Pediatric Graves Disease

Although Perry was first to report hyperthyroidism in English, the classic description, in 1835, by Graves became most widely accepted. Europeans often prefer to recognize the description by Basedow.

The most common association with childhood Graves disease is a history of other family members with thyroid disease. On the other hand, concordance for Graves disease in identical twins is only 30-50%, indicating that genetic and environmental factors play a role in this disease.

Complications

Graves disease is potentially life threatening. The most severe manifestation of Graves disease is thyroid storm, which carries a mortality risk approaching 100% in untreated adults. Series conducted with newer treatments, including beta-adrenergic blocking agents, show a reduced risk of death near 20%. This is such a rare disorder in children that no comparable figures are available.

Even children and adolescents with less severe manifestations of Graves disease can display long-term consequences of this disorder, including problems with schooling and chronic loss of bone mineral.

Patient education

Instruct patients treated with antithyroid drugs as to possible adverse effects and the need for close follow-up.[1] Patients treated with surgery and RAI must understand the rationale for the development of hypothyroidism and the need for close follow-up.

For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems.

The reasons for the development of Graves disease are presently unknown. Patients likely have defective immune tolerance, leading to the development of specific autoantibodies directed against various thyroid antigens and against proteins with putatively similar antigenic sites in other tissues, notably the subcutaneous tissues and extraocular muscles. The TSH receptor is the most significant thyroid autoantigen in this disorder. However, children with Graves disease also produce immunoglobulins directed against thyroperoxidase (anti-TPO) and thyroglobulin, as well as TSH receptor–blocking antibodies, as may be found in chronic lymphocytic thyroiditis (Hashimoto thyroiditis).

One study conducted a genome-wide association study in 1536 individuals with Graves disease and further evaluated a group of associated single nucleotide polymorphisms (SNPs) in a second set of 3994 cases. The data confirmed previously reported loci (TSHR, CTLA4, and FCRL3), and identified 2 new susceptibility loci (RNASET2-FGFR1OP-CCR6 region at 6q27), and an intergenic region at 4p14. These newly associated SNPs were associated with the expression levels of RNASET2 at 6q27, of CHRNA9, and of a previously uncharacterized gene at 4p14, respectively. Strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves disease were also identified.[2]

Because other antibodies can coexist with TSI, not all children with Graves disease are thyrotoxic. However, thyrotoxicosis is the hallmark of most cases of Graves disease. In general, thyrotoxic Graves disease is considered in this article. Onset of Graves disease in susceptible individuals has variously been attributed to acute infections and to physical and emotional stress.

The thyroid is enlarged because of constant TSH receptor stimulation and the presence of activated T lymphocytes and plasma cells in pseudofollicular patterns. The thyroid often has a firm, rubbery consistency when palpated, and the pyramidal lobe may be prominent. When overstimulated by TSI, the thyroid becomes quite vascular, and an audible bruit is not uncommon. If the thyroid becomes very large, it may cause pressure symptoms and signs, including difficulty swallowing and hoarseness. Rarely, children may report associated pain.

Thyroid hormone excess, as a result of thyroid hyperstimulation, affects all organ systems. Patients with thyroid hyperstimulation are irritable and restless, have poor sleep habits, and often report daytime tiredness associated with nocturnal insomnia. Inability to concentrate and tremor translate in children into scholastic inattention, poor handwriting, and deteriorating school performance. Neuropsychiatric symptoms can mimic attention deficit hyperactivity disorder (ADHD), yet few children with ADHD are actually discovered to be thyrotoxic. ADHD and thyrotoxicosis are usually easily distinguished by thyroid examination and measurement of pulse and blood pressure (BP).

Cardiovascular stimulation by thyroid hormone leads to a rapid pulse rate and a dynamic precordium. Patients sometimes subjectively report palpitations. The patient typically shows a widened pulse pressure. Hypermetabolism usually leads to weight loss with increased appetite. Heat intolerance is often subtle.

Muscle wasting is present, with decreased muscle strength. Typically, atrophy of the thenar and hypothenar eminences may be observed. The hair becomes fine, and temporal hair loss often occurs. Rare genetically determined individuals may develop thyrotoxic periodic paralysis. Darkening of the skin may occur, most noticeably in darker-skinned individuals, and intense pruritus may also occur. The skin is typically very fine and moist. Sweating is increased. Thickening of the skin (localized myxedema) is almost never observed in childhood Graves disease.

In individuals with severe hypermetabolism, abnormal liver function may be observed with elevations of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT). Increases in gut motility result in diarrhea and frequent bowel movements. Graves disease with thyrotoxicosis leads to loss of bone mineral, decreased bone density, and resultant hypercalcuria. Hypercalcuria, as well as hyposthenuria, as a direct effect of thyroid hormone on the renal tubule, leads to nocturia, and, in some susceptible children, it leads to nocturnal enuresis. Nocturnal enuresis occasionally is the first finding noted in children with Graves disease.

Growth in height may be enhanced by hypermetabolism, and bone age may be advanced.[3] Puberty may be affected. Girls with Graves disease may have irregular, sparse menses, and boys may have excess estrogen effect because of increased metabolism of steroids to estrogen. Symptoms of gynecomastia and decreased libido in older adolescents are not uncommon.

Graves disease is a humorally mediated autoimmune disorder in which hyperthyroidism is induced by TSH receptor–stimulating antibodies. In most children and adults, these antibodies are endogenous; however, transplacental passage of immunoglobulin G (IgG) antibodies from women with Graves disease to their infants may lead to the development of neonatal Graves disease. This is a self-limited disorder that resolves when the immunoglobulins are cleared by the neonate and may be followed by transient hypothyroidism if fetal pituitary TSH remains suppressed.

The presence of a long-acting thyroid stimulator (LATS) was postulated by Adams and Purves in 1956 and was confirmed by the identification of the stimulatory immunoglobulins some years later. These immunoglobulins bind to the TSH receptor and mimic TSH action.

