Hyperthyroidism in Children and Adolescents

Current Issues in Pediatric and Adolescent Endocrinology

0031-3955/90 $0.00

+ .20

Hyperthyroidism in Children and Adolescents

Donald Zimmerman, MD, * and Margaret Gan-Gaisano, MDt

The English physician Caleb Hillier Parry saw the first of five female patients with palpitation, cardiac enlargement, and thyromegaly in 1786. This patient's eyes " ... were protruded from their sockets, and the countenance exhibited an appearance of agitation and distress .... "114 His observations were published posthumously in 1825. Similar patients were described by the Irishman, Robert J. Graves, in 183557 and by the German physician, Carl A. von Basedow, in 1840. 164 The disease characterized by diffuse thyromegaly with thyrotoxicosis, ophthalmopathy, and dermopathy (in various combinations) has three eponyms: Graves' disease, Basedow's disease, and Parry's disease. This disease is responsible for hyperthyroidism in most thyrotoxic children. Graves believed that his patients' thyroid enlargement was produced by alteration in their cardiac function. "The sudden manner in which the thyroid in the above three females used to increase and again diminish in size and the connection of this with the state of the heart's action, are circumstances which may be considered as indicating that the thyroid is slightly [analogous] in structure to the tissues properly called erectile. "57 Parry seems to have held a similar view, because he referred to a patient in whom "the bronchocele [goiter] succeeded to the affection of the heart. "114 Palpitations and other thyrotoxic symptoms and signs are now known to result from excessive secretion of hormones from the thyroid gland. This concept was made particularly plausible after George Redmayne Murray administered thyroid extracts to a patient for treatment of myxedema in 1891. 107 This experiment comprised the first successful hormone replace*Consultant, Section of General Pediatrics and Pediatric Endocrinology and Metabolism, Mayo Clinic and Mayo Foundation; and Associate Professor of Pediatrics, Mayo Medical School, Rochester, Minnesota tFellow in Endocrinology, Mayo Graduate School of Medicine; and Instructor in Pediatrics, Mayo Medical School, Rochester, Minnesota

Pediatric Clinics of North America-Vol. 37, No.6, December 1990

1273

1274

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

ment therapy in humans. 131 Not infrequently, administration of thyroid gland extracts produced symptoms of thyrotoxicosis. These side effects of treatment with thyroid extracts, together with the success of thyroidectomy in decreasing thyrotoxic symptoms in patients with Graves' disease (first reported by Tilbuy in 1880 and Rehn in 188462), prompted Osler to speculate in 1909 that the symptoms of Graves' disease were ". . . due to disturbed function of the thyroid gland, probably to hypersecretion of certain materials, which induce a sort of chronic intoxication. "1l3 NORMAL THYROID PHYSIOLOGY The principal thyroid hormones are thyroxine (T4) and triiodothyronine (T3)' The structures of these compounds are shown in Figure 1. Both T3 and T4 are derived from tyrosine (Fig. 2). The source of tyrosine is the glycoprotein, thyroglobulin. This large glycoprotein is produced by thyroid follicular cells and is transported out of the cells into thyroid follicular lumens for storage (process 1 in Fig. 2).158 As thyroglobulin is transported into the follicular lumen, its tyrosyl residues are iodinated by the enzyme thyroid peroxidase (process 2 in Fig. 2).llO The iodine for the iodination reaction is collected by an iodide transporter, which concentrates thyroidal iodide (process 3 in Fig. 2).174 Before iodide can be bound to tyrosyl residues, it must be oxidized by thyroid peroxidase in the presence of H 20 2 • 68 After tyrosine residues within thyroglobulin are iodinated, they are coupled (also by thyroid peroxidase) to form T3 and T4 within the thyroglobulin molecule (process 2 in Fig. 2).51 The process of hormone secretion begins with pinocytosis of thyroglobulin stored within the follicular lumen (process 4 in Fig. 2).20 Vesicles containing thyroglobulin then fuse with cytoplasmic lysosomes that contain enzymes to degrade incorporated thyroglobulin into amino acids and into T4 and T3 (process 5 in Fig. 2).86 T4 and T3 then diffuse into the circulation (process 6 in Fig. 2). Iodotyrosines are deiodinated by a microsomal deiodinase that allows most of the "unused" iodine to be recycled into thyroid hormone. 123

HO~ )=1I

0

h )=J-

CH2-r.:.COOH

~

I

3,5,3',5'··tetraiodothyroxine (thyroxine or T4 )

3,5,3' --triiodothyronine (T 3)

Figure 1. Structures of the major thyroid hormones.

1275

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

Figure 2. Synthesis of thyroid hormones by thyroid follicular cells. Thyroglobulin (TG), a large glycoprotein, is synthesized (process 1) and then transported to the luminal surface of the cell. At this surface, thyroglobulin is iodinated (I-TG; process 2). Iodine for this process is concentrated in follicular cells by iodine transporters (process 3). Thyroglobulin, stored in follicular lumens, is endocytosed (process 4). Endocytic vesicles fuse with lysosomes to cleave thyroid hormones from thyroglobulin (process 5). Thyroid hormones diffuse into the circulation (process 6).

IiOdine transport I

Capillary

All of the steps of thyroid hormone synthesis and secretion are stimulated by thyroid-stimulating hormone (TSH).12. 32. 89. lOS. 115 This glycoprotein is secreted by the anterior pituitary gland in response to low levels of thyroid hormones in the general circulation and in response to high levels of thyrotropin releasing hormone in the pituitary portal vessels. TSH binds to a receptor associated with the thyroid follicular cell plasma membrane. The actions ofTSH are mediated, at least in part, by activation of thyroid adenylate cyclase. 43 • 46. 87 Thyroid hormones in the circulation are tightly bound to plasma proteins. Only 0.02% ofT4 and 0.3% ofT3 are unbound. 26 Only the unbound fraction of circulating thyroid hormones is capable of producing effects in most target tissues,31, 103 because these hormones must traverse target tissue plasma membranes and nuclear membranes to occupy nuclear receptors (Fig, 3). lll. 154, 167 These T3-activated nuclear receptors bind to chromatin and thereby stimulate or inhibit transcription of RNAs coding for a number of proteins, lll, 129 These proteins comprise some enzymes, hormones, growth factors, receptors, and structural proteins. 50, 77, 85, 91, 105, 129

PATHOPHYSIOLOGY OF THYROTOXICOSIS A large body of information has accumulated concerning effects of thyroid hormones on target tissues; however, many of the molecular bases for the clinical findings in thyrotoxicosis (Table 1) remain elusive.

I

1276

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

Figure 3. The mechanism of thyroid hormone actions on target tissues. T3 bound to plasma proteins cannot enter cells and cannot affect target tissues. Free T3 enters cells and occupies nuclear receptors. T3 bound to nuclear receptors interacts with chromatin to stimulate transcription of mRNA. In turn, mRNA gives rise to translation of proteins that mediate T3 actions.

Many of the symptoms and signs of hyperthyroidism resemble clinical findings in patients with catecholamine excess. In particular, patients with both disease states may have tachycardia and increased pulse pressure. In both conditions, patients may manifest increased metabolism with findings such as weight loss (despite apparently adequate food intake), heat intolerance, and diaphoresis. Finally, patients with both conditions may have tremor, stare (with eyelid retraction), and irritability. Table 1. Signs and Symptoms of Thyrotoxicosis CHARACTERISTIC

Symptoms Nervousness Heat intolerance Weight loss Irritability Fatigue Restless sleep Palpitation Decreased attention span Diarrhea Insomnia Menstrual irregularities Signs Tachycardia Tremor Warm, moist skin Muscle weakness Eyelid lag Eyelid retraction Brisk tendon reflexes Systolic hypertension Growth acceleration

PATIENTS

64

45 37

32 27 27 17 13 10 7 6 64

50 36

25 22 16 12 6

(%)

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

1277

Most of the clinical features of thyrotoxicosis that are shared by states of catecholamine excess are ameliorated by l3-adrenergic receptor blockade. 91 This observation has given l3-adrenergic receptor blockers a prominent role in treatment of thyrotoxic patients. This treatment is efficacious, in part, because thyroid hormones increase catecholamine sensitivity of some tissues by increasing the number of l3-adrenergic receptors. 91 , 172 Thyroid hormones may increase thermogenesis (and therefore heat intolerance and diaphoresis in thyrotoxic patients), in part by increasing metabolic responses to catecholamines. Thyroid hormones increase primarily the basal metabolic rate, however; catecholamines increase the metabolic rate above the basal rate in response to environmental stimuli. 172 Some evidence suggests that thyroid hormones increase thermogenesis by increasing synthesis of the sodium-potassium ATPase enzyme. The resulting increase in ATP hydrolysis increases requirements for ATP generation. Increased mitochondrial ATP generation requires increased O 2 consumption. O2 consumption produces approximately 5 kcal of heat per liter O 2 • 60

