The causes of hypothyroidism after the neonatal period are listed in Table 15-9.The most frequent cause is chronic lymphocytic thyroiditis (CLT), an autoimmune disease that is closely related to Graves' disease. Although in CLT lymphocyte and cytokine-mediated thyroid destruction predominates whereas in Graves' disease antibody-mediated thyroid stimulation occurs, overlap may occur in some patients. Both a goitrous (Hashimoto's thyroiditis) and a nongoitrous (primary myxedema) variant of thyroiditis have been distinguished. The disease has a striking predilection for females and a family history of autoimmune thyroid disease (both CLT and Graves' disease) is found in 30% to 40% of patients. During childhood the most common age at presentation is adolescence, but the disease may occur at any age, even infancy (191).
There is an increased prevalence of CLT in patients with insulin dependent diabetes mellitus, 20% of whom have positive thyroid antibodies and 5% of whom have an elevated serum TSH level (192). CLT may also occur as part of an autoimmune polyglandular syndrome (APS) (193). In APS 1, also called APECED (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) syndrome, CLT is found in approximately 10% of patients (194). APS 1, a disorder associated with defective cell-mediated immunity that tends to present in childhood, has been shown recently to result from a mutation in the AIRE (autoimmune regulator) gene (195). CLT and diabetes mellitus with or without adrenal insufficiency (APS 2, also referred to as Schmidt's syndrome) tends to occur later in childhood or in the adult. In addition to these polyglandular syndromes, there is an increased incidence of CLT in patients with certain chromosomal abnormalities (Down syndrome, Turner syndrome, Klinefelter syndrome) as well as in patients with Noonan syndrome (196). Rarely, CLT may be associated with chronic uriticaria (197) and with immune-complex glomerulonephritis (198).
Antibodies to thyroglobulin and thyroid peroxidase (TPO), the thyroid antibodies measured in routine clinical practice, are detectable in over 95% of patients with CLT. Therefore, they are useful as markers of underlying autoimmune thyroid damage, TPO antibodies being more sensitive and specific. TSH receptor antibodies also are found in a small proportion of patients with CLT. When stimulatory TSH receptor antibodies are present, they may give rise to a clinical picture of hyperthyroidism, the coexistence of CLT and Graves' disease being known as Hashitoxicosis. Blocking antibodies, on the other hand, have been postulated to underlie both the hypothyroidism and the absence of goiter in some patients with primary myxedema, but are detectable in only a minority of children (199). In rare instances, the disappearance of blocking antibodies has been associated with a normalization of thyroid function in previously hypothyroid patients (200). Goiter, present in approximately two-thirds of children with CLT results primarily from lymphocytic infiltration and in some patients, from a compensatory increase in TSH. The role of antibodies in goitrogenesis is controversial (201). Contrary to previous beliefs, accumulating evidence now suggests that primary myxedema arises as a result of independent immune mechanisms and does not represent the "burned out" phase of CLT (199). Children with CLT may be euthyroid, or may have compensated or overt hypothyroidism. Rarely children may experience an initial thyrotoxic phase due to the discharge of preformed T4 and T3 from the damaged gland. Alternatively, as indicated above, thyrotoxicosis may be due to concomitant thyroid stimulation by TSH receptor stimulatory antibodies (Hashitoxicosis).
Long term follow up studies of children with CLT have suggested that while most children who are hypothyroid initially remain hypothyroid, spontaneous recovery of thyroid function may occur, particularly in those with initial compensated hypothyroidism (202-204). On the other hand, some initially euthyroid patients will become hypothyroid with observation. Therefore, close follow up is necessary.
Occasionally, patients with thyroid dysgenesis will escape detection by newborn screening and present later in childhood with non goitrous hypothyroidism or with an enlarging mass at the base of the tongue or along the course of the thyroglossal duct. Similarly, children with inborn errors of thyroid hormonogesis may only be recognized later in childhood because of the detection of a goiter.