Almost all patients producing TSI also produce other immunoglobulins more commonly associated with chronic lymphocytic thyroiditis, such as antibodies directed against thyroperoxidase and thyroglobulin. This suggests a close relation between Graves disease and chronic lymphocytic thyroiditis. Indeed, many individuals have thyrotoxic components to their chronic lymphocytic thyroiditis, and the natural history of untreated Graves disease is that a percentage of individuals with Graves eventually become hypothyroid. Moreover, lymphocytic infiltrates similar to those of chronic lymphocytic thyroiditis are found in the thyroids of patients with Graves disease.

Immunoglobulins produced in this disorder may be measured by numerous in vitro assays. Because these assays may measure different aspects of immunoglobulin function, results in different assays may be discrepant. For instance, TSH-receptor binding is measured in assays of thyroid-binding immunoglobulins (TBI), whereas TSH-receptor activation (eg, increased activation of adenyl cyclase) is measured by TSI or thyroid-stimulating antibodies (TSAb).

Some immunoglobulins may bind to the TSH receptor without stimulating it and may actually block the action of TSH (so-called blocking antibodies). These may be produced in individuals with Graves disease or chronic lymphocytic thyroiditis, further complicating the picture occasionally in individuals with these disorders.

The mechanism of the failure of immune tolerance that leads to the development of Graves disease is not entirely understood, and competing hypotheses have not yet been definitively evaluated.

Nonetheless, histocompatibility antigen haplotypes commonly associated with other autoimmune disorders (B8, DR3) have also been linked to Graves disease.

An infectious etiology of thyrotoxicosis has been postulated based on occurrence frequency in unrelated family members. An association with Yersinia enterocolitica infection has been described but has not been fully confirmed.

Case-controlled studies have suggested an association with recent life stress. The familial occurrence of thyrotoxicosis, as well as other autoimmune thyroid disorders, suggests a genetic link that may be more powerful than that of the histocompatibility antigen association.

Occurrence in the United States

The prevalence of Graves disease in childhood in the United States has not been quantitated. An incidence of 0.2-0.4% has been speculated but is probably an overestimation. Approximately 10% of infants born to women with Graves disease have elevations of thyroid hormone levels, but only 1-2% have clinical symptoms of thyrotoxicosis.

International statistics

A Danish study identified a national incidence density for thyrotoxicosis of 0.79 cases per 100,000 person-years in children aged 0-14 years.[4] Incidence density increases during childhood, with a peak incidence of 0.48 cases per 100,000 persons for boys and 3.01 cases per 100,000 persons for girls, aged 10-14 years.

Race-, sex-, and age-related demographics

No race predilection for Graves disease is apparent. It has been reported in every population studied. In whites, Graves disease is associated with certain histocompatibility antigens (ie, DR3, DR1) that have previously been linked to other autoimmune disorders. The link between histocompatibility antigen subtypes and Graves disease identified in Whites is weaker in Blacks.

At any age, Graves disease is much more common in girls than in boys. The female preponderance has been estimated to be 4-7 girls for every boy affected.

The incidence of Graves disease increases with age, reaching a childhood peak during adolescence. Graves disease is a very rare cause of thyrotoxicosis in children younger than age 5 years.

Graves disease is a chronic illness without a true cure. None of the management options for this disorder actually remove the underlying immunologic disorder. Therefore, the prognosis of the disorder greatly depends on the form of therapy chosen.

Antithyroid drug therapy

In one review, 46.8% of patients had a permanent remission following drug treatment for a variable number of years, and 29% had a relapse. Of this population of 651 children, culled from a number of reports, 5.6% of patients developed granulocytopenia, 2.3% had arthritis, 1.9% had liver disease, and 8% developed a skin rash. The likelihood of remission is greater if the thyroid gland is smaller, the radioactive iodine uptake (RAIU) is relatively low, and TSI levels are lower.

A statistical analysis of children who had long-term drug treatment suggested that approximately 25% of children have remission every 2 years. This remission rate is generous, and it is lower than the remission rate observed in adults.

Subtotal thyroidectomy

A review of outcomes in 555 children, taken from several large series, suggested that 42% of patients undergoing subtotal thyroidectomy become hypothyroid and that 10% have recurrence. In this combined series, 2% of patients had hypoparathyroidism, 1.2% had vocal cord paralysis, 0.2% had bleeding, 1.7% had keloid formation, and 1.5% were discovered to have papillary cancer by histology.

Radioactive iodine therapy

In a review of outcomes of 555 children, taken from several large series, 69% of children who underwent radioactive iodine therapy became hypothyroid, 98% experienced cure of hyperthyroidism, 12% required retreatment, and 4.4% had histologically benign nodules. The practice today in most centers is to aim for hypothyroidism, which would change these figures.

Complications

Hyperthyroidism leads to hypercalciuria and loss of bone mineral during childhood and adolescence. In severely thyrotoxic individuals, assessment of bone mineral by dual energy radiographic absorptiometry (DRA) may be advisable.

Thyroid storm is the most severe form of thyrotoxicosis and can be provoked by surgical or medical stress in an undiagnosed thyrotoxic individual.

Other autoimmune disorders can be associated with Graves disease, including type 1 diabetes mellitus, Addison disease, vitiligo, alopecia, and lupus.

Treatment complications include the following:

• Severe drug reaction to methimazole or propylthiouracil (PTU), including liver disease, lupus, and agranulocytosis[5]

• Surgical complications, including hypoparathyroidism or recurrent laryngeal nerve damage

• Rare induction of hypoparathyroidism post-RAI therapy and a questionable slight increase in the risk of thyroid cancer

• Fetus with thyroid ablation in women treated with RAI during pregnancy

Children with Graves disease are usually initially identified because of an enlarged thyroid, weight loss, or behavioral changes. Exophthalmos, which is common in adults with Graves disease, is less common in children. The reason for this difference is not clear; however, smoking is a well-recognized risk factor for exophthalmos.