CAUSES OF HYPERTHYROIDISM Conditions that are associated with hyperthyroidism in children are shown below. • • • • • • • •

Graves' disease Neonatal Graves' disease Thyroiditis Iodine-induced hyperthyroidism McCune-Albright syndrome Thyroid neoplasms TSH hypersecretion Thyroid hormone ingestion

Because each condition has a distinctive pathogenesis and clinical course, appropriate management depends on precise diagnosis. Diagnosis is rarely problematic, however, because Graves' disease is the predominant cause of childhood thyrotoxicosis. Graves' Disease Graves' disease comprises the tetrad of hyperthyroidism-diffuse goiter, ophthalmopathy, and dermopathy. Frequently, only some of these features are present. Etiology. Graves' disease arises from autoimmune processes which include production of immunoglobulins against antigens in thyroid,27, 142 orbital tissues,7, 76 and dermis.7, 18 The appearance of antibodies against all three tissues may reflect the presence within these tissues of common antigens. 7, 18, 76, 126, 127 Antithyroid antibodies in patients with Graves' disease include antibodies directed against the thyroid hormone receptor. These antibodies

1278

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

produce hyperthyroidism and thyromegaly by mimicking the actions of TSH. The initial stimulus for formation of TSH antibodies may be infection with Yersinia enterocolitica or other microorganisms that have plasmidencoded capsular proteins that bind TSH. 169, 170 Antibodies against these bacterial proteins may cross-react with the thyroid's TSH receptor. The plausibility of this hypothesis is bolstered by the observation that antibodies against Yersinia have been detected in 72% of patients with Graves' disease. 136 Another possible mechanism for initiation of antibody production directed against the TSH receptor is viral infection of the thyroid. Lymphocytes infiltrating the thyroid in response to viral infection secrete lymphokines such as interferon-"Y. In turn, interferon-"Y is capable of inducing the expression of major histocompatibility complex (MHC) class II antigens on the surface of thyroid follicular cells. ll7 These antigens are normally expressed on antigen-presenting cells, B cells, and activated T cells. MHC class II antigens may signal nearby T cells to regard chemical structures in their vicinity (such as the TSH receptor) as antigenic. In response, these T cells secrete interleukins that induce activation and proliferation of other nearby T and B lymphocytes. 27 Antithyroid antibodies then appear in the wake of (presumably viral) subacute thyroiditis. 163 These antibodies are usually only transient because suppressor T lymphocytes normally inhibit robust production of these autoantibodies. Patients with autoimmune thyroid disease are unable to suppress production of antibodies directed against the thyroid, however. 33. 63 This inability to suppress antithyroid antibody production may be inherited with an autosomal dominant pattern of inheritance but with incomplete penetrance in men. U6 Incidence. Graves' disease affects girls between four and five times more frequently than it does boys (Gan-Gaisano M, Zimmerman D: Unpublished data, 1990).73 It affects children of all ages. However, the frequency increases with increasing age in childhoods, 47, 146 and peaks in the third and fourth decades. 47 Clinical Features. The onset of Graves' disease is usually insidious. Frequently, subtle symptoms precede, by weeks or months, the intensified manifestations that prompt recognition of the condition. Disease severity typically varies. Spontaneous remissions may occur and may last for many years; however, they are often followed by relapse. In some patients, the disease progresses relentlessly.130 Nervousness, heat intolerance, weight loss despite increased appetite, emotional lability, irritability, fatigue (especially after slight exertion), and restless sleep are the most common symptoms (see Table 1). Insomnia may be prominent. School performance commonly declines with shortening of the attention span; penmanship deteriorates with worsening tremor. Muscle weakness is common and may be most noticeable when climbing stairs. Although stool frequency typically increases, frank diarrhea occurs only occasionally. With prolonged illness, loss of subcutaneous fat and muscle mass becomes obvious. The most commonly observed sign in Graves' disease is thyromegaly. It is detectable in approximately 95% of patients (Gan-Gaisano M, Zim-

1279

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

merman D: Unpublished data, 1990). The gland usually is diffusely and symmetrically enlarged. Increased blood How to the thyroid is reHected in thyroid bruits and thrills. Other signs include tachycardia, fine tremor, increased skin warmth and moisture, muscle weakness, exaggerated deep tendon reHexes, and increased pulse pressure (see Table 1). Growth acceleration may be observed, but concomitant advancement of the skeletal age prevents increase in ultimate height. 133 Ophthalmic abnormalities are clinically evident in more than half of the children with Graves' disease, 156 whereas they are found in only 25% of adults with Graves' disease. 49 These include proptosis, lid lag, lid retraction, stare, chemosis, conjunctival injection, periorbital edema, and restricted eye movements. Patients may complain of eye discomfort or diplopia (Table 2). Severe ophthalmopathyassociated with marked chemosis, periorbital ecchymosis, eyelid eversion, severe proptosis, corneal ulceration, eye muscle paralysis, or optic atrophy with loss of vision-is extremely rare in childhood Graves' disease. 156, 175 It occurs more frequently in adolescents than in younger children 156 but is much more common in adults (occurring in approximately 10%).65 Like severe ophthalmopathy, some clinical features of adult Graves' disease are particularly rare in children with this disease. These features include Graves' dermopathy (pretibial myxedema), heart failure, cardiac dysrhythmia (except sinus tachycardia), and apathetic thyrotoxicosis. Laboratory Evaluation. Laboratory confirmation of hyperthyroidism due to Graves' disease documents that circulating levels of the active thyroid hormones, T4 and T3, are increased. Measurement of T3 is particularly helpful because T3 levels in Graves' disease are often increased to a greater extent than are T4 levels,92 Patients occasionally have increased T3 levels but normal T4 levels. 66 Radioimmunoassays for measurements of T3 and T4 are readily available, but these assays measure both the physiologically active free hormones and the inactive protein-bound hormones. Because thyroid hormones that are bound to plasma proteins are physiologically inactive, the quantity of this bound hormone may be increased or decreased without affecting the body's exposure to active (unbound) hormone, 9, 103 Thus, a euthyroid patient with increased circulating levels of thyroid hormone-binding proteins may have normal levels of free thyroid hormones but increased levels of bound (and therefore of total) Table 2. Eye Signs and Symptoms CHARACTERISTIC

Proptosis Lid lag Lid retraction Stare Chemosis Conjunctival injection Periorbital edema Excess lacrimation Discomfort Diplopia Pain

PATIENTS

40

22 16 15 7 7

5 5 3 2 1

(%)

1280

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

thyroid hormone. Measurement of free thyroid hormones may help to avoid erroneous diagnosis of hyperthyroidism in such a patient. Similarly, a hyperthyroid patient with decreased circulating levels of thyroid hormonebinding proteins may have increased levels of free thyroid hormones but low levels of bound (and therefore of total) thyroid hormones. Measurement of free thyroid hormones might, in this instance, help to avoid the erroneous conclusion that such a patient was euthyroid or hypothyroid. Because of these considerations, measurement of free T4 and free T3 levels may be helpful in the laboratory diagnosis of hyperthyroidism. Several laboratory tests may be used to estimate circulating levels of free thyroid hormones. The most reliable tests at present are immunoassay after equilibrium dialysis, immunoassay after ultrafiltration, or back titration with labeled hormone after incubation of serum with solid-phase antihormone antibody.31.70 The T3 resin uptake and the one-step tracer analogue technique (in which a radiolabeled T4 analogue competes with free T4 for binding to antibody) are less reliable in those clinical settings in which estimates of free hormone levels are most useful. 31, 70 TSH measurements are now particularly useful in the diagnosis of hyperthyroidism. The development of immunometric assays has increased the sensitivity of TSH measurement; TSH levels below the normal range are now measurable.104 In those types of hyperthyroidism that arise independently of TSH secretion, increased circulating levels of thyroid hormones inhibit pituitary TSH secretion. Thus, in hyperthyroidism caused by mechanisms other than TSH hypersecretion, circulating TSH levels are low. The mechanisms producing hyperthyroidism have important implications for treatment. Therefore, laboratory investigation of these mechanisms may be helpful in patient management. Estimation of serum thyroidstimulating immunoglobulins (TSI) by measuring serum stimulation of cyclic AMP (cAMP) generation in cultured thyroid follicular cells of rat is 95% sensitive and 96% specific for the diagnosis of Graves' hyperthyroidism. 70 Hyperthyroid patients with suppressed levels ofTSH but absent TSI should undergo thyroidal radioiodine uptake studies (measurements at 6 and 12 hours after administration of radioiodine). Patients with Graves' disease have high thyroidal radioiodine uptake. Patients with thyrotoxicosis due to follicular disruption in subacute thyroiditis have low radioiodine uptake. Patients with nonsuppressed TSH levels may have TSH-secreting pituitary tumors, which can be imaged by computed tomography (CT) or by magnetic resonance imaging. Alternatively, thyroid hormone resistance (either central or generalized) may produce nonsuppressibility ofTSH. 81 , 168 Central thyroid hormone resistance can be documented by demonstrating exaggerated TSH response to infusion of thyrotropin releasing hormone. This exaggerated response is difficult to suppress by administering supplemental T3. Peripheral thyroid hormone resistance can be established by demonstrating unresponsiveness of basal metabolic rate, pulse rate, and serum lipids and of urinary levels of hydroxyproline, creatinine, and carnitine to various doses of thyroid hormones. 1l9 Treatment. For 35 years, autoimmune mechanisms have been known to cause Graves' disease; however, the side effects of immunosuppressive

