Stephen H. Lafranchi
Cheryl E. Hanna
Thyrotoxicosis is less common in children and adolescents than in adults, and it is rare in neonates. In all three groups, the cause is nearly always Graves' disease, as in adults. Most aspects of thyrotoxicosis (and Graves' disease) in neonates, children, and adolescents are similar to those in adults, but a few are age specific. For example, in neonates, the thyrotoxicosis is transient, and it has effects on growth and development of the nervous system. In children, thyrotoxicosis has effects on growth, pubertal development, and the skeleton that do not occur in adults. Graves' ophthalmopathy is seldom as severe as in adults, and localized myxedema is extremely rare. Furthermore, the differential diagnosis of hyperthyroxinemia is different in childhood; thyrotoxicosis is the most frequent cause, rather than pregnancy and estrogen therapy, and generalized resistance to thyroid hormones and inherited abnormalities in thyroxine (T4) transport proteins are relatively more common than in adults. With respect to treatment of Graves' thyrotoxicosis, there is more reluctance to undertake destructive therapy than in adults, although radioiodine therapy is gaining acceptance in adolescents.
NEONATAL THYROTOXICOSIS
Incidence
Neonatal thyrotoxicosis is rare, accounting for at most 1% of the cases of thyrotoxicosis in childhood, and is nearly always associated with maternal Graves' disease. Usually, the mother has a history of Graves' thyrotoxicosis; in many cases, the mother had thyrotoxicosis during the pregnancy, but sometimes she had received destructive antithyroid treatment before the pregnancy and was taking T4 during it. A few mothers have had chronic autoimmune thyroiditis (Hashimoto's disease) rather than Graves' disease. Neonatal Graves' thyrotoxicosis occurs in fewer than 2% of infants born to mothers who had Graves' thyrotoxicosis during or before the pregnancy (1), although a few neonates with mild thyrotoxicosis may escape detection. The condition occurs with equal frequency in boys and girls.
Pathogenesis
Graves' thyrotoxicosis in neonates is caused by the transplacental passage of thyrotropin (TSH) receptor–stimulating antibodies (TSHR-SAbs) (2,4,5,6), meaning that the mother must be producing these antibodies late in gestation. The mothers of many affected neonates have thyrotoxicosis during that pregnancy, but that is not essential, as noted above. In those mothers who did have thyrotoxicosis during pregnancy, the clinical severity of their thyrotoxicosis is a poor predictor of neonatal thyroid status, but measurements of TSHR-SAbs in maternal serum are useful in this regard (2,7,8,9,10,11). Thyrotoxicosis is likely only in infants of mothers who have high serum TSHR-SAb values, for example, greater than 500% of control values in assays based on inhibition by serum of binding of radiolabeled TSH to TSH receptors (10,11). Assays of this type do not measure biologic activity, and the prediction of neonatal thyrotoxicosis is more accurate when TSHR-SAbs are measured by biologic assays (7,9) (see Chapter 15 and section Pathogenesis in Chapter 23).
Serum TSHR-SAbs should be measured in mid- or late pregnancy in pregnant women with Graves' thyrotoxicosis to identify at-risk neonates, and measurements in the neonates also may be useful in identifying those likely to develop thyrotoxicosis if it is not present then, as in neonates of mothers who are receiving an antithyroid drug (12). The occurrence of thyrotoxicosis only in neonates whose mothers have high serum TSHR-SAb values indicates that transplacental passage of the antibodies is limited.
Transplacental passage of maternal TSHR-SAbs can cause fetal as well as neonatal thyrotoxicosis. Placental transport of TSHR-SAbs from maternal to fetal circulation increases from 5% to 8% of maternal levels at 15 weeks' gestation to approximately maternal levels by 30 weeks' gestation (13). Fetuses with thyrotoxicosis have tachycardia, hyperactivity, and poor growth, skeletal and brain maturation may be accelerated, and fetal hydrops has been described. Intrauterine death may also occur, particularly if the mother has severe (and usually untreated) thyrotoxicosis (13). How often fetal thyrotoxicosis occurs is not known, but in mothers treated with an antithyroid drug, it is probably uncommon (see Chapter 80).
Graves' thyrotoxicosis in neonates subsides spontaneously as the maternal TSHR-SAbs disappear from the infant's serum. The serum half-life of immunoglobulin G in neonates is about 14 days; depending on the serum TSHR-SAb concentrations at the time of delivery, the thyrotoxicosis disappears in 3 to 12 weeks.
A rarer form of neonatal thyrotoxicosis is not associated with maternal autoimmune thyroid disease and persists indefinitely (13,14,15). It is caused by germ line mutations in the transmembrane region of the TSH receptor that result in constitutive activation of the receptor (see Chapter 25). These mutations may be inherited as an autosomal-dominant trait or occur sporadically as new mutations (15,16,17,18,19). Not all affected patients are neonates; the thyrotoxicosis may first become evident during childhood or even later. Cases of neonatal thyrotoxicosis associated with McCune-Albright syndrome also have been reported (20); these are caused by somatic activating mutations in the α subunit of the guanine nucleotide-binding protein (G protein), which is a component of the adenylyl cyclase signal transduction pathway.
Clinical Manifestations
The birth weight of neonates with thyrotoxicosis is often low. Delivery may be premature, according to postconception estimates, although skeletal maturation may be accelerated as a result of thyrotoxicosis (21). They may have microcephaly, enlargement of their cerebral ventricles (22), frontal bossing, or triangular facies. Hyperphagia is common, but weight gain is poor despite a high caloric intake. They are irritable and difficult to console. Fever and diarrhea may also occur. Most have prominent eyes and a small diffuse goiter; rarely, the goiter may be large enough to cause tracheal obstruction. Tachycardia and bounding pulses are almost invariably present, and cardiomegaly, congestive heart failure, cardiac arrhythmias, systemic and pulmonary hypertension, jaundice, hepatosplenomegaly, and thrombocytopenia also may occur. Premature infants with thyrotoxicosis have similar abnormalities (23).in utero
The onset, severity, and duration of symptoms in neonates with Graves' thyrotoxicosis are variable. Some are thyrotoxic at birth, but those whose mothers were receiving an antithyroid drug at the time of delivery may not become thyrotoxic for several days, until the drug is metabolized. Rarely, antibodies that block TSH action as well as those that mimic TSH action are passed transplacentally to the fetus; in one case, the blocking antibodies prevented the effect of the stimulating antibodies for 4 to 6 weeks, thus delaying the onset of thyrotoxicosis (24).
Diagnosis and Treatment
The diagnosis of neonatal thyrotoxicosis should be confirmed by measurements of serum total and free T4 and serum TSH (see Chapter 44). Indeed, cord blood for these measurements should be obtained in any infant delivered by a woman with a history of Graves' thyrotoxicosis. It is important to note that the ranges for serum total and free T4 [and triiodothyronine (T3)] are higher in normal neonates than in normal adults (see Chapter 74).
