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Thyroid Disease in ChildrenThyroid Disease in ChildrenPaul Paul HruzHruz MD PhDMD PhD
Department of Department of PediactricsPediactricsSeptember 2005September 2005
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Introduction• Thyroid Disease is the Most Common
Endocrinopathy Observed in Children
• While the Disease Processes Present are Similar to Those in Adults, the Incidences, Presentations, and Clinical Consequences Can Differ Markedly
• Failure to Diagnose and Treat Promply May Lead to Irreversible Neurologic Damage
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Lecture Outline
• Disorders of Thyroid Development• Thyroid Disease in the Newborn• Hypothyroidism in Children• Hyperthyroidism in Children• Thryoid Nodules
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Thyroid Physiology of the Fetus and Newborn
• Normal Thyroid Development• Thyroid Status in Premature Infants• Transplacental Passage of Thyroid Ab• Newborn Screening• Congenital Hypothyroidism
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Thyroid Development• Orignates from thyroid diverticulum
and ultimobranchial bodies• Ontogeny influenced by several
transcription factors (TTF, PAX8, HOX3)
• Largely complete by 10-12 weeks• Gradual Maturation in Hypothalamic
-Pituitary-Thyroid Axis
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Genetic Factors Impacting Thyroid Development
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Fetal Thyroid Maturation
• TSH detectable by 12 wks• Feedback mechanisms
established by 20 wks• T3 levels remain low• Reverse T3 levels high
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Placental and Fetal Thyroid Metabolism
• Independent fetal axis– Limited T4 exchange– Placental type 3 deiodoinase
• Effect of maternal hypothyroidism– Most important in first
trimester
• Permeable to TRH, IgGand thionamides
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Thyroid Changes at Birth
• TSH surge at birth followed by T4 and T3rise
• Important for interpreting newborn screen results
• Lower rise in preterm infants
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Cord Blood Thryoid Levels
• Influenced by gestational age
• Progressive increase with approach to term
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Thyroid Status in Premature Infants
• Relative immaturity of axis• Nadir at 2-3 wks• Influences
– Illness, – Iodine exposure, – T4 clearance, – Iodine stores
• TSH usually not elevated
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Principles of Newborn Screening
• Relatively High Prevalence• Deleterious Consequence of
Delayed Diagnosis• Difficult Clinical Recognition• Reliable Method of Screening
(sensitive & specific)• Safe, Effective Treatment
Available
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Thyroid Effects in the Fetus and Neonate
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Congenital Hypothryoidism• Incidence 1:4000
– Slightly higher in female infants– Higher in Asian babies– Lower in Black babies
• Primarily Sporadic Occurance• Overt symptoms may not be present at birth• Profound effects on brain development• Reliable testing available (T4 and/or TSH)• No sequelae if treatment initiated by 4 wks
– 10-15 mcg/kg/d
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Etiology of Primary Congenital Hypothryoidism
• Extensive testing for precise etiology is generally not necessary (will not change immediate care plans)
• May allow assessment of risk in future pregnancies
• May allow early determination of transient vspermanent disease
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Transient Congenital Hypothyroidism• Defined as abnormal newborn screen with
abnormal confirmatory labs– 75-80% of abnormal screens due to false +
• Incidence estimated to be ~10% of cases• Most common in premature infants• Causes:
– Iodine deficiency or excess– Maternal antithyroid medication– Maternal TSH receptor blocking antibodies
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Maternal TSH receptor blocking antibodies
• Incidence estimated at 1:180,000• Often history of treated Graves in mom
– Mothers may have unrecognized hypothryoidism• Infant will not have goiter
– Difficult to distinguish from thyroid dysgenesis• May have permanent neurocognitive deficit if
present in utero• Resolves in 2-3 months as antibody clears
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Treatment Guidelines• Confirm all abnormal newborn screens with
laboratory TSH and free T4– Borderline results may require repeat testing in 2-4
wks• If repeat labs abnormal, begin thryoxine (25-37.5
mcg/day)– Goal is to start treatment within first month of life
• Recheck q 2-3 months and adjust dose if necessary
• If no need to increase dose by 2 ½ -3 yrs, give 4 wk trial off of thyroxine
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Hypothyroidism• Congenital
– Primary• Thryoid Agenesis• Dyshormonogenesis• Iodine Deficiency
– Secondary• Hypopituitarism
– Isolated– Multiple hormone deficiency
• Acquired– Primary
• Surgery• Radiation• Autoimmune• Iodine Deficiency
– Secondary• Surgery• Radiation• Infiltrative• Tumor
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Common Symptoms and Signs of Hypothyroidism in Children
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Growth Failure in Childhood Hypothyroidism
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Hypothyroidism: Treatment
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Hashimotos Thyroiditis
