Pediatric Hyperthyroidism 

Updated: Nov 03, 2015
Author: Sunil Kumar Sinha, MD; Chief Editor: Stephen Kemp, MD, PhD 

Overview

Background

To discuss hyperthyroidism, particularly pediatric hyperthyroidism, begin by defining terms. Although "hyperthyroidism" and "thyrotoxicosis" are often used synonymously, these terms actually refer to distinct conditions that should be differentiated.

Hyperthyroidism refers to overactivity of the thyroid gland, which leads to excessive release of thyroid hormones and consequently accelerated metabolism in the peripheral tissues. Thyrotoxicosis, however, refers to the clinical effects of unbound thyroid hormones, whether or not the thyroid gland is the primary source.

Hyperthyroidism is a relatively rare condition in children. The vast majority of cases are caused by Graves disease. Numerous therapeutic options are available, so most patients do well. The risk of relapse or subsequent hypothyroidism is substantially higher in adults than in children and adolescents. In atypical cases, a small number of patients may have hyperthyroidism due to other causes (see Etiology).

The following image depicts the hypothalamic-pituitary-thyroid negative/positive feedback system.

Schematic representation of the negative/positive Schematic representation of the negative/positive feedback system with respect to the hypothalamic-pituitary-thyroid axis. TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.

See also Pediatric Graves Disease; Hyperthyroidism; Hyperthyroidism, Thyroid Storm, and Graves Disease in Emergency Medicine; Pediatric Hypothyroidism; Graves Disease; Orbital Decompression for Graves Disease; and Thyroid-Associated Orbitopathy.

Pathophysiology

Understanding the normal physiology of the thyroid gland is necessary to understand the pathophysiology of hyperthyroidism. Secretion of thyroid hormone is controlled by the interaction of stimulatory and inhibitory factors. The thyroid, like other endocrine glands, is controlled by a complex feedback mechanism (see the image below).

Schematic representation of the negative/positive Schematic representation of the negative/positive feedback system with respect to the hypothalamic-pituitary-thyroid axis. TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.

The release of thyrotropin, or thyroid-stimulating hormone (TSH), from the anterior pituitary gland is stimulated by low circulating levels of thyroid hormones (negative feedback) and is under the influence of thyrotropin-releasing hormone (TRH), somatostatin, or dopamine. Thyrotropin then binds to TSH receptors on the thyroid gland, setting off a cascade of events within the thyroid gland, leading to the release of the thyroid hormones, primarily thyroxine (T4) and, to a lesser degree, triiodothyronine (T3). Elevated levels of these hormones, in turn, act on the hypothalamus and anterior pituitary gland, decreasing synthesis of TSH. Under physiologic conditions, the levels of circulating free thyroid hormones are tightly regulated.

The TSH receptor belongs to one of the families of proteins known as G-protein–coupled receptors. The TSH receptor is a large protein embedded in the cell membrane. It contains an extracellular domain (that binds) TSH and an intracellular domain that acts via a G-protein second messenger system to activate thyroid adenyl cyclase, yielding cyclic adenosine monophosphate (cAMP). Effects of TSH are largely mediated through this second messenger system.

Synthesis of thyroid hormone depends on an adequate supply of iodine. Dietary inorganic iodide is transported into the gland by an iodide transporter (iodide pump on the surface of thyroid follicular cells). Iodide is then converted to iodine and bound to tyrosine residues on thyroglobulin by the enzyme thyroid peroxidase via a process called organification. The result is the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT). Coupling of MIT and DIT results in the formation of T3 and T4, which are then stored with thyroglobulin in the extracellular colloid of the thyroid’s follicular lumen. The thyroid contains a large supply of its preformed hormones.

To release thyroid hormones, thyroglobulin is first endocytosed into the follicular cell and then degraded by lysosomal enzymes. Stored T4, and T3 to a lesser degree, then diffuse into the peripheral circulation. Most T4 and T3 in the peripheral circulation are bound to plasma proteins and are inactive. Only 0.02% of T4 and 0.3% of T3 molecules are free (unbound to other proteins). T4 can be monodeiodinated to form either T3 or reverse T3 (rT3), but only free T3 is metabolically active. T3 acts by binding to nuclear receptors (DNA-binding proteins in cell nuclei), regulating the transcription of various cellular proteins.

Any process that causes an increase in the peripheral circulation of unbound thyroid hormone can cause signs and symptoms of hyperthyroidism. Disturbances of the normal homeostatic mechanism can occur at the level of the pituitary gland, the thyroid gland, or in the periphery. Regardless of etiology (see Etiology), the result is an increase in transcription in cellular proteins causing an increase in the basal metabolic rate. In many ways, signs and symptoms of hyperthyroidism resemble a state of catecholamine excess, and adrenergic blockade can improve these symptoms.

Etiology

Hyperthyroidism (thyroid causes of thyrotoxicosis) in childhood include the following:

  • Graves disease

  • Toxic adenoma, toxic nodular goiter

  • McCune-Albright syndrome

  • Subacute (viral) thyroiditis

  • Chronic lymphocytic thyroiditis (ie, hashitoxicosis in its early stage)

  • Bacterial thyroiditis

Pituitary causes of thyrotoxicosis in childhood include pituitary adenoma and pituitary resistance to T4. Other causes of thyrotoxicosis in childhood include the following:

  • Exogenous thyroid hormone

  • Iodine-induced hyperthyroidism (ie, Jod-Basedow phenomenon)

  • Human chorionic gonadotropin (hCG)–secreting tumors

Thyroid causes of thyrotoxicosis

Childhood Graves disease

Classic Graves disease includes the triad of hyperthyroidism, ophthalmopathy, and dermopathy. Dermopathy is characterized by localized myxedema and is extremely unusual in children. Graves disease accounts for the majority of cases of hyperthyroidism in children and adolescents.