1281

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

treatments (such as glucocorticoids and cyclosporine) are legion. Therefore, treatment of Graves' hyperthyroidism continues to intervene at a later pathogenic step than production of TSI. The presently available treatments seek to directly decrease thyroid hormone production by surgical or radiochemical thyroid ablation or by medical inhibition of hormone synthesis. Antithyroid Drugs. The three currently used antithyroid drugs (propylthiouracil, methimazole, and carbimazole) are heterocyclic ring derivatives of thiourea (thioureylenes). Their activity depends on the presence of the thiocarbamide group (Fig. 4).5.99 Recent studies suggest that antithyroid drugs decrease production of TSpo2 in association with an increase in suppressor T lymphocytes. 97,155 However, these immunologic improvements may be the result, rather than the cause, of decreased levels of thyroid hormone in treated patients. 162 Antithyroid drugs directly inhibit thyroid hormone synthesis through mechanisms that interfere with the actions of thyroid peroxidase (process 2 in Fig. 2).21, 152. Because thioureylenes inhibit synthesis but not secretion of thyroid hormones, preformed hormones continue to be secreted by the thyroid until hormone stores are exhausted. Thyroid hormone stores usually are depleted within 6 to 12 weeks after beginning antithyroid drug treatment. Thus, diminution of hormone secretion and circulating hormone levels occurs within this time frame. 21 For this reason, when thyrotoxic symptoms are marked, ~-adrenergic receptor blockers may be used in conjunction with antithyroid drugs until thyroid hormone levels normalize. Propranolol therapy may be started at a dose of 80 mg/m 2/day (divided into four doses or into two doses of time-release caspsules). The dose should be adjusted to return the pulse rate to normal. Propylthiouracil is administered in daily doses of 5 to 7 mg/kg, 157 whereas methimazole doses are 0.5 to 0.7 mg/kg.37 Often, the daily dose is initially divided into three equal portions; however, single daily doses of methimazole 137 have been effective. Propylthiouracil may be less effective than methimazole when given in a single daily dose. 61 However, its ability to inhibit conversion ofT4 to T3 (T3 being more potent) makes propylthiouracil particularly useful in severe hyperthyroidism. 22 I

I

,

I' "

IS=C

I I

H N-CH

NH 2

Thiourea [Thiocarbamide group]

NH2

II

S=<

Methimazole

N-CH

I

CH 3

o

/

s=c \

H /I N-C

\ CH Propylthiouracil II

N-C

H

I

C3 H 7

Figure 4. Antithyroid drugs.

Carbimazole

1282

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

When thyroid hormone levels decrease to the normal range, three options may be considered. Many physicians attempt to induce sufficient blockade of hormone synthesis to cause primary hypothyroidism; L-thyroxine then is added to return circulating levels of thyroid hormones and TSH to normal. Alternatively, the dose of antithyroid drugs can be titrated to normalize thyroid hormone levels. The former method may induce a higher incidence of toxic side reactions, because relatively higher doses are used. 21 The latter method may be associated with more frequently abnormal thyroid hormone levels because of changing levels of TSI. In addition, the latter method usually results in use of lower doses of antithyroid drugs and lower doses may be associated with a lower incidence of disease remission. 122 Some physicians favor discontinuing antithyroid drugs as soon as normal thyroid hormone levels are achieved. 59 This method also may be associated with a lower remission rate than is achievable with more prolonged drug treatment. 2. ISO Childhood cases of Graves' disease may be particularly resistant to this latter approach because only approximately 12.5% of affected children receiving antithyroid drugs achieve remission during each year of treatment. ISO Several indicators of possible remission may be used to select a propitious time to discontinue antithyroid drug treatment. These include a small goiter,l44 decreased ratio of T3 to T4 ,152 nonsuppressed sensitive TSH,l34 lowered early radioiodine uptake, 8. 165 and lowered TSI levels. 2 • 41 Table 3 summarizes advantages and disadvantages of antithyroid drug treatment. Radioiodine. 131 I is presently the preferred treatment for adults with Graves' hyperthyroidism in a large number of medical centers (including Table 3. Treatment with Antithyroid Drugs* TREATMENT OUTCOME

PATIENTS

Advantages Effective in relieving thyrotoxicosis Avoids surgery Avoids radiation exposure

>95

Disadvantages Slow effect (6-8 weeks) Prolonged treatment required (median 4.5 years)"" Noncompliance in children

7 20

Toxicity

Granulocytopenia Agranulocytosis Arthritis Liver disease Skin rash Others3, 8, 75..., 120 Frequent relapse 5 years l7B 10 years7'

(%)

4.5 0.4 2.4 2

9 10

20

*Review of nine series, including 538 children. See references 3, 8, 16, 63, 72, 90, 96, 98, 157.

1283

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

the Mayo Clinic). 29 Its efficacy and apparent safety have prompted increasing use of radioiodine in treating children with Graves' disease. 23, 63, 95 J3-Radiation from 1311 directly damages thyroid tissue. In response, radiation thyroiditis supervenes. This is followed by endarteritis and interstitial fibrosis, with progressive atrophy of thyroid tissue. 67 In planning a treatment program, the thyroid weight is estimated. Radioiodine uptake is measured at 6 hours and at 24 hours. The larger of these uptake values is used in calculating the 1311 dose. In our institution (and some others),95 a dose of 131 1 is chosen that will deliver to the thyroid approximately 150 !-lCi per gram of thyroid tissue. Dose

(Thyroid weight X 150 !-lCi/g) Radioiodine uptake

Extremely large thyroid glands may require doses delivering up to 200 mCi/g; small glands may be ablated with doses exposing the thyroid to only 100 !-lCi/g. Propranolol may be given concurrently with radioiodine. In addition, thioureylene drugs or stable iodine may be given beginning approximately 1 week after 1311 administration. Advantages and disadvantages of radioiodine treatment are shown in Table 4. Surgery. Although thyroid storm was a historically common sequel to Table 4. Treatment with Radioiodine* PATIENTS

TREATMENT OUTCOME

Advantages Effectiveness Relapse Easiest treatment Usually simple oral dose No hospitalization

!

[

I ,I

98 1

Disadvantages Slow effect Usually 6 to 8 weeks Occasionally multiple doses required Radiation thyroiditis Increased thyroid hormone levels l4• Occasional thyroid tendemess lOl , 135 Radiation-induced genetic damage Theoretically, increase in genetic disease l , 121 No increase evident in available studies Radiation-induced thyroid tumor Theoretically, tenfold increase l66 Studies show no increase at 6 years" and 13 years'· Parathyroid dysfunction Hyperparathyroidism34 ,94 Occasional hypoparathyroidism"" 45 Post-treatment hypothyroidism l7 Dose dependent in first year Subsequent years, per year *Review of six series including 490 children.

(%)

44 , 53, 63, 71, 00, 146

33

3-6.4

=6

2-4

1284

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

thyroidectomy for Graves' disease, it did not occur in 472 operated patients described in nine recent reports. 6 , 8, 16, 63, 73, 90, 98, 132 Avoidance of thyroid storm is accomplished by pretreatment with stable iodine, propranolol, or thioureylenes. At the Mayo Clinic, we treat with a combination of stable iodine (Lugor s solution, 5 drops, three times daily) and propranolol (80 to 160 mg/m 2 per day titrated to normalize the pulse rate and given every 6 hours or, with use of time-release capsules, every 12 hours) for 10 to 14 days. With effective pretreatment and removal of adequate amounts of thyroid tissue, the patient's thyrotoxicosis is usually relieved by the time of hospital dismissal. The advantages and disadvantages of surgical treatment are summarized in Table 5. Summary of Treatments. Because each of the treatments of Graves' hyperthyroidism is associated with distinct advantages and disadvantages, all three treatments continue to be useful under various circumstances. Patients with small goiters and mild hyperthyroidism may enter remission sooner than other patients; such patients might be good candidates for thioureylene treatment. Patients with large goiters and severe thyrotoxicosis may benefIt from surgical treatment. Patients in whom thyrotoxicosis is unremitting despite many years of thioureylene treatment and patients with complications of thioureylene treatment should be considered for surgical or radioiodine treatment. Radioiodine treatment should be considered in patients with recurrent thyrotoxicosis after thyroidectomy because reoperation is associated with a much higher incidence of complications than is the initial operation. 10 Patients who are poor surgical candidates because of underlying medical problems also may benefIt from 1311 therapy.