In addition to antithyroid medication, a number of drugs used in childhood may affect thyroid function, including certain anticonvulsants, lithium, amiodarone, aminosalicylic acid, aminoglutethimide and sertraline (71,205, 205a). Similarly, a large number of naturally occurring goitrogens (broccoli, cabbage, sweet potatoes, cauliflower, soya beans, cassava and water pollutants) have been identified (71,206, 206a). Both radioiodine therapy and thyroidectomy, occasionally used in childhood for the definitive treatment of Graves' disease, frequently cause permanent hypothyroidism.
Worldwide, iodine deficiency continues to be an important cause of hypothyroidism, affecting at least 800 million people living largely in developing countries and, to a lesser extent, an additional 100-120 million individuals in certain parts of Europe (71). Although one rarely sees iodine deficiency in North America, an iodine sufficient area, a recent report described a 6 year old boy with goitrous hypothyroidism due to iodine deficiency. In this case, the iodine deficiency was due to severe dietary restriction due to multiple food allergies and was complicated by a large intake of thiocyanate-containing foods (broccoli, sweet potatoes and cauliflower) that blocked organification of iodine (207).
Secondary or 3o hypothyroidism in less severely affected children with the congenital abnormalities noted earlier in this chapter may be recognized only later in childhood. Alternatively, 2o or 3o hypothyroidism may develop as a result of acquired damage to the pituitary or hypothalamus, e.g., by tumors (particularly craniopharyngioma), granulomatous disease, head irradiation, infection (meningitis), surgery or trauma. Usually other trophic hormones are affected, particularly growth hormone.
In contrast to the neonatal period, children with GRTH usually come to attention when thyroid function tests are performed because of poor growth, hyperactivity, a learning disability or other nonspecific signs or symptoms. A small goiter may be appreciated. The high incidence of attention deficit hyperactivity disorder in children with this syndrome has been emphasized recently(113). Thyroid hormone resistance has also been described in patients with cystinosis.
Rarely, the thyroid gland may be involved in generalized infiltrative (cystinosis), granulomatous (histiocytosis X), or infectious disease processes that are of sufficient severity to result in a disturbance in thyroid function. Alternatively, hypothyroidism may be a long term complication of mantle irradiation for Hodgkins' disease or lymphoma. External irradiation of brain tumors in the posterior fossa of the brain may be associated with both 1o and 2o hypothyroidism because of the inclusion of the neck in the radiation field. Rarely, hypothyroidism has been reported in infants with large hemangiomas. In these cases, the hypothyroidism was shown to be due to increased inactivation of T4 by the D3 activity of these tumors (207a).
The onset of hypothyroidism in childhood is insidious. Affected children often are recognized either because of the detection of a goiter on routine examination or because of a poor interval growth rate present for several years prior to diagnosis. Because the deceleration in linear growth tends to be more affected than weight gain, these children are relatively overweight for their height, although they rarely are significantly obese (Figure 15-11). If the hypothyroidism is severe and longstanding, immature facies with an underdeveloped nasal bridge and immature body proportions (increased upper-lower body ratio) may be noted. Dental and skeletal maturation are delayed, the latter often significantly. Patients with 2o or 3o hypothyroidism tend to be even less symptomatic than are those with 1o hypothyroidism.
 |
| Figure 15-11. (Upper panel) Infant with severe, untreated congenital hypothyroidism diagnosed prior to the advent of newborn screening. (Lower panel) Infant with congenital hypothyroidism identified through newborn screening. Note the striking difference in the severity of the clinical features. |
The classical clinical manifestations of hypothyroidism can be elicited on careful evaluation, though they often are not the presenting complaints. These include lethargy, cold intolerance, constipation, dry skin or hair texture, and periorbital edema. School performance is not usually affected, in contrast to the severe irreversible neurointellectual sequelae that occur frequently in inadequately treated babies with congenital hypothyroidism.