The enlarged thyroid may be big enough to cause dysphagia, with reports of difficulty swallowing. Usually, the enlarged thyroid is identified by a parent or physician and is not overtly symptomatic. Weight loss accompanied by a voracious appetite and excessive growth in height can lead to initial evaluation. Often, children begin to have distractibility in the classroom, trouble sleeping, and mood changes, resulting in the identification of thyroid enlargement and elevated levels of circulating thyroid hormone.

The astute clinician may identify these children when they are referred for evaluation of symptoms of attention deficit disorder (ADD). Adolescents with this disorder may also report pruritus, temporal hair loss, thinning of the hair, darkening of the skin, palpitations, and, in girls, amenorrhea or infrequent or light menses. Frequent stools or frank diarrhea and symptoms of heat intolerance are common. A strong family history of Graves disease or other autoimmune thyroid disease may be noted.

Symptoms include the following:

• Dysphagia

• Irritability and emotional lability

• Sleeplessness and restlessness

• Inability to concentrate

• Deterioration of handwriting and school performance

• Frequent stools or diarrhea

• Palpitations

• Pruritus

• Weight loss

• Increased appetite

• Nocturia, increase in urination, and thirst

• Infrequent or light menses

• Weakness and tiredness

• Exercise intolerance

• Heat intolerance

Upon initial inspection, children and adolescents with thyrotoxicosis are usually tall and thin, with a fixed staring gaze and fidgety behavior. Children with thyrotoxicosis may sit on their hands or clasp their hands to control fidgeting. A widened pulse pressure and a rapid heart rate are typically found.

Ocular findings

Ocular findings are often independent of the degree of thyrotoxicosis and may appear before the onset of hyperthyroidism.[6, 7, 8, 9, 10]

Exophthalmos may be present and is usually mild. Weakness of the extraocular muscles is rare, but may be elicited by checking the capacity for convergence and looking for lid lag. Some adolescents may have true inability to close the eyelids because of more severe exophthalmos. Severe exophthalmos can be associated with a sandy, gritty feeling in the eyes upon awakening or with corneal irritation or ulceration (exceedingly rare). Exophthalmos may be unilateral.

Nonspecific signs include lid reaction, wide palpebral aperture (ie, Dalrymple sign, confirmed when the sclera is visible above the superior limbal margin), lid lag (von Graefe sign), stare or appearance of fright, infrequent blinking (Stellwag sign), and absent wrinkling of forehead skin on upward gaze (Joffroy sign). Signs unique to orbitopathy in Graves disease include the following:

• Upper eyelid retraction (the most common sign of Graves ophthalmopathy)

• Infrequent or incomplete blinking (Stellwag sign)

• Lid lag upon infraduction (Von Graefesign) or globe lag on supraduction (Kocher sign)

• Widened palpebral fissure during fixation (Dalrymple sign)

• Incapacity to close eyelids completely (lagophthalmos)

• Prominent stare (Binswanger sign)

• Inability to keep the eyeballs converged (Mobius sign)

• Limited extraocular gaze (especially upward)

• Diplopia

• Blurred vision due to inadequate convergence and accommodation

• Swollen orbital contents and puffy lids

• Chemosis

• Irritated eye

• Globe pain

• Exophthalmos

• Enlarged lacrimal glands (visible on inspection and palpable)

• Visible swelling of lateral rectus muscles at insertion sites into the globe and injection of overlying vessels

• Dysfunctional lacrimal glands with decreased quantity and abnormal composition of tears

• Corneal injection, ulceration, punctate epithelial erosions, or superior limbic keratoconjunctivitis (rare)

• Decreased visual acuity due to papilledema, retinal edema, retinal hemorrhages, or optic nerve damage (rare)

Always perform thyroid function tests (TFTs) in addition to local imaging studies in children with unilateral exophthalmos or proptosis to rule out orbital tumor.

Exophthalmos can be quantitated using an exophthalmometer, which measures the extension of the eye beyond the bony socket. This measurement is standardized for adults. Values for young children are not readily available, but these findings may still be useful to measure progression of the eye disease.

Thyroidal findings

The thyroid is firm and usually smooth and rubbery. A bosselated gland may suggest the thyrotoxic phase of chronic lymphocytic thyroiditis.

A gland with a single nodule suggests an autonomously functioning nodule inducing thyrotoxicosis, whereas a multinodular gland indicates a multinodular goiter, a reasonably rare finding in children living in an iodine-replete environment. Malignancy is rarely associated with such hyperfunctioning lesions.

The finding of hyperthyroidism without a goiter suggests the possibility of exogenous administration of thyroid hormone.

Cardiopulmonary manifestations

Cardiac examination may reveal the murmur of mitral valve prolapse. A rapid heart rate and prominent precordium are noted. Atrial fibrillation may rarely be induced by thyrotoxicosis in children. In the most severe form of thyrotoxicosis associated with Graves disease, thyroid storm, high-output heart failure is observed.

Neuromuscular findings

Deep tendon reflexes are exaggerated. Thenar and hypothenar wasting may be noted. Muscle weakness can be profound.

In some genetically prone individuals, periodic paralysis associated with hypokalemia may be induced by thyrotoxicosis. Although thyrotoxic periodic paralysis is described as an adult disorder, it has been observed in adolescents.

Dermal manifestations

The skin is usually fine and moist. Excoriations may be present because of pruritus. Skin darkening may be observed in some darker-skinned individuals. Thyrotoxicosis may intensify the lesions of acanthosis nigricans. The presence of irregular café au lait spots may suggest the diagnosis of thyrotoxicosis associated with McCune-Albright syndrome rather than Graves disease. 

