Thyroid Disease in ChildrenThyroid Disease in ChildrenPaul Paul HruzHruz MD PhDMD PhD

Department of Department of PediactricsPediactricsSeptember 2005September 2005

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

Lecture Outline

• Disorders of Thyroid Development• Thyroid Disease in the Newborn• Hypothyroidism in Children• Hyperthyroidism in Children• Thryoid Nodules

Thyroid Physiology of the Fetus and Newborn

• Normal Thyroid Development• Thyroid Status in Premature Infants• Transplacental Passage of Thyroid Ab• Newborn Screening• Congenital Hypothyroidism

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

Genetic Factors Impacting Thyroid Development

Fetal Thyroid Maturation

• TSH detectable by 12 wks• Feedback mechanisms

established by 20 wks• T3 levels remain low• Reverse T3 levels high

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

Thyroid Changes at Birth

• TSH surge at birth followed by T4 and T3rise

• Important for interpreting newborn screen results

• Lower rise in preterm infants

Cord Blood Thryoid Levels

• Influenced by gestational age

• Progressive increase with approach to term

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

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

Thyroid Effects in the Fetus and Neonate

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

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

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

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

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

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

Common Symptoms and Signs of Hypothyroidism in Children

Growth Failure in Childhood Hypothyroidism

Hypothyroidism: Treatment

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

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

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

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

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)

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

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

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

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)

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

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)

Thyroid Cancer in MEN

• Agressiveness: MEN2B>MEN2A>familial MTC

• Prophylactic thryoidectomy– MEN2B <6 months– MEN2A <5 years

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?

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.

Case #1 (continued)

• Synthroid discontinued, TSH repeated 4 weeks later– Normal (4 mcIU/ml)

• Diagnosis?– Transient congenital hypothyroidism

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?

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