Causes of hypothyroidism associated with a goiter (CLT, inborn errors of thyroid hormonogenesis, GRTH) should be distinguished from nongoitrous causes (primary myxedema, thyroid dysgenesis, 2o or 3o hypothyroidism). The typical thyroid gland in CLT is diffusely enlarged and has a rubbery consistency. Although the surface is classically described as "pebbly" or bosselated, occasionally asymmetric enlargement occurs and must be distinguished from thyroid neoplasia. A palpable lymph node superior to the isthmus ("Delphian node") is often found and may be confused with a thyroid nodule. The thyroid gland, in thyroid hormone synthetic defects, on the other hand, tends to be softer and diffusely enlarged. A delayed relaxation time of the deep tendon reflexes may be appreciated in more severe cases.
In patients with severe hypothyroidism of longstanding duration, the sella turcica may be enlarged due to thyrotrope hyperplasia. There is an increased incidence of slipped femoral capital epiphyses in hypothyroid children. The combination of severe hypothyroidism and muscular hypertrophy which gives the child a "Herculian" appearance is known as the Kocher-Debre-Semelaign syndrome (208).
Puberty tends to be delayed in hypothyroid children in proportion to the retardation in the bone age, although in longstanding severe hypothyroidism sexual precocity has been described (209). Females with sexual precocity have menstruation, and breast development but relatively little sexual hair. Multicystic ovaries, the etiology of which is unknown, may be demonstrated on ultrasonography. Galactorrhea may occasionally occur. In boys, isolated testicular enlargement may be found (210). An elevation in serum gonadotropins and prolactin, the latter possibly due to elevated TRH which is known to stimulate prolactin as well as TSH, has been described in some cases. A number of hypotheses have been proposed to explain this syndrome of "pseudopuberty" in hypothyroid patients. These include stimulation of gonadotropin secretion by a paracrine effect of TRH-stimulated second messenger or stimulation of the follicle stimulating hormone (FSH) receptor by TSH (211). It is of interest that, consistent with the latter hypothesis, there is little increase in serum testosterone as might be expected if the FSH, but not luteinizing hormone (LH) receptor is involved and serum gonadotropins are frequently not increased.
Measurement of TSH is the best initial screening test for the presence of primary hypothyroidism. If the TSH is elevated, then evaluation of the free T4 or free thyroxine index (total T4 and T3 resin uptake) will distinguish whether the child has compensated (normal free T4 or free thyroxine index) or overt (low free T4 or free thyroxine index) hypothyroidism.
Measurement of TSH, on the other hand, is not helpful in 2o or 3o hypothyroidism. In these cases hypothyroidism is demonstrated by the presence of a low free T4 (or free thyroxine index). If desired a hypothalamic versus pituitary origin of the hypothyroidism can be distinguished by TRH testing (TRH 7 µg/kg). Hypothalamic hypothyroidism is characterized by a delayed peak in TSH secretion at 60-90 minutes in contrast to normal individuals in whom the peak is observed at 15-30 minutes. In hypopituitarism, on the other hand, there is little or no TSH response to TRH, but the reliability of this test has been questioned (171). Occasionally mild TSH elevation is seen in individuals with hypothalamic hypothyroidism, a consequence of the secretion of a TSH molecule with impaired bioactivity but normal immunoreactivity. Thyroid hormone resistance is characterized by elevated levels of T4 and T3 and an inappropriately normal or elevated TSH concentration.
A diagnosis of CLT is made by the demonstration of elevated titers of anti-thyroglobulin and/or anti-TPO antibodies. Ancillary investigations (thyroid ultrasonography and/or thyroid uptake and scan) may be performed if thyroid antibody tests are negative or if a nodule is palpable, but are rarely necessary. In fact, the typical picture of spotty uptake of radioactive iodine that is seen in adults is rare in children (212). If thyroid antibody tests are negative and no goiter is present, thyroid ultrasonography and/or scan are helpful in identifying the presence and location of thyroid tissue, and therefore, of distinguishing primary myxedema from thyroid dysgenesis. Inborn errors of thyroid hormonogenesis beyond a trapping defect are usually suspected by an increased radioiodine uptake, and a large gland on scan. Other etiologies of hypothyroidism usually are evident on history.