Mental health conditions

Although the etiology is not well characterized, the prevalence of psychiatric conditions reported in the literature has increased, with a clear female predominance. Associated conditions include depression, anxiety, attention deficit hyperactivity disorder (ADHD), suicidal ideation, adjustment disorder, and bipolar disorder.[11]

The following laboratory studies may be indicated:

• Thyroid-stimulating hormone

• Thyroxine

• Free thyroxine (free T4)

• Triiodothyronine

• Antithyroid antibodies (thyrotropin receptor antibody, thyroid stimulating immunoglobulin)

• Thyroid hormone binding index 

• Complete blood count (CBC)

• Liver function tests (LFTs, such as circulating levels of SGPT, SGOT, GGT, and bilirubin)

• Antinuclear antibody

• Serum calcium, urine calcium-to-creatinine ratio[13]

Thyroid-stimulating hormone

TSH levels are suppressed in Graves disease and in all forms of thyrotoxicosis except thyrotoxicosis due to a TSH-secreting tumor of pituitary or other origin. Children with pituitary thyroid hormone resistance also have elevated TSH levels.

Thyroxine

Total serum thyroxine (TT 4 ) levels are elevated in almost all patients with thyrotoxicosis except those with pure elevations in T 3 (T 3 toxicosis) and individuals with decreased T 4 binding. Acutely ill individuals with sick syndrome may appear euthyroid when they are thyrotoxic.

FT 4 may also be measured and is elevated except in patients with pure T 3 toxicosis or the sick syndrome. T 4 and FT 4 are elevated in patients with pituitary insensitivity to thyroid hormone.

Triiodothyronine

T 3 is elevated in all patients with thyrotoxicosis unless they are acutely or chronically ill, malnourished, or taking medication (eg, PTU) that interferes with the conversion of T 4 to T 3 peripherally.

T 3 is slightly elevated in obesity and in overfeeding. Also, T 3 levels are higher in children in the first several years of life than in older children. Children with pituitary resistance to thyroid hormone also have elevated serum T 3 .

Thyroid hormone binding index

The thyroid hormone binding index (THBI), sometimes referred to as the T 3 resin uptake (T 3 RU), measures binding of thyroid hormone to serum proteins. In combination with the TT 4 , THBI estimates FT 4 . 

THBI is elevated in almost all patients with thyrotoxicosis except for those with pure T 3 toxicosis. THBI is also elevated in patients with decreased serum thyroid binding proteins (TBG deficiency).

THBI may not be elevated in acutely ill individuals with sick syndrome. Like T 4 , THBI is elevated in patients with pituitary insensitivity to thyroid hormone. Recent free T4 assays overcome most of the limitations of THBI. 

Antithyroid antibodies

Graves disease is almost always associated with measurable markers of autoimmunity in the form of suppressive or destructive antibodies.

Elevated levels of anti-TPO, antimicrosomal, or antithyroglobulin antibodies (in order of sensitivity) usually confirm the autoimmune nature of the thyrotoxicosis without recourse to the more difficult in vitro bioassays for TBI or TSI.

Thyroid-stimulating or thyroid-binding immunoglobulins

Measures of these antibodies by in vitro bioassay confirm Graves disease but are rarely necessary for diagnosis. Occasionally, these are not measurable even in patients with clinically proven Graves disease. Maternal titers of these antibodies may be predictive of the severity of neonatal thyrotoxicosis.

CBC

Graves disease may be associated with a leukopenia and relative increase in lymphocytes, as well as a mild anemia. In a child who is treated with an antithyroid drug, a baseline CBC may be reassuring if later CBC counts reveal a slight leukopenia, because PTU or methimazole may induce neutropenia.

Liver function tests

Severe thyrotoxicosis may be associated with elevations in liver enzymes and in bilirubin (thyroid storm).

If antithyroid drugs are to be used to treat thyrotoxicosis, initial liver enzyme levels (aspartate aminotransferase [AST] or SGPT is usually sufficient) that are within the reference range are reassuring, because these drugs can induce hepatitis.

Other measures of autoimmune function, including antinuclear antibody

Thyrotoxicosis may be associated with lupus. In patients with nonspecific symptoms of joint and muscle pain, a negative antinuclear antibody (ANA) can be reassuring. The ANA may become positive during treatment with antithyroid drugs if an immune response to the medication occurs, and this is associated with arthritis or arthralgia.

Serum calcium, urine calcium-to-creatinine ratio

Rare individuals have symptoms of polyuria, nocturia, and thirst as a result of hypercalcuria. Documentation of hypercalcuria and reference range serum calcium levels may be useful.

Additional tests

Ultrasonography of the thyroid may help to define anatomy in puzzling cases but is almost never indicated in classic Graves disease.

If cardiovascular complications are a concern, an electrocardiogram can be beneficial but is not routinely done in practice. 

Fine-needle aspiration biopsy of the thyroid is rarely indicated in the diagnosis of Graves disease, but biopsy of a suspicious nodular lesion can usually be conducted without incident, even in the presence of the vascular gland of Graves disease.

Thyroid scanning is rarely indicated for the diagnosis of classic Graves disease. If a thyroid nodule is identified and autonomously functioning nodular disease is suspected, perform iodine I-123 (123 I) scanning.

Technetium scans reveal the thyroid, but quantitation of uptake is not usually possible. Technetium is taken up by the thyroid but not organified; thus, discrepancies between iodine and technetium scanning results may be observed. Administration of123 I also facilitates calculation of RAIU, which is not necessary for the diagnosis of Graves disease.

Because iodine sufficiency in the North American diet widely varies, standards for RAIU are quite wide and may be confusing in the diagnosis of thyrotoxicosis. However, RAI scanning and uptake can be useful when a goiter is not noted in a hyperthyroid patient or other disorders are suspected. For instance, the hyperthyroidism of subacute thyroiditis is associated with the release of thyroid hormone from a damaged thyroid gland. Therefore, despite thyrotoxicosis, the RAIU is very low. Similarly, in factitious hyperthyroidism because of thyroid hormone ingestion or the rare hyperthyroidism associated with struma ovarii, the RAIU is suppressed.

