OVERVIEW OF THYROID DISORDERS IN CHILDREN

Marielisa Rincon, MD

Learning Objectives

Review of anatomy, embryology and physiology of the hypothalamic-pituitarythyroid axis Recognize, evaluate and initiate treatment of the following conditions:

Congenital hypothyroidism Acquired hypothyroidism Hyperthyroidism Thyroid nodules

Embriology

Derived from primitive pharyngeal floor and paired lateral anlagen from fourth pharyngobronchial pouch At 20 weeks the hypothalamus releases TRH stimulating TSH, resulting in increased levels of T3 and T4 (independent of mothers H-P-T axis)

The H-P-Thyroid Axis and Extrathyroidal Pathways of Thyroid Hormone Metabolism

Surks, M. I. et al. N Engl J Med 1995;333:1688-1694

Thyroid Hormone Transport in Serum and Hormone Action

Surks, M. I. et al. N Engl J Med 1995;333:1688-1694

Effects of thyroid hormones

CNS: migration, maturation and myelinization Growth: Growth factors

Thermogenic effects
Metabolic effects include potentiation of hormone synthesis, glucose transport and stimulation of adrenergic receptor binding

Conditions that alter T4 requirements

Growth, puberty, pregnancy GI disorders, including bypass surgeries Drugs that interfere with absorption

Bran Cholestyramine Ferrous sulfate Aluminum hydroxide Lovastatin Rifampicin, Carbamazepine, phenytoin Amiodarone

Drugs that increase clearance

Drugs blocking conversion of T4 to T3

Congenital Hypothyroidism

Incidence

Incidence: 1: 3000-4000 Affects 1/7,700 boys and 1/4,000 girls Higher incidence in Middle East and Mexico: 1:1400-1:2000

Rare in African American: 1: 3200 Children with Downs Syndrome have a 35 fold increased risk

Prevalence by etiology

Thyroid dysgenesis (aplasia, hypoplasia or

ectopy): 1:4000 (75%)

Thyroid dyshormonogenesis: 1: 40,000 (10%)

Hypothalamic-pituitary hypothyroidism:
1:100,000 (5%)

Transient hypothyroidism: 1:40,000 (10%)

Transient causes

Iodine deficiency Maternal blocking antibodies Maternal or neonatal drug exposure

Excess iodine (Wolff-Chaikoff effect) Other drugs (corticosteroids and dopamine)

Dyshormonogenesis

Clinical findings

Macroglossia Large fontanelles Goiter Delayed bone age Poor growth Developmental delay Coarse facial features good babies because they rarely cry and sleep most of the time
Medscape

Clinical findings

Prolonged jaundice Umbilical hernia Constipation Poor feeding and weight gain Hypotonia Hoarse cry Mottled, cool, and dry skin Hypothermia
Medscape

Why dont all infants with hypothyroidism demonstrate these features?

Although the placenta is impermeable to TSH, small amounts of maternal T3 and T4 can pass to fetus A compensatory increase in maternal thyroid hormone transfer and increase in deiodinase activity can protect the fetus

Associated conditions

Cardiac conditions including sick sinus syndrome, PDA, ASD, PS, and TA have been associated in 12% of kids with congenital hypothyroidism. CH due to impaired hormone synthesis could be associated with deafness (Pendred syndrome)

NB Screening for CH

Added in 1980 in Tennessee Goals: To identify all infants with primary CH and initiate therapy by day 14 of life Normal Values: <24hrs old=Inconclusive 1-7 Days old

Normal = <33U/ml Borderline = 33-55U/ml Positive = >55U/ml Normal = <13U/ml Positive = >13U/ml

8 days-6 months old

NB Screening for CH
Pitfalls:

Early samples inconclusive due to TSH surge at birth Only TSH in Tennessee: screening identifies primary CH Does not identify children with secondary hypothyroidism (low T4, normal TSH) Some (VLBW) infants with CH display delayed TSH rise