Hyperthyroidism in Graves disease is caused by thyroid-stimulating immunoglobulins (TSIs) of the immunoglobulin G1 (IgG1) subclass. These antibodies bind to the extracellular domain of the thyroid-stimulating hormone (TSH) receptor and activate it, causing follicular growth and activation and release of thyroid hormones. Patients may have a number of other antithyroid antibodies, some of which are also thyroid receptor antibodies (TRAbs) but which may not activate the receptor. Interplay between these various antibodies likely determines the course and severity of disease.

Initial stimulus for the formation of TSI is not known. Some microorganisms, such as Yersinia species, have proteins that bind TSH. Infection with these organisms possibly induces antibodies that cross-react with the TSH receptor. Some clinical evidence supports this hypothesis. Other evidence suggests that viral infection of the thyroid may be involved. Viruses may induce expression of major histocompatibility (MHC) class II antigens on the surface of thyroid follicular cells, leading to an immune response and autoantibody formation.

Ophthalmopathy of Graves disease is multifactorial. Some symptoms, such as lid lag and lid retraction, are caused by sympathomimetic effects of the thyrotoxicosis and resolve when the patient becomes euthyroid. Other symptoms may be a result of an autoimmune reaction against the muscles or fibroblasts of the orbit. These symptoms may not resolve with correction of the thyroid dysfunction. Theoretically, a shared antigen or antigens between the thyroid gland and the contents of the orbit may be present.

Neonatal Graves disease

Graves disease in neonates accounts for fewer than 1% of all cases of hyperthyroidism in pediatric patients. The frequency of neonatal Graves disease is equal in males and females, reflecting the underlying pathophysiology. Pathogenesis and course of the disorder in this age group are unique. Virtually all patients have a maternal history of Graves disease, either during the pregnancy or at some time in the past.

Neonatal Graves disease is caused by the transplacental passage of TSI. The mother may have clinical hyperthyroidism, may be on antithyroid medication, or may have a history of radioablation or thyroid surgery. Rarely, the mother has a history of chronic lymphocytic (Hashimoto) thyroiditis. Maternal elevation of TSI titers is a consistent finding in these cases.

Neonatal Graves disease is rare even among mothers with known hyperthyroidism. Only 1 in 70 infants of thyrotoxic mothers has clinical symptoms. A maternal TSI level must be very high (>5 times normal) to produce clinical disease in the neonate.

Because neonatal Graves disease is caused by maternal IgG antibodies, it is self-limited and resolves when the child is aged 3-4 months. Symptoms of hyperthyroidism rarely persist longer. More persistent hyperthyroidism in neonates is likely to reflect a different pathogenesis, such as an activating mutation of the TSH receptor.

Prenatally, the thyroid gland is fully responsive at 28 weeks' gestation. These babies can be treated with methimazole, which is given to the mother. Methimazole may be preferable to propylthiouracil (PTU), because methimzaole binds less to plasma proteins and therefore crosses the placenta more easily. However, the risk of cutis aplasia may be increased in infants born to mothers who have taken methimazole during pregnancy. PTU is associated with a higher incidence of idiopathic liver failure.

If the mother is taking antithyroid drugs, infants are usually born asymptomatic. Signs and symptoms may become manifest when antithyroid medications that have crossed the placenta are cleared from the infant's bloodstream. Signs are similar to those in older children with thyrotoxicosis, such as tachycardia, wide pulse pressure, irritability, tremor, and hyperphagia with poor weight gain. The baby may have exophthalmos and goiter.

Neonates have a much higher risk of morbidity and mortality from cardiac disease. In severe cases, congestive heart failure (CHF) can be observed. In addition, the goiter can occasionally be large enough to cause airway compression.

Long-term effects can include craniosynostosis and developmental delay. This latter finding occurs even in the face of early diagnosis and treatment, which suggests that prenatal exposure to high levels of thyroid hormone may have early effects that cannot be overcome after birth.

Toxic adenomas, toxic nodular goiter, carcinomas

Isolated toxic adenoma (Plummer disease) and toxic nodular goiter of adulthood are rare in children. Although follicular or papillary carcinomas can appear as a thyroid mass, they are virtually always nonfunctioning and therefore rarely cause hyperthyroidism.

McCune-Albright syndrome

Hyperthyroidism associated with McCune-Albright syndrome is rare. This syndrome includes polyostotic fibrous dysplasia, café-au-lait spots, or other endocrinopathies. The most common endocrinopathy is precocious puberty, but hyperthyroidism also can be observed.

In addition to other signs and symptoms of hyperthyroidism, patients initially present with a diffuse goiter. The goiter may become a multinodular goiter over time.

Hyperthyroidism in McCune-Albright syndrome is due to a mutation in the α subunit of the G regulatory protein that links the TSH receptor with adenylate cyclase. This mutation results in constitutive activation of the protein and production of cAMP, bypassing the normal requirement for TSH activation of the receptor. Biopsies revealed some tissue with the normal protein and other tissue with the mutated protein, suggesting that the mutation may occur postfertilization and providing an explanation for its heterogeneous expression.

Unlike the hyperthyroidism of Graves disease, McCune-Albright syndrome does not spontaneously remit. Treatment with antithyroid medications provides only temporary benefit. Therefore, the treatment of choice is surgical resection (thyroidectomy) or radioactive iodine ablation. Injection of ethanol into toxic nodules under ultrasonographic guidance has been used with some success in adults.

Subacute thyroiditis

Subacute thyroiditis is generally associated with a viral upper respiratory infection. Signs and symptoms of hyperthyroidism are mild and generally overshadowed by fever and thyroid tenderness. The area surrounding the thyroid may be erythematous and warm, and the gland is always tender to touch.

Hyperthyroidism in these patients is caused by inflammation of the thyroid gland and subsequent release of preformed thyroid hormone. Laboratory studies reveal elevated thyroid hormones and decreased TSH. Unlike iodine 1 123 (123 I) or technetium TC 99m (99m Tc) radionuclide scans in patients with Graves disease, radionuclide scans in patients with subacute thyroiditis show decreased uptake by the thyroid gland. Once the inflammation resolves, thyroid-related symptoms resolve.