Because of higher radiation exposure, RAIUs using iodine I-131 (131 I) are now limited to patients who undergo RAI therapy for treatment of thyrotoxicosis or for visualization of residual thyroid malignancy.

The TSH receptor antibodies that are etiologic in Graves disease stimulate the thyroid gland and produce diffuse hyperplasia. Loss of normal thyroid colloid and a hyperemic gland is observed. The formation of many small, new follicles is noted, and the thyroid cells form tall, columnar structures. The blood vessels are larger than normal. Patchy lymphocytic infiltrates are found between follicles, and lymphoid hyperplasia may be seen. T cells and B cells may be identified.[14] The outflow from the thyroid gland is enriched with anti-TSH receptor antibodies, suggesting that these mononuclear cells are a major source of the autoantibodies that maintain the disorder.

Fluid accumulates in periorbital tissues. Extraocular muscles may be infiltrated with lymphocytes.

Thickening of the subcutaneous tissues because of deposition of glycosaminoglycans (pretibial myxedema) may rarely be found in children.

The adverse effects of all treatments for Graves disease, but particularly antithyroid drug therapy, are considerable, and obtaining true collaborative informed consent is important.[15]

Neonatal thyrotoxicosis caused by transplacental passage of maternal TSI is transient but leads to prenatal deaths due to arrhythmia and cardiac failure. Postnatally, poor weight gain, rapid heart rate, and jaundice may indicate the severity of the disorder. These children require special attention after treatment of thyrotoxicosis and remission, because TSI have been attenuated and long-term TSH suppression may render the patients hypothyroid for variable periods.

Management of Graves disease during pregnancy requires careful therapy with PTU and maintenance of thyroid hormone levels in the high range typical of pregnancy. Overtreatment can lead to fetal hypothyroidism and goiter, with concomitant poor intellectual outcome. Undertreatment can lead to fetal loss. Surgery also can lead to fetal loss and should be carried out only if absolutely necessary.

Assess adolescent girls treated for Graves disease for pregnancy risk and start contraception if indicated. Do not administer RAI therapy to a sexually active adolescent girl until she is known to have a negative pregnancy test result. Destruction of the fetal thyroid by RAI produces severe in utero hypothyroidism.

None of the treatments presently available for Graves disease is fully satisfactory. All are aimed at the thyroid, which is simply the target of potent autoantibodies rather than the cause of the disorder. Two medical therapies (antithyroid drugs and RAI ablation) and one surgical therapy (subtotal thyroidectomy) are acceptable approaches to treatment. These therapeutic options reduce thyroid gland mass or action and, as a limited side benefit, may reduce the mass or activity of the mononuclear cells producing the TSH receptor–stimulating antibodies etiologic in the disorder.

Antithyroid drugs of the thiourea class have been available since the late 1940s, and their uses and limitations have been well defined. The 2 agents available for use in the United States are methimazole (Tapazole) and PTU.[16] These drugs inhibit the synthesis of thyroid hormone by inhibition of the organification of iodide and by inhibition of the coupling of iodotyrosines (inhibition of thyroperoxidase). In addition, PTU specifically inhibits the peripheral conversion of T4 to T3, making the use of this drug advantageous when a rapid reduction in active thyroid hormone is indicated, as in thyroid storm.

Some evidence suggests that both drugs inhibit the production of TSI. This immunosuppressive effect may explain the reduction in thyroid gland size often observed during therapy with the thioamide drugs. Methimazole has a longer half-life in serum than PTU and, therefore, can be administered as a once- or twice-daily dose. PTU is usually administered three times daily.

Both agents have a rather significant array of adverse effects, but complete overlap does not occur. The most common adverse effect is a pruritic skin rash. Both agents can induce autoimmune or allergic responses ranging from skin rashes and fever to arthralgia, arthritis, and frank lupus-like findings with positive ANAs and vasculitis. Leukopenia may be induced by both drugs and may be dose related. Arthralgia, urticaria, rash, and fever may occur in 5% of patients treated with these drugs.

Other complications are much less common. Idiosyncratic agranulocytosis is reported in less than 1% of individuals and appears more common in elderly persons. Liver disease is a rare complication of both agents, but methimazole administration leads to cholestatic jaundice. Fulminant hepatic failure leading to death, liver transplantation, or both has been reported with PTU, and prompted a label warning by the US Food and Drug Administration (FDA) since May 2010. Less significant adverse effects include ageusia or dysgeusia.

PTU is the drug of choice in pregnant women with Graves disease. Methimazole has been associated with fetal scalp aplasia cutis. Methimazole also crosses to the fetus much more easily than PTU and, therefore, is more likely to be a fetal goitrogen, even when cautiously used.

The FDA had 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 cases of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, RAI, 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 PTU. Among the adults, 12 deaths and 5 liver transplants occurred; among the pediatric patients, 1 death and 6 liver transplants occurred. PTU remains available for select cases of hyperthyroidism (ie, true thyroid storm, during pregnancy, or unamenable to other medical and surgical interventions).

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 to be a second-line drug therapy, except in patients who are allergic or have an intolerance to methimazole or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy.

The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert)[17] :

• Reserve PTU for use during first trimester of pregnancy or in patients who are allergic or have an intolerance to methimazole (as stated above)

• 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, evaluate for evidence of liver injury, and provide supportive care

• PTU should not be used in pediatric patients unless the patient is allergic or has an intolerance to methimazole and no other treatment options are available

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

Antithyroid drugs are often administered with a beta-blocking agent during the initial weeks of treatment. The rate of remission while taking these agents is much higher in adults than in children. Remission rates are enhanced if drug withdrawal is not completed until the thyroid gland is essentially of normal size. Nonetheless, remission figures in childhood and adolescence are rather poor, ranging from 25% for each year of therapy in one series to much lower remission figures in prepubertal children.