OTHER CAUSES OF HYPERTHYROIDISM Neonatal Graves' Disease This condition usually results from transplacental passage of maternal TSI to the fetus. 140, 147 Maternal levels of TSI must be extremely high (more Table 5. Surgical Treatment* TREATMENT OUTCOME

Advantages Longest experience 62 Most rapidly effective Recurrence (at 11 years) (Gan-Gaisano M, Zimmerman D: Unpublished data, 1990) Most effective treatment of large goiters Disadvantages Rare surgical mortality (none after 1950) Injury to neck structures Recurrent laryngeal nerve Hypoparathyroidism Laryngeal edema Hemorrhage Keloid formation Postoperative hypothyroidism Stress of hospitalization *Review of nine series describing 472 children. 6, 8, 16, 63, 73, 90, 98,132,157

PATIENTS

3

1 2 0.4

0.2

2.8

32

(%)

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

1285

than five times control values) to produce clinical disease in the infant. 176 Thus, only 1 in 70 thyrotoxic pregnancies is associated with neonatal thyrotoxicosis. 69 Maternal TSI values may be sufficiently high to produce neonatal thyrotoxicosis despite absence of maternal hyperthyroidism. This may occur when the maternal thyroid has been rendered unresponsive to TSI by previous ablative treatment or by concurrent chronic thyroiditis. 13, 106, 161 The first manifestation of neonatal Graves' disease may be fetal tachycardia, with heart rates greater than 160 beats/minute in the third trimester. 36, 171 Many affected infants are born prematurely. Thyrotoxic signs in the neonate are usually evident within hours after birth 106; however, delays of 2 to 10 days may occur when the newborn's thyroid remains suppressed by antithyroid drugs taken by the mother. Delays of 4 to 6 weeks may result from maternal passage of TSH receptor-blocking antibodies along with passage ofTSI. 177 Thyrotoxic signs include irritability, tremor, flushing, hyperactivity, gastrointestinal dysfunction (weight loss, vomiting, diarrhea; voracious appetite or, less commonly, difficulty feeding), and cardiac dysfunction (tachycardia, other arrhythmias, or congestive heart failure). Thyromegaly is common and may produce suffocation. Hepatosplenomegaly occasionally may be associated with jaundice and hypoprothrombinemia. Other problems include thrombocytopenia, craniosynostosis (with advanced bone age), and ophthalmopathy.38, 48, 78, 138, 139 Mortality in affected neonates is approximately 16%.78 Survivors frequently are intellectually impaired, often in association with craniosynostosis. 24, 78 If fetal thyrotoxicosis is suspected because of fetal tachycardia, maternal TSI levels should be measured. If TSI levels are high, then treatment of the mother should be instituted with propylthiouracil, 150 to 300 mg/day divided into three daily doses, The dose should be titrated with the fetal heart rate so that the lowest dose maintaining the fetal heart rate below 160 beats/minute is used. Diagnosis in the neonate is confirmed by demonstrating increased levels of total and free T4 and T3 and suppressed levels of TSH. Treatment of the neonate should include Lugol's solution (1 drop three times daily) and propylthiouracil, 5 to 10 mg/day divided into three daily doses. Sodium ipodate (100 mg/day) may be given as well. Adjunctive treatment with propranolol (1-2 mg/kg per day divided into four doses) should be considered. Supportive treatment with digoxin and diuretics may be required if congestive heart failure is present,38, 88, 95 Thyroiditis Several thyroiditis syndromes may be associated with hyperthyroidism. Because the clinical courses of these conditions differ, optimal therapy for thyrotoxicosis in some conditions differs from that in others. Chronic lymphocytic thyroiditis (Hashimoto's disease) produces slowly progressive immune-mediated destruction of thyroid parenchyma. Over time, hypothyroidism ultimately develops. 54 Usually, however, the immune system of an affected patient directs antibodies and lymphoid cells against various thyroid antigens, Although some immune mechanisms tend to destroy or inhibit the thyroid, others may be stimulatory.27 Thus 5 to 10% of young patients

1286

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

with Hashimoto's thyroiditis present with thyrotoxicosis. 40 Often, the thyrotoxicosis is mild and is replaced in time by hypothyroidism. 15 Thyroid glands of children with chronic lymphocytic thyroiditis usually are enlarged, firm, bosselated, and nontender. Antibodies against thyroid microsomal antigen and thyroglobulin usually are present in serum samples. 39 The erythrocyte sedimentation rate is normal. Aspiration cytology is characteristic but usually is not required for diagnosis. Optimal treatment of hyperthyroidism in patients with chronic lymphocytic thyroiditis depends on the degree of hyperthyroidism. Patients with moderate or severe thyrotoxicosis should be treated with the same modalities used to treat Graves' disease. Mild hyperthyroidism may be treated for a time with f3-adrenergic receptor blockers until increased thyroid hormone levels normalize. Subacute thyroiditis may occur in one of two forms. The first form, painful granulomatous thyroiditis, often is preceded by an upper respiratory illness and frequently is associated with malaise (probably resulting from a viral infection). Thyroid tenderness is characteristic, but redness and heat are not observed in the skin overlying the thyroid. The erythrocyte sedimentation rate is increased, and, in approximately 40%, antithyroid antibodies are transiently present. Granuloma formation is a specific finding on cytologic or histologic examination. 160 The second form of subacute thyroiditis is painless lymphocytic thyroiditis. Unlike chronic lymphocytic thyroiditis, this condition usually is not associated with increased circulating levels of antithyroid antibodies. Unlike painful granulomatous thyroiditis, painless lymphocytic thyroiditis is not associated with increase of the erythrocyte sedimentation rate. 160 In both forms of subacute thyroiditis, disruption of thyroid follicles discharges follicular contents (including thyroid hormones) into the circulation, producing hyperthyroidism. High circulating levels of thyroid hormone suppress pituitary secretion of TSH. Suppressed levels of TSH (and absence of TSI) result in low levels of TSH-stimulated thyroid functions, such as iodine uptake and new thyroid hormone synthesis. Because thyroid hormone synthesis is suppressed, the hyperthyroid phase of the illness resolves when intrathyroidal thyroglobulin stores are depleted (usually within 1-5 months). Because of thyroglobulin depletion and TSH suppression, a hypothyroid phase often supervenes that persists for weeks to months. 55 Because thyrotoxicosis is often of mild to moderate severity and of brief duration, symptomatic treatment with f3-adrenergic receptor blockers is frequently adequate. Occasionally, glucocorticoid treatment is used for relief of pain in painful thyroiditis and for relief of thyrotoxicosis in painless thyroiditis. 58. 109 Thyroid Hormone Ingestion Thyroid hormone taken deliberately or inadvertently may produce thyrotoxicosis. Because circulating thyroid hormone levels are increased in these patients, TSH secretion is suppressed. Low circulating TSH levels result in low thyroidal radioiodine uptake. Because thyroid hormone is not derived from endogenous thyroglobulin, circulating thyroglobulin levels are low in patients ingesting thyroid hormone (unlike the increased levels in