Because antithyroid medications do not prevent the release of preformed thyroid hormones, these agents are not useful.

Cardiac symptoms can be alleviated with propranolol. Anti-inflammatory medications, such as aspirin and corticosteroids, offer symptomatic relief.

Chronic lymphocytic thyroiditis

Like Graves disease, chronic lymphocytic (ie, Hashimoto) thyroiditis is an autoimmune disorder. However, in patients with chronic lymphocytic thyroiditis, antithyroglobulin and antithyroid peroxidase antibodies predominate. If present, TSI titers are low.

The hyperthyroid phase of chronic lymphocytic thyroiditis (hashitoxicosis) is self-limited and responds to antithyroid therapy. Antithyroid T lymphocytes and antibodies cause destruction of thyroid follicular cells, and hypothyroidism occurs over time.

The duration of the hyperthyroid phase of Hashimoto thyroiditis may be as long as 6 months.

One study found that 11.5% of patients with Hashimoto thyroiditis presented with hyperthyroidism.

Pituitary causes of thyrotoxicosis

Pituitary adenoma

Clinical hyperthyroidism and elevated or normal TSH levels in the face of high T 3 and T 4 levels indicate inappropriate secretion by the pituitary gland. This constellation of findings can occur in 2 disorders, TSH-secreting pituitary adenoma and pituitary resistance to thyroid hormone.

TSH-secreting pituitary adenomas are extremely rare. These tumors may also secrete growth hormone and prolactin. Magnetic resonance imaging (MRI) may reveal a microadenoma or a macroadenoma. Treatment is transsphenoidal surgical resection. As in other hyperthyroid conditions, correction of the hyperthyroidism is indicated before surgery.

Pituitary resistance to T 4

Pituitary resistance to T 4 is also very rare. It can occur as a spontaneous mutation or can be inherited as an autosomal dominant trait. Because the pituitary gland is not fully inhibited by T 4 , TSH levels are high, and thyroid hormones continue to be secreted. Peripheral tissues respond normally to thyroid hormones, thus symptoms and signs of hyperthyroidism result.

Pituitary resistance to T 4 is in contrast to the syndrome of generalized resistance to thyroid hormone, which includes both peripheral and pituitary resistance to thyroid hormone. Patients with generalized resistance to thyroid hormone are clinically hypothyroid or euthyroid but have high concentrations of T 3 , T 4 , and TSH.

Pituitary resistance to thyroid hormone can be distinguished from adenoma by a TRH stimulation test. Patients with resistance to thyroid hormone have a normal rise in TSH in response to TRH administration. In contrast, patients with adenomas have a high baseline TSH but little or no response to TRH stimulation.

Attention deficit hyperactivity disorder (ADHD) has been associated with the syndrome of pituitary resistance to thyroid hormone.

Patients can be difficult to treat. The pituitary may respond to inhibition with dopamine agonists or T3. Symptomatic therapy with beta-blockers can be helpful. Antithyroid medications reduce symptoms of hyperthyroidism but increase goiter size.

Exogenous thyroid hormone ingestion

Acute or chronic ingestion of thyroid hormone can cause symptoms of hyperthyroidism. If T 4 is ingested, it is converted to T 3 in the periphery and inhibits pituitary release of thyrotropin. Laboratory studies reveal elevated concentrations of T 4 and T 3 and suppressed concentrations of TSH.

Ingestion of T 3 results in similar findings, except T 4 levels are low. In either case, goiter is absent, and radioiodine uptake is low. Treatment is cessation of the medication and symptomatic therapy with beta-blockers.

Iodine-induced hyperthyroidism (ie, Jod-Basedow phenomenon)

Iodine can be found in radiocontrast materials, topical antiseptics such as povidone-iodine, and medications such as amiodarone. Diets very high in iodine may also increase the risk of hyperthyroidism. Ingestion can cause hyperthyroidism, especially in patients with previous hyperthyroidism from Graves disease or toxic nodular goiter.

Laboratory evaluation demonstrates increased levels of plasma thyroglobulin. Discontinuation of the offending agent is the treatment of choice. Symptomatic therapy with an adrenergic beta-blocker can be helpful.

hCG-secreting tumors

Adolescents with hCG-secreting tumors, such as a hydatidiform mole and choriocarcinoma, can present with symptoms of hyperthyroidism. The hCG directly binds to the TSH receptor and stimulates thyroid hormone release.

Epidemiology

Because Graves disease accounts for more than 95% of childhood cases of hyperthyroidism in the United States, the frequency of Graves disease approximates the frequency of all cases of hyperthyroidism. Prevalence of Graves disease is approximately 1 in 10,000 in the pediatric population[1] , accounting for fewer than 5% of the total US cases of Graves disease.

Graves disease is associated with human leukocyte antigen (HLA)-B8 and HLA-DR3 and is more common in some families than in others. Inheritance is polygenic. Monozygotic twins show 50% concordance for the disease, suggesting interplay between environmental and genetic factors.

Associations between Graves disease and other autoimmune diseases are well described and include associations with diabetes mellitus (DM), Addison disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis, vitiligo, immune thrombocytopenic purpura (ITP), and pernicious anemia. Graves disease is more common in patients with trisomy 21 than in patients without trisomy 21.

One study estimated the incidence of hyperthyroidism in the United States in 2008 based on the number of new prescriptions of thionamides by age group and date from the 2008 US Census.[2] The study concluded that the incidence among individuals aged 0-11 years was 0.44 cases per 1000 population and that the incidence among individuals aged 12-17 years was 0.59 cases per 1000 population. Thus, the incidence increases throughout childhood, with a peak incidence in children aged 10-15 years.

Sexual differences in incidence

Although females are affected by Graves disease more often than males, with a reported female-to-male ratio of 3-6:1, the frequency of neonatal Graves disease is equal in males and females.