Primary Care Provider Responsibilities for Follow-up:

Specimens Within Normal Limits (WNL)to inform parent/guardian of the results Unsatisfactory Specimensto repeat specimen Process for Presumptive Positive for Diseaseto obtain further testing

confirmatory blood sample for (free)T4 and TSH by venipuncture

ExceptionsWhen MCH and/or the physician are unable to contact/locate an infant for repeat testing due to unsatisfactory or abnormal results, the local health department will be contacted to assist in locating the infant

Implications for treatment

Children with positive screening and borderline levels of TSH and free T4 should be treated until 3 years of age At that time, thyroid hormone replacement can be discontinued and additional diagnostic studies performed It is essential that any infant or child who manifests symptoms consistent with hypothyroidism be retested by the PCP regardless of the results of the newborn screen

Treatment

L-thyroxin (Synthroid):

10-15 mcg/kg/day; or 50 mcg daily for two weeks, then 10mcg/kg/day

Precautions:

Never mix with milk or juice in the bottle Tablets have better bioavailability (do not prescribe compounds) Soy can interfere with absorption Any time of day, though some people prefer mornings

Before and after treatment

Medscape

Before and after treatment

Medscape

Monitoring treatment

Signs and symptoms

Growth, especially length/height Dentition Excess treatment : Diarrhea, weight loss , sleep disturbances, craniosynostosis

Developmental milestones Laboratory test:

TSH and free T4 in primary hypothyroidism free T4 in secondary hypothyroidism Do levels 4-6 weeks after introduction of treatment or change in dose

Monitor child every 2-3 months during first 2 years of life

The incidence of congenital hypothyroidism in otherwise normal newborns is closest to: a) 1 in 10,000 b) 1 in 100,000 c) 1 in 4,000 d) 1 in 400 e) 1 in 1,000,000

Acquired Juvenile Hypothyroidism

Symptoms

Signs

Weakness Lethargy Decreased appetite Cold intolerance Constipation Weight gain

Growth failure Goiter Delayed dentition Delayed or precocious puberty Galactorrhea Carotenemia Pale, dry skin

Causes

Autoimmune or Hashimotos thyroiditis Exposure to Goitrogenic agents

Goitrin in cabbage family of vegetables Linamarin in cassava Soybeans Metals such as cobalt, arsenic, lithium Drugs such as amiodarone

Endemic goiter (iodine deficiency) Thyroid ectopia

Thyroid hormone dyshormonogenesis

Secondary to irradiation or surgical excision of the thyroid gland

Hashimotos thyroiditis

Most common cause over 6 years of age Histological changes; lymphocytic infiltration, formation of lymphoid follicles and follicular cell hyperplasia Positive antibody formation against thyroid peroxidase, thyroglobulin Family history in 30-40% Onset insidious Most have euthyroid goiter or hypothyroid, but 5-10% have hyperthyroid symptoms Gland enlarged, firm, bosselated, NOT painful Spontaneous remission in 30% Yearly incidence of hypothyroidism is 5-7% Associated with other autoimmune disorders

Evaluation

HPI, PE and Laboratory data:

Free T4 TSH Microsomal antibodies (not needed for treatment)

Treatment

L-thyroxine

1-3 mcg/Kg/day (depending on age group) Usually starting at 25-50 mcg/day

Monitor TSH level every 4-6 weeks after dose start up or changes Increase L-thyroxine by 12.5 mcg increments until TSH is normal Monitor TSH every 6 months Excess treatment: Diarrhea, weight loss, sleep disturbances

Euthyroid Sick syndrome

Present during acute or chronic severe illness, surgery, trauma or malnutrition Secondary to decrease activity of 5-deiodinase enzyme, so there is accumulation of reverse T3 and decreased T3 There is poor response of TSH to low T4 and T3 Biochemical evaluation:

T4: low T3: low rT3: High TSH: Normal

www.shevet.org

In a 12 year old boy with hypothyroidism, the best indicator of treatment outcome is:
a) T3 b) Total T4 c) Free T4 d) TSH e) Microsomal antibodies

