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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
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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
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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
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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
Inukai et al Eur J Endocrinol 2007, 156:623
Relationship between
Hashimoto (HT) and Graves
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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
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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 age
Major Clinical Features (%)
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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 age
Minor Clinical Features (%)
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Deterioration of school performances 45%
Intolerance to heat
40%
Palpitations
40%
Disorders of diuresis
25%
Diarrhea
20%
Headache
20%
Basedow Ophthalmopathy
in pediatric age
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Frequency varies widely in different
series (35-70%)
Quite rare and rarely severe in children
Especially rare disorders of ocular
motility and function
More common in countries with higher
incidence of youth smoking habit
Krassas et al, Eur J Endocrinol 2004, 150:407
Eye symptoms
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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
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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
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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
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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
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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)
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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
Graves’ Disease
Hashimoto’s Thyroiditis
Other diagnostic tests in GD
(1)
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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 antithyroglobulin even less so
Other diagnositic tests in
GD (2)
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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
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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
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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
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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
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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
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Exogenous hyperthyroidism
Hyperthyroidism in McCune Albright
syndrome (MAS)
Jod-Basedow thyrotoxicosis
HCG producing tumors
TSH-secreting pituitary tumor
GD Therapy (1)
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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)
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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 nonpharmacological therapies were
obtained in 37.7% of cases
De Luca et al, EJE 2010:162:591
Conclusions
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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