Other causes of hyperthyroidism have no male or female preponderance. These include the hyperthyroidism of McCune-Albright syndrome, although the variant of this syndrome that includes precocious puberty is more common in girls than in boys.

Prognosis

The vast majority of pediatric patients with hyperthyroidism have an excellent prognosis. Signs of congestive heart failure (CHF) are rare in children. Ophthalmopathy of Graves disease is usually mild but may persist despite resolution of the hyperthyroidism. The European Group on Graves' Orbitopathy released a consensus statement regarding the management of Graves' orbitopathy.[3, 4]

Although the course of neonatal Graves disease is self-limited, the prognosis is considerably worse than that in older children. As a result of their disease, patients are prone to prematurity, airway obstruction, and heart failure. The mortality rate from these conditions has been as high as 16%. Even patients who are successfully treated may develop craniosynostosis and eventual developmental delay.

Complications from hyperthyroidism include the following:

  • Congestive heart failure (CHF)

  • Craniosynostosis (neonates)

  • Developmental delay (neonates)

  • Hypothyroidism

  • Hypercalcemia is occasionally seen in patients with hyperthyroidism.

Remission rates of Graves disease vary from 34-64% in patients taking antithyroid medication. Recurrence can occur months or years after the discontinuation of therapy. Treatment with radioiodine or surgical subthyroidectomy is very effective, but most patients develop hypothyroidism and require lifelong thyroid replacement.

Patient Education

Compliance

Patients who choose treatment with antithyroid medications should understand the importance of compliance. Inadequate compliance can be a problem in these patients. Patients with hyperthyroidism are prone to forgetting their medicine because of short attention span. Some patients skip their medicine as a way of controlling their weight.

Treatment adverse effects

Counsel patients regarding the common and uncommon adverse effects of treatment. At the first sign of a serious adverse effect, such as fever, rash, jaundice, arthritis, or mucocutaneous ulcer, their antithyroid medications should be discontinued; laboratory evaluation may be appropriate.

Patients and their parents should also be warned about excessive weight gain as the hyperthyroidism is corrected. Treatment of hyperthyroidism is associated with excessive weight gain, unless food intake is decreased.

Thyroid storm, thyrotoxicosis, hypothyroidism, and adrenergic agents

Patients with Graves disease and their parents should be also advised to take necessary precautions to avoid trauma to the neck area, as this could precipitate thyroid storm.

All patients monitored for hyperthyroidism should be aware of the signs and symptoms of thyrotoxicosis (should they have a relapse) and the signs and symptoms of hypothyroidism. Symptoms of hypothyroidism include fatigue, cold intolerance, hoarseness, constipation, muscle cramps, menstrual irregularities, and weight gain. Signs of hypothyroidism include dry skin, bradycardia, edema, and delayed relaxation of deep tendon reflexes.

In addition, because thyrotoxic symptoms largely mimic those of adrenergic excess, patients with hyperthyroidism should avoid taking any adrenergic agents. Advise patients not to take over-the-counter (OTC) cold remedies because many contain sympathomimetic agents (eg, pseudoephedrine) and can therefore exacerbate thyrotoxic symptoms.

 

Presentation

History

In children and adolescents, the symptoms of Graves disease, such as hyperthyroidism, may appear insidiously over months. Early diagnosis requires a high degree of suspicion.

The common symptoms of hyperactivity, nervousness, and emotional lability are often attributed to other causes, most frequently attention deficit hyperactivity disorder (ADHD). Alterations in mental status may be seen in almost one half of all patients with thyroid dysfunction.

Deterioration of behavior and school performance in a child who previously did well may be the earliest warning signal.

The combination of thyrotoxicosis and ophthalmopathy makes the diagnosis of Graves disease relatively straightforward. The reported incidence of ophthalmopathy in patients with Graves disease is 50-80%. Eye findings may occur months before or after the initial presentation of thyroid disease.

Other symptoms of Graves disease can include the following:

  • Weight loss (50%) despite excellent appetite (increased appetite in 60%)

  • Sweating (49%)

  • Hyperactivity (44%)

  • Heat intolerance (33%)

  • Palpitations (30%)

  • Fatigue (16%)

  • Diarrhea (13%)

  • Insomnia

  • Deterioration in handwriting

  • Menstrual irregularities

  • Muscle weakness manifested as exercise intolerance or difficulty climbing stairs

  • Eye symptoms, which may include pain or diplopia but are rarely severe in children

Physical Examination

Patients with Graves disease present with diffuse, nontender, symmetric enlargement of the thyroid gland. Goiter is rarely the presenting complaint, but it is invariably present (99%); absence of a goiter makes the diagnosis of Graves disease subject to question.

A thyroid bruit caused by increased blood flow to the thyroid gland is detectable in approximately 53% of patients.

Cardiac examination may reveal tachycardia (82%) and wide pulse pressure (50%) or hypertension. Signs of congestive heart failure (CHF) are rare in pediatric patients with Graves disease beyond the neonatal period.

Patients may have a wide variety of eye findings, including the following:

  • Exophthalmos (proptosis) (66%), occasionally unilateral; however, severe ophthalmopathy is quite rare in children

  • Lid lag, lid retraction

  • Stare

  • Conjunctival injection

  • Chemosis

  • Periorbital edema

  • Ophthalmoplegia

  • Optic atrophy

Other physical findings include the following:

  • Smooth sweaty skin

  • Tremor or muscle fasciculations (61%)

  • Exaggerated deep-tendon reflexes (DTRs)

  • Proximal muscle weakness

  • Systemic hypertension

  • Accelerated growth and early epiphyseal closure (over time)

  • Graves dermopathy, or localized myxedema, which is exceedingly rare in children; if it occurs, it is likely to be noticed in the pretibial area

 

DDx

Diagnostic Considerations

Onset of hyperthyroidism symptoms can be gradual, and patients are often referred for psychiatric or neurologic evaluation before the correct diagnosis is made.

