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

The Hypothalamic-Pituitary-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 andHormone 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

Development of thyroid gland

Median anlagen derived from primitive pharyngeal floor and paired lateral anlagen from fourth pharyngobronchial pouch. Visible by D16-17. D50 median and lateral anlagen fuse, buccal stalk ruptures and thyroid gland in anatomical location D70 onwards is functional At 20 weeks the hypothalamus releases TRH stimulating TSH, resulting in increased levels of T3 and T4 Completely independent of mothers pituitarythyroid axis

Congenital Hypothyroidism

Congenital hypothyroidism

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 of congenital hypothyroidism

Prevalence of thyroid disorders

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 (most common cause worldwide) Maternal Antibodies If baby receives maternal TSH receptor blocking antibodies this can last for a few weeks. Maternal or neonatal drug exposure

Excess iodine can result in decreased thyroid hormone synthesis, this is known as the Wolff-Chaikoff effect Other drugs associated with transient hypothyroidism (corticosteroids and dopamine). The duration depends on the half life of these drugs.

Dyshormonogenesis (usually leads to permanent congenital hypothyroidism)

Signs and symptoms in NB period

Prolonged jaundice (31%) Umbilical hernia (23%) Constipation (21%) Macroglossia (21%) Poor feeding and weight gain (19%) Hypotonia (16%) Hoarse cry (16%) Large fontanelles (13%) Mottled, cool, and dry skin (10%) Hypothermia (5%) Goiter (2%) Delayed bone age (40%) Poor growth Developmental delay Coarse facial features good babies because they rarely cry and sleep most of the time.

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)

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

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 Confirmed Positives 2004 = 209 N = 80,987 births Normal Values: <24hrs old=Inconclusive 1-7 Days old Normal = <33U/ml Borderline = 33-55U/ml Positive = >55U/ml 8 days-6months old Normal = <13U/ml Positive = >13U/ml

NB Screening for CH
Pitfalls: Early samples inconclusive due to TSH surge at birth. Only TSH in Tennessee: screening identifies primary CH. Some (VLBW) infants with CH display delayed TSH rise

Other states employ a two-tiered screening approach (TN prior to 1996): The first measurement made on infants blood is of T4; only the infants whose T4 levels are in the lowest 10% are selected to have TSH measurements made on the same sample Advantage: identifies more children with secondary hypothyroidism (low T4, but normal TSH), while it also will pick up individuals with other conditions that result in low T4, but arent necessarily pathologic, such as prematurity or deficiencies of thyroxine binding globulin (TBG) In favor of primary TSH screening is its lower cost and the better reproducibility of TSH measurements on filter paper blood samples

NB Screening for CH
Primary Care Provider Responsibilities for Follow-up

A. Specimens Within Normal Limits (WNL)Reports of normal specimens are mailed within 7 working days from receipt of specimen to provider listed and hospital of collection. No follow-up from the provider is needed, although providers are responsible for making sure their patient has had a newborn screen , reviewed and interpreted results with respect to blood transfusion and diet status. Provider is also responsible for informing parent/guardian of the results. B. Unsatisfactory SpecimensMedical Technologists closely examine each specimen for quality and quantity before performing tests. When a specimen is identified as unsatisfactory, the lab notifies the provider and hospital of collection by mail the next working day. MCH also notifies the provider and parents by mail, and requests repeat specimen to be obtained. It is the responsibility of the parents and provider once notified to obtain a repeat specimen. Specimens are mailed to the state laboratory; a second unsatisfactory specimen at this point can cause a costly delay in diagnosis and treatment. A description of unsatisfactory specimens is available upon request. C. Process for Presumptive Positive for DiseaseThe laboratory reports a presumptive positive result to MCH as soon as it has been determined, generally within 24-48 hours after the specimen is received. MCH notifies the provider listed on the newborn screening form by telephone and fax to initiate confirmatory testing, follow-up, and treatment of the patient. MCH also notifies the appropriate Endocrinologist, Genetic or Sickle Cell Center. Results will be mailed to provider and hospital of collection when other tests are completed, within 7 days from receipt of specimen. Remember, this is a screening program and further testing will need to be performed prior to diagnosis and treatment. D. 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.