Treatment should be initiated promptly in neonates with obvious thyrotoxicosis without awaiting laboratory confirmation. Either methimazole (MMI), 0.5 to 1 mg/kg daily, or propylthiouracil (PTU), 5 to 10 mg/kg daily, should be administered orally every 8 to 12 hours to inhibit thyroid hormone synthesis. The response to an antithyroid drug may be erratic in extremely premature infants, and they require more careful monitoring than do infants of more mature gestational age (23). In severely ill infants, propranolol, 2 mg/kg daily, is helpful in slowing the pulse rate and reducing hyperactivity. Inorganic iodine also may be given to inhibit thyroid hormone synthesis and release, in the form of low doses of Lugol's solution or potassium iodide (see Chapter 45). A more experimental, but apparently effective, method for giving iodine has been to administer iopanoic acid, an iodinated cholecystographic agent, in a dose of 100 to 200 mg daily or 500 mg every third day; this iodine-rich agent inhibits thyroid secretion and extrathyroidal conversion of T4 to T3 (it is no longer aailable in the United States) (25,26,27). Neonates with severe clinical thyrotoxicosis are often given a glucocorticoid, which in high doses decreases extrathyroidal conversion of T4 to T3 and also may inhibit thyroid secretion. Digoxin may be necessary for treatment of heart failure.
The rare neonates with thyrotoxicosis resulting from a TSH-receptor mutation or McCune-Albright syndrome also should be treated with an antithyroid drug initially. Because their thyrotoxicosis is permanent, however, they should be treated with radioiodine or thyroidectomy later (16,17,18,19,28).
With respect to fetal thyrotoxicosis, it should be suspected in a fetus with a heart rate exceeding 160 beats/min after 22 weeks' gestation, hyperactivity, and poor growth. Fetal thyrotoxicosis may have deleterious skeletal and neurologic effects; therefore, treatment should be considered if it is severe. Thyrotoxic fetuses may be treated by giving the mother an antithyroid drug; the dose should be adjusted to maintain a fetal heart rate of about 140 beats/min (29). Treatment should be monitored clinically and by ultrasonography; an enlarging thyroid gland is evidence of overtreatment. Normal reference values for fetal thyroid gland size throughout gestation have been established (30). Fetal blood sampling by cordocentesis can be done for laboratory tests (31,32), but can result in complications including fetal loss (13). Maternal and fetal thyrotoxicosis discovered during labor has been effectively treated with labetalol (33).
Prognosis
In most neonates, improvement is rapid, and treatment can be withdrawn in several weeks or months, according to the results of clinical examination and measurements of serum T4 and TSH. In the rare infants in whom thyrotoxicosis persists longer than 3 to 4 months, it more likely is due to a TSH receptor mutation or the McCune-Albright syndrome than Graves' disease.
The mortality rate secondary to prematurity, congestive heart failure, and airway obstruction was estimated to be as high as 25% in the past, but is considerably lower now. Long-term morbidity, which includes growth retardation, craniosynostosis, hyperactivity, and impairment of intellectual function, is common (14,22,34), and may occur even in neonates treated promptly and adequately, suggesting that fetal thyrotoxicosis permanently affects the developing skeleton and brain. In addition, central (pituitary) hypothyroidism, which may be secondary to prenatal exposure of the hypothalamus and pituitary to high serum thyroid hormone concentrations during a critical stage of development, has been reported to follow neonatal thyrotoxicosis (35,35a).
THYROTOXICOSIS IN CHILDHOOD
The vast majority of cases of thyrotoxicosis in children and adolescents are caused by Graves' disease, and the proportion caused by Graves' disease is higher than in adults. It may begin in infancy, but it is rare in children less than 5 years old (30,32,33). The incidence progressively increases throughout childhood, with a peak incidence in children 11 to 15 years of age (36,37,38). Childhood Graves' thyrotoxicosis is still uncommon, however, accounting for fewer than 5% of all cases. The prevalence in children approximates 0.02%. Girls are more commonly affected than boys, with a female:male ratio of 3:1 to 6:1 (36,37,38,39). The incidence of Graves' disease in children varies on a geographic or racial/ethnic basis. In Denmark, the incidence was 0.79/100,000/year between 1982 and 1988 (40). In Hong Kong Chinese children under 15 years of age, the incidence was 3.2/100,000/year for the time period 1989 to 1993, and it was 6.5/100,00/year in 1994 to 1998 (41); the increase in incidence rate for girls was statistically significant (41).
Most children with Graves' thyrotoxicosis have a family history of some type of autoimmune thyroid disease (38), and some have other autoimmune endocrine diseases, such as type 1 diabetes mellitus and Addison's disease (42). Nonendocrine autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, vitiligo, idiopathic thrombocytopenic purpura, and pernicious anemia, also have been described in these children (42). Human leukocyte antigen DR haplotypes differ in patients according to their age of onset (see Chapter 20) (43). In addition, Graves' thyrotoxicosis is more common in children with Down syndrome than in normal children (24,42). Graves' disease may also be part of the clinical spectrum associated with the 22q11.2 deletion (DiGeorge's) syndrome (44).
Clinical Features
The main clinical features of thyrotoxicosis in children and adolescents are similar to those in adults (36,37,38,39) (Table 76.1). Excluding weight loss and atrial fibrillation, the common symptoms and signs of thyrotoxicosis are at least as frequent in children as in adults (45). Onset is often insidious, and many children have what they and their parents recall as just a few symptoms for several months or even years before the child is brought for care, even though at that time a history of many symptoms is often elicited. In children, emotional lability and hyperactivity are often attributed to behavioral or other factors, and a small goiter and prominent eyes may go unnoticed. Prepubertal children tend to have a longer duration of symptoms at presentation than pubertal children (46).
TABLE 76.1. FREQUENCY OF SYMPTOMS AND SINGS OF THYROTOXICOSIS IN CHILDREN AND ADOLESCENTS
Perecentage
Goiter
99
Tachycardia
83
Nervousness
80
Increased pulse pressure
77
Hypertension
71
Exophtension
66
Tremor
61
Increased appetite
60
Weight loss
54
Thyroid bruit
53
Increased perspiration
49
Hyperactivity
44
Heart murmur
43
Palpitations
34
Heat intolerance
33
Fatigue
16
Headache
15
Diarrhea
13
Data from references 36,37,38,39
Nervousness, emotional lability, behavioral changes, and deteriorating school performance are the symptoms likely to bring the child to medical attention. These symptoms often are noted by a parent or teacher rather than by the child. Referral for evaluation of hyperactivity and possible attention deficit disorder is common. Emotional outbursts, difficulty sleeping, and mood swings may lead to referral to a child psychiatrist or counselor. Fatigue, weakness, and dyspnea may lead to a reduction in activity and cessation of athletic activities.
Diffuse goiter is present in virtually all children with thyrotoxicosis caused by Graves' disease. The degree of thyroid enlargement is variable, but typically is not great. Thus, thyroid enlargement is usually not the chief complaint, and children rarely have symptoms from the enlargement. The thyroid gland is nontender, smooth, and firm, and a thyroid bruit may be heard. Thyroid nodules may be present; in a recent study of 468 patients 12 to 75 years of age, 12.8% had nodules. In six patients (1.3), the nodule was a thyroid cancer (47).
Some ophthalmopathy is common, but severe ophthalmopathy is rare. Most children have stare and wide palpebral fissures, which are signs of thyrotoxicosis. Ophthalmic symptoms and signs such as tearing and eyelid, periorbital, or conjunctival swelling occur in about 10% to 15% of children (48,49,50,51). In the largest series (72 girls and 11 boys), 12% had exophthalmos, and punctate corneal erosions were seen in 13% (51). Exophthalmos is rarely the presenting complaint (52). Eye pain, diplopia, and ophthalmoplegia are rare. The stare and wide palpebral fissures improve with treatment of thyrotoxicosis; ophthalmopathy may persist but rarely requires treatment (see section Ophthalmopathy in Chapter 23).