Failure to diagnose hyperthyroidism, particularly in patients with psychiatric disorders, can have serious consequences for both the patients and individuals in their communities.

Thyroid storm is a life-threatening condition characterized by fever, altered mental status, and exaggerated signs and symptoms of hyperthyroidism. It is quite rare in children, especially since the advent of pretreatment for surgery and radiotherapy. Because no specific laboratory findings define this condition, any suspicion that a patient has thyroid storm should result in immediate referral to a pediatric intensive care unit and consultation with a pediatric endocrinologist.

Trauma to the neck area in a patient with Graves disease could precipitate thyroid storm.

Differential Diagnoses

 

Workup

Approach Considerations

Absence of goiter, asymmetric goiter, or atypical laboratory test results should raise the suspicion for other causes of hyperthyroidism besides Graves disease.

Although thyroid is quite rare in children and because no specific laboratory findings define this condition, any suspicion that a patient has life-threatening condition should result in immediate referral to a pediatric intensive care unit and consultation with a pediatric endocrinologist.

Thyroid Function Tests

Hyperthyroidism can be confirmed simply and quickly with measurements of T4, T3, T3 resin uptake (T3RU), and thyroid-stimulating hormone (TSH). Patients with Graves disease have elevated levels of T4, T3, and T3 RU and low or undetectable levels of TSH.

T4 levels

The T4 level measures the total concentration of T4 in serum (ie, free and bound). Patients who are clinically euthyroid but have elevated levels of T4 may have increased plasma proteins, primarily T4 -binding globulin (TBG). Biochemically, these patients can be distinguished easily from truly hyperthyroid patients by measuring either free T4, which is normal, or T3 RU, which is decreased.

Free T4 and T3RU levels

Free T4 can be measured directly by means of immunoassay. Alternatively, T3RU levels can be obtained. T3RU levels correlate inversely with the available binding sites on TBG. Conditions that cause elevated TBG levels (eg, pregnancy) increase the number TBG binding sites for T4 and T3 and decrease the T3 RU level. In contrast, conditions causing hyperthyroidism decrease the number of free TBG binding sites and, therefore, increase T3 RU. The number derived from multiplication of the total T4 and the T3RU, variably called the free T4 index, T7, or T12, has been used as a surrogate for measured free T4.

T3 RU is no longer commonly used and is being replaced by better and more sensitive thyroid hormone testing (such as free T4 by equilibrium dialysis).

TSH and TSI levels

An elevated TSH level in a patient with thyrotoxicosis is extremely unusual and indicates altered regulation at the level of the pituitary gland. Patients may potentially have either a TSH-secreting pituitary adenoma or isolated pituitary resistance to thyroid hormone.

Measurement of TSH receptor–stimulating autoantibodies (ie, thyroid-stimulating immunoglobulins [TSI]) is rarely necessary for diagnosis of Graves disease. TSI titers are high in Graves disease. This test has 95% sensitivity and 96% specificity for Graves disease; however, the test is also labor intensive, expensive, and not widely available. TSI levels are suggested to correlate with remission of Graves disease; however, this has not been confirmed in clinical studies.

Graves disease vs hashitoxicosis

Markedly elevated antithyroglobulin and antithyroid peroxidase antibodies without TSI may help to distinguish the hyperthyroid phase of chronic lymphocytic thyroiditis (hashitoxicosis) from Graves disease.

A more reliable method to distinguish the 2 conditions is a thyroid iodine-123 (123 I) uptake and scan. In Graves disease, the uptake is elevated and diffuse, whereas in Hashimoto thyroiditis, the uptake is generally low and patchy in distribution.

A newer, rapid, fully automated electrochemiluminescent immunoassay reportedly provides the same or better results as existing commercial products for levels of thyrotropin receptor autoantibodies and shortens the measuring time.[5]

Complete Blood Cell Count

Obtaining a complete blood cell (CBC) count before the initiation of antithyroid medications may be valuable for separating patients with underlying leukopenia or thrombocytopenia from patients who develop drug toxicity.

Mild leukopenia can be observed in many patients with Graves disease, whereas agranulocytopenia is a rare side effect of antithyroid medications. Because the onset of agranulocytosis is unpredictable and idiosyncratic, routine blood counts during follow-up do not aid in the treatment of patients with hyperthyroidism. However, if a patient on propylthiouracil (PTU) or methimazole develops fever or ulcerations in the mouth, a prompt CBC count is necessary.

Nuclear Imaging

In general, diagnostic radioiodine I-131 (131 I) uptake is rarely performed. Either technetium 99m (99m Tc) or123 I scan may be useful if the gland does not have a uniform consistency. Functioning nodules trap radioactive iodine and technetium, yielding a hot area of increased uptake on the scintiscan. If the patient is hyperthyroid from such a hot nodule, the remaining thyroid does not take up iodine because of the suppression of thyroid stimulating hormone (TSH) and the absence of thyroid-stimulating immunoglobulins (TSIs).

 

Treatment

Approach Considerations

The treatment administered for pediatric hyperthyroidism depends on the child's age and severity of their disease. Treatment approaches include antithyroid medications, radioiodine ablation, and thyroidectomy[6] ; because each of these treatments has advantages and disadvantages, the therapeutic choice must be individualized.

Once treatment is initiated, careful monitoring is essential because patients are at risk for either recurrent thyrotoxic symptoms or hypothyroidism. Patients who receive inadequate treatment may have bone demineralization and subsequently be at increased risk for osteoporosis and fractures.

Inpatient care is rarely required in children with hyperthyroidism, and serious complications of medical therapy (eg, agranulocytosis, hepatitis, lupuslike syndrome) are quite rare. Nonetheless, patients should be carefully monitored for complications.

Surgical Intervention

Surgery is the oldest treatment for Graves disease and is quite effective.[7] Generally, patients are initially treated with antithyroid medications. Iodide then is added before surgery to decrease the vascularity of the thyroid gland. To minimize risk of recurrence, most of the gland is removed. Consequently, the risk of permanent hypothyroidism is high. Patients may require lifelong T4 replacement.