RAI treatment of thyrotoxicosis has proved efficacious for 50 years. Nonetheless, the concern has been that this therapy carries increased risk of malignancy in children. Meta-analyses and long-term follow-up (over 35 y) suggest that if increased risk is observed, it is very small compared with the real and serious risks of other forms of therapy.[18]

Some consider RAI the treatment of choice for all nonpregnant patients with Graves disease who are older than age 10 years. If possible, younger children are maintained on antithyroid drugs until they enter into remission or reach this age. This practice is not based on strong data, suggesting that younger children might be at greater risk of malignancy.

The idea that the outcome of RAI treatment should be thyroid ablation is fairly well accepted. Therefore, thyroid hormone replacement therapy is generally required after the RAI has exerted its full effect. This treatment may take 3-4 months or more to be effective. During the first month, treatment with iodine drops or a return to antithyroid drugs may restore euthyroidism. Do not start iodine drops or antithyroid medication for 5-7 days after treatment, so that the full effect of the RAI on the thyroid can be realized.

Adjunctive therapy with a beta-blocking agent can also be useful. Monitor the patient closely so that thyroid hormone can be instituted as soon as hypothyroidism is detected. In rare instances, more than 1 treatment with RAI is necessary.

Subtotal thyroidectomy was the treatment of choice for Graves disease before experience with RAI developed. In the hands of an experienced thyroid surgeon, subtotal thyroidectomy carries little risk; however, do not forget the risks of surgery and anesthesia, hypoparathyroidism, and injury to the recurrent laryngeal nerve. The thyroid surgeon must weigh the risk of recurrence against that of hypothyroidism when the thyroidectomy is carried out. Hypothyroidism is usually considered a suitable outcome today, because this greatly reduces the risk of later recurrence.[19]

Medical management of the candidate for subtotal thyroidectomy preoperatively and postoperatively is very important. Although anesthetic management of the thyrotoxic patient has been made easier with the availability of newer anesthetic agents and short-acting beta-blocking drugs, most surgeons prefer to operate on a euthyroid patient with a small, minimally vascular gland. Therefore, pretreatment with antithyroid thioureylene drugs until a euthyroid state is reached and 10 days to 2 weeks of treatment with daily iodide drops (eg, a saturated solution of potassium iodide [SSKI]) is considered the standard of care at most institutions.

After surgery, careful assessment of calcium status and of thyroid hormone status permits institution of supplemental calcium as necessary and indicates the appropriate time to begin thyroid hormone therapy. Adolescents with a long history of thyrotoxicosis may have rather depleted calcium stores and develop hungry bone syndrome after surgery, requiring large amounts of calcium intravenously until the calcium stores are replete and the patients’ parathyroid glands return to peak functioning.

Inpatient care is only indicated in the event of thyroid storm or for a few days of the postoperative period after subtotal thyroidectomy.

After subtotal thyroidectomy, assess serum calcium and laryngeal nerves. Damage to these tissues is very unusual in the hands of an experienced thyroid surgeon; nonetheless, having calcium for injection by the bedside is reasonable to treat severe, acute hypocalcemia. If the patient is hypocalcemic because of transient or permanent hypoparathyroidism, commence treatment with calcium and vitamin D as soon as necessary.

Outpatient care is predicated on the treatment option chosen.

Antithyroid drug therapy

Monitor the patient at 6-week to 3-month intervals with TFTs (TSH, total T3, and free T4 levels), LFTs, and CBC. Assess other potential adverse effects of the agent by history.

If beta-adrenergic blocking agents have been started, discontinue when the patient is euthyroid.

At each visit, assess thyroid gland size and firmness. Risk of recurrence upon discontinuation of therapy is great unless the thyroid gland is close to normal in size. After 1-2 years of therapy, if the thyroid is still large and the drug dose has not been able to be decreased to relatively low levels (eg, one half to one fourth of the initial dose), consider alternative therapies.

Radioactive iodine treatment

The purpose of this treatment should be to render the patient hypothyroid and, therefore, decrease the risk of recurrence. In severe thyrotoxicosis, adding Lugol solution or SSKI drops to the regimen 5-7 days after treatment may enhance the speed of remission. Antithyroid drugs may also be started or restarted after 5-7 days, and beta-adrenergic blocking agents may be continued until remission, which may take 4-6 months for full effect.

If the patient is not in remission by 6 months, consider a second treatment. Repeat thyroid hormone and TSH levels at about 4- to 6-week intervals and start supplementation with levothyroxine (L-T 4 ) when indicated by these tests. Long-term follow-up is essential for the adjustment of thyroid hormone.

Subtotal thyroidectomy

TFTs performed after surgery should provide evidence of hypothyroidism. Individuals who are euthyroid have a very high recurrence rate.

Start thyroid hormone treatment as indicated and monitor the appropriate dose at 3-month intervals for several visits and then at 6-month intervals during childhood.

Transfer

An experienced pediatric endocrinologist should care for children with Graves disease. If care involves RAI therapy, transfer of the patient to the temporary care of the treating endocrinologist or nuclear medicine physician is indicated. If care involves surgery, transfer of the patient to the care of an experienced thyroid surgeon is warranted.

Children and adolescents with thyrotoxicosis are often voracious eaters. When they are treated for their condition, if they continue to eat in the same manner, they often gain weight and begin to struggle with obesity.

Anticipatory guidance before and in the early phases of treatment can be very useful. Appropriate food choices can be discussed, and early referral for nutritional counseling can be considered.

Many children with Graves disease self-limit their activity. While they are thyrotoxic, they probably should not compete in stressful competitive sports.

The following consultations may be indicated:

• Endocrinologist - An experienced pediatric endocrinologist can adjust medication and plan medical management, as well as assist the patient and family in decision-making as to appropriate long-term therapy options

• Nuclear medicine specialist or endocrinologist - Certification in the therapeutic use of RAI is required for this form of therapy; few pediatric endocrinologists are certified in this use (most refer to the locally certified individuals who may be specialists in nuclear medicine or endocrinologists)

• Thyroid surgeon - If a family opts for their child to have a subtotal thyroidectomy, having the thyroidectomy performed by an experienced endocrine or pediatric surgeon is important to maintain the lowest possible risk of complications

Novel therapeutic approaches include monoclonal antibody targeting B-cell, TSHR-targeted therapies.