Cardiac findings include tachycardia, a widened pulse pressure, and hyperactive precordium. Occasional children complain of heart “racing” or pounding. Left ventricular reserve may decrease, accounting at least in part for exercise intolerance (53), but arrhythmias and congestive heart failure almost never occur.
Most children with thyrotoxicosis have an increased appetite. Although weight loss is not as common as in adults, the children do not gain weight normally, indicating that the increase in appetite is inadequate to meet their caloric needs. On the other hand, some children truly overeat and therefore gain an excessive amount of weight. Increased stool frequency occurs in a minority of children, but diarrhea is rare. Once antithyroid treatment is instituted, some children continue to eat excessively and then may become obese. A conscious effort should be made to decrease excessive caloric intake after therapy is initiated.
Acceleration of linear growth is common in children with thyrotoxicosis, and many have an increase in height percentiles on the growth chart. The acceleration in growth is accompanied by increased epiphyseal maturation and advancement in bone age. Thus, epiphyseal closure may occur earlier. There is no increase in adult height. Thyrotoxicosis may impair mineralization of bone (54). At the time of diagnosis, bone mineral density is decreased; in one series 42% of children had severe osteopenia (55). Effective therapy results in restoration of normal bone mass for age (55).
Most children with thyrotoxicosis have a fine tremor and brisk deep tendon reflexes. The seizure threshold may decrease, and seizures are a rare presenting feature of thyrotoxicosis (56). In children under 3 years of age, thyrotoxicosis may cause language delay or more global developmental delay, which may or may not be reversible with treatment (57). Muscle weakness and fatigue are common but seldom severe. Periodic paralysis has been described in children (58), but it is probably even rarer than in adults.
Heat intolerance and excessive perspiration occur in more than 30% of children. The skin is often warm and moist, and occasionally it is flushed. Localized myxedema and thyroid acropachy almost never occur in children with Graves' disease.
Diagnosis
For children and adolescents who present with obvious symptoms and signs of thyrotoxicosis, diffuse goiter, and ophthalmopathy, there should be no confusion regarding the diagnosis of thyrotoxicosis or its cause. In such children, laboratory tests confirm the presence of thyrotoxicosis, gauge its biochemical severity, and establish a baseline for treatment.
In others, the diagnosis of thyrotoxicosis may not be so obvious. These patients include seemingly asymptomatic children with diffuse or painful goiter or a thyroid nodule, and children with only a few symptoms or signs of thyrotoxicosis, such as weight loss, weakness, or change in behavior. In these children, laboratory tests are indicated primarily to identify the presence of thyrotoxicosis. (In other children, the possibility of thyrotoxicosis is considered only after thyroid function tests are done for some other reason, such as hyperactivity.)
The most appropriate tests in either group are measurements of serum TSH and free T4, with measurement of serum T3 if the serum free T4 value is normal (see Chapters 13 and Chapter 44). Nearly all children with thyrotoxicosis, like adults, have low serum TSH and high serum total and free T4 and T3concentrations. If the serum TSH value is normal (or high), the possibility of resistance to thyroid hormone should be considered (59) (see Chapter 81), and a TSH-secreting pituitary adenoma must be sought (see Chapter 24).
More than 75% of children with Graves' thyrotoxicosis have high serum concentrations of antithyroid peroxidase and antithyroglobulin antibodies, but the concentrations are not usually as high as in children with chronic autoimmune thyroiditis (60). These antibodies need not be measured unless evidence is being sought against the presence of Graves' disease. Similarly, TSHR-SAbs are present in the serum of more than 90% of children with Graves' disease, whether measured by receptor assay or bioassay (61,62). These antibodies also need not be measured routinely for diagnostic purposes. Measurements after some period of antithyroid drug therapy may provide information about the persistence of Graves' disease and, therefore, the likelihood of recurrent thyrotoxicosis if the drug is discontinued. The presence of TSHR-SAbs then would indicate a high probability of recurrence (see Chapter 15 and Chapter 45) (62,63).
Measurements of radioiodine uptake and radionuclide imaging are seldom needed in children. An uptake test may be helpful in those who have few clinical manifestations of thyrotoxicosis and low serum TSH but normal serum T4 and T3 concentrations (i.e., subclinical thyrotoxicosis); a high-normal or high value indicates Graves' disease, and a low value indicates thyroiditis or exogenous thyroid hormone ingestion. Thyroid radionuclide imaging is indicated only when one or more thyroid nodules are palpated. Although the coexistence of papillary thyroid cancer is uncommon, there may an increased risk in adults with Graves' thyrotoxicosis [1.8% in one study (64)]; palpable nodules in children should be evaluated for carcinoma.
Among the causes of thyrotoxicosis in children other than Graves' disease, the most common is probably an autonomously functioning thyroid adenoma. Painless or silent thyroiditis is virtually unreported in children (65) (see Chapter 27); subacute thyroiditis, toxic multinodular goiter, and exogenous thyrotoxicosis are rare; and TSH-secreting pituitary adenomas are extremely rare in all age groups (see Chapter 24). A thyroid adenoma should be detectable by physical examination; virtually all adenomas causing thyrotoxicosis are at least 2 cm in diameter. Most occur as isolated tumors, some of which contain activating mutations of the TSH receptor (see Chapter 25). A toxic thyroid adenoma (or a diffuse or toxic multinodular goiter) may occur as part of the McCune-Albright syndrome (cafZ^-au-lait pigmentation, precocious puberty, and polyostotic fibrous dysplasia) (20). Autosomal-dominant or sporadic nonautoimmune thyrotoxicosis due to germ line mutations in the TSH receptor can occur in children as well as in neonates (16,17); these children have diffuse goiters but no ophthalmopathy, and they may have a family history of thyrotoxicosis but not ophthalmopathy or chronic autoimmune thyroiditis. Exogenous thyrotoxicosis can be iatrogenic, occurring when high doses of T4 are given to children with thyroid carcinoma or to decrease the size of a goiter. It can be surreptitious, for example, an adolescent taking thyroid hormone to lose weight. It can also be accidental, such as when a child takes a handful of thyroid pills belonging to another family member. The dose must be large (e.g., 0.5 mg/kg of T4 or more), and even then not all children become thyrotoxic (66,67).
Disorders that must be distinguished from thyrotoxicosis are the thyroid hormone resistance syndromes (68) (see Chapter 81), and those disorders associated with increased serum binding of T4 and T3. The former may be associated with clinical thyrotoxicosis if the resistance is limited to the pituitary gland. Increased serum binding of T4 results in hyperthyroxinemia (high serum total T4 concentrations) but not thyrotoxicosis (see Chapter 13).
Treatment
Children and adolescents with Graves' thyrotoxicosis, like adults, can be treated effectively with an antithyroid drug, radioiodine, and thyroidectomy (69) (see Chapter 45). Both the natural history of Graves' disease and the effects (and side effects) of the three types of treatment are similar in the three age groups. Therefore, in children and adolescents, like in adults, choices are made more on the basis of physician, patient, and parent preferences than any other consideration. These are all treatments for the thyroid hypersecretion that causes thyrotoxicosis, not treatments for Graves' disease, unless antithyroid drugs indeed have immunosuppressive actions, as has been suggested (see Chapter 45). Among the three treatments, there are some differences in the time needed to reduce thyroid hypersecretion to normal, the required degree of patient and family compliance with treatment and follow-up visits, and the short- and long-term likelihood of recurrent thyrotoxicosis and hypothyroidism.