Surgical complications can include hypoparathyroidism and damage to the recurrent laryngeal nerve. In a recent study, incidental parathyroid excision was reported in 19.4% of pediatric thyroidectomies.[8]  Transient hypocalcemia is another potential complication, even without incidental parathyroid excision. In the hands of an experienced surgeon, these risks are 1-3%. The surgical mortality rate is very low, but referring patients to experienced surgeons who report both their case volumes and complication rates is prudent.

Remission

Remission, which can takes months to years, is defined as persistent euthyroidism after discontinuation of therapy. The reported remission rate with medical therapy is 34-64% within 5 years of diagnosis. In the first 24-48 months of therapy, the remission rate increases with the duration of therapy. After the first few years, however, spontaneous remission is less likely. Patients may have a relapse weeks or years after discontinuation of therapy. Variation in the reported relapse rate is, in part, related to differences in the length of follow-up.

Attempts to define positive prognostic indicators of long-term remission have not been successful thus far.

Long-Term Monitoring

Patients treated medically should have thyroid function tests (T 4 , T 3 , thyroid-stimulating hormone [TSH]) every 2-3 months. TSH levels are suppressed for several months after the initiation of therapy; therefore, T 3 and T 4 levels are better initial chemical markers of the euthyroid state.

Besides thyroid function tests, routine laboratory evaluation is generally not required. Although hepatitis, thrombocytopenia, and agranulocytosis are known side effects of propylthiouracil (PTU) and methimazole, they are rare enough and of such sudden onset that routine laboratory screening is rarely helpful.

Ghrelin and insulinlike growth factor – binding protein-1 (IGFBP-1) levels may have a role in the hunger-satiety signal pathway in patients with Graves thyrotoxicosis. Ghrelin levels in untreated patients are low and increase with medical therapy, whereas fasting IGFBP-1 levels, which are initially elevated, fall.

Glucocorticoid therapy should be considered in patients (both adults and children) with severe ophthalmopathy. Pulse therapy may provide a favorable response in up to 88% of patients.

Patients treated with radioiodine or surgery should have thyroid function tests annually.

Symptomatic Treatment

Self-limited causes of hyperthyroidism, such as subacute thyroiditis, iodine-induced hyperthyroidism, and exogenous administration of T 4 , can be treated symptomatically. For more significant cardiovascular symptoms, beta-adrenergic blockade with propranolol can be helpful.

Initial response to antithyroid medications depends on the level of preformed thyroid hormone. Because antithyroid medications do not block the release of preformed hormone, patients may need 3-12 weeks on therapy before they become clinically and chemically euthyroid. Propranolol can be a useful adjunct during this period. See Antithyroid Agents.

Neonatal Graves disease

To date, no treatments can correct the underlying immune dysfunction in Graves disease. Treatment is directed at correcting the clinical and biochemical abnormalities.

For neonatal Graves disease, various approaches may be used. In mild cases, symptomatic treatment with a beta-blocker (eg, propranolol) may be tried. In some cases, this is adequate, because the disease is usually transient. In more severe cases, antithyroid medications are necessary. In very severe cases, iodides in the form of Lugol iodine solution or saturated solution of potassium iodide (SSKI) are used.

Iodide inhibits the release of preformed T 4 and T 3 from the thyroid gland and therefore has a more rapid onset of action than the thionamides. Glucocorticoids may be necessary in severe cases. These inhibit the peripheral conversion of T 4 to T 3 and protect the infant against adrenal insufficiency, which can occur because T 4 increases the metabolism of cortisol. Note that iodide or thionamide therapy may render the neonate hypothyroid, which is clearly not desirable. Therefore, thyroid function tests must be monitored very closely, and the dose of thionamide reduced or T 4 must be added if the infant becomes hypothyroid. In rare cases of congestive heart failure (CHF), digoxin is a useful adjunct.

Maternal hyperthyroidism and breastfeeding

Medical treatment of maternal hyperthyroidism is not a contraindication to breastfeeding. In this case, the drug of choice is propylthiouracil (PTU), because it is bound mostly to plasma proteins and does not cross the blood-milk barrier to a significant degree.

Antithyroid Agents

Treatment with antithyroid medications is considered to be the treatment of choice in children and adolescents. This treatment is a relatively safe option, provided that patients are willing to participate in prolonged therapy.

In the United States, methimazole is the only antithyroid medication currently used.[9] A third medication, carbimazole, is similar in action to methimazole and is primarily used in Europe and Asia. PTU has been discouraged as routine practice due to its more adverse risk profile. These antithyroid medications belong to the thionamides class and have been used for more than 60 years.

Dosage and administration

Dosage and frequency of administration for these medications have not been well established. The usual pediatric dose of methimazole is 0.4-0.7 mg/kg/d, with a lower maintenance dose (one third to one half the starting dose). Its half-life is 4-6 hours. Pharmacokinetically, it would seem that neither methimazole nor PTU should be effective as once-daily therapy; yet, because the thyroid accumulates these drugs, methimazole given once daily is clinically effective. However, PTU is administered 3 times a day.

Lower per-kilogram doses of methimazole (< 0.5 mg/kg/d) have been shown to prolong the free T4 elevations for almost 3 times as long as the higher per-kilogram doses (> 0.5 mg/kg/d).

Because antithyroid medications affect the thyroid principally at the level of hormone biosynthesis, patients may continue to secrete preformed hormone for 6-12 weeks after initiation of therapy. In patients with marked cardiac manifestations of hyperthyroidism, a beta-blocker (eg, propranolol, 80 mg/m2/d given once in the morning) is added to the regimen until hyperthyroidism is under control.