T

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

1287

Graves' disease and in thyroiditis). Thus, the combination of hyperthyroidism with low radioiodine uptake by the thyroid and low circulating levels of thyroglobulin is suggestive of thyroid hormone ingestion. Treatment with l3-adrenergic receptor blockers and ipodate usually is effective. 19 Iodine-induced Hyperthyroidism Ingestion of excess iodine or iodide may produce hyperthyroidism. Iodine may be taken as a component of radiocontrast materials (such as iothalamate), topical antiseptics (such as povidone-iodine), or other medicines (such as amiodarone and clioquinol). Most commonly, iodine induces thyrotoxicosis in older patients with nodular goiters who live in endemic goiter areas. 159 Patients with Graves' disease also may be particularly susceptible to iodine-induced hyperthyroidism. 159 This condition seems particularly uncommon in children. 42 It should be suspected if a history of iodine ingestion is obtained and can be confirmed by finding low radioiodine uptake in the thyroid, increased circulating levels of thyroglobulin, and increased urinary iodine levels. Treatment should begin with discontinuation of iodine administration (if possible). I3-Adrenergic receptor blockers may be helpful, particularly in the weeks after withholding of iodinecontaining medications when thyrotoxicosis may transiently increase. Thioureylene drugs may be required in patients with severe hyperthyroidism or in patients who require continued treatment with iodine-containing medications, such as amiodarone. 1OO Some patients receiving amiodarone have drug-induced thyroiditis l43 that may be controlled by high doses of glucocorticoids.173 McCune-Albright Syndrome McCune-Albright syndrome comprises polyostotic fibrous dysplasia with cafe au lait pigmentation of the skin and several endocrine abnormalities. 25 The most common endocrine abnormalities associated with this condition are gonadotropin-independent precocious puberty and TSHindependent hyperthyroidism. 25 The thyroid is diffusely enlarged early in life 93 and subsequently becomes a multinodular goiter. 64 Although TSH levels are low and TSI is (with the exception of one reported patient) undetectable, radioiodine uptake in the thyroid is increased. 4, 128, 151 Because, unlike Graves' disease, hyperthyroidism in McCune-Albright syndrome does not spontaneously remit, thioureylene drug treatment must be continued indefinitely in this condition. Thus, ablative treatments often are preferred. Surgical excision has been the most frequently used treatment of this condition in childhood. Thyroid Neoplasms Thyrotoxicosis due to multinodular goiter (Plummer's disease) is extremely uncommon in childhood and adolescence. Most commonly, it occurs in association with other features of the McCune-Albright syndrome. 25,64 When it is unassociated with other McCune-Albright stigmata, it affects girls more frequently than boys.80, 124 Subtotal thyroidectomy has been the treatment for young patients with this unusual condition. Hyperthyroidism produced by a single thyroid adenoma is also rare in

1288

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

children. The overwhelming majority of children with this condition are girls. 56, 112, 118, 153 Surgical treatment comprises removal of the hyperfunctioning nodule; the remainder of the gland is left intact. Thyroid carcinoma produces thyrotoxicosis only rarely. The few thyroid tumors reported to have produced hyperthyroidism in children have been papillary carcinomas with follicular elements. 80, 148 These tumors are removed in association with subtotal or total thyroidectomy. TSH Hypersecretion TSH hypersecretion may be associated with a pituitary tumor. 168 Such tumors usually secrete only TSH but also may secrete growth hormone 141 or prolactin. 82 Most secrete excess a-subunit which may be measured in serum. 168 Such tumors may be treated by transsphenoidal tumor removal; however, approximately 60%14 of operated patients require postoperative pharmacologic treatment with bromocriptine35 or octreotide. 11 Some patients with TSH hypersecretion do not have demonstrable pituitary tumors. Some of these patients have central (hypothalamic and pituitary) resistance but peripheral sensitivity to thyroid hormones. 52 Occasionally, bromocriptine ameliorates the hyperthyroidism in such patients35 ; a more potent dopaminergic agonist, pergolide, is sometimes more efficacious. l45 Octreotide may be helpful in such patients, but its effect is frequently transient. 11, 84 The T3 analogue-3, 5, 3' -triiodothyroacetic acid-recently has been reported to be effective in treating thyrotoxicosis in patients with central resistance to thyroid hormone. 125

SUMMARY Hyperthyroidism in infants and children usually is caused by Graves' disease; however, several other diseases can also produce hyperthyroidism in these age groups. Because the pathophysiology and clinical course of these conditions differ, optimal treatment depends on precise diagnosis.

REFERENCES 1. Advisory Committee on the Biological Effects of Ionizing Radiations: The Effects on Populations of Exposure to Low Levels of Ionizing Radiation. Washington, DC, National Academy Press, 1980 2. 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 70:675, 1990 3. Amrhein JA, Kenny FM, Ross D: Granulocytopenia, lupus-like syndrome, and other complications of propylthiouracil therapy. J Pediatr 76:54, 1970 4. Andrews BS, Posen S, Podolsky S: Thyrotrophin in Albright's syndrome with hyperthyroidism (letter to the editor). Ann Intern Med 81:561, 1974 5. Astwood EB, Bissell A, Hughes AM: Further studies on the chemical nature of compounds which inhibit the function of the thyroid gland. Endocrinology 37:456, 1945 6. Bacon GE, Lowrey GH: Experience with surgical treatment of thyrotoxicosis in children. J Pediatr 67:1, 1965

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

1289

7. Bahn RS, Gorman CA, Johnson CM, et al: Presence of antibodies in the sera of patients with Graves' disease recognizing a 23 kilodalton fibroblast protein. J Clin Endocrinol Metab 69:622, 1989 8. Barnes HV, Blizzard RM: Antithyroid drug therapy for toxic diffuse goiter (Graves' disease): 30 years' experience in children and adolescents. J Pediatr 91:313, 1977 9. Bartalena L: Recent achievements in studies on thyroid hormone-binding proteins. Endocr Rev 11:47, 1990 10. Beahrs OH, Vandertoll DJ: Complications of secondary thyroidectomy. Surg Gynecol Obstet 117:535, 1963 11. Beck-Peccoz P, Mariotti S, Guillausseau pJ, et al: Treatment of hyperthyroidism due to inappropriate secretion of thyrotropin with the somatostatin analog SMS 201-995. J Clin Endocrinol Metab 68:208, 1989 12. Bjorkman V, Ekholm R, Ericson LE: Effects of thyrotropin on thyroglobulin exocytosis and iodination in the rat thyroid gland. Endocrinology 102:460, 1978 13. Blackett PR, Seely JR, Atmiller DH: Neonatal thyrotoxicosis following maternal hypothyroidism. J Pediatr 92:159, 1978 14. Brennergati L, Gershengorn MC: Thyroid-stimulating hormone-induced hyperthyroidism. In Imura H (ed): The Pituitary Gland. New York, Raven Press, 1985, p 467 15. Buckingham BA, Costin G, Kogut MD, et al: Pathologic and immune factors in thyroid disease. J Pediatr 91:728, 1977 16. Buckingham BA, Costin G, Roe TF, et al: Hyperthyroidism in children: A reevaluation of treatment. Am J Dis Child 135:112, 1981 17. Cevallos JL, Hagen GA, Maloof F, et al: Low-dosage 131 1 therapy of thyrotoxicosis (diffuse goiters): A five-year follow-up study. N Engl J Med 290:141, 1974 18. Cheung HS, Nicoloff JT, Kamiel MB, et al: Stimulation of fibroblast biosynthetic activity by serum of patients with pretibial myxedema. J Invest Dermatol 71:12, 1978 19. Cohen JH III, Ingbar SH, Braverman LE: Thyrotoxicosis due to ingestion of excess thyroid hormone. Endocr Rev 10:113, 1989 20. Consiglio E, Salvatore G, Rail JE, et al: Thyroglobulin interactions with thyroid plasma membranes: The existence of specific receptors and their potential role. J Bioi Chern 254:5065, 1979 21. Cooper DS: Antithyroid drugs. N Engl J Med 311:1353, 1984 22. Cooper DS, Saxe VC, Meskell M, et al: Acute effects of propylthiouracil (PTV) or thyroidal iodide organification and peripheral iodothyronine deiodination: Correlation with serum PTV levels measured by radioimmunoassay. J Clin Endocrinol Metab 54:101, 1982 23. Crawford JD: Hyperthyroidism in children: A reevaluation of treatment. Am J Dis Child 135:109, 1981 24. Daneman D, Howard NJ: Neonatal thyrotoxicosis: Intellectual impairment and craniosynostosis in later years. J Pediatr 97:257, 1980 25. Danon M, Crawford JD: The McCune-Albright syndrome. Ergeb Inn Med Kinderheilkd 55:81, 1987 26. DeGroot LJ, Larsen PR, Refetoff S, et al: The Thyroid and Its Diseases, ed 5. New York, John Wiley & Sons, 1984, p 62 27. DeGroot LJ, Quintans J: The causes of autoimmune thyroid disease. Endocr Rev 10:537, 1989 28. Dobyns BM, Sheline GE, Workman JB, et al: Malignant and benign neoplasms of the thyroid in patients treated for hyperthyroidism. A report of the cooperative thyrotoxicosis therapy follow-up study. J Clin Endocrinol Metab 38:976, 1974 29. Dunn JT: Choice of therapy in young adults with hyperthyroidism of Graves' disease: A brief, case-directed poll of fifty-four thyroidologists. Ann Intern Med 100:891, 1984 30. Eipe J, Johnson SA, Kiamko RT, et al: Hypoparathyroidism following 131 1 therapy for hyperthyroidism. Arch Intern Med 121:270, 1968 31. Ekins R: Measurement of free hormones in blood. Endocr Rev 11:5, 1990 32. Engstrom G, Ericson LE: Effect of graded doses of thyrotropin on exocytosis and early phase of endocytosis in the rat thyroid. Endocrinology 108:399, 1981 33. Ericsson V-B, Christensen SB, Thorell JI: A high prevalence of thyroglobulin autoantibodies in adults with and without thyroid disease as measured with a sensitive solidphase immunosorbent radioassay. Clin Immunol Immunopathol 37:154, 1985

