anti-peroxidase Evaluation of anti-peroxidase antibody is not very specific, and antibody is not very specific, and anti-thyroglobulin even less soanti-thyroglobulin even less so

Other diagnositic tests Other diagnositic tests in GD (2)in GD (2) Echographic picture is not Echographic picture is not

different from that of HTdifferent from that of HT

Scintigraphy has lost much of its Scintigraphy has lost much of its traditional value but may be traditional value but may be useful with suspected toxic useful with suspected toxic adenomaadenoma

Neonatal GDNeonatal GD

Incidence of < 1% of all pediatric casesIncidence of < 1% of all pediatric cases No gender predominanceNo gender predominance Caused by transplacental passage of TSICaused by transplacental passage of TSI Clinical signs: tachycardia, hypertension, Clinical signs: tachycardia, hypertension,

tremors and hyperphagia without weight tremors and hyperphagia without weight gaingain

Goiter and exophthalmos may be absentGoiter and exophthalmos may be absent Complications: craniosynostosis and Complications: craniosynostosis and

mental retardationmental retardation Spontaneous resolution after 3-4 monthsSpontaneous resolution after 3-4 months

Subclinical Subclinical hyperthyroidismhyperthyroidism More frequent in older patientsMore frequent in older patients The only biochemical sign is the suppression The only biochemical sign is the suppression

of TSH with normal FT4 and FT3 valuesof TSH with normal FT4 and FT3 values Increased risk of osteopenia and atrial Increased risk of osteopenia and atrial

fibrillationfibrillation Spontaneous remission in 40% of casesSpontaneous remission in 40% of cases Antithyroid therapy is justified in only the Antithyroid therapy is justified in only the

patients aged > 65 yr and in those with patients aged > 65 yr and in those with cardiovascular and/or osteoporosis problemscardiovascular and/or osteoporosis problems

Ginsberg, Can Med Ass J 2003, 4:168Ginsberg, Can Med Ass J 2003, 4:168

HashitoxicosisHashitoxicosis

Not a disease in itself but is the Not a disease in itself but is the hyperthyroid phase of HThyperthyroid phase of HT

Detectable in 10-15% of all cases at onset Detectable in 10-15% of all cases at onset of HTof HT

Short duration (usually< 6 months)Short duration (usually< 6 months) Concurrent with an increase in TPOA and Concurrent with an increase in TPOA and

TGA and only rarely in TRABTGA and only rarely in TRAB Generally auto-resolution occurs, Generally auto-resolution occurs,

developing into euthyroidism or developing into euthyroidism or hypothyroidismhypothyroidism

Responds to antithyroid therapyResponds to antithyroid therapy

Toxic adenomaToxic adenoma

Very rare in pediatric ageVery rare in pediatric age Mostly benign (not always!)Mostly benign (not always!) Hashitoxicosis can present in a Hashitoxicosis can present in a

biochemical fashion that is similar biochemical fashion that is similar to Graves diseaseto Graves disease

Negative autoimmunityNegative autoimmunity Typical scintigraphic imageTypical scintigraphic image

Other rare causes of Other rare causes of hyperthyroidismhyperthyroidism Exogenous hyperthyroidismExogenous hyperthyroidism Hyperthyroidism in McCune Hyperthyroidism in McCune

Albright syndrome (MAS)Albright syndrome (MAS) Jod-Basedow thyrotoxicosisJod-Basedow thyrotoxicosis HCG producing tumorsHCG producing tumors TSH-secreting pituitary tumorTSH-secreting pituitary tumor

GD Therapy (1)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 2010:162:591De Luca et al, EJE 2010:162:591

GD Therapy (2)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 2010:162:591De Luca et al, EJE 2010:162:591

ConclusionsConclusions

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 2010:162:591De Luca et al, EJE 2010:162:591