In contrast to neonatal hypothyroidism, rapid replacement is not essential in the older child. This is particularly true in children with long standing, severe thyroid underactivity in whom rapid normalization may result in unwanted side effects (deterioration in school performance, short attention span, hyperactivity, insomnia, and behavior difficulties) (213). In these children it is preferable to increase the replacement dose slowly over several weeks to months. Severely hypothyroid children should also be observed closely for complaints of severe headache when therapy is initiated because of the rare development of pseudotumor cerebri (214). In contrast, full replacement can be initiated at once without much risk of adverse consequences in children with mild hypothyroidism.
Treatment of children and adolescents with subclinical hypothyroidism (normal free T4, elevated TSH) is controversial. In adults in whom the risk of progression to overt hypothyroidism is significant, particularly if they are over the age of 60 years, treatment has been recommended whenever the serum TSH concentration is >10 mIU/L; if the TSH is 6-10 mIU/L treatment on a case by case basis is suggested (214a). In children and adolescents with subclinical hypothyroidism due to CLT, available data suggests a significant likelihood of remission, at least for several years (202-204). Consequently, if there is not a strong family history of hypothyroidism and the patient is not symptomatic, a reasonable option is to reassess thyroid function in 3- 6 months prior to initiating therapy because of the possibility that the thyroid abnormality will be transient.
The typical replacement dose of levothyroxine in childhood is approximately 100 ug/M2 or 4 to 6 ug/kg for children 1 to 5 years of age, 3 to 4 ug/kg for those ages 6 to 10 years, and 2 to 3 ug/kg for those 11 years of age and older. In patients with a goiter a somewhat higher levothyroxine dosage is used so as to keep the TSH in the low normal (0.3 to 1.0 mU/L in an ultrasensitive assay), and thereby minimize its goitrogenic effect.
T4 and TSH should be measured after the child has received the recommended dosage for at least 6-8 weeks. Once a euthyroid state has been achieved, patients should be monitored every 6 to 12 months. Close attention is paid to interval growth and bone age as well as to the maintenance of a euthyroid state. Some children with severe, long standing hypothyroidism at diagnosis may not achieve their adult height potential even with optimal therapy, emphasizing the importance of early diagnosis and treatment (215). Treatment is usually continued indefinitely.
Goiter, the most common thyroid disorder in pediatrics, occurs in 4% to 6% of schoolchildren in North America (202). Like thyroid disease in general, there is a female preponderance, the female: male ratio being 2 to 3:1. Patients with goiter may be euthyroid, hypothyroid or hyperthyroid, euthyroid goiters being by far the most common. The most frequent cause of asymptomatic goiter in North America is CLT, discussed above. Causes of goiter that are associated with abnormal thyroid function are discussed elsewhere in this chapter.
Colloid goiter is the second most common cause of euthyroid thyroid enlargement in childhood. Not infrequently there is a family history both of goiter, CLT and Graves' disease, leading to the suggestion that colloid goiter, too, might be an autoimmune disease. Thyroid growth immunoglobulins have been identified in a proportion of patients with simple goiter (216), but their etiological role is controversial (201). It is important to distinguish patients with colloid goiter from CLT because of the risk of developing hypothyroidism in patients with CLT, but not colloid goiter. Whereas many colloid goiters regress spontaneously, others appear to undergo periods of growth and regression, resulting ultimately in the large nodular thyroid glands later in life.
Evaluation of thyroid function by measurement of the serum TSH concentration is the initial approach to diagnosis. In euthyroid patients, the most common situation, CLT should be distinguished from colloid goiter. Clinical examination in both instances reveals a diffusely enlarged thyroid gland. Therefore, the distinction is dependent upon the presence of elevated titers of TPO and thyroglobulin antibodies in CLT but not colloid goiter. All patients with negative thyroid antibodies initially should have repeat examinations because some children with CLT will develop positive titers with time.
Thyroid suppression in children with a euthyroid goiter is controversial. There is no evidence of efficacy in CLT (202,217) and no long term studies are available in children with colloid goiter. A therapeutic trial may be tried when the goiter is large.