In contrast to adults, in whom radioiodine therapy alone or a relatively short course of an antithyroid drug followed by radioiodine therapy if remission does not occur is probably the most common therapeutic approach (70), most children with Graves' thyrotoxicosis are treated with an antithyroid drug for a long time. There are several reasons for this choice. First, in time, many patients do have a remission of the Graves' disease, and therefore remain euthyroid, and with normally regulated thyroid secretion, for long periods if not indefinitely after treatment is discontinued. Second, physicians, patients, and parents worry that radioiodine therapy may yet prove to have some long-term side effects, despite current evidence to the contrary. Third, few children or their parents accept subtotal thyroidectomy, and it requires careful medical preparation and experienced anesthesiologists and surgeons to avoid operative morbidity. Thus, even though radioiodine therapy or thyroidectomy is considered preferable initial treatment at some centers, we prefer antithyroid drug treatment in the hope that a remission of the Graves' disease will occur; radioiodine is a reasonable second choice in older children if the patient cannot tolerate drug therapy or does not have a remission.
Antithyroid Drug Treatment
The antithyroid drugs MMI, carbimazole, and PTU inhibit thyroid hormone biosynthesis (71) (see Chapter 45). PTU also inhibits extrathyroidal conversion of T4to T3. In adults, and presumably also in children, MMI (and carbimazole) has a longer serum half-life, about 4 to 6 hours, as compared with 1 to 2 hours for PTU, and its intrathyroidal actions are considerably more prolonged (72,73); therefore single daily doses are adequate in most patients. The recommended initial dose of MMI is 0.5 to 1.0 mg/kg daily, given once daily, and that of PTU is 5 to 10 mg/kg daily, given three times daily. Children who are older, with longer duration of symptoms, larger goiters, or higher serum T
4 and T3 concentrations, should be given the higher doses. Once the patient becomes euthyroid, the dose and frequency (in patients taking PTU) can usually be decreased. Conversely, occasionally the dose needs to be increased because the initial dose was too small or the thyrotoxicosis worsens. MMI is preferable to PTU because single daily doses are effective in most patients, and fewer tablets per day are needed because the MMI tablets that are available (5 and 10 mg) contain relatively more drug than the PTU tablet that is available (50 mg).
Antithyroid drugs, although they inhibit thyroid hormone synthesis, do not inhibit the release of preformed, stored hormone. Therefore, there is a lag period between initiation of therapy and achievement of the euthyroid state. The length of this period is correlated with the size of the patient's goiter, varying from 3 weeks to 2 months. During this period, propranolol, 0.5 to 2 mg/kg daily in divided doses, or another β-adrenergic antagonist drug may be given to alleviate the symptoms of thyrotoxicosis (74,75).
The results of eight studies of antithyroid drug treatment in children with Graves' thyrotoxicosis are shown in Table 76.2 (36,38,76,77,78,79,80,81). Thyrotoxicosis was controlled initially in 87% to 100% of the patients; failure of initial control was more likely if the patient had a large goiter or more severe clinical or biochemical thyrotoxicosis, or was poorly compliant with therapy. For these children, an alternative form of therapy must be selected. Although poor compliance with an antithyroid drug may be an indication for radioiodine or surgical treatment, the need for compliance often simply changes from compliance with an antithyroid drug to compliance with T4.
TABLE 76.2. RESULTS OF ANTITHYROID DRUG TREATMENT OF CHILDREN AND ADOLESCENTS WITH GRAVES' THYROTOXICOSIS
Study Location Reference
No. of Patients
Patients Achieving Control initially (%)
Duration of Therapy yr (mean)
Remission (%)a
Relapse (%)b
Philadelphia (38)
95
87
2-4 (3.2)
40
13
Baltimore (36)
104
100
1-9 (2.9)
61
10
Helsinki (80)
38
100
1.6-6 (3)
50
6
USC (76)
60
100c
1-7 (2.9)
34
22c
Detroit (78)
182
87
0.5-10 (2)
38
36
UCLA (79)
63
97
0.4-12.4 (4.3)
25% every 2 yr
3
Boston (77)
53
98
0.25-8.7 (2.5)
64
47
London (81)
72
100
0.5-7 (3.3)
38
62
aPercentage of patients remaining euthyroid for a defined period after discontinuation of antithyoid drug therapy. This posttherapy period ranged from 1 to 3 months to 1 or more years in the different studies.
bPercentage of patients who became thyrotoxic after remaining euthyroid for a defined (variable) period after discontinuation of antithyroid drug therapy.
cEstimated; results not reported directly
Once the patient is euthyroid, either of two treatment plans may be implemented. One is to reduce the dose of antithyroid drug so as to maintain euthyroidism; the other is to continue the same dose and add T4 to prevent hypothyroidism. The first approach requires good clinical judgment, particularly because treatment may lead to low-normal serum T4 and high-normal T3 concentrations (82). Assessment of clinical status and measurements of serum TSH should lead to the correct therapeutic decisions. Because prolonged thyrotoxicosis may result in persistent suppression of TSH secretion, serum TSH measurements cannot be relied on to indicate overtreatment for 6 to 8 weeks after a patient becomes euthyroid (83). The second approach requires not only that the patient take two medications, when one would suffice, but the presence of thyrotoxicosis also may lead to confusion about whether to increase the antithyroid drug or decrease the dose of T4. In addition, patients taking higher doses of antithyroid drug may have a higher risk for drug side effects, and the administration of T4 makes it more difficult to determine if a remission of Graves' disease has occurred. Thus, we prefer the first approach.
Antithyroid drug treatment is continued either for a fixed time interval or until the patient remains euthyroid for several months while receiving a low dose of the drug. Treatment then is stopped to determine whether a remission has occurred, as defined by persistent euthyroidism. In the eight studies listed in Table 76.2, 34% to 64% of children had a remission after mean treatment periods of 2 to 4 years. Patients treated for fixed periods, usually 1 to 2 years, are less likely to have a remission than those treated indefinitely. Prepubertal children seem to need more prolonged treatment; in a study of 89 children, the median time to remission was 8 years in prepubertal children, compared with 4 years in pubertal children (46). In a study of 63 children and adolescents in which remission was analyzed by survival analysis, 25% had a remission every 2 years, and the 5-year remission rate was 50% (79).
Recurrence of thyrotoxicosis after cessation of antithyroid drug therapy occurs in 3% to 62% of children (Table 76.2).
This wide range reflects to some extent different treatment approaches and different definitions of recurrence. In general, the rate of recurrence of thyrotoxicosis is higher in patients in whom the duration of treatment was shorter. Recurrence of thyrotoxicosis within a few weeks or months after cessation of therapy suggests that the patient had not had a remission of Graves' disease, but simply cessation of drug action in a patient with continuing Graves' disease. In contrast, later recurrence suggests that the patient had a remission of Graves' disease, but the disease then recurred. Late recurrence is less common, for example, occurring in only 3% of the patients in one study who remained euthyroid for 1 year after cessation of therapy (79).
In a study from Japan, the rate of recurrence was much lower in adults treated with MMI and T4, and then T4 alone, than in those treated only with MMI (84). In several subsequent studies, however, some of which included children, remissions of Graves' disease were no more common in patients treated with an antithyroid drug and T4 than in those treated with an antithyroid drug alone (85,86,87). No studies of the two regimens have been conducted primarily in children. For the practical reasons described earlier, we do not recommend combination antithyroid drug and T4 therapy.
Several clinical and biochemical markers may help to predict whether a recurrence of thyrotoxicosis is likely to occur before antithyroid drug therapy is begun or when it is discontinued, but their sensitivity and specificity are limited. A lower body mass index at the time of diagnosis favored recurrence in one study (88). Goiter size when treatment is discontinued is the best clinical predictor; the smaller the gland, the less likely a recurrence will occur (89). The most helpful biochemical marker appears to be measurement of serum TSHR-SAbs when therapy is discontinued; in one report, all children who had recurrent thyrotoxicosis tested positive for TSHR-SAbs at that time, and 78% of the children who remained euthyroid tested negative (61). In another study, the predictive value of this measurement was much lower (90). In practice, treatment simply should be discontinued and the patient followed periodically.
From 5% to 32% of children given MMI or PTU have a side effect of the drug, usually within the first several months of treatment, and care should be taken to inform all children and their parents about these side effects (36,38,76,77,78,79,80,81) (Table 76.3). The most common minor side effects are urticarial or papular skin rashes and transient granulocytopenia [< 2,000/mm3 (< 2×109/L)], which occur in 1% to 9% of children. Others are hair loss, nausea, headache, abnormal taste sensation, and arthralgia. These side effects are dose dependent (91). In patients with nonhematologic side effects, the drug should be discontinued for a few days and then treatment with the other drug initiated; patients with symptomatic skin rashes may benefit from antihistamine or glucocorticoid therapy for a few days. Granulocytopenia is usually transient and does not necessitate discontinuation of therapy, but when the granulocyte count falls below 1,000/mm3 (1×109/L), discontinuing the drug may avert agranulocytosis (92). From 0.1% to 0.2% of children develop agranulocytosis [< 250/ mm3 (< 0.25×109/L)]; it usually is accompanied by pharyngitis, fever, and other systemic symptoms of infection. We recommend white blood cell counts before initiation of treatment and during treatment if any of the findings that have been mentioned occur. Other serious drug toxic effects include a lupuslike syndrome, with rash, arthritis, and glomerulonephritis, mostly caused by PTU, and hepatitis (see Chapter 45) (93). The occurrence of any of these serious side effects necessitates immediate discontinuation of the drug; the other drug should not be given, but rather radioiodine therapy or thyroidectomy should be planned. Women of childbearing age who are taking MMI should be warned that it has been associated with an embryopathy, including cutis aplasia (94,95).
TABLE 76.3. COMPLICATIONS OF ANTITHYROID DRUG TREATMENT OF CHILDREN AND ADOLESCENTS WITH GRAVES' THYROTOXICOSIS
Minor Toxicity
Study Location (Reference)
Poor Compliance (%)
Overall Toxicity (%)
Major Toxicitya (%)
Rash (%)
↓WBC (%)
Hypothyroidism (%)
Philadelphia (33)
17
5
0
1
3
8
Baltimore (31)
16
14
6
8
1
NR
Helsinki (57)
5
5
0
1.5
1.5
0
USC (61)
7
32
14
7.5
9
6
Detroit (63)
9
17
6
8
3
5
UCLA (64)
2
NR
2
NR
NR
NR
Boston (62)
13
11
4
7
2
11
London (81)
NR
5
3
3
0
0
aAgranulocytosis, lupus-like syndrome (e.g., rash, arthritis, glomerulonephritis), or hepatitis. WBC, white blood cells; NR, not reported.
Radioiodine Therapy
Radioiodine (131I) therapy has proved to be an effective therapy for children and adolescents with thyrotoxicosis due to Graves' disease. It is the preferred treatment in some centers, and in most others it is recommended for any patient who has a serious side effect or tires of antithyroid drug therapy. The dose, which is given orally, usually is calculated to deliver 50 to 200 µCi (1.85–7.4 MBq) of radioiodine per gram of thyroid tissue, estimated by physical examination or imaging, according to the following formula (96):
Younger children with smaller goiters usually are given lower doses, and those with larger goiters, higher doses. It is better to give more rather than less because the likelihood of persistent thyrotoxicosis, with need for retreatment, is lower. For example, among a group of children given 200 µCi (7.4 MBq) of 131I/g of thyroid, 83% became euthyroid (78). In contrast, 54% of those given 50 µCi (1.85 MBq) of 131 I/g of thyroid had persistent thyrotoxicosis (97). Higher doses also may be associated with a lower risk for thyroid tumors (98). Pretreatment with an antithyroid drug is not necessary, but if used the drug should be discontinued 7 days before treatment to prevent interference with the uptake of radioiodine. Because the effects of a dose of radioiodine are not complete for several months or longer, adjunctive treatment with a β-adrenergic antagonist, as previously described, is recommended for patients with many symptoms. An antithyroid drug may also be given for a short time. The advantages of radioiodine treatment are its ease of administration, the lack of need for an antithyroid drug, and the high rate of permanent amelioration of thyrotoxicosis.
The major consequence of radioiodine therapy is hypothyroidism. It occurs in 20% to 40% of children in the first year after treatment and 2% to 3% per year thereafter, so most children eventually become hypothyroid (99). To ensure that thyrotoxicosis does not recur (and to reduce the risk for thyroid tumors), some pediatric endocrinologists believe that the dose should always be sufficient to result in hypothyroidism. In this regard, a recent study reported that doses of 110 µCi (4.1 MBq) of 131I/g, 220 µCi (8.1 MBq) of 131I/g, and 330 µCi (12.2 MBq) of 131I/g resulted in hypothyroidism in 50%, 70%, and 95% of children with Graves' thyrotoxicosis, respectively (100). In another study in children given fixed doses of radioiodine (13.8–15.6 mCi [511–577 MBq]), all became hypothyroid on average 77 days after treatment (range 28–194 days) (101).
The main reservations about radioiodine therapy in children have centered around possible thyroid or other tumors and genetic damage. In a national collaborative study of 322 patients who received radioiodine therapy before age 20 years, the incidence of benign thyroid adenomas increased from an expected 0.6% to 1.9% (102). This risk appeared to be higher in patients given lower doses of radioiodine. In the same study, thyroid carcinomas were no more common in radioiodine-treated patients than those treated with an antithyroid drug or thyroidectomy. With respect to tumor formation, the thyroid glands of infants and young children are more susceptible to the effects of external radiation, and the same probably applies to radioiodine (see section Pathogenesis in Chapter 70) (103). In several long-term studies, mostly of adults, no evidence for an increased risk for leukemia or other cancers was found, with the possible exception of stomach cancer (relative risk 1.3) and breast cancer (relative risk 1.9) (104,105,106,107). Thyroid storm after radioiodine therapy has been reported in a single child; this child had earlier been treated with an antithyroid drug (108).
Another potential adverse effect of radioiodine therapy is the development or worsening of ophthalmopathy. In prospective studies in adults, ophthalmopathy was more likely to appear or worsen after treatment with radioiodine than during antithyroid drug therapy or after thyroidectomy (see Chapter 45) (109,110). In a retrospective study of children treated with radioiodine, eye signs improved in 90%, did not change in 8%, and worsened in 3% (99); much of the improvement was probably due to improvement in stare and lid retraction rather than infiltrative eye signs. In a recent study of eight children 4 to 14 years of age, none had deterioration of eye disease after radioiodine therapy (111).
Studies of offspring of children and adolescents previously treated with radioiodine revealed a 3% incidence of congenital anomalies, similar to that found in the general population (99). Karyotype studies revealed no increase in chromosomal aberrations of the type found after exposure to ionizing radiation (97). Furthermore, there are no reports of impaired fertility or an increase in miscarriage rate or fetal loss among girls treated with radioiodine, although continued surveillance is warranted.
In summary, there is little evidence of an increase in thyroid tumors or nonthyroid problems in more than 1,000 children treated with radioiodine for Graves' thyrotoxicosis with follow-up for up to 40 years. Given the increased sensitivity of the thyroid gland of young children to the effects of radiation, however, Rivkees et al. hypothesized in their review that the risk for thyroid cancer may be slightly increased; for this reason, most pediatric endocrinologists prefer not to treat children until they are 10 years of age or older (98). Surveillance should continue.
Thyroidectomy
Thyroidectomy is the most rapidly effective treatment for thyrotoxicosis. With appropriate preoperative preparation, the risks are similar to those of other major surgical procedures.
It may be the best treatment for patients with markedly enlarged thyroid glands or those with severe ophthalmopathy who do not have a remission during antithyroid drug therapy (112).
To minimize surgical risks, the patient should be euthyroid, or nearly so, at the time of surgery. This is usually accomplished by administration of an antithyroid drug for several weeks and then addition of inorganic iodide for 7 to 14 days; the latter has an antithyroid action and also may reduce thyroid blood flow (see Chapter 45). Alternatively, patients may be prepared for surgery by administration of a β-adrenergic antagonist and inorganic iodine.
The operation of choice is near-total thyroidectomy; when less than 4 g of thyroid tissue remains, the likelihood of recurrent thyrotoxicosis is small (113,114). The likelihood of recurrence is even smaller after total thyroidectomy, but the morbidity rate is considerably higher. In a recent review of nine series, one death occurred in 555 children who underwent thyroidectomy for Graves' thyrotoxicosis (115). Subsequently, 42% became hypothyroid, 2% had hypoparathyroidism, and 1.2% had vocal cord paralysis. Bleeding, which may require tracheostomy, occurred in 0.25% and keloid formation in 1.7%. This summary covered the experience of many years. Because thyroidectomy is rarely done for Graves' thyrotoxicosis now, complications may well be more common.
OUTCOME OF CHILDHOOD GRAVES' DISEASE
Although there are potential complications unique to antithyroid drug, radioiodine, or surgical treatment of Graves' thyrotoxicosis, all may result in hypothyroidism or persistent thyrotoxicosis. In children treated with an antithyroid drug with follow-up of 8 to 22 years, about 10% eventually developed hypothyroidism caused by chronic autoimmune thyroiditis, either with destruction of the thyroid or production of antibodies that block the binding of TSH to its receptors (36,38,76,77,78,79,80,81,116) (Table 76.3). As noted earlier, hypothyroidism is common in children treated with radioiodine or subtotal thyroidectomy. On the other hand, persistent or recurrent thyrotoxicosis is fairly common in patients treated with an antithyroid drug. Therefore, whichever treatment is chosen, the child or adolescent requires lifelong follow-up.
REFERENCES
1. Ramsay I, Kaur S, Krassas G. Thyrotoxicosis in pregnancy: results of treatment by antithyroid drugs combined with T4. 1983;18:73.Clin Endocrinol (Oxf)
2. Dirmikis SM, Munro DS. Placental transmission of thyroid-stimulating immunoglobulins. 1975;2:665.BMJ
3. McKenzie JM. Neonatal Graves' disease. 1964;24:660.J Clin Endocrinol Metab
4. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. 1992;2:155.Thyroid
5. Smallridge RC, Wartofsky L, Chopra IJ, et al. Neonatal thyrotoxicosis: alterations in serum concentrations of LATS-protector, T4, T3, reverse T3, and 3, 38 T2. 1978;93:118.J Pediatr
6. Sunshine P, Kusumoto H, Kriss JP. Survival time of circulating long-acting thyroid stimulator in neonatal thyrotoxicosis: implications for diagnosis and therapy of the disorder. 1965;36:869.Pediatrics
7. Matsura N, Konishi J, Fujieda K, et al. TSH-receptor antibodies in mothers with Graves' disease and outcome in their offspring. 1988;1:14.Lancet
8. Munro DS, Dirmikis SM, Humphries H, et al. The role of thyroid stimulating immunoglobulins of Graves' disease in neonatal thyrotoxicosis. 1978;85:837.Br J Obstet Gynaecol
9. Tamaki H, Amino N, Aozasa M, et al. Universal predictive criteria for neonatal overt thyrotoxicosis requiring treatment. 1988;5:152.Am J Perinatal
10. Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. 1983;57:1036.J Clin Endocrinol Metab
11. Peleg D, Cada S, Peleg A, et al. The relationship between maternal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. 2002;99:1040.Obstet Gynecol
12. Skuza KA, Sills IN, Stene M, et al. Prediction of neonatal hyperthyroidism in infants born to mothers with Graves' disease. 1996;128:264.J Pediatr
13. Zimmerman D. Fetal and neonatal hyperthyroidism. 1999;9:727.Thyroid
14. Hollingsworth DR, Mabry CC. Congenital Graves' disease: four familial cases with long-term follow-up and perspective. 1976;130:148.Am J Dis Child
15. Polak M. Hyperthyroidism in early infancy: pathogenesis, clinical features and diagnosis with a focus on neonatal hyperthyroidism. 1998;8:1171.Thyroid
16. Duprez L, Parma J, van Sande J, et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. 1994;7:396.Nat Genet
17. Schwab KO, Gerlich M, Broecker M, et al. Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism. 1997;131:899.J Pediatr
18. Kopp P, van Sande J, Parma J, et al. Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. 1995;332:150.N Engl J Med
19. de Roux N, Polak M, Couet J, et al. A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. 1996;81:2023.J Clin Endocrinol Metab
20. Mastorakos G, Mitsiades NS, Doufas AG, et al. Hyperthyroidism in McCune-Albright syndrome with a review of thyroid abnormalities sixty years after the first report. 1997;7:433.Thyroid
21. Farrehi C. Accelerated maturity in fetal thyrotoxicosis. 1968;7:134.Clin Pediatr
22. Kopelman AE. Delayed cerebral development in twins with congenital hyperthyroidism. 1983;137:842.Am J Dis Child
23. Smith C, Thomsett M, Choong C, et al. Congenital thyrotoxicosis in premature infants. 2001;54:371.Clin Endocrinol (Oxf)
24. Zakarija M, McKenzie JM, Hoffman WH. Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism. 1986;62:368.J Clin Endocrinol Metab