1290

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

34. Esselstyn CB Jr, Schumacher OP, Eversman J, et al: Hyperparathyroidism after radioactive iodine therapy for Graves disease. Surgery 92:811, 1982 35. Faglia G, Beck-Peccoz P, Piscitelli G, et al: Inappropriate secretion of thyrotropin by the pituitary. Horm Res 26:79, 1987 36. Fisher DA: Neonatal thyroid disease in the offspring of women with autoimmune thyroid disease. Thyroid Today 9:1, 1986 37. Fisher DA: Pediatric aspects. In Werner SC, Ingbar SH (eds): The Thyroid: A Fundamental and Clinical Text, ed 4. Hagerstown, Maryland, Harper & Row, 1978, p 805 38. Fisher DA: The thyroid. In Kaplan SA (ed): Clinical Pediatric Endocrinology, ed 2. Philadelphia, WB Saunders, 1990, p 87 39. Fisher DA, Oddie TH, Johnson DE, et al: The diagnosis of Hashimoto's thyroiditis. J Clin Endocrinol Metab 40:795, 1975 40. Fisher DA, Pandian MR, Carlton E: Autoimmune thyroid disease: An expanding spectrum. Pediatr Clin North Am 34 no. 4:907, 1987 41. Foley TP Jr, White C, New B: Juvenile Graves disease: Usefulness and limitations of thyrotropin receptor antibody determinations. J Pediatr 110:378, 1987 42. Fradkin JE, Wolff J: Iodide-induced thyrotoxicosis. Medicine (Baltimore) 62:1, 1983 43. Frazier-Seabrook L, Segaloff DL, Seeburg PH, et al: Isolation of a putative TSH receptor cDNA (abstract). Program and Abstracts. 71st Annual Meeting, Endocrine Society, 1989, p 290 44. Freitas JE, Swanson DP, Gross MD, et al: Iodine-131: Optimal therapy for hyperthyroidism in children and adolescents? J Nucl Med 20:847, 1979 45. Fulop M: Hypoparathyroidism after 1311 therapy (letter to the editor). Ann Intern Med 75:808, 1971 46. Furmaniak J, Jones ED, Buckland PR, et al: Assessment of the shape and molecular size of TSH-TSH receptor complexes. Mol Cell Endocrinol 48:31, 1986 47. Furszyfer J, Kurland LT, McConahey WM, et al: Graves' disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clin Proc 45:636, 1970 48. Gaisford W, Mann NM: Neonatal thyrotoxicosis. Proc R Soc Med 61:304, 1968 49. Gamblin GT, Harper DG, Galentine P, et al: Prevalence of increased intraocular pressure in Graves' disease: Evidence of frequent subclinical ophthalmopathy. N Engl J Med 308:420, 1983 50. Gardner DG, Hane S, Gertz BJ: Expression of the gene for atrial natriuretic factor is regulated by thyroid hormone (abstract). Program and Abstracts. 68th Annual Meeting, Endocrine Society, 1986, p 60 51. Gavaret J-M, Cahnmann HJ, Nunez J: Thyroid hormone synthesis in thyroglobulin: The mechanism of the coupling reaction. J Bioi Chem 256:9167, 1981 52. Gershengorn MC, Weintraub BD: Thyrotropin-induced hyperthyroidism caused by selective pituitary resistance to thyroid hormone: A new syndrome of "inappropriate secretion of TSH." J Clin Invest 56:633, 1975 53. Goldsmith RE: Radioisotope therapy for Graves' disease. Mayo Clin Proc 47:953, 1972 54. Gordin A, Lamberg B-A: Spontaneous hypothyroidism in symptomless autoimmune thyroiditis. A long-term follow-up study. Clin Endocrinol 15:537, 1981 55. Gorman CA, Duick DS, Woolner LB, et al: Transient hyperthyroidism in patients with lymphocytic thyroiditis. Mayo Clin Proc 53:359, 1978 56. Granoff AB, Hershman JM: Suppression of pituitary TSH in a child with a hyperfunctioning thyroid nodule. J Pediatr 90:83, 1977 57. Graves RJ: Newly observed affection of the thyroid gland in females. In Major RH (ed): Classic Descriptions of Disease: With Biographical Sketches of the Authors, ed 3. Springfield, Illinois, Charles C Thomas, 1945, p 280 58. Greene IN: Subacute thyroiditis. Am J Med 51:97, 1971 59. Greer MA, Kammer H, Bouma DJ: Short-term antithyroid drug therapy for the thyrotoxicosis of Graves's disease. N Engl J Med 297:173, 1977 60. Guernsey DL, Edelman IS: Regulation of thermogenesis by thyroid hormones. In Oppenheimer JH, Samuels HH (eds): Molecular Basis of Thyroid Hormone Action. New York, Academic Press, 1983, p 293 61. Gwinup G: Prospective randomized comparison of propylthiouracil. JAM A 239:2457, 1978

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

1291

62. Halsted WS: The operative story of goitre: The author's operation. Johns Hopkins Hospital Reports 19:71, 1920 63. Hamburger JI: Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab 60:1019, 1985 64. Hamilton CR Jr, Maloof F: Unusual types of hyperthyroidism. Medicine (Baltimore) 52:195, 1973 65. Hamilton HE, Schultz RO, De Gowin EL: The endocrine eye lesion in hyperthyroidism: Its incidence and course in 165 patients treated for thyrotoxicosis with iodine 131. Arch Intern Med 105:675, 1960 66. Harland PC, McArthur RG, Fawcett DM: T3 toxicosis in children. Acta Paediatr Scand 66:525, 1977 67. Hartzband PA, Solomon DH: The treatment of hyperthyroidism. Dis Mon 27(10):1, 1981 68. Hati RN, DeGroot LJ: Studies on the mechanism of iodination supported by thyroidal NADPH-cytochrome c reductase. Acta Endocrinol (Copenh) 74:271, 1973. 69. Hawe P, Francis HH: Pregnancy and thyrotoxicosis. Br Med J 2:817, 1962 70. Hay ID, Klee GG: Thyroid dysfunction. Endocrinol Metab Clin North Am 17(3):473, 1988 71. Hayek A, Chapman EM, Crawford JD: Long-term results of treatment of thyrotoxicosis in children and adolescents with radioactive iodine. N Engl J Med 283:949, 1970 72. Hayles AB, Chaves-Carballo E: Exophthalmic goiter in children: a therapeutic trial with antithyroid drugs. Mayo Clin Proc 40:884, 1965 73. Hayles AB, Kennedy RLJ, Beahrs OH, et al: Exophthalmic goiter in children. J Clin Endocrinol Metab 19:138, 1959 74. Hershman JM, Givens JR, Cassidy CE, et al: Long-term outcome of hyperthyroidism treated with antithyroid drugs. J Clin Endocrinol Metab 26:803, 1966 75. Hirata Y: Methimazole and insulin autoimmune syndrome with hypoglycaemia (letter to the editor). Lancet 2:1037, 1983 76. Hiromatsu Y, Fukazawa H, Guinard F, et al: A thyroid cytotoxic antibody that crossreacts with an eye muscle cell surface antigen may be the cause of thyrOid-associated ophthalmopathy. J Clin Endocrinol Metab 67:565, 1988 77. Holder AT, Wallis M: Actions of growth hormone, prolactin and thyroxine on serum somatomedin-like activity and growth in hypopituitary dwarf mice. J Endocrinol 74:223, 1977 78. Hollingsworth DR, Mabry CC: Congenital Graves disease: Four familial cases with longterm follow-up and perspective. Am J Dis Child 130:148, 1976 79. Holm L-E, Dahlqvist I, Israelsson A, et al: Malignant thyroid tumors after iodine-131 therapy: A retrospective cohort study. N Engl J Med 303:188, 1980 80. Hopwood NJ, Carroll RG, Kenny FM, et al: Functioning thyroid masses in childhood and adolescence. J Pediatr 89:710, 1976 81. Hopwood NJ, Sauder SE, Shapiro B, et al: Familial partial peripheral and pituitary resistance to thyroid hormone: A frequently missed diagnosis? Pediatrics 78:1114, 1986 82. Horn K, Erhardt F, Fahlbusch R, et al: Recurrent goiter, hyperthyroidism, galactorrhea and amenorrhea due to a thyrotropin and prolactin-producing pituitary tumor. J Clin Endocrinol Metab 43:137, 1976 83. litaka M, Aguayo JF, Iwatani Y, et al: In vitro induction of anti-thyroid microsomal antibody secreting cells in peripheral blood mononuclear cells from normal subjects. J Clin Endocrinol Metab 67:749, 1988 84. Isales CM, Tamborlane W, Gertner JM, et al: Effect of short-term somatostatin and long-term triiodothyronine administration in a child with non tumorous inappropriate thyrotropin secretion. J Pediatr 112:51, 1988 85. Izumo S, Lompnl A-M, Matsuoka R, et al: Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy: Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest 79:970:1987 86. Jablonski P, McQuillan MT: The distribution of proteolytic enzymes in the thyroid gland. Biochim Biophys Acta 132:454, 1967 87. Kajita Y, Rickards CR, Buckland PR, et al: Analysis of thyrotropin receptors by photoaffinity labeling: Orientation of receptor subunits in the cell membrane. Biochem J 227:413, 1985