Painful thyroid enlargement is rare in pediatrics and suggests the probability of either acute (suppurative) or subacute thyroiditis (218). Rarely CLT may be associated with intermittent pain and be confused with the latter disorders. In acute thyroiditis, progression to abscess formation may occur rapidly so prompt recognition and antibiotic therapy is essential. Recurrent attacks and involvement of the left lobe suggest a pyriform sinus fistula between the oropharynx and the thyroid as the route of infection. In the latter case, surgical extirpation of the pyriform sinus will frequently prevent further attacks. Subacute thyroiditis, rare in childhood, is discussed in Chapter 19.
More than 95% of cases are due to Graves' disease, an autoimmune disorder that, like CLT, occurs in a genetically predisposed population (219). There is a strong female predisposition, the female:male ratio being 6 to 8:1. Graves' disease is much less common in childhood than in the adult. Although it can occur at any age, it is most common in adolescence. Prepubertal children tend to have more severe disease, to require longer medical therapy and to achieve a lower rate of remission as compared with pubertal children (220). This appears to be particularly true in children who present at <5 years of age. Graves' disease has been described in children with other autoimmune diseases, both endocrine and non endocrine. These include diabetes mellitus, Addison's disease, vitiligo, systemic lupus erythematosis, rheumatoid arthritis, myasthenia gravis, periodic paralysis, idiopathic thrombocytopenia purpura and pernicious anemia. There is an increased risk of Graves' disease in children with Down syndrome (trisomy 21).
Unlike CLT in which thyrocyte damage is predominant, the major clinical manifestations of Graves' disease are hyperthyroidism and goiter. Graves' disease is caused by TSH receptor antibodies that mimic the action of TSH. Binding of ligand results in stimulation of adenyl cyclase and thyroid hormonogenesis and growth. As noted earlier, TSH receptor blocking antibodies, in contrast, inhibit TSH-induced stimulation of adenyl cyclase. Both stimulatory and blocking TSH receptor antibodies bind to the extracellular domain of the receptor and appear to recognize apparently discrete linear epitopes antigen in the context of a three-dimensional structure, but the specific epitope(s) with which they interact is different (221). Studies from several laboratories have suggested that blocking antibodies bind to the carboxy-terminal domain while stimulatory antibodies bind to more amino-terminal loci, but this is controversial. Studies employing monoclonal TSH receptor antibodies cloned from patients and recombinant mutant TSH receptor have demonstrated that there exist multiple TSH receptor antibodies each with different specificities and functional activities. In general, blocking antibodies are more potent inhibitors of TSH binding than are stimulatory ones. Some blocking antibodies inhibit TSH but not stimulatory antibody-binding to the TSH receptor (179). Evidence from other laboratories has suggested that stimulatory antibodies are mostly lambda and of the IgG1 subclass, strongly suggesting that they are monoclonal or pauciclonal (221a,221b). Blocking antibodies, on the other hand, are not similarly restricted.
There are 2 classes of assays for TSH receptor antibodies. Competitive Binding assays (radioreceptor assay or, more recently, ELISA), take advantage of the ability of these antibodies to inhibit the binding of TSH to either thyroid membranes or to recombinant human TSH receptor transfected into Chinese hamster ovary cells. Bioassays measure directly the stimulation (or inhibition of TSH-induced stimulation) of adenyl cyclase. (Table 15-10). The ELISA (also called ‘coated tube’ assay) is more sensitive than the radioreceptor assay. Since both stimulatory and blocking antibodies inhibit TSH binding to the receptor, the radioreceptor assay or ELISA are excellent screening methods to test for the presence of TSH receptor antibodies but they do not provide information about function. A reasonable strategy is to test for the presence of TSH receptor antibodies by a competitive binding assay initially, reserving bioassay to subsequent elucidation of the biological activity.