25. Joshi R, Kulin HE. Treatment of neonatal Graves' disease with sodium ipodate. 1993;32:181.Clin Pediatr
26. Karpman BA, Rapoport B, Filetti S, et al. Treatment of neonatal hyperthyroidism due to Graves' disease with sodium ipodate. 1987;64:119.J Clin Endocrinol Metab
27. Transue D, Chan J, Kaplan M. Management of neonatal Graves' disease with iopanoic acid. 1992;121:472.J Pediatr
28. Holzapfel H-P, Wonerow P, von Petrykowski W, et al. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. 1997;82:3879.J Clin Endocrinol Metab
29. Cove DH, Johnston P. Fetal hyperthyroidism: experience of treatment in four siblings. 1985;1:430.Lancet
30. Radaelli T, Cetin I, Zamperini P, et al. Intrauterine growth of normal thyroid. 2002;16:427.Gynecol Endocrinol
31. Wenstrom KD, Weiner CP, Williamson RA, et al. Prenatal diagnosis of fetal hyperthyroidism using funipuncture. 1990;76:513.Obstet Gynecol
32. Nachum Z, Rakover Y, Weimer E, et al. Grave's disease in pregnancy: prospective evaluation of a selective invasive treatment protocol. 2003;189:159.Am J Obstet Gynecol
33. Bowman ML, Bergmann M, Smith JF. Intrapartum labetalol for the treatment of maternal and fetal thyrotoxicosis. 1998;8:795.Thyroid
34. Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. 1980;97:257.J Pediatr
35. Mandel SH, Hanna CE, LaFranchi SH. Diminished thyroid-stimulating hormone secretion associated with neonatal thyrotoxicosis. 1986;109:662.J Pediatr
35a. Kempers MJ, van Tijn DA, van Trostenburg AS, et al. Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. 2003;88:5851.J Clin Endocrinol Metab
36. Barnes H, Blizzard RM. Antithyroid drug therapy for toxic diffuse goiter (Graves' disease): thirty years experience in children and adolescents. 1977;91:313.J Pediatr
37. Saxena KM, Crawford JD, Talbot NB. Childhood thyrotoxicosis: a long-term perspective. 1964;2:1153.BMJ
38. Vaidya VA, Bongiovanni AM, Parks JS, et al. Twenty-two years experience in the medical management of juvenile thyrotoxicosis. 1974;54:565.Pediatrics
39. Kogut MD, Kaplan SA, Collip PJ, et al. Treatment of hyperthyroidism in children. 1965;272:217.N Engl J Med
40. Lavard L, Ranlov I, Perrild H, et al. Incidence of juvenile thyrotoxicosis in Denmark. 1982–88. A nationwide study. 1994;130:565.Eur J Endocrinol
41. Wong GWK, Cheng PS. Increasing incidence of childhood Graves' disease in Hong Kong: a follow-up study. 2001;54:547.Clin Endocrinol (Oxf)
42. Friedman JM, Fialkow PJ. The genetics of Graves' disease. 1978;7:47.Clin Endocrinol Metab
43. Chen Q-Y, Huang W, She J-X, et al. HLA-DRB1*08, DRB1*03/DRB3*0101, and DRB3*0202 are susceptibility genes for Graves' disease in North American Caucasians, whereas DRB1*07 is protective. 1999; 84:3181.J Clin Endocrinol Metab
44. Kawame H, Adachi M, Tachibana K, et al. Graves' disease in patients with 22q11.2 deletion. 2001;139:892.J Pediatr
45. Nordyke RA, Gilbert FI, Harada ASM. Graves' disease: influence of age on clinical findings. 1988;148: 626.Arch Intern Med
46. Shulman D, Muhar I, Jorgensen V, et al. Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy. 1997;7:755.Thyroid
47. Carnell NE, Valente WA. Thyroid nodules in Graves' disease: classification, characterization, and response to treatment. 1998;8:647.Thyroid
48. Young LA. Dysthyroid ophthalmopathy in children. 1979;16:105.J Pediatr Ophthalmol Strabismus
49. Uretsky SH, Kennerdell JS, Gutai JP. Graves' ophthalmopathy in childhood and adolescence. 1980;98:1963.Arch Ophthalmol
50. Gruters A. Ocular manifestations in children and adolescents with thyrotoxicosis. 1999;107 (suppl 5):172.Exp Clin Endocrinol Diabetes
51. Chan W, Wong GWK, Fan DSP, et al. Ophthalmopathy in childhood Graves' disease. 2002;86:740Br J Ophthalmol
52. Gorman CA. Temporal relationship between the onset of Graves' ophthalmopathy and the diagnosis of thyrotoxicosis. 1983;58:515.Mayo Clin Proc
53. Cavallo A, Casta A, Fawcett HD, et al. Is there a thyrotoxic cardiomyopathy in children? 1985;107:531.J Pediatr
54. Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk-a meta-analysis. 2003;13:585.Thyroid
55. Lucidarme N, Ruiz JC, Czernichow P, et al. Reduced bone mineral density at diagnosis and bone mineral recovery during treatment in children with Graves' disease. 2000; 137:56.J Pediatr
56. Radetti G, Dordi B, Mengarda G, et al. Thyrotoxicosis presenting with seizures and coma in two children. 1993;147:925.Am J Dis Child
57. Segni M, Leonardi E, Mazzoncini B, et al. Special features of Graves' disease in early childhood. 1999;9:871.Thyroid
58. Drash PW, Money J. Motor impairment and hyperthyroidism in children: report of two cases. 1966;8:741.Dev Med Child Neurol
59. Caldwell G, Gow SM, Sweeting VM, et al. Value and limitations of a highly sensitive immunoradiometric assay for thyrotropin in the study of thyrotropin function. 1987;33:303.Clin Chem
60. Lavard L, Perrild H, Jacobsen BB, et al. Prevalence of thyroid peroxidase, thyroglobulin and thyrotropin receptor antibodies in a long-term follow-up of juvenile Graves' disease. 2000;32:167.Autoimmunity
61. Foley TP Jr, White C, New A. Juvenile Graves' disease: usefulness and limitations of thyrotropin receptor antibody determinations. 1987;110:378.J Pediatr
62. Botero D, Brown RS. Bioassay of the thyrotropin receptor antibodies with Chinese hamster ovary cells transfected with recombinant human thyrotropin receptor: clinical utility in children and adolescents with Graves' disease. 1998;132:612.J Pediatr
63. McKenzie JM, Zakarija M. The clinical use of thyrotropin receptor antibody measurements. 1989; 69:1093.J Clin Endocrinol Metab
64. Stocker DJ, Foster SS, Solomon BL, et al. Thyroid cancer yield in patients with Graves' disease selected for surgery on the basis of cold scintiscan defects. 2002;12:305.Thyroid
65. Fisher DA. The thyroid. In: Kaplan SA, ed. , 2nd ed. Philadelphia: WB Saunders, 1990:110.Clinical pediatric endocrinology
66. Litovitz TL, White JD. Levothyroxine ingestions in children: an analysis of 78 cases. 1985;3:297.Am J Emerg Med
67. Lewander WJ, Lacouture PG, Silva JE, et al. Acute thyroxine ingestion in pediatric patients. 1989;84:262.Pediatrics
68. Gharib H, Klee GG. Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones. 1985;60:9.Mayo Clin Proc
69. Franklyn JA. The management of hyperthyroidism. 1994;330:1731.N Engl J Med
70. Wartofsky L, Glinoer D, Solomon B, et al. Differences and similarities in the diagnosis and treatment of Graves' disease in Europe, Japan, and the United States. 1991;1:129.Thyroid
71. Cooper DS. Antithyroid drugs in the management of patients with Graves' disease: an evidence-based approach to therapeutic controversies. 2003;88:3474.J Clin Endocrinol Metab
72. Shiroozu A, Okamura K, Ikenoue H, et al. Treatment of hyperthyroidism with a small single daily dose of methimazole. 1986;63:125.J Clin Endocrinol Metab