NB Screening for CH

After a child has been identified to the PCP as having a positive result in the screen, the next step is to obtain a confirmatory blood sample for (free)T4 and TSH by venipuncture. Other blood measurements may be warranted Diagnosis of primary congenital hypothyroidism is based on an elevated TSH and usually, but not always, a low T4. Normal T4 values for infants in the first weeks of life are substantially higher than for the normal adult population and for older children. Once the diagnosis is established, the PCP or endocrinologist may then embark on studies to determine the form of hypothyroidism:

1) radionuclide scans (123I or 99Tc) and ultrasound 2) skeletal radiographs (bone age) 3) blood measurements of TSH blocking immunoglobulins (

NB Screening for CH

Given the implications of hypothyroidism on the neurological and intellectual development of the child, it is important to treat such children with thyroxine until they reach three (3) years of age when the effects of thyroid hormone deprivation on the central nervous system are much reduced. 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 50 mcg daily for two weeks, then 10mcg/kg/day 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

Precautions:

Monitoring treatment

Symptoms Growth, especially length/height Dentition Milestones TSH and free T4 measurements in primary and free T4 in secondary hypothyroidism 4-6 weeks after introduction of treatment or change in dose Monitor child every 2-3 months during first 2 years of life Excess treatment : Diarrhea, loss of weight, sleep disturbances, craniosynostosis

OVERVIEW OF THYROID DISORDERS IN CHILDREN

Marielisa Rincon, MD

Acquired Juvenile Hypothyroidism

Symptoms

Signs

Weakness Lethargy Decreased appetite Cold intolerance Constipation Weight gain

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

OK135S058

Causes of Acquired Hypothyroidism

Autoimmune 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, PAS etc PCBs, PBBs

Endemic goiter (iodine deficiency) Thyroid ectopia Thyroid hormone dyshormonogenesis Secondary to irradiation or surgical excision of the thyroid gland

Acquired Juvenile Hypothyroidism

Hashimotos thyroiditis:

Most common cause of hypothyroidism 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, Loss of weight, Sleep disturbances

Differential diagnosis

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

Free T4

TSH

Antibodies + +
+ in mom and baby

Diagnosis
Hypothyroidism, congenital
Sick thyroid syndrome Secondary hypothyroidism

Acquired hypothyroidism Graves disease Neonatal Graves disease Subacute thyroiditis

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

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, weight loss and tachycardia Elevated free T4 and low TSH Thyroid stimulating immunoglobulins Radioactive iodide uptake scan

Eye signs in Graves disease

Palpebral edema Widening of palpebral fissures Unilateral lid retraction Palpebral swelling Conjunctival injection and chemosis Failure of eye closure, corneal scarring

Pathogenesis of Graves' Disease

Weetman, A. P. N Engl J Med 2000;343:1236-1248

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: PTU or Methimazole Usually need treatment for 4-6 months

Hashitoxicosis

5-10% of patients with Autoimmune thyroiditis have hyperthyroid symptoms 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 Gland enlarged, firm, bosselated, NOT painful Spontaneous remission in 30% Associated with other autoimmune disorders

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 Beta blockers, aspirin or glucocorticoids Antithyroid drugs DO NOT WORK

Treatment:

McCune Albright Syndrome

Polyostotic fibrous dysplasia Cafe-au-lait skin lesions Endocrinopathies: precocious puberty, hyperthyroidism, growth hormone excess, hyperprolactemia, and hypercortisolism

Treatment options

Antithyroid agents

Propyl thiouracil (PTU) 5-10 mg/Kg div TID 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

Effects of Antithyroid Drugs

Cooper, D. S. N Engl J Med 2005;352:905-917

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

TFT interpretation and Questions

Free T4

TSH

Antibodies + +
+ in mom and baby

Diagnosis
Hypothyroidism, congenital
Sick thyroid syndrome Secondary hypothyroidism

Acquired hypothyroidism Graves disease Neonatal Graves disease Subacute thyroiditis