1292

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

88. Karpman BA, Rapoport B, Filetti S, et al: Treatment of neonatal hyperthyroidism due to Graves' disease with sodium ipodate. J Clin Endocrinol Metab 64:119, 1987 89. Knopp J, StoIc V, Tong W: Evidence for the induction of iodide transport in bovine thyroid cells treated with thyroid-stimulating hormone or dibutyryl cyclic adenosine 3' ,5' -monophosphate. J BioI Chern 245:4403, 1970 90. Kogut MD, Kaplan SA, Collipp pJ, et al: Treatment of hyperthyroidism in children: Analysis of forty-five patients. N Eng! J Med 272:217, 1965 91. Landsberg L, Young JB: Catecholamines and the sympathoadrenal system. In Ingbar SH, Braverman LE (eds): Werner's The Thyroid: A Fundamental and Clinical Text, ed 5. Philadelphia, JB Lippincott, 1986, p 910 92. Larsen PR: Thyroid hormone concentrations. In Ingbar SH, Braverman LE (eds): Werner's The Thyroid: A Fundamental and Clinical Text, ed 5. Philadelphia, JB Lippincott, 1986, p 479 93. Levitsky LL, Trias E, Grossman MS: Spontaneous thyrotoxicosis in infancy: Report of a case. Pediatrics 46:627, 1970 94. Levy WJ, Schumacher OP: Long term follow-up of children and adolescents treated with P" for Grave's disease (abstract). Program and Abstracts. 63rd Annual Meeting, Endocrine Society, 1981, p 266 95. Levy WJ, Schumacher OP, Gupta M: Treatment of childhood Graves' disease: A review with emphasis on radioiodine treatment. Cleve Clin J Med 55:373, 1988 96. 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 64:1241, 1987 97. Ludgate ME, McGregor AM, Weetman AP, et al: Analysis of T cell subsets in Graves' disease: Alterations associated with carbimazole. Br Med J 228:526, 1984 98. Maenpaa J, Kuusi A: Childhood hyperthyroidism: Results of treatment. Acta Paediatr Scand 69:137, 1980 99. Marchant B, Lees JFH, Alexander WD: Antithyroid drugs. Pharmacol Ther 3:305, 1978 100. Martino E, Baschieri L, Aghini-Lombardi F, et al: Successful treatment of amiodaroneassociated thyrotoxicosis (AAT) with KCIO. and methimazole (abstract). Ann Endocrinol (Paris) 45:15, 1984 101. McDermott MT, Kidd GS, Dodson LE Jr, et al: Radioiodine-induced thyroid storm: Case report and literature review. Am J Med 75:353, 1983 102. McLachlan SM, Pegg CAS, Atherton MC, et al: The effect of carbimazole on thyroid autoantibody synthesis by thyroid lymphocytes. J Clin Endocrinol Metab 60:1237, 1985 103. Mendel CM: The free hormone hypothesis: A physiologically based mathematical model. Endocr Rev 10:232, 1989 104. Miller PVH, Myrtle JF, Wang R: TSH quantification in human serum by a sensitive and specific immunoradiometric assay (abstract). Clin Chern 29:1160, 1983 105. Mukku VR: Regulation of epidermal growth factor receptor levels of thyroid hormones. J BioI Chern 25:6453, 1984 106. Munro DS, Dirmikis SM, Humphries H, et al: The role of thyroid stimulating immunoglobulins of Graves's disease in neonatal thyrotoxicosis. Br J Obstet Gynaecol 85:837, 1978 107. Murray GR: Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. Br Med J 2:796, 1891 lOB. Nagasaka A, Hidaka H: Quantitative modulation of thyroid iodide peroxidase by thyroid stimulating hormone. Biochem Biophys Res Commun 96:1143, 1980 109. Nikolai TF, Coombs GJ, McKenzie AK, et al: Treatment oflymphocytic thyroiditis with spontaneously resolVing hyperthyroidism (silent thyroiditis). Arch Intern Med 142:2281, 1982 110. Nunez J, Jacquemin C, Brun D, et al: Protc~ines iodees particulaires thyroi'diennes. II. Biosynthese Proteique et iodation. Biochim Biophys Acta 107:454, 1965 Ill. Oppenheimer JH, Schwartz HL, Mariash CN, et al: Advances in our understanding of thyroid hormone action at the cellular level. Endocr Rev 8:288, 1987 112. Osburne RC, Goren EN, Bybee DE, et al: Autonomous thyroid nodules in adolescents: Clinical characteristics and results of TRH testing. J Pediatr 100:383, 1982 113. Osler W: The Principles and Practice of Medicine, ed 7. New York, D Appleton, 1909, p765

T

HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

1293

114. Parry CH: Collections from the Unpublished Medical Writings, vol II. London, Underwoods, 1825, p III 115. Peak RL, Cates RJ, Deiss WP Jr: Thyroglobulin degradation: Particulate intermediates produced in vivo. Endocrinology 87:494, 1970 116. Phillips D, McLachlan S, Stephenson A, et al: Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. J Clin Endocrinol Metab 70:742, 1990 117. Piccinni LA, MacKenzie W A, Platzer M, et al: Lymphokine regulation of HLA-DR gene expression in human thyroid cell monolayers. J Clin Endocrinol Metab 64:543, 1987 118. Popma BH, Cloutier MD, Hayles AB: Thyroid nodule producing T3 toxicosis in a child. Mayo Clin Proc 48:273, 1973 119. Refetoff S: Thyroid hormone resistance syndromes. In Ingbar SH, Braverman LE (eds): Werner's The Thyroid: A Fundamental and Clinical Test, ed 5. Philadelphia, JB Lippincott, 1986, p 1292 120. Reynolds LR, Bhathena D: Nephrotic syndrome associated with methimazole therapy. Arch Intern Med 139:236, 1979 121. Robertson JS, Gorman CA: Gonadal radiation dose and its genetic significance in radioiodine therapy of hyperthyroidism. J Nucl Med 17:826, 1976 122. Romaldini JH, Bromberg N, Werner RS, et al: Comparison of effects of high and low dosage regimens of antithyroid drugs in the management of Graves' hyperthyroidism. J Clin Endocrinol Metab 57:563, 1983 123. Rosenberg IN, Goswani A: Purification and characterization of a flavoprotein from bovine thyroid with iodotyrosine deiodinase activity. J BioI Chem 254:12318, 1979 124. Rosenbloom AL, Pierson KK: Nodular toxic goiter (Plummer's disease) in a child. J Pediatr 84:104, 1974 125. Salmela PI, Wide L, Juustila H, et al: Effects of thyroid hormones (T4' T3), bromocriptine and triac on inappropriate TSH hypersecretion. Clin Endocrinol 28:497, 1988 126. Salvi M, Fukazawa H, Bernard N, et al: Role of autoantibodies in the pathogenesis and association of endocrine autoimmune disorders. Endocr Rev 9:450, 1988 127. Salvi M, Zhang Z-G, Haegert D, et al: Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalities. J Clin Endocrinol Metab 70:89, 1990 128. Samuel S, Gilman S, Maurer HS, et al: Hyperthyroidism in an infant with McCuneAlbright syndrome: Report of a case with myeloid metaplasia. J Pediatr 80:275, 1972 129. Samuels HH, Forman BM, Horowitz ZD, et al: Regulation of gene expression by thyroid hormone. J Clin Invest 81:957, 1988 130. Sattler H; Marchand GW, Marchand JF, trans: Basedow's disease. New York, Grune & Stratton, 1952, p 367 131. Sawin CT: Defining thyroid hormone: Its nature and control. In McCann SM (ed): Endocrinology: People and Ideas. Bethesda, Maryland, American Physiological Society, 1988, p 149 132. Saxena KM, Crawford JD, Talbot NB: Childhood thyrotoxicosis: A long-term perspective. Br Med J 2:1153, 1964 133. Schlesinger S, MacGillivray MH, Munschauer RW: Acceleration of growth and bone maturation in childhood thyrotoxicosis. J Pediatr 83:233, 1973 134. Schleusener H, Schwander J, Fischer C, et al: Prospective multicenter study on the prediction of relapse after antithyroid drug treatment in patients with Graves' disease. Acta Endocrinol (Copenh) 120:689, 1989 135. Shafer RB, Nuttall FQ: Thyroid crisis induced by radioactive iodine. J Nucl Med 12:262, 1971 136. Shenkman L, Bottone EJ: Antibodies to Yersinia enterocolitica in thyroid disease. Ann Intern Med 85:735, 1976 137. Shiroozu A, Okamura K, Ikenoue H, et al: Treatment of hyperthyroidism with a small single daily dose of methimazole. J Clin Endocrinol Metab 63:125, 1986 138. Sinclair JC, Silverman WA: Congenital thyrotoxicosis (letter to the editor). Lancet 2: 1068, 1964 139. Singer J: Neonatal thyrotoxicosis. J Pediatr 91:749, 1977 140. Smallridge RC, Wartofsky L, Chopra II. et al: Neonatal thyrotoxicosis: Alterations in serum concentrations of LATS-protector, T., T3 , reverse T3 , and 3,3'T2 • J Pediatr 93:118, 1978