Table 15-10. Differential Diagnosis of Juvenile Hypothyroidism |
|
1o HYPOTHYROIDISM Congenital Abnormality Iodine Deficiency (endemic goiter) Drugs or Goitrogens Miscellaneous 2o OR 3o HYPOTHYROIDISM Congenital Abnormality Surgery Radiation |
A confusing number of terms have been applied to TSH receptor antibodies, depending on the assay used for their detection (Table 15-10). When measured by radioreceptor assay or ELISA, these antibodies are referred to as TSH receptor antibodies (TRAbs) or TSH binding-inhibitory immunoglobulins (TBII). When evaluated by bioassay, the stimulatory antibodies have been termed thyroid-stimulating antibodies (TSAbs) or thyroid-stimulating immunoglobulins (TSI). In contrast, the blocking antibodies are called TSH receptor-blocking antibodies (TRBAbs) or TSH stimulation-blocking Immunoglobulins (TSI-block). The incidence of TSH receptor antibodies depends on the method used for their detection and on its sensitivity. Unfortunately, until recently results obtained in different research laboratories could not be compared because of the lack of a uniform standard and because the FRTL-5 cell lines being used for bioassay in different laboratories varied in their sensitivity to TSH, particularly after repeated passage (222). Technical improvements in both the binding inhibition assay (223-223d) and the bioassay (223d) as well as their commercial availability have greatly improved assay sensitivity and reliability.The availability of commercial assays, of CHO cells transfected with human TSH receptor, and most recently, a stimulating human anti-TSH receptor monoclonal Ab (should improve standardization of results and assay sensitivity. When measured by radioreceptor assay, TSH receptor antibodies were detected in 80 to 100% of children with active Graves' disease; results by bioassay were similar (223e). Most children with Graves' disease also have TPO and thyroglobulin antibodies in their sera, but measurement of the latter antibodies is less sensitive and less specific than measurement of TSH receptor antibodies (223e).
Rarely, hyperthyroidism may be caused by a functioning thyroid adenoma, by constitutive activation of the TSH receptor or it may be seen as part of the McCune Albright syndrome. Hyperthyroidism also may be due to inappropriately elevated TSH secretion, the result of either a TSH-secreting pituitary adenoma or selective pituitary resistance to thyroid hormone.
Miscellaneous causes of thyrotoxicosis without hyperthyroidism include the toxic phase of CLT, mentioned above, and thyroid hormone ingestion (thyrotoxicosis factitia).
All but a few children with Graves' disease present with some degree of thyroid enlargement, and most have symptoms and signs of excessive thyroid activity, such as tremors, inability to fall asleep, weight loss despite an increased appetite, proximal muscle weakness, heat intolerance and tachycardia. Often the onset is insidious. Shortened attention span, and emotional lability may lead to behavioral and school difficulties. Some patients complain of polyuria and of nocturia, the result of an increased glomerular filtration rate. Acceleration in linear growth may occur, often accompanied by advancement in skeletal maturation (bone age). Adult height is not affected. In the adolescent child, puberty may be delayed. If menarche has occurred, secondary amenorrhea is a common concomitant. If sleep is disturbed, the patient may complain of fatigue.
Physical examination reveals a diffusely enlarged, soft or "fleshy" thyroid gland, smooth skin and fine hair texture, excessive activity, and a fine tremor of the tongue and fingers. A thyroid bruit may be audible. In contrast, the finding of a thyroid nodule suggests the possibility of a toxic adenoma. The hands are often warm and moist. Tachycardia, a wide pulse pressure, and a hyperactive precordium are common. Cafe au lait spots, particularly in association with precocious puberty, on the other hand, suggests a possible diagnosis of McCune Albright syndrome while if a goiter is absent, thyrotoxicosis factitia should be considered. The ophthalmopathy characteristic of Graves' disease in adults is considerably less common in children, although a stare and mild proptosis are observed frequently.
The clinical diagnosis of hyperthyroidism is confirmed by the finding of increased concentrations of circulating thyroid hormones (T4 and, as necessary, free T4 (or free T4 index) and T3). In hyperthyroidism, the circulating T3 concentration frequently is elevated out of proportion to the T4 because, like TSH, TSH receptor antibodies stimulate increased T4 to T3 conversion. Demonstration of a suppressed TSH excludes much rarer causes of thyrotoxicosis, such as TSH-induced hyperthyroidism and pituitary resistance to thyroid hormone in which the TSH is inappropriately "normal" or slightly elevated. If the latter diseases are suspected, free alpha subunit should be measured and a TRH test performed. Alternatively, an elevated T4 in association with an inappropriately "normal" TSH may be due to an excess of thyroxine-binding globulins (either familial or acquired, for example a result of oral contraceptive use) or rarer binding protein abnormalities (for example, familial dysalbuminemic hyperthyroxinemia). In the latter cases, serum TBG concentration should be measured.
If the diagnosis of Graves' disease is unclear, TSH receptor antibodies should be measured. As noted earlier in this chapter, a binding-inhibition assay is appropriate for initial screening because it is sensitive and is technically relatively simple, rapid and reproducible. The ELISA is more sensitive than the radioreceptor assay (223a,223b). Bioassay, though of no advantage in screening, may be useful in the occasional Graves' disease patient who is negative in the binding assay or in treated patients whose clinical picture is discordant with results in the binding assay (223e). Some individuals, initially negative in the radioreceptor assay, become positive several weeks later (223e). It has been hypothesized that in these patients, TSH receptor antibody synthesis is restricted at first to residing within the thyroid gland itself, or, alternately, that TSH receptor antibodies escape detection because of binding by soluble TSH receptor circulating in serum. Measurement of TSH receptor antibodies may be particularly useful in distinguishing the toxic phase of CLT (TSH receptor antibody negative) from patients with both CLT and Graves' disease ("Hashitoxicosis", TSH receptor antibody positive). As noted above, measurement of thyroglobulin and TPO antibodies, on the other hand is neither sensitive nor specific in the diagnosis of Graves' disease in childhood (223e).
In contrast to adults, radioactive iodine uptake and scan are used to confirm the diagnosis of Graves' disease only in atypical cases (for example, if measurement of TSH receptor antibodies is negative, if the thyrotoxic phase of either CLT or subacute thyroiditis or if a functioning thyroid nodule is suspected).
The choice of which of the three therapeutic options (medical therapy, radioactive iodine, or surgery) to use, should be individualized and discussed with the patient and his/her family. Each approach has its advantages and disadvantages with respect to efficacy, both short and long term complications, the time required to control the hyperthyroidism, and the requirement for compliance (224). In general, medical therapy with one of the thiouracil derivates (PTU or MMI) is the initial choice of most pediatricians although radioiodine is gaining increasing acceptance, particularly in non compliant adolescents, in children who are mentally retarded, and in those about to leave home (for example, to go to college). Alternately, surgery, the oldest form of therapy, may be the initial choice in specific cases if an experienced pediatric thyroid surgeon is available
Both PTU, MMI and carbimazole (converted to MMI) exert their antithyroid effect by inhibiting the organification of iodine and the coupling of iodotyrosine residues on the thyroglobulin molecule to T3 and T4. MMI is preferred by many pediatric endocrinologists because for an equivalent dose it requires taking fewer tablets and because it has a longer half-life. As a result, MMI requires less frequent medication, an advantage particularly in non compliant adolescents. On the other hand, PTU but not MMI inhibits the conversion of T4 to the more active isomer T3, a potential advantage if the thyrotoxicosis is severe. The initial dosage of PTU is 5 mg/kg/day given tid and that of MMI is 0.5 mg/kg/day given bid. In severe cases, a beta-adrenergic blocker (propranolol, 0.5-2.0 mg/kg/day given every 8 hours) can be added to control the cardiovascular overactivity until a euthyroid state is obtained. Patients should be followed every 4 to 6 weeks until the serum concentration of T4 (and total T3) normalizes. It should be noted that the TSH concentration may not return to normal until several months later. Therefore, measurement of TSH is useful as a guide to therapy only after it has normalized but not initially. Once the T4 and T3 have normalized, one can either decrease the dosage of thioamide drug by 30% to 50% or, alternatively, wait until the TSH begins to rise and add a small, supplementary dose of l-thyroxine (e.g., 1 mg/kg/day). Maintenance doