Thyroid Disorders

Before the advent of newborn screening, congenital hypothyroidism was the most common cause of preventable developmental delay.

• The most common cause of acquired hypothyroidism is Hashimoto thyroiditis, also known as autoimmune thyroiditis or chronic lymphocytic thyroiditis.

• The most common cause of acquired hyperthyroidism is Graves disease, in which an antibody stimulates the thyroid-stimulating hormone (TSH) receptor, causing autonomous production of thyroid hormone.

In this section we provide an overview of thyroid hormones, thyroid function tests, the thyroid exam, congenital hypothyroidism, acquired hypothyroidism, acquired hyperthyroidism, and thyroid nodules.

Thyroid Hormones

Levothyroxine (T4) is the predominant circulating thyroid hormone and is secreted from the thyroid gland in a 10:1 ratio to triiodothyronine (T3) secretion. T4 has lower affinity than T3 for the thyroid hormone receptor, and most (99.9%) circulates bound to protein (primarily thyroid-binding globulin, transthyretin, and albumin).

Triiodothyronine (T3) in the circulation is mostly from peripheral conversion of T4 via types 1 and 2 deiodinase. It has 10 to 15 times higher affinity for the thyroid hormone receptor than T4.

Reverse T3 is generated via type 3 deiodinase and is inactive.

Key Steps in Thyroid Hormone Synthesis. Monoiodotyrosine and diiodotyrosine are synthesized from the iodination of tyrosyl residues within thyroglobulin. After organification, iodinated donor and acceptor iodotyrosines are fused in the coupling reaction to form either triiodothyronine (T3) or thyroxine (T4), a process that involves only a small fraction of iodotyrosines. Thyroglobulin is then engulfed by thyrocytes through pinocytosis and digested in lysosomes, and T4 and T3 are secreted into the bloodstream. Monoiodotyrosine and diiodotyrosine are deiodinated by iodotyrosine deiodinase, and the released iodide is recycled. (Source: Reduce, Recycle, Reuse — Iodotyrosine Deiodinase in Thyroid Iodide Metabolism. N Engl J Med 2008.)

Thyroid Binding Globulin and Other Carriers of Thyroid Hormone in the Circulation

More than 99% of levothyroxine (T4) and triiodothyronine (T3) in the circulation is bound to proteins, primarily thyroid binding globulin (TBG) and, to a lesser degree, transthyretin (TTR) and albumin. Thyroid hormone bound to TBG, TTR, or albumin is not biologically active, whereas free (unbound) T4 and free T3 are biologically active. Euthyroid individuals with high levels of TBG (see table below) may have elevated total T4 levels with normal free T4 levels, and euthyroid individuals with low levels of TBG may have low total T4 levels with normal free T4 levels.

Thyroid Function Tests

Thyroid function testing generally includes TSH either with free T4 measurement or with “reflex” to free T4 and/or T3, if TSH is abnormal. The rationale for measuring both TSH and free T4 in children, rather than using the reflex assay, is because secondary hypothyroidism (TSH deficiency) may be associated with TSH levels in the “normal” range that are actually inappropriately low in the context of low free T4. Most free T4 assays are immunoassays that indirectly measure free T4 and are unreliable in states of substantially altered thyroid-binding globulin (TBG; see table below). In such cases, measurement of free T4 via equilibrium dialysis, which physically separates free thyroxine from protein-bound thyroxine before measurement, or measurement of total T4 is more appropriate. Measurement of total T3 is appropriate when hyperthyroidism is suspected. Measurement of free T3 is not generally indicated.

Conditions that affect TBG are expected to affect measurements of total T4 and total T3 but not free T4, with the caveat that the free T4 assay is not reliable at extremes of TBG. For example, in women receiving estrogen, TBG is elevated and likely results in elevated total T4 but normal free T4 measurement. Similarly, critical illness decreases TBG, which may result in low total T4 but normal free T4 measurement.

Thyroid Exam

Overall appearance of jitteriness and anxiousness may be indicative of hyperthyroidism, whereas puffiness/edema may indicate hypothyroidism.

Everyone has a preferred style for performing a thyroid exam; it can be achieved from either in front of or behind the patient.

• The thyroid lies caudal to the cricoid cartilage.

• Before feeling the thyroid, have the patient look skyward and swallow. When they swallow, you should see the thyroid gland moving up.

• Palpate both lobes of the thyroid with your fingers in a systematic way to feel for any nodules. Also palpate the “isthmus” between the lobes. A lymph node at the isthmus may be present in Hashimoto disease and is called the Delphian node.

• If a goiter is present, listen over it with your stethoscope to see if you hear a bruit.

• To measure the thyroid, some people use the longest dimension of each lobe (from the upper outer corner to the lower inner corner) measured with a ruler, whereas others estimate volume (15 cc equals one tablespoon). Measuring with length may be more exact, particularly when you are learning.

• Also assess for cervical lymphadenopathy.

Perform a skin exam: Note warmth, moisture, and smoothness/coarseness for clues of hypo- (coarse, cool, dry) vs. hyper- (smooth, warm, moist) thyroid states. Thinning of the outer third of the eyebrows can be a sign of hypothyroidism.

Perform an eye exam: Extraocular movements are used to assess for lid lag (when the upper eyelid does not lower normally with downward gaze). “Thyroid stare” is a startled look from excessive eyelid retraction due to adrenergic stimulus and is characterized by seeing more of the “white” of the eye than normal above and below the pupil. Exophthalmos is an actual protrusion or bulging of the eye. Both of these may be present in hyperthyroidism.

Check deep tendon reflexes: These are brisk in hyperthyroidism, whereas a delayed relaxation phase is characteristic of hypothyroidism. The latter is often easy to see if a child kneels on the exam table and you check the Achilles tendon reflex (the foot will show slow return to neutral position).

Check pulses: Assess for brady- or tachycardia as well as the quality of the pulse, which is often “bounding” in hyperthyroidism. In hyperthyroidism, a flow murmur on auscultation can sometimes be heard.

Assess for tongue fasciculation and tremors: Ask the patient to stick out their tongue to assess for tongue fasciculation and, separately, to hold their hands out in front of them to assess for tremors.

Medications That Affect the Thyroid Gland

• High-dose glucocorticoids, dopamine, dobutamine, opiates, and octreotide decrease TSH secretion.

• Phenobarbital, phenytoin, carbamazepine, oxcarbazapine, and rifampin increase the metabolism of T3 and T4.

• Amiodarone may have various effects on thyroid function, including hypothyroidism and hyperthyroidism.

• Lithium may have various effects on thyroid function, including goiter, hypothyroidism, and less commonly, hyperthyroidism. Thyroid function tests should be monitored regularly in patients on lithium.

• Other medications can affect thyroid function and thyroid assay results. For example, use of high doses of the supplement biotin can interfere with the immunoassays for both TSH and thyroxine. Always check a full list of the patient’s medications and supplements.

Congenital Hypothyroidism

Congenital hypothyroidism occurs in 1:2000 to 1:4000 newborns. The most common cause is dysgenesis of the thyroid gland, leading to athyreosis (no thyroid gland), a hypoplastic gland, and/or an ectopic thyroid (see image below). A less common cause is dyshormonogenesis, in which case the thyroid gland is present but one or more of the genes required for proper synthesis of thyroid hormone is absent.

Screening

Signs of hypothyroidism in the immediate newborn period may be subtle. Many countries include congenital hypothyroidism in the newborn screen to detect the condition as early as possible in an effort to prevent developmental sequelae.

Each state has a different newborn screening protocol, employing one of the following three possible strategies. All strategies have benefits and limitations. Note that the strategy of primary TSH measurement may miss infants with central hypothyroidism.

• Primary T4 measurement with TSH measured only in those samples with T4 below a certain threshold

• Primary TSH measurement with T4 measurements only in those samples with TSH above a certain threshold

• Simultaneous measurement of T4 and TSH

Each newborn screening program has an algorithm for managing abnormal thyroid function. Some important considerations are:

• TSH levels surge right after birth, so TSH should not be measured until 24 or ideally 48 hours after birth.

• In premature infants, the rise in TSH levels is delayed. Therefore, many neonatal intensive care units (ICUs) have protocols to repeat screening in premature infants at 2 and 4 weeks of age in order to detect delayed TSH rise indicating hypothyroidism.

• Abnormal TSH or thyroxine on newborn screen should be confirmed by laboratory testing, but when TSH is above a certain level (typically around 40 µU/mL, although protocols may vary), treatment should not be delayed until the receipt of test results. Rather, levothyroxine should be started at 10 to 15 mcg/kg/day.

• Mild abnormalities in TSH should be followed until normalization. TSH levels are slightly higher in newborns after a few days of life, and age-appropriate laboratory normal ranges should be consulted. For mild persistent TSH elevations, many err on the side of treatment given the excellent safety profile of levothyroxine.

• Thyroid hormone is critical for neurodevelopment, particularly during the first 3 years. Infants with mild congenital hypothyroidism (mildly elevated TSH) may undergo a trial off therapy at age 3 years.

• Practice varies regarding imaging of the thyroid gland in infants with congenital hypothyroidism. Some pediatric endocrinologists order thyroid ultrasound or technetium scans of the thyroid to assess for athyreosis or ectopic thyroid.

Ectopic thyroid glands are usually found at the base of the tongue (referred to as a lingual thyroid) or high in the neck and result from failure of complete migration of the thyroid from the base of the tongue to its position in the neck via the thyroglossal duct during embryogenesis. These are not always apparent in infancy and may present in childhood with hypothyroidism.

Lingual thyroid in a healthy 4-½-year-old girl with decreased growth velocity and high TSH level of 55 µU/mL (normal range, 0.7 to 6.4) and thyroxine level of 3.5 µg/dL (normal range, 6.0 to 14.2). (Source: Lingual Thyroid. N Engl J Med 2008.)

Ectopic thyroid in the thyroglossal tract in a 12-year-old girl with hypothyroidism and receiving levothyroxine. Image on right shows a technetium-99 thyroid scan demonstrating uptake in the area of the mass but not in the region of a normally located thyroid. (Source: Ectopic Thyroid Gland. N Engl J Med 2012.)

Acquired Hypothyroidism

Hypothyroidism is characterized by elevated TSH and low free T4 and/or total T4 levels. The most common cause is Hashimoto thyroiditis, also known as chronic lymphocytic thyroiditis. Subclinical hypothyroidism is characterized by elevated TSH but normal free T4 or total T4 levels. Normal ranges for TSH and thyroxine levels vary somewhat by laboratory, and each lab’s specific ranges should be consulted.

Causes

Acquired hypothyroidism due to Hashimoto thyroiditis: When acquired hypothyroidism is suspected, anti-thyroid peroxidase (anti-TPO) and antithyroglobulin antibody tests are often ordered; positive antibodies confirm a diagnosis of Hashimoto thyroiditis. In subclinical hypothyroidism due to Hashimoto thyroiditis, treatment is generally started when TSH is >10 µU/mL. For mild elevations in TSH (typically <10 µU/mL), treatment can be deferred if the patient wishes. The goiter in acquired hypothyroidism is due to lymphocytic infiltration of the thyroid tissue. Treatment with levothyroxine does not generally change thyroid size.

Hypothyroidism due to pituitary insufficiency (i.e., secondary hypothyroidism): Secondary hypothyroidism is less common than primary hypothyroidism. Isolated secondary hypothyroidism in the absence of known trauma, radiation, or brain lesion is not common, and care should be taken to confirm the diagnosis. In secondary hypothyroidism, dosing must be titrated to the patient’s serum free T4 levels. The usual goal is to maintain free T4 levels in the upper half of the normal range, although decisions are patient-specific and depend on symptoms the patient may be experiencing.

Other causes of hypothyroidism:

• infiltrative diseases (e.g., hemochromatosis)

• cystinosis (may cause primary hypothyroidism)

• trisomy 21 and Williams syndrome (usually associated with subclinical hypothyroidism)

  • infants with trisomy 21 may have mild elevations in TSH

  • older children with trisomy 21 are at high risk for Hashimoto thyroiditis and less commonly, Graves disease

  • individuals with Williams syndrome often have mild subclinical hypothyroidism in the absence of thyroid autoantibodies

Treatment

Acquired hypothyroidism is treated with levothyroxine. Dosing varies by age because infants and children metabolize thyroid hormone more rapidly than adults. Age- and weight-based pediatric dosing of levothyroxine can be found here. Dose is also selected based on severity of hypothyroidism. (For very mild hypothyroidism, a lower dose is prescribed even for a large adult.)