T 1294

DONALD ZIMMERMAN AND MARGARET GAN-GAISANO

141. Smallridge RC, Wartofsky L, Dimond RC: Inappropriate secretion of thyrotropin: Discordance between the suppressive effects of corticosteroids and thyroid hormone. J Clin Endocrinol Metab 48:700, 1979 142. Smith BR, McLachlan SM, Furmaniak J: Autoantibodies to the thyrotropin receptor. Endocr Rev 9:106, 1988 143. Smyrk TC, Goellner JR, Brennan MD, et al: Pathology of the thyroid in amiodaroneassociated thyrotoxicosis. Am J Surg Pathol 11:197, 1987 144. Solomon DH, Beck JC, VanderLaan WP, et al: Prognosis of hyperthyroidism treated by antithyroid drugs. JAMA 152:201, 1953 145. Sriwatanakul K, McCormick K, Woolf P: Thyrotropin (TSH)-induced hyperthyroidism: Response of TSH to dopamine and its agonists. J Clin Endocrinol Metab 58:255, 1984 146. Starr P, Jaffe HL, Oettinger L Jr: Later results of l3lI treatment of hyperthyroidism in 73 children and adolescents: 1967 followup. J Nue! Med 10:586, 1969 147. Sunshine P, Kusumoto H, Kris JP: Survival time of circulating long-acting thyroid stimulator in neonatal thyrotoxicosis: Implications for diagnosis and therapy of the disorder. Pediatrics 36:869, 1965 148. Sussman L, Librik L, Clayton GW: Hyperthyroidism attributable to a hyperfunctioning thyroid carcinoma. J Pediatr 72:208, 1968 149. Tamagna El, Levine GA, Hershman JM: Thyroid-hormone concentrations after radioiodine therapy for hyperthyroidism. J Nue! Med 20:387, 1979 150. Tarnai H, Nakagawa T, Fukino 0, et al: Thionamide therapy in Graves' disease: Relation of relapse rate to duration of therapy. Ann Intern Med 92:488, 1980 151. Tanaka T, Suwa S: A case of McCune-Albright syndrome with hyperthyroidism and vitamin D-resistant rickets. Helv Paediatr Acta 32:263, 1977 152. Takamatsu J, Kuma K, Mozai T: Serum triiodothyronine to thyroxine ratio: A newly recognized predictor of the outcome of hyperthyroidism due to Graves' disease. J Clin Endocrinol Metab 62:980, 1986 152a. Taurog A: Hormone synthesis: Thyroid iodine metabolism. In Ingbar SH, Braverman LE (eds): Werner's The Thyroid: A Fundamental and Clinical Text, ed 5. Philadelphia, JB Lippincott, 1986, p 53 153. Taylor HC: Solitary hyperfunctioning thyroid adenoma in a child: Elevated T3 and T4 levels with normal TSH level. JAMA 234:1253, 1975 154. Thompson CC, Weinberg C, Lebo R, et al: Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science 237:1610, 1987 155. T6tterman TH, Karlsson E, Bengtsson M, et al: Induction of circulating activated suppressor-like T cells by methimazole therapy for Graves' disease. N Engl J Med 316: 15, 1987 156. Uretsky SH, Kennerdell JS, Gutai JP: Graves' ophthalmopathy in childhood and adolescence. Arch Ophthalmol 98:1963, 1980 157. Vaidya VA, Bongiovanni AM, Parks JS, et al: Twenty-two years' experience in the medical management of juvenile thyrotoxicosis. Pediatrics 54:565, 1974 158. Van Herle AJ, Vassart G, Dumont JE: Control of thyroglobulin synthesis and secretion. N Engl J Med 301:239, 1979 159. Vidor GI, Stewart JC, Wall JR, et al: Pathogenesis of iodide-induced thyrotoxicosis: Studies in northern Tasmania. J Clin Endocrinol Metab 37:901, 1973 160. Volpe R: Subacute thyroiditis. In Delange F, Fisher DA, Malvaux P (eds): Pediatric Thyroidology. Basel, S Karger, 1985, p 252 161. Volpe R, Ehrlich R, Steiner G, et al: Graves' disease in pregnancy years after hypothyroidism with recurrent passive-transfer neonatal Graves' disease in offspring. Am J Med 77:572, 1984 162 Volpe R, Karlsson A, Jansson R, et al: Evidence that antithyroid drugs induce remissions in Graves' disease by modulating thyroid cellular activity. Clin Endocrinol 25:453, 1986 163. Volpe R, Row VV, Ezrin C: Circulating viral and thyroid antibodies in subacute thyroiditis. J Clin Endocrinol Metab 27:1275, 1967 164. Von Basedow CA: Exophthalmos by hypertrophy of the cellular tissue in the orbital cavity. In Major RH (ed): Classic Descriptions of Disease: With Biographical Sketches of the Authors, ed 3. Springfield, Illinois, Charles C Thomas, 1945, p 282 165. Wai-Nang PL, Mpanias PD, Wimmer RJ, et al: Use of 1-123 in early radioiodide uptake

T HYPERTHYROIDISM IN CHILDREN AND ADOLESCENTS

166. 167. 168. 169. 170.

171. 172.

173. 174. 175. 176. 177.

178.

1295

and its suppression in children and adolescents with hyperthyroidism. J Nucl Med 19:985, 1978 Waterhouse J, Muir C, Correa P, et al: Cancer Incidence in Five Continents, vol 3. Lyon, International Agency for Research on Cancer, 1976 Weinberger C, Thompson CC, Ong ES, et al: The c-erh A gene encodes a thyroid hormone receptor. Nature 324:641, 1986 Weintraub BD, Gershengorn MC, Kourides lA, et al: Inappropriate secretion of thyroidstimulating hormone. Ann Intern Med 95:339, 1981 Weiss M, Ingbar SH, Winblad S, et al: Demonstration of a saturable binding site for thyrotropin in Yersinia enterocolitica. Science 219:1331, 1983 Wenzel BE, Heesemann J, Wenzel KW, et al: Patients with autoimmune diseases have antibodies to plasmid-encoded proteins of enteropathogenic Yersinia. J Endocrinol Invest 11: 139, 1988 White C: A foetus with congenital hereditary Graves's disease. J Obstet Gynaecol Br Emp 21:231, 1912 Williams RS, Lefkowitz RJ: The effects of thyroid hormone on adrenergic receptors. In Oppenheimer JH, Samuels HH (eds): Molecular Basis of Thyroid Hormone Action. New York, Academic Press, 1983, p 325 Wimpfheimer C, Staubli M, Schadelin J, et al: Prednisone in amiodarone-induced thyrotoxicosis. Br Med J 284:1835, 1982 Wolff J: Transport of iodide and other anions in the thyroid gland. Physiol Rev 44:45, 1964 Young LA: Dysthyroid ophthalmopathy in children. J Pediatr Ophthalmol Strabismus 16:105, 1979 Zakarija M, McKenzie JM, Hoffman WH: Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism. J Clin Endocrinol Metab 62:368, 1986 Zakarija M, McKenzie JM, Munro DS: Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves' disease. J Clin Invest 72:1352, 1983 Zimmerman D, Hayles AB: Treatment of Graves' disease in children. In Mellinger JF, Stickler GB (eds): Critical Problems in Pediatrics. Philadelphia, JB Lippincott, 1983, p 69

Address reprint requests to Donald Zimmerman, MD Mayo Clinic 200 First Street SW Rochester, MN 55905