Filippo De Luca

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GRAVES DISEASE IN ADOLESCENTS

• Filippo De Luca
• Pediatric Unit
• Department of Pediatrics
• University of Messina, Italy

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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 3-61
• Incidence rate 0.8/100.000/year
• Peak Incidence in children aged 10-15 years
• Monozygotic twins show 50 concordance for GD

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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)

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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

Inukai et al Eur J Endocrinol 2007, 156623
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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)

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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, 73473 De Luca
et al, EJE 2010,162591
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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

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GD in pediatric ageMinor Clinical Features ()

• Deterioration of school performances 45
• Intolerance to heat 40
• Palpitations
  40
• Disorders of diuresis 25
• Diarrhea
  20
• Headache 20

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Basedow Ophthalmopathy in pediatric age

• 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, 150407
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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!
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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)

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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

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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 1999,9871 Lazar et al, JCEM
2000, 853678 Cassio et al, Clin Endocrinol
2006,6453
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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, 71110 De
Luca et al, EJE 2010,162591
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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 gt 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, 54713
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TrAb positivity
Hashimotos Thyroiditis
Graves Disease
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Other diagnostic tests 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

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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

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Neonatal GD

• Incidence of lt 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

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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 gt 65 yr and in those with
  cardiovascular and/or osteoporosis problems

Ginsberg, Can Med Ass J 2003, 4168
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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 (usuallylt 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

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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

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Other rare causes of hyperthyroidism

• Exogenous hyperthyroidism
• Hyperthyroidism in McCune Albright syndrome (MAS)
• Jod-Basedow thyrotoxicosis
• HCG producing tumors
• TSH-secreting pituitary tumor

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GD Therapy (1)

• In our very recent multicenter experience
  methimazole treatment (initial and maintenance
  dosages 0.460.1 and 0.150.03 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 2010162591
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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 2010162591
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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 2010162591
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