• Most common cause of acquired hypothyroidism• Female:Male (3:1)• Most children present with asymptomatic goiter• Clinical Symptoms may be nonspecific• More frequent in Down and Turner Syndrome
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Goiter: Differential Diagnosis• Congenital
– Dyshormonogenesis– Maternal Antibodies
• Blocking• Stimulating
– Maternal Antithyroid drug• PTU, methimazole
– TSH receptor Activating Mutation
– McCune Albright Syndrome– Thyroid Tumor
• Acquired– Inflammation– Colloid– Iodine Deficiency– Goiterogen– Infiltrative disease– Toxic goiter– Thyroglossal duct
cyst– Adenoma– Carcinoma
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Endemic Goiter• Usually euthryoid• Diffuse gland enlargement• Rare in US (iodized salt provides adequate iodine
source)• Rule out autoimmune thyroiditis• Treament Doses in Children (6-12 months)
– Infants 100 mcg/d– Children 200 mcg/day– Adolescents 200-300 mcg/d
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Hyperthyroidism• Graves Disease (>95% of Cases)
– Relatively rare in children– Incidence increases with puberty– Female:Male (3-5:1)
• Neonatal Graves– Transplacental Antibodies
• Hashitoxicosis• TSH receptor mutations (gain of function)
– McCune Albright syndrome• Subacute Thyroiditis• Exogenous thyroxine Exposure
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Neonatal Hyperthyroidism• Almost always transient• Usually associated with maternal Graves
– Transplacental passage of TSI– Blocking and stimulating Abs may coexist
• Incidence ~1:50,000 infants– 1-2% of moms with Graves disease
• Often presents in first week of life– Emerges with clearance of maternal thionamide
• Treatment – PTU or Methimazole– SSKI (If severe symptoms)– Propranolol (If significant sympathetic symptoms (HR>160)
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Clinical Signs of Hyperthyroidism in Children• Change in School Performance• Insomnia• Restlessness and Irritability• Nocturia• Bone age advancement• Infants
– Premature birth, Craniosynostosis, Poor feeding, Failure to Thrive
• Other classic signs– Weight Loss, Polyphagia, Tachycardia, Increased Pulse
Pressure, Heat Intolerance, Diarrhea, Tremor
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Graves Disease: Diagnosis
• Suppressed TSH• Elevated T4, Free T4, T3 levels• Positive Thyroid Stimulating Antibodies:
(May be helpful if exophthalmos absent)– Thyroid Peroxidase– Thyroglobulin– Thyroid Stimulating Immunoglobulin
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Treatment of Graves’ Disease• Radioactive Iodine
– Preferred treatment in older children and adolescents– Theoretical risk of radiation not established– Possible increased risk of thryoid cancer (<5yrs)
• Thionamides (methimazole, PTU)– Agranulocytosis, hepatitis, rash– Poor long term remission rates– Difficult to titrate dose, frequent monitoring– Poor compliance in adolescents
• Surgical Thyroidectomy– Rarely indicated
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Colloid (Nontoxic) Goiter• Diffuse enlargement of thryoid gland evident
usually during pubertal years• Normal thyroid function tests• Often family history• May represent mild autoimmune thryoiditis
– TPO Ab titer may be helpful to distinguish• May be associated with nodular goiter as adults• Therapy usually not necessary
– May respond to thryoid suppression (controversial)
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Thryoid Nodules
• Low Prevalence in Children (0.2% <16 yrs)
• Higher Incidence of Malignancy (18-22%)
• Evaluation– Ultrasound can assist in detection but not helpful to distinguish
benign from malignant nodules– Uptake scan generally not helpful (Hot nodules can be malignant)– Fine needle aspiration (90% accuracy)– Excisional biopsy
• Majority are due to colloid cysts or follicular adenomas
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Thyroid Cancer• Carcinoma is rare (1.5% in kids <15 yrs)
– Papillary Carcinoma ~85-90%– Medullary Carcinoma ~5%– Follicular and Anaplastic Carcinoma
• Risk Factors– Ionizing Radiation (esp if < 5 yrs)– Iodine Deficiency– Autoimmune thyroiditis– Prolonged TSH elevation– Family history (MEN)
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Thyroid Cancer in MEN
• Agressiveness: MEN2B>MEN2A>familial MTC
• Prophylactic thryoidectomy– MEN2B <6 months– MEN2A <5 years
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Case #1
• Term 3.25 kg male newborn infant with newborn screen (obtained on DOL #3) reported on DOL#10 with T4 of 20 mcg/dL and TSH 12.5. Infant doing well. No family history of thryoid disease. Mom healthy. 3 healthy sibs– What would you do next?
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Case #1 (Continued)
• Repeat TSH: 8.5 mcIU/ml, free T4: 1.2 ng/dL– What would you do now?
• Follow-up labs in 2 weeks:– TSH 8, T4 8.5 mcg/dL
• Started 25 mcg Synthroid q day, repeat labs 4 weeks later with TSH 2.5, T4 10.5
• At 2 ½ years of age, pt is still on 25 mcg Synthroid with normal TFTs.
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Case #1 (continued)
• Synthroid discontinued, TSH repeated 4 weeks later– Normal (4 mcIU/ml)
• Diagnosis?– Transient congenital hypothyroidism
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Case #2
• 3 wk old former 25 wk EGA female infant followed in NICU. On ventillator, PDA, TPN dependent, Wt 700 gm. TSH 2.3, free T4 0.6 ng/dL.– To treat or not to treat?
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Case #3
• 13 year old girl with declining growth velocity for “several years”. No pubertal changes. Height currently at -3 S.D., Wt at 25%ile. Quiet personality. Presented with hip pain. No goiter
• Initial labs showed TSH >300, T4 1.6 mcg/dL