Levothyroxine dose is titrated based on periodic monitoring of TSH and/or free T4 levels. For patients with primary hypothyroidism, the goal TSH level is generally <2.5 µU/mL. For patients with secondary hypothyroidism, the goal is generally to keep free T4 in the upper half of the normal range. Growth parameters and symptoms should also be considered when titrating doses.

Acquired Hyperthyroidism

Hyperthyroidism in children is most often due to Graves disease, in which TSH-receptor antibodies cause excess thyroid hormone production. The differential diagnosis of hyperthyroidism includes hashitoxicosis, subacute thyroiditis, and excess consumption of levothyroxine. In hashitoxicosis, autoimmune destruction of thyroid tissue in individuals with Hashimoto thyroiditis causes dysregulated release of preformed thyroid hormone. Subacute thyroiditis is caused by transient, acute inflammation of the thyroid gland, thought to be triggered by viral infection. Normal ranges for TSH and thyroxine levels vary somewhat by laboratory, and each lab’s specific ranges should be consulted.

Diagnosis

Hyperthyroidism is characterized by suppressed TSH, elevated T4 or free T4, and elevated T3. In Graves disease, elevated total T3 is often the predominant abnormality, necessitating measurement of both free T4 and total T3. Hyperthyroidism due to excess TSH production is rare in children; if TSH and free T4 are high, thyroid hormone resistance should be considered.

Differential diagnosis: Once a diagnosis of hyperthyroidism is established, the next step is to differentiate between Graves disease and hyperthyroidism due to thyroid destruction (hashitoxicosis or subacute thyroiditis).

Clues for differential diagnosis of hyperthyroidism include:

• Bruit heard over the thyroid gland is consistent with Graves disease.

• Thyroid gland that is tender to palpation is most consistent with subacute thyroiditis.

• A large goiter and possibly exophthalmos are usually associated with Graves disease (but goiter and periorbital edema that mimic the appearance of exophthalmos can also occur in patients with Hashimoto disease).

• Other tests to differentiate between Graves and destructive hyperthyroidism include:

  • Thyroid-stimulating immunoglobulins (TSIs) and/or TSH-receptor antibodies (TRAbs): Positive results confirm Graves disease.

  • Technetium uptake scan or iodine uptake scan: High uptake indicates an “overactive” thyroid and is consistent with Graves disease, whereas decreased uptake is consistent with a destructive process.

• If testing is negative for Graves disease:

  • Thyroid peroxidase (TPO) antibodies or thyroglobulin antibodies can help confirm Hashimoto.

  • Tenderness of the thyroid gland on exam followed by return to euthyroid state over time (typically a few weeks to a few months) can help confirm subacute thyroiditis.

• Patients with Graves often also have positive TPO and thyroglobulin antibodies, so positivity of these antibodies alone, without a confirmatory uptake scan or negative TSIs or TRAbs, does not help differentiate Graves disease from hashitoxicosis.

Management

Patients with tachycardia and/or hypertension should be treated with beta-blockers, typically propranolol or atenolol. Beta-blockers can be used regardless of etiology and are useful for symptom relief. Patients who are highly symptomatic and have very high T4 or T3 are at risk of thyroid storm and should be evaluated in an emergency department.

Treatment for Graves disease is usually with methimazole. Propylthiouracil is no longer used in children due to liver toxicity. Methimazole is generally well tolerated but is associated with risk of liver toxicity, aplastic anemia, and lupus-like syndrome. If successful in controlling hyperthyroidism, methimazole is generally continued for 1 to 2 years, followed by attempted weaning to see if the condition remits. Children with conditions that do not remit may remain on long-term methimazole or opt for either thyroidectomy or radioactive iodine therapy.

Thyroid Nodules

Thyroid nodules in children are more likely to be malignant than in adults. Therefore, children with thyroid nodules >1 cm should be referred for fine-needle aspiration. Nodules that measure <1 cm and do not have suspicious features such as calcifications on ultrasound may be followed with serial ultrasound.