73. Okuno A, Yano K, Inyaku F, et al. Pharmacokinetics of methimazole in children and adolescents with Graves' disease. Studies on plasma and intrathyroidal concentrations. 1987;115:112.Acta Endocrinol
74. Codaccioni JL, Orgiazzi J, Blanc P, et al. Lasting remissions in patients treated for Graves' hyperthyroidism with propranolol alone: a pattern of spontaneous evolution of the disease. 1988;67:656.J Clin Endocrinol Metab
75. Feely J, Peden N. Use of β-adrenoceptor blocking drugs in hyperthyroidism. 1984;27:425.Drugs
76. Buckingham BA, Costin G, Roe TF, et al. Hyperthyroidism in children: a reevaluation of treatment. 1981; 135:112.Am J Dis Child
77. Gorton C, Sadeghi-Nejad A, Senior B. Remission in children with hyperthyroidism treated with propylthiouracil: long-term results. 1987;141:1084.Am J Dis Child
78. Hamburger JI. Management of hyperthyroidism in children and adolescents. 1985;60:1019.J Clin Endocrinol Metab
79. Lippe BM, Landau EM, Kaplan SA. Hyperthyroidism in children treated with long term medical therapy: twenty-five percent remission every two years. 1987; 64:1241.J Clin Endocrinol Metab
80. Maenpaa J, Kuusi A. Childhood hyperthyroidism. Results of treatment. 1980;69:137.Acta Paediatr Scand
81. Raza J, Hindmarsh PC, Brook CGD. Thyrotoxicosis in children: thirty years experience. 1999;88:937.Acta Paediatr
82. Chen JJS, Ladenson PW. Discordant hypothyroxinemia and hypertriiodothyroninemia in treated patients with hyperthyroid Graves' disease. 1986;63:102.J Clin Endocrinol Metab
83. Sills IN, Horlick MNB, Rapaport R. Inappropriate suppression of thyrotropin during medical treatment of Graves' disease in childhood. 1992;121:206.J Pediatr
84. Hashizume K, Ichikawa K, Sakurai A, et al. Administration of thyroxine in treated Graves' disease: effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. 1991; 324:947.N Engl J Med
85. McIver B, Rae P, Beckett G. Lack of effect of thyroxine in patients with Graves' hyperthyroidism who are treated with an antithyroid drug. 1996;334:220.N Engl J Med
86. Rittmaster RS, Abbott EC, Douglas R, et al. Effect of methimazole, with or without L-thyroxine, on remission rates in Graves' disease. 1998;83:814.J Clin Endocrinol Metab
87. Hoermann R, Quadbeck B, Roggenbuck U, et al. Relapse of Graves' disease after successful ocutome of antithyroid drug therapy: results of a prospective randomized study on the use of levothyroxine. 2002;12:1119.Thyroid
88. Glaser N, Styne D. Predictors of early remission of hyperthyroidism in children. 1997;82:1719.J Clin Endocrinol Metab
89. Siok-Hoon T, Bee-Wah L, Hock-Boon W, et al. Relapse markers in childhood thyrotoxicosis. 1987;26: 136.Clin Pediatr
90. Ikenoue H, Okamura K, Kuroda T, et al. Prediction of relapse in drug-treated Graves' disease using thyroid stimulation indices. 1991;125:643.Acta Endocrinol
91. Reinwein D, Benker G, Lazarus JH, et al, and the European Multicenter Study Group on Antithyroid Drug Treatment. A prospective randomized trial of antithyroid drug dose in Graves' disease therapy. 1993;76:1516.J Clin Endocrinol Metab
92. Tajiri J, Joguchi S, Murakami T, et al. Antithyroid drug-induced agranulocytosis: the usefulness of routine white blood cell count monitoring. 1990;150:621.Arch Intern Med
93. Werner MC, Romaldini JH, Bromberg N, et al. Adverse effects related to thionamide drugs and their dosage regimen. 1989;297:216.Am J Med Sci
94. Clementi M, Di Giannantonio E, Pelo E, et al. Methimazole embryopathy: delineation of the phenotype. 1999;83:43.Am J Med Genet
95. Martin-Denavit T, Edery P, Plauchu H, et al. Ectodermal abnormalities associated with methimazole intrauterine exposure. 2000;94:338.Am J Med Genet
96. Levy WJ, Schumacher P, Gupta M. Treatment of childhood Graves' disease: a review with emphasis on radioiodine treatment. 1988;55:373.Cleve Clin J Med
97. Rapoport B, Caplan R, DeGroot LJ. Low-dose sodium iodide I 131 therapy in Graves' disease. 1973;244:1610.JAMA
98. Rivkees SA, Sklar C, Freemark M. The management of Graves' disease in children, with special emphasis on radioiodine treatment. 1998;83:3767.J Clin Endocrinol Metab
99. Safa AM, Schumacher OP, Rodriguez-Antunez A. Long-term follow-up results in children and adolescents treated with radioactive iodine for hyperthyroidism. 1975;292: 167.N Engl J Med
100. Rivkees SA, Cornelius EA. Influence of Iodine-131 dose on the outcome of hyperthyroidism in children. 2003;111: 745.Pediatrics
101. Nebesio TD, Siddiqui AR, Pescovitz OH, et al. Time course to hypothyroidism after fixed-dose radioablation therapy of Graves' disease in children. 2002 141:99.J Pediatr
102. 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. 1974;38:976.J Clin Endocrinol Metab
103. Brill AB, Becker DV. The safety of 131I treatment of hyperthyroidism. In: Van Middlesworth L, Givins JR, eds. Chicago: Year Book Medical, 1986:347.The thyroid: a practical clinical treatise.
104. Hall P, Boice JD Jr, Berg G, et al. Leukaemia incidence after iodine-131 exposure. 1992;340:1.Lancet
105. Holm L-E, Hall P, Wiklund K, et al. Cancer risk after iodine-131 therapy for hyperthyroidism. 1991;83:1072.J Natl Cancer Inst
106. Goldman MB, Maloof F, Monson RR, et al. Radioactive iodine therapy and breast cancer. 1988;127:969.Am J Epidemiol
107. Ron E, Doody MM, Becker DV, et al. Cancer mortality following treatment for adult hyperthyroidism. 1998;280:347.JAMA
108. Kadmon PM, Noto RB, Boney CM, et al. Thyroid storm in a child following radioactive iodine (RAI) therapy: a consequence of RAI versus withdrawal of antithyroid medication. 2001;86:1865.J Clin Endocrinol Metab
109. Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves' hyperthyroidism. 1992;326:1733.N Engl J Med
110. Bartelena L, Marcocci C, Bagozzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. 1998;338:73.N Engl J Med
111. Cheetham TD, Wraight P, Hughes IA, et al. Radioiodine treatment of Graves' disease in young people. 1998;49:258.Horm Res
112. Bergman P, Auldist AW, Cameron F. Review of outcome of management of Graves' disease in children and adolescents. 2001;37:176.J Paediatr Child Health
113. Andrassy RJ, Buckingham BA, Weitzman JJ. Thyroidectomy for hyperthyroidism in children. 1980;15:501.J Pediatr Surg
114. Hayles AB, Chaves-Carballo E, McConahey WM. The treatment of hyperthyroidism (Graves' disease) in children. 1967;42:218.Mayo Clin Proc
115. Zimmerman D, Lteif AN. Thyrotoxicosis in children. 1998;27:109.Endocrinol Metab Clin North Am
116. Tamai H, Kasagi K, Takaichi Y, et al. Development of spontaneous hypothyroidism in patients with Graves' disease treated with antithyroid drugs: clinical, immunological, and histological findings in 26 patients. 1989;69:49.J Clin Endocrinol Metab