Titration

The dosage of PTU or methimazole is titrated to maintain free T4 and total T3 concentrations within the normal range. As the disease comes under control and thyroid-stimulating hormone (TSH) levels rise, the dose is decreased and eventually discontinued. An obsolete approach was to give a larger dose of medication to induce hypothyroidism, then to add exogenous T4 to correct the hypothyroidism. Such rest of the thyroid by an addition of T4 appeared to result in a higher rate of remission, although the preponderance of evidence does not support this conclusion. Moreover, this complex approach requires administration of 2 drugs and, because of the higher dose of antithyroid drugs, could increase the risk of adverse effects.

Adverse effects

Adverse effects of these medications are relatively common and may be dose-related. Approximately 1-9% of patients develop a drug-induced rash that resolves with discontinuation of therapy. Drug cross-reactivity between PTU and methimazole may be as high as 50%. Other minor adverse effects include a bitter taste, nausea, and headache. An asymptomatic, mild, transient granulocytopenia is observed in as many as 12% of patients receiving methimazole or PTU. However, these patients can generally continue on the medication, provided that the WBC count is closely monitored.

More severe adverse effects are less common. Arthritis, fever, and mucosal ulcerations are observed in a small number of patients. Other serious adverse effects include agranulocytosis, hepatitis, glomerulonephritis, arthritis, and a lupuslike syndrome. These effects, thought to be idiosyncratic reactions, can occur at any time during the course of therapy. Medication should be stopped immediately. Reactions usually resolve within a few weeks.

Boxed warning for PTU

On April 21, 2010, the US Food and Drug Administration (FDA) added a boxed warning to the prescribing information for PTU that emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients receiving PTU.[10] The boxed warning also states that PTU should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

For more information, see the FDA Safety Alert[10] as well as the Medication section. The FDA recommends the following criteria be considered for prescribing PTU[10] :

  • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole; the dose of PTU is 5-7 mg/kg/d, divided 3 times daily.

  • Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

  • For suspected liver injury, promptly discontinue PTU therapy, and evaluate for evidence of liver injury and provide supportive care.

  • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and no other treatment options are available.

  • Counsel patients to promptly contact their healthcare provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Radioactive Iodine Ablation of the Thyroid Gland

Ablation of the thyroid gland with radioiodine is the treatment of choice for most adults. Pregnancy is the sole contraindication to this therapy. After more than 50 years of widespread use, no evidence of an increased risk of malignancy or genetic damage is noted. Nonetheless, because of the theoretic risk, frequency of radioiodine therapy is much lower in pediatric patients.

131 I is administered orally in 1-2 doses by mouth in a controlled setting (ie, the hospital). Ablation may take about 2-3 months to achieve hypothyroid state, and hyperthyroid symptoms may continue until that time. Propranolol may be used to ameliorate these symptoms.

The major undesirable effect of radioiodine ablation is hypothyroidism. Most patients eventually become hypothyroid regardless of the radiation dose. Patients treated with this method should expect to require lifelong thyroid replacement with T4.

Long-term follow-up (36 y) of over 100 children who were treated with radioactive iodine before age 20 years revealed no increase in the rates of thyroid cancer or birth defects in offspring of these children.[11]

Consultations

Consultations with the following specialists may be necessary:

  • A pediatric endocrinologist should monitor patients with hyperthyroidism

  • Ophthalmologic evaluation is necessary in patients with significant ophthalmopathy

  • A nuclear radiologist should be consulted for radionuclide studies or radioactive iodine therapy

  • Consultation with a competent neck surgeon is required if a subtotal thyroidectomy is contemplated

Activity

Patients with symptomatic hyperthyroidism may present with restlessness or fatigue and decreased exercise tolerance. Generally, these symptoms resolve with therapy. Activity may be guided by tolerance and should be limited until the hyperthyroidism is controlled.

 

Medication

Medication Summary

Overall, treatment with antithyroid medications is a relatively safe option, provided that patients are willing to participate in prolonged therapy. Currently, this is considered to be the treatment of choice in children and adolescents.

The antithyroid medication currently used in the United States is methimazole. Carbimazole is similar in action to methimazole but is primarily used in Europe and Asia. PTU is used in increasingly limited circumstances. All 3 antithyroid medications belong to the class of compounds known as thionamides and have been used for more than 60 years.

These medications inhibit thyroid hormone biosynthesis by decreasing the oxidation of iodide and iodination of tyrosine. In addition, PTU diminishes the peripheral conversion of T4 into T3. Some evidence suggests that antithyroid drugs modify the immune response and decrease circulating levels of thyroid autoantibodies; however, whether this is a direct effect of these medications or simply a fortuitous side effect of the reduction of circulating thyroid hormone levels is unclear.

Dosage and administration

Dosage and frequency of administration for these medications have not been well established. The initial pediatric dose of methimazole is administered at 0.4-0.7 mg/kg/d. Its half-life is 4-6 hours. The usual pediatric dose of PTU is 5-7 mg/kg/d; its serum half-life is 75 minutes. Pharmacokinetically, it would seem that neither of these should be effective as once-daily therapy; yet, because the thyroid accumulates the drugs, methimazole given once daily is clinically effective. However, PTU should be administered 3 times a day.

Lower per-kilogram doses of methimazole (< 0.5 mg/kg/d) have been shown to prolong the free T 4 elevations for almost 3 times as long as the higher per-kilogram doses (>0.5 mg/kg/d).

Because antithyroid medications affect the thyroid principally at the level of hormone biosynthesis, patients may continue to secrete preformed hormone for 6-12 weeks after initiation of therapy. In patients with marked cardiac manifestations of hyperthyroidism, a beta-blocker (eg, propranolol, 80 mg/m2/d) is added to the regimen until hyperthyroidism is under control.

Dosage of PTU or methimazole is titrated to maintain T 4 concentration within the normal range. As the disease comes under control and thyroid-stimulating hormone (TSH) levels rise, the dose is decreased and eventually discontinued. An alternative approach is to give a larger dose of medication to induce hypothyroidism, and exogenous T 4 is added to the regimen to correct the hypothyroidism. The addition of T 4 has been suggested to result in a higher rate of remission, although studies are conflicting. This approach requires administration of 2 drugs and, because of the higher dose of antithyroid drugs, may increase the risk of adverse effects.

Adverse effects

Adverse effects of these medications are relatively common and may be dose-related. Approximately 1-9% of patients develop a drug-induced rash that resolves with discontinuation of therapy. Drug cross-reactivity between PTU and methimazole may be as high as 50%. Other minor adverse effects include a bitter taste, nausea, and headache. An asymptomatic, mild, transient granulocytopenia is observed in as many as 12% of patients; however, patients can generally continue on the medication, provided that the white blood cell (WBC) is closely monitored.

More severe adverse effects are less common. Arthritis, fever, and mucosal ulcerations are observed in a small number of patients. Other serious adverse effects include agranulocytosis, hepatitis, glomerulonephritis, arthritis, and a lupuslike syndrome. These effects, thought to be idiosyncratic reactions, can occur at any time during the course of therapy. Medication should be stopped immediately. Reactions usually resolve within a few weeks.

Boxed warning for PTU

On April 21, 2010, the US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients using this agent.[10] The boxed warning also states that PTU should be reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil (PTU). Among adults, 12 deaths and 5 liver transplantations occurred; among the pediatric patients, 1 death and 6 liver transplantations occurred. PTU is indicated for hyperthyroidism due to Graves disease.

These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death). PTU is considered as a second-line drug therapy, except in patients who are allergic or intolerant to methimazole, or for women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy.

For more information, see the FDA Safety Alert.[10] The FDA recommends the following criteria be considered for prescribing PTU[10] :

  • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.

  • Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

  • For suspected liver injury, promptly discontinue PTU therapy, and evaluate for evidence of liver injury and provide supportive care.

  • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and no other treatment options are available.

  • Counsel patients to promptly contact their healthcare provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Neonatal Graves disease

For neonatal Graves disease, various approaches may be used. In mild cases, symptomatic treatment with a beta-blocker (eg, propranolol) may be tried. In some cases, this is adequate, because the disease is usually transient. In more severe cases, antithyroid medications are necessary. In very severe cases, iodides in the form of Lugol iodine solution or saturated solution of potassium iodide (SSKI) are used.

Iodide inhibits the release of preformed T 4 and T 3 from the thyroid gland and therefore has a more rapid onset of action than the thionamides. Glucocorticoids may be necessary in severe cases. These inhibit the peripheral conversion of T 4 to T 3 and protect the infant against adrenal insufficiency, which can occur because T 4 increases the metabolism of cortisol. Note that iodide or thionamide therapy may render the neonate hypothyroid, which is clearly not desirable. Therefore, thyroid function tests must be monitored very closely, and the dose of thionamide reduced or T 4 must be added if the infant becomes hypothyroid. In rare cases of congestive heart failure (CHF), digoxin is a useful adjunct.

Maternal hyperthyroidism and breastfeeding

Medical treatment of maternal hyperthyroidism is not a contraindication to breastfeeding. In this case, the drug of choice is PTU, because it is bound mostly to plasma proteins and does not cross the blood-milk barrier to a significant degree.

Thionamides

Class Summary

Thionamide agents block the synthesis of thyroid hormone.

Propylthiouracil (PTU)

In addition to inhibiting thyroid hormone biosynthesis by decreasing the oxidation of iodide and iodination of tyrosine, propylthiouracil diminishes peripheral conversion of T4 into T3.

Methimazole (Tapazole)

Methimazole is the treatment of choice for fetal hyperthyroidism.

Iodide Agents

Class Summary

Iodide agents block iodide uptake by the thyroid, thereby transiently decreasing T4 synthesis. This effect lasts for about 2 weeks. Various iodide preparations, including strong iodine solution (ie, Lugol iodine solution, first made in 1829), saturated solution of potassium iodine (SSKI), and iodinated radiographic contrast agents (sodium ipodate) have been used.

Radiographic contrast agents are effective, not only because they release iodide, but also because they inhibit conversion of T4 to T3. Sodium iodide may be administered intravenously (IV) if oral (PO) intake is compromised. Damaged or immature thyroid glands (eg, after treatment with radioactive iodine or neonatal thyrotoxicosis) are particularly susceptible to the suppressive effects of iodides and are less likely to rebound from these effects.

Potassium Iodide and Iodine (Lugol Solution, SSKI)

Lugol iodine solution contains about 6.3 mg elemental iodine per drop (gtt). Saturated solution of potassium iodide (SSKI) contains about 38 mg of potassium iodide per drop.

Sodium ipodate and sodium iopanoic acid are iodinated contrast agents that act by liberating iodide. Sodium ipodate contains 308 mg iodine/capsule, whereas sodium iopanoic acid contains 333 mg iodine/capsule. This is advantageous, because these agents are also thought to inhibit extrathyroidal conversion of T4 to T3.

Beta-Adrenergic Blocking Agents

Class Summary

Beta-adrenergic blocking agents are used for symptomatic treatment of cardiac complications of hyperthyroidism.

Propranolol (Inderal, InnoPran XL)

Cardiac symptoms can be alleviated with propranolol.

Antithyroid Agents

Class Summary

Radioiodide (iodide I 131) is used for radioablation as an alternative to medical or surgical therapy.

Sodium Iodide I-131 (Hicon, Iodotope)

One to 2 doses of radioiodide is sufficient for radioablation. Some physicians give the standard dose, but others calculate the dose based on measured radioiodine uptake.

Glucocorticoids

Class Summary

Stress doses of glucocorticoid agents are used primarily to treat thyroid storm. Their effects are thought to be due to reduction in conversion of T 4 to T 3 , reduction in autoantibody formation, and protection from adrenal insufficiency. High-dose glucocorticoids may also be used for severe sight-threatening ophthalmopathy.

Hydrocortisone (A-Hydrocort, Solu-Cortef, Cortef)

Hydrocortisone elicits anti-inflammatory properties and causes profound and varied metabolic effects. This agent modifies the body's immune response to diverse stimuli.