Management of neonates born to mothers with Graves disease

A study by van der Kaay et al established a literature-based management algorithm for neonates born to mothers with Graves’ disease. The following eight suggestions were included[20, 21] :

1. Evaluate initial risk assessment on maternal thyroid stimulating hormone (TSH) receptor antibodies. If levels are negative, no need for follow-up; if positive, or not available, newborns should be considered "at risk" for hypothyroidism.

2. Newborns with negative TSH-receptor antibodies can be discharged from follow-up so test cord blood for TSH-receptor antibodies as soon as possible.

3. Measurement of cord fT4 and TSH levels is not indicated.

4. Evaluate fT4 and TSH levels at day 3 to 5, repeat at day 10 to 14, and follow clinically until 2 to 3 months.

5. The testing schedule is the same for neonates born to mother with treated or untreated Graves’ disease.

6. Methimazole (MMI) is the treatment of choice when warranted. Beta blockers can be added for sympathetic hyperactivity. Patients with refractory symptoms can also be given potassium iodide along with MMI. It is not clear whether asymptomatic infants with biochemical hyperthyroidism should be treated. It is not known whether asymptomatic infants with biochemical hyperthyroidism need to be treated.

7. Until they are stable, assess the MMI-treated newborn weekly and then every one to two weeks, with a decrease of medications as tolerated. The length of MMI treatment is generally one to two months.

8. Be mindful that central or primary hypothyroidism can develop in these newborns.

Medical management of Graves orbitopathy

Clinical practice guidelines for the medical management of Graves orbitopathy by the European Group on Graves' Orbitopathy were published in August 2021 in the European Journal of Endocrinology.[22]

Give oral prednisone/prednisolone prophylaxis to patients who have been treated with radioactive iodine (RAI) and who are at risk for progression or de novo development of Graves orbitopathy. These include smokers and those with severe/unstable hyperthyroidism or high serum thyrotropin receptor antibody (TSHR-Ab). Use the following regimen:

• High risk: 0.3–0.5 mg/kg/body weight as starting dose, tapered, and withdrawn after 3 months
• Low risk: 0.1–0.2 mg/kg/body weight, tapered, and withdrawn after 6 weeks

Patients with longstanding and stably inactive GO can receive RAI without prednisone/prednisolone cover if risk factors for GO progression (particularly smoking and high serum TSHR-Ab titers) are absent. Avoid uncontrolled post-RAI hypothyroidism.

All patients with GO should receive extensive local treatment with artificial tears at all times during the course of their disease unless corneal exposure requires higher protection than ophthalmic gels or ointment, especially at nighttime.

Treat mild GO with local treatments and general measures to control risk factors; give a 6-month selenium supplementation to patients with mild and active GO of recent onset, because it improves eye manifestations and quality of life, and usually prevents GO progression to more severe forms.

Do not exceed a cumulative dose of 8 g of IV glucocorticoids for each cycle; do not give IV glucocorticoids to patients with GO who have evidence of recent viral hepatitis, significant hepatic dysfunction, severe cardiovascular morbidity, or uncontrolled hypertension; diabetes should be well controlled before starting treatment. The authors strongly recommend only applying such treatment in centers with experience managing potentially serious adverse events.

Give an intermediate dose of IV glucocorticoids (ie, a starting dose of methylprednisolone 0.5 g IV once weekly for 6 weeks, followed by 0.25 g once weekly for 6 weeks, with a cumulative dose of 4.5 g) in most cases of moderate-to-severe and active GO.

Reserve high-dose treatment (ie, a starting dose of methylprednisolone 0.75 g IV once weekly for 6 weeks, followed by 0.5 g once weekly for 6 weeks, with a cumulative dose of 7.5 g) for the more severe cases (constant/inconstant diplopia, severe proptosis, severe soft-tissue pathology or involvement) within the moderate-to-severe and active GO spectrum.

Intravenous methylprednisolone in combination with oral mycophenolate sodium (or mofetil) represents the first-line treatment for moderate-to-severe and active GO.

Monotherapy with methylprednisolone at the highest cumulative dose (7.5 g per cycle) represents an additional valid first-line treatment for those with more severe forms of moderate-to-severe and active GO, including constant/inconstant diplopia, severe inflammatory signs, and exophthalmos >25 mm.

Severe corneal exposure should be urgently treated medically or by means of progressively more invasive surgeries to avoid progression to corneal breakdown, the latter of which requires immediate surgery.

Sight-threatening GO is an emergency; treatment is an absolute priority; treat hyperthyroidism with antithyroid drugs until treatment of GO is completed.

Drugs used in the treatment of Graves disease include thiourea antithyroid medications, iodide or iodine preparations, beta-blocking agents, and thyroid hormone.

Treat all symptomatic patients with beta-adrenergic blocking agents unless an exacerbation of severe bronchospastic disease is a strong concern even with a selective beta1 antagonist. Other treatment plans depend on the therapeutic approach chosen.

Begin antithyroid drug therapy with methimazole and carefully monitor. The US Food and Drug Administration (FDA) issued a black box warning regarding the use of PTU in pediatric patients due to the higher risk of hepatotoxicity and hepatic failure except in special settings such as pregnancy. L-T4 can be added to the regimen when the dose of methimazole decreases and the thyroid gland is still large and firm, in order to establish an equilibrium during therapy. This addition of T4 does not enhance the rapidity of remission and is generally not required.

Discontinue antithyroid drugs 4 days before RAI therapy. Antithyroid drugs can be restarted 1 week after treatment or, alternatively, iodine drops can be administered until remission. In most cases, L-T4 therapy is started within 4-7 days after subtotal thyroidectomy.

Class Summary

Drugs used in the treatment of Graves disease include thiourea antithyroid medications, iodide or iodine preparations, beta-blocking agents, and thyroid hormone.

Treat all symptomatic patients with beta-adrenergic blocking agents unless an exacerbation of severe bronchospastic disease is a strong concern even with a selective beta1 antagonist. Other treatment plans depend on the therapeutic approach chosen.

Begin antithyroid drug therapy with methimazole or PTU promptly and carefully monitor. L-T 4 can be added to the regimen when the dose of methimazole or PTU decreases and the thyroid gland is still large and firm, in order to establish an equilibrium during therapy. This addition of T 4 does not enhance the rapidity of remission.

Discontinue antithyroid drugs 4 days before RAI therapy. Antithyroid drugs can be restarted 1 week after treatment or, alternatively, iodine drops can be administered until remission. In most cases, L-T 4 therapy is started within 4-7 days after subtotal thyroidectomy.

Methimazole (Tapazole)

Methimazole is typically the drug of choice except in pregnant women. It does not inhibit peripheral conversion of T4 to T3; thus, it does not have an immediate needed effect in the most severely thyrotoxic individuals. Methimazole possesses a longer half-life than PTU does, allowing daily or twice-daily administration. Methimazole has never been associated with life-threatening hepatitis. It is weakly associated with neonatal aplasia cutis following in utero exposure.

Propylthiouracil (PTU)

This is the drug of choice for thyroid storm, because it inhibits peripheral conversion of T4 to T3. It is also the drug of choice in lactation or pregnancy, because it does not cross the placenta to the extent that methimazole does and has not been associated with cutis aplasia in the fetus.

Class Summary

These agents decrease iodide transport, iodide oxidation, and organification and suppress thyroid hormone release from the thyroid. Various iodide preparations, including strong iodine solution (ie, Lugol 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 T 4 to T 3 . Sodium iodide may be intravenously administered if oral intake is compromised. It must be specially prepared by a pharmacy with that capability. Damaged or immature thyroid glands (eg, post-RAI treatment, thyrotoxic neonate) are particularly susceptible to the suppressive effects of iodides and are less likely to rebound from these effects.

Strong iodine solution (Lugol solution)

Lugol solution contains 100 mg KI and 50 mg elemental iodine per 1 mL, or approximately 8 mg iodine per drop. It is usually administered preoperatively to reduce gland vascularity or after RAI therapy to induce a more rapid remission.

Lugol solution may be used as part of the initial therapy of thyroid storm. It may also be used as monotherapy in children with neonatal Graves disease because of transplacental passage of maternal antibodies. Breakthrough from iodide suppression and intensification of Graves disease symptoms may occur; thus, do not use Lugol solution as monotherapy in older children except in the mildest cases of thyrotoxicosis. The salty metallic taste may be masked by orange juice or tomato juice.

Potassium iodide (SSKI)

SSKI is equally effective as Lugol solution, and it may be used in the same manner. One mL of SSKI contains 750 mg of iodide (ie, 35-50 mg per drop). The taste can be partially disguised by mixing in orange or tomato juice.

Sodium iodide

Acquire sodium iodide from a sterile compounding pharmacy.

Class Summary

These agents rapidly decrease tachycardia, palpitations, tremor, and widened pulse pressure. Children feel better after starting a beta-blocking agent despite the minimal effect on thyroid hormone levels. Weight loss is not affected, nor is thyroid size. Central nervous system (CNS) effects are related to the lipid solubility of the agent. Use beta1 selective agents in children with asthma.

Beta-blocking agents are used for initial treatment before antithyroid drugs are administered or in patients awaiting remission after receiving RAI. They are used for primary management in neonatal Graves disease or during subtotal thyroidectomy without other preparation; however, these 2 indications are not recommended. All of the symptoms and signs of hyperthyroidism are not masked.

Propranolol (Inderal)

This is the drug of choice in children who do not have asthma. It is a nonselective beta-adrenergic antagonist.

Atenolol (Tenormin)

Atenolol is a selective beta1-receptor blocking agent recommended for children with a history of asthma. Because of its decreased lipid solubility, this agent does not cross the blood-brain barrier as well as propranolol does; thus, some of the CNS effects of thyrotoxicosis (eg, irritability, sleeplessness) may not respond as well to atenolol as they do to propranolol.

Esmolol (Brevibloc)

This is a very short-acting, intravenous (IV) beta1-specific blocking drug. It should be reserved for use to treat tachycardia or atrial fibrillation in severe Graves disease or thyroid storm or during surgery and anesthesia in an individual discovered to have active thyrotoxicosis. Dilute the concentrated preparation in IV fluid before administration.

Class Summary

Hypothyroidism is readily treated by lifelong replacement therapy with levothyroxine.

Levothyroxine (T4, Synthroid, Levothroid, Levoxyl)

Levothyroxine is the drug of choice for thyroid hormone replacement after the treatment of Graves disease with RAI or surgery or during long-term maintenance on a balanced regimen of antithyroid drug and thyroid hormone.

Levothyroxine is metabolized in the periphery by outer ring deiodinases to T3, the active form of thyroid hormone. Therefore, T4 and T3 preparations or T3 alone are not needed. These preparations provide T3 peaks and produce levels of T4 and T3 that are less smooth than those that result when the levothyroxine product is administered alone.

Patients with thyrotoxicosis may need a smaller dose than the recommended dose of 0.1-0.2 mg/d, because they do not readily suppress the remaining endogenous thyroid function.

Reevaluate thyroid tests 4-6 weeks after starting T4. TSH may not be an adequate means of assessment if the patient has had a suppressed TSH level for a long time. Rarely, the TSH level may stay suppressed and not rise adequately until the axis recovers; therefore, FT4 or the FT4 index (FT4I) may provide more accurate monitoring.