Hyperthyroidism

Signs and symptoms of hyperthyroidism

Nervousness Increased sweating Heat intolerance Palpitations Fatigue Weight loss Tachycardia Goiter Increased pulse pressure

Dyspnea Weakness Increased appetite Eye complaints

Proptosis

Swelling of legs Diarrhea Tremors

N Engl J Med 2011; 364:1955

N Engl J Med 2010; 362:e60

Causes of hyperthyroidism

Excess production of T4

Graves disease Toxic adenoma McCune-Albright Syndrome TSH-producing pituitary tumor Pituitary resistance to thyroid hormone Subacute thyroiditis Hashitoxicosis Iodine-induced hyperthyroidism

Excess release of T4

Excess T4 intake

Evaluation of hyperthyroidism

Graves can be clinically diagnosed in the presence of eye involvement, goiter, and tachycardia Elevated free T4 and low TSH Thyroid stimulating immunoglobulins Radioactive iodide uptake scan

Graves disease

Most common cause Graves can be clinically diagnosed in the presence of eye involvement, goiter, and tachycardia TSH receptors activating antibodies

Neonatal Graves Disease

Due to maternal transfer of stimulating autoantibodies Elevated free T4 and low TSH Signs and Symptoms:

Premature birth, LBW Goiter Irritability Fever, flushing Tachycardia, heart failure Proptosis, lid retraction Poor weight gain or weight loss Diarrhea

Treatment: Methimazole for 4-6 months

Hashitoxicosis

5-10% of patients with Autoimmune thyroiditis have hyperthyroid symptoms Released of preformed hormone

Subacute Thyroiditis

Etiology: Postviral syndrome Physical exam: Painful swelling of thyroid Hyperthyroidism Laboratory data: High T4, low TSH, high ESR, absent TSI Low radioactive uptake scan Treatment: Beta blockers, aspirin or glucocorticoids Antithyroid drugs DO NOT WORK

McCune Albright Syndrome

Caused by a de novo mutation in the GNAS gene early in development (mosaicism) Polyostotic fibrous dysplasia Cafe-au-lait skin lesions Endocrinopathies: precocious puberty, hyperthyroidism, growth hormone excess, hyperprolactemia, and hypercortisolism

Treatment options

Antithyroid agents

Propylthiouracil (PTU) only for thyroid storm Methimazole 0.5-1 mg/Kg QD-TID Both have side effects: (5%) rash, nausea, headache, pruritus, alopecia, arthralgia/arthritis, agranulocytosis, hepatic toxicity, lupus-like syndrome, myalgia, etc. 45-50% of Graves patients will enter remission within 3 years

I131 radioactive ablation Thyroidectomy

Thyroid storm or crisis

Rare potentially life-threatening complication of hyperthyroidism Characterized by:

Fever(often above 40C/104F) Tachycardia +/- arrythmias +/- Heart failure Vomiting, diarrhea Agitation Death

Most episodes occur during interrupted treatment or intercurrent illness Treatment: in ICU

Iodide (Lugol's ) PTU Betablockers Acetaminophen Corticosteroids Other support measurements

Rounds.com

Thyroid Nodule

Thyroid Nodules

Uncommon in children Risk for malignancy in a solitary thyroid nodule is about 33% (1/3) in children Consider history of MEN2a and MEN2b in the family and previous exposure to radiation to head or neck Images: Scan or US Surgical excision of solid nodules is indicated FNAB: standard of care in adults

NEJM, 2005

Is it a nodule?

Free T4

TSH

Antibodies - or +

Diagnosis
Primary Hypothyroidism
Sick thyroid syndrome, Secondary hypothyroidism

Normal or

+ +
+ in mom and baby

Acquired hypothyroidism (Hashimotos) Hyperthyroidism, Graves disease

Neonatal Graves disease Subacute thyroiditis