AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

The terms hyperthyroidism and thyrotoxicosis are often used synonymously; however, they refer to slightly different conditions and should be differentiated from each other. Hyperthyroidism refers to overactivity of the thyroid gland leading to excessive synthesis of thyroid hormones and accelerated metabolism in the peripheral tissues. Thyrotoxicosis, on the other hand, refers to the clinical effects of an unbound thyroid hormone, 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. A number of therapeutic options are available, and most patients do well, although the risk of relapse or subsequent hypothyroidism is substantial. In atypical cases, keep in mind that a small number of patients may have hyperthyroidism due to other causes.

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.

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 freethyroid 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 mediated largely through this second messenger system.

Synthesis of thyroid hormone is dependent on an adequate supply of iodine. Dietary inorganic iodide is transported into the gland by an iodide transporter (iodide pump). Iodide is then converted to iodine and bound to tyrosine residues on thyroglobulin by the enzyme thyroid peroxidase in 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 within the thyroglobulin in the extracellular thyroid follicular lumen. Unlike other endocrine glands, the thyroid has a large supply of stored preformed hormone.

When thyroid hormones are secreted, thyroglobulin is endocytosed into the follicular cell and is degraded by lysosomal enzymes. Stored T4 and, to a lesser degree, T3 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 are free and participate in metabolic activity. T4 can be monodeiodinated to form either T3 or reverse T3 (rT3), but only T3 is metabolically active. T3 acts by binding to nuclear receptors, 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, 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.

Frequency

United States

Because Graves disease accounts for more than 95% of childhood cases of hyperthyroidism, the frequency of Graves disease approximates the frequency of all cases of hyperthyroidism. Prevalence of Graves disease is approximately 0.02% in childhood, accounting for fewer than 5% of the total cases of Graves disease. Graves disease is associated with 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, Addison disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, vitiligo, immune thrombocytopenic purpura, and pernicious anemia. Graves disease is more common in patients with trisomy 21 than in patients without trisomy 21.

Mortality/Morbidity

• 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 it may persist despite resolution of the hyperthyroidism.
• 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.
• Hypercalcemia is occasionally seen in patients with hyperthyroidism.

Sex

• Females are affected by Graves disease more often than males, with a reported female-to-male ratio of 3-6:1. 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.

Age

• Incidence increases throughout childhood, with a peak incidence in children aged 10-15 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

In children and adolescents, the symptoms of Graves disease 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. 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.
• Other symptoms can include the following:
• • Weight loss despite excellent appetite
  • Insomnia
  • Fatigue
  • Palpitations
  • Heat intolerance
  • Sweating
  • Diarrhea
  • 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
• 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.

Physical

• 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.
• 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 half of patients.
• Cardiac examination may reveal tachycardia and wide pulse pressure or hypertension. Signs of 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), 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
  • Exaggerated deep-tendon reflexes
  • Proximal muscle weakness
  • Systemic hypertension
  • Over time, Graves disease can result in accelerated growth and early epiphyseal closure.
  • Graves dermopathy, or localized myxedema, is exceedingly rare in children. If it occurs, it is likely to be noticed in the pretibial area.
• The frequency of symptoms of Graves disease are as follows:
• • Increased appetite (60%)
  • Weight loss (50%)
  • Increased sweating (49%)
  • Hyperactivity (44%)
  • Heat intolerance (33%)
  • Palpitations (30%)
  • Fatigue (16%)
  • Diarrhea (13%)
• The frequency of signs of Graves disease are as follows:
• • Goiter (99%)
  • Tachycardia (82%)
  • Exophthalmos (66%)
  • Tremor (61%)
  • Thyroid bruit (53%)
  • Increased pulse pressure (50%)

Causes

• Thyroid causes of thyrotoxicosis in childhood
• • Graves disease
  • Toxic adenoma
  • Toxic nodular goiter
  • McCune-Albright syndrome
  • Subacute (viral) thyroiditis
  • Chronic lymphocytic thyroiditis (ie, hashitoxicosis)
• Pituitary causes of thyrotoxicosis in childhood
• • Pituitary adenoma
  • Pituitary resistance to T4
• Other causes of thyrotoxicosis in childhood
• • Exogenous thyroid hormone
  • Iodine-induced hyperthyroidism (ie, Jod-Basedow phenomenon)
  • Human chorionic gonadotropin (hCG)–secreting tumors
• 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 most 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 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) 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 exist.
• Neonatal Graves disease
• • Graves disease in neonates accounts for fewer than 1% of all cases of hyperthyroidism in pediatric patients. 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.
  • The frequency of neonatal Graves disease is equal in males and females, reflecting the underlying pathophysiology.
  • Because neonatal Graves disease is caused by maternal immunoglobulin G (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 of gestation. The fetus may have hyperthyroidism in utero and have tachycardia (>160 beats/min). These babies can be treated with propylthiouracil (PTU) or methimazole, which is given to the mother. Theoretically, the latter may be preferable because it 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.
  • 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. Signs include 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, 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. McCune-Albright syndrome includes polyostotic fibrous dysplasia, café-au-lait spots, and 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.
  • Recent evidence indicates that the hyperthyroidism in McCune-Albright syndrome is associated with a mutation in the a 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. Biopsy reveals 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 remit spontaneously. Treatment with antithyroid medications provides only temporary benefit. Therefore, the treatment of choice is surgical resection 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 show elevated thyroid hormones and decreased TSH. Unlike 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, they 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. TSIs, if present, 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.
  • A recent study found that 11.5% of patients with Hashimoto thyroiditis presented with hyperthyroidism.
• Pituitary adenoma
  • Clinical hyperthyroidism and elevated or normal TSH levels in the face of high T3 and T4 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 prior to surgery.
• Pituitary resistance to T4
  • Pituitary resistance to T4 is also very rare. It can occur as a spontaneous mutation, or it can be inherited as an autosomal dominant trait. Because the pituitary gland is not fully inhibited by T4, 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 T4 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 T3, T4, 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 T4 is ingested, it will be converted to T3 in the periphery and inhibit pituitary release of thyrotropin. Laboratory studies reveal elevated concentrations of T4 and T3 and suppressed concentrations of TSH.
  • Ingestion of T3 results in similar findings, except T4 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.
• Human chorionic gonadotropin–secreting tumors
  • Adolescents with human chorionic gonadotropin (hCG)-secreting tumors, such as a hydatidiform mole and choriocarcinoma, can present with symptoms of hyperthyroidism.
  • The hCG binds directly to the TSH receptor and stimulates thyroid hormone release.

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Hyperthyroidism can be confirmed simply and quickly with measurements of T4, T3, T3 resin uptake (T3RU), and TSH. Patients with Graves disease have elevated levels of T4, T3, and T3RU and low or undetectable levels of TSH.
• 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 T3RU, which is decreased.
• Free T4 can be measured directly by means of immunoassay. Alternatively, T3RU can be obtained. T3RU correlates inversely with the available binding sites on thyroid-binding globulin (TBG). Conditions that cause elevated TBG levels (eg, pregnancy) increase the number TBG binding sites for T4 and T3 and decrease the T3RU level. In contrast, conditions causing hyperthyroidism decrease the number of free TBG binding sites and, therefore, increase T3RU. 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. T3RU is no longer commonly used and is being replaced by better and more sensitive thyroid hormone testing.
• 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, 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.
• 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 is a thyroid iodine I 123 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.
• Obtaining a CBC 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 PTU or methimazole develops fever or ulcerations in the mouth, a prompt CBC is necessary.

Imaging Studies

• Currently, diagnostic radioiodine I 131 uptake is performed rarely. Either technetium Tc 99m or ¹²³I 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 TSH and the absence of TSI.

TREATMENT

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Medical Care

• To date, no treatments can correct the underlying immune dysfunction in Graves disease. Treatment is directed at correcting the clinical and biochemical abnormalities. Because each of the following 3 treatments currently used has advantages and disadvantages, the therapeutic choice must be individualized.
• • Medical therapy with antithyroid drugs
  • Ablation of the thyroid gland with radioactive iodine
  • Subtotal thyroidectomy
• Self-limited causes of hyperthyroidism, such as subacute thyroiditis, iodine-induced hyperthyroidism, and exogenous administration of T4, can be treated symptomatically. For more significant cardiovascular symptoms, beta-adrenergic blockade with propranolol can be helpful.

Surgical Care

• Surgery is the oldest treatment for Graves disease and is quite effective. 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 the hands of an experienced surgeon, these risks are 1-3%. The surgical mortality rate is very low.

Consultations

A pediatric endocrinologist should monitor patients with hyperthyroidism. Ophthalmologic evaluation is necessary in patients with significant ophthalmopathy. Consultation with a competent neck surgeon is required if a subtotal thyroidectomy is contemplated. A nuclear radiologist should be consulted for radioactive iodine therapy.

Diet

No special diet is required.

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

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Antithyroid medications

Two antithyroid medications currently used in the United States are propylthiouracil (PTU) and methimazole. A third medication, carbimazole, is similar in action to methimazole and is primarily used in Europe and Asia. All 3 antithyroid medications belong to the class of compounds known as thionamides and have been used for more than 50 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 frequency of administration have not been well established for these medications. The usual pediatric dose of PTU is 5-7 mg/kg/d. Its serum half-life is 75 minutes. The more potent methimazole is administered at 0.5-0.7 mg/kg/d. Its half-life is 4-6 hours. Pharmacokinetically, it would seem that neither of these should be effective as once-daily therapy; however, because the thyroid accumulates the drugs, methimazole given once daily is clinically effective. PTU, on the other hand, 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 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) is added to the regimen until hyperthyroidism is under control.

Dosage of PTU or methimazole is titrated to maintain T4 concentration within the normal range. As the disease comes under control and 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 T4 is added to the regimen to correct the hypothyroidism. The addition of T4 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.

Remission is defined as persistent euthyroidism after discontinuation of therapy. The reported remission rate with medical therapy is 34-64%. 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.

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 WBC is monitored closely.

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.

For neonatal Graves disease, a variety of approaches may be taken. 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 T4 and T3 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 T4 to T3 and protect the infant against adrenal insufficiency, which can occur because T4 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 T4 must be added if the infant becomes hypothyroid. In rare cases of CHF, digoxin is a useful adjunct.

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

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.

Radioiodine

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 exists. Nonetheless, because of the theoretical risk, frequency of radioiodine therapy is much lower in pediatric patients.

¹³¹I is administered orally in 1-2 doses. Ablation may take several weeks to months, 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 approximately 100 children who were treated with radioactive iodine prior to age 20 years revealed no increase in the rates of thyroid cancer or birth defects in offspring of these children.

Drug Category: Thionamides

These agents block the synthesis of thyroid hormone.

Drug Category: Iodide

This agent blocks 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), 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 if oral intake is compromised. Damaged or immature thyroid glands (eg, posttreatment with radioactive iodine, thyrotoxicosis in the neonate) are particularly susceptible to the suppressive effects of iodides and are less likely to rebound from these effects.

Drug Category: Beta-adrenergic blocking agents

These agents are used for symptomatic treatment of cardiac complications of hyperthyroidism.

Drug Category: Radioiodine (I 131)

This agent is used for radioablation as an alternative to medical or surgical therapy.

Drug Category: Glucocorticoids

Stress doses used primarily to treat thyroid storm. Effects are thought to be due to reduction in conversion of T4 to T3, reduction in autoantibody formation, and protection from adrenal insufficiency. High-dose glucocorticoids may also be used for severe sight-threatening ophthalmopathy.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care is rarely required in children with hyperthyroidism.

Further Outpatient Care

• 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 weeks to 3 months on therapy before they become clinically and chemically euthyroid. Propanolol can be a useful adjunct during this period.
• 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 cold remedies because many contain sympathomimetic agents (eg, pseudoephedrine) and can therefore exacerbate thyrotoxic symptoms.
• Patients treated medically should have thyroid function tests (T4, T3, TSH) every 2-3 months. TSH levels are suppressed for several months after the initiation of therapy; therefore, T3 and T4 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 PTU and methimazole, they are rare enough and of such sudden onset that routine laboratory screening is rarely helpful.
• Patients should be aware of the adverse effects of their antithyroid medications. At the first sign of a serious adverse effect, such as fever, rash, jaundice, arthritis, or mucocutaneous ulcer, these medications should be discontinued, and laboratory evaluation may be appropriate.
• 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.
• Patients and their parents should 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.
• Ghrelin and 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, while IGFBP-1 levels, which initially are elevated, fall.
• As noted in the Medication section, remission can takes months to years. Attempts to define positive prognostic indicators of long-term remission have not been successful thus far.
• 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.
• 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.

Complications

• CHF
• Craniosynostosis (neonates)
• Developmental delay (neonates)
• Hypothyroidism

Prognosis

• 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

• Patients who choose treatment with antithyroid medications should understand the importance of compliance.
• Counsel patients regarding the common and uncommon adverse effects of treatment.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Onset of 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.
• Absence of goiter, asymmetric goiter, or atypical laboratory test results should raise the suspicion for other causes of hyperthyroidism besides Graves disease.
• 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.
• Serious complications of medical therapy (eg, agranulocytosis, hepatitis, lupuslike syndrome) are quite rare. Nonetheless, patients should be carefully monitored for these complications.
• 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. Patients with Graves disease and their parents should be advised to take necessary precautions.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Schematic representation of the hypothalamic-pituitary-thyroid negative/positive feedback system.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Allannic H, Fauchet R, Orgiazzi J, et al. Antithyroid drugs and Graves'' disease: a prospective randomized evaluation of the efficacy of treatment duration. J Clin Endocrinol Metab. Mar 1990;70(3):675-9. [Medline].
• Bazakis AM, Kunzler C. Altered mental status due to metabolic or endocrine disorders. Emerg Med Clin North Am. Aug 2005;23(3):901-8, x-xi. [Medline].
• Buckingham BA, Costin G, Roe TF, et al. Hyperthyroidism in children. A reevaluation of treatment. Am J Dis Child. Feb 1981;135(2):112-7. [Medline].
• Collen RJ, Landaw EM, Kaplan SA, Lippe BM. Remission rates of children and adolescents with thyrotoxicosis treated with antithyroid drugs. Pediatrics. Mar 1980;65(3):550-6. [Medline].
• Cooper DS. Antithyroid drugs. N Engl J Med. Nov 22 1984;311(21):1353-62. [Medline].
• Dallas J, Foley T. Hyperthyroidism. In: Pediatric Endocrinology. 3rd ed. 1996:401-415.
• Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr. Aug 1980;97(2):257-9. [Medline].
• Gorton C, Sadeghi-Nejad A, Senior B. Remission in children with hyperthyroidism treated with propylthiouracil. Long-term results. Am J Dis Child. Oct 1987;141(10):1084-6. [Medline].
• Hayek A, Chapman EM, Crawford JD. Long-term results of treatment of thyrotoxicosis in children and adolescents with radioactive iodine. N Engl J Med. Oct 29 1970;283(18):949-53. [Medline].
• Hershman JM. Does thyroxine therapy prevent recurrence of Graves'' hyperthyroidism?. J Clin Endocrinol Metab. May 1995;80(5):1479-80. [Medline].
• Karpman BA, Rapoport B, Filetti S, Fisher DA. Treatment of neonatal hyperthyroidism due to Graves'' disease with sodium ipodate. J Clin Endocrinol Metab. Jan 1987;64(1):119-23. [Medline].
• Kubo T, Shimizu J, Furujo M, et al. An infant case of Graves' disease with ophthalmopathy. Endocr J. Oct 2005;52(5):647-50. [Medline].
• LaFranchi S, Mandel SH. Graves disease in the neonatal period and childhood. 1996;1000-1008.
• Lippe BM, Landaw EM, Kaplan SA. Hyperthyroidism in children treated with long-term medical therapy: twenty-five percent remission every two years. J Clin Endocrinol Metab. Jun 1987;64(6):1241-5. [Medline].
• McIver B, Rae P, Beckett G, et al. Lack of effect of thyroxine in patients with Graves'' hyperthyroidism who aretreated with an antithyroid drug. N Engl J Med. Jan 25 1996;334(4):220-4. [Medline].
• Nabhan ZM, Kreher NC, Eugster EA. Hashitoxicosis in children: clinical features and natural history. J Pediatr. Apr 2005;146(4):533-6. [Medline].
• Pagliara AS, Caplan RH, Gundersen CB, et al. Peripheral resistance to thyroid hormone in a family: heterogeneity of clinical presentation. J Pediatr. Aug 1983;103(2):228-32. [Medline].
• Read CH, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves' patients. J Clin Endocrinol Metab. Sep 2004;89(9):4229-33. [Medline]. [Full Text].
• Rojdmark S, Calissendorff J, Danielsson O, Brismar K. Hunger-satiety signals in patients with Graves' thyrotoxicosis before, during, and after long-term pharmacological treatment. Endocrine. Jun 2005;27(1):55-61. [Medline].
• Ruiz M, Rajatanavin R, Young RA, et al. Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis. N Engl J Med. Mar 18 1982;306(11):635-9. [Medline].
• Safa AM, Schumacher OP, Rodriguez-Antunez A. Long-term follow-up results in children and adolescents treated with radioactive iodine (131I) for hyperthyroidism. N Engl J Med. Jan 23 1975;292(4):167-71. [Medline].
• Shiroozu A, Okamura K, Ikenoue H, et al. Treatment of hyperthyroidism with a small single daily dose of methimazole. J Clin Endocrinol Metab. Jul 1986;63(1):125-8. [Medline].
• Sills IN. Hyperthyroidism. Pediatr Rev. Nov 1994;15(11):417-21. [Medline].
• Slyper AH, Wyatt D, Boudreau C. Effective methimazole dose for childhood Graves' disease and use of free triiodothyronine combined with concurrent thyroid-stimulating hormone level to identify mild hyperthyroidism and delayed pituitary recovery. J Pediatr Endocrinol Metab. Jun 2005;18(6):597-602. [Medline].
• Tamai H, Hayaki I, Kawai K, et al. Lack of effect of thyroxine administration on elevated thyroid stimulating hormone receptor antibody levels in treated Graves'' disease patients. J Clin Endocrinol Metab. May 1995;80(5):1481-4. [Medline].
• Vaidya VA, Bongiovanni AM, Parks JS, et al. Twenty-two years'' experience in the medical management of juvenile thyrotoxicosis. Pediatrics. Nov 1974;54(5):565-70. [Medline].
• Zimmerman D, Gan-Gaisano M. Hyperthyroidism in children and adolescents. Pediatr Clin North Am. Dec 1990;37(6):1273-95. [Medline].
• Zimmermann MB, Ito Y, Hess SY, et al. High thyroid volume in children with excess dietary iodine intakes. Am J Clin Nutr. Apr 2005;81(4):840-4. [Medline]. [Full Text].

Article Last Updated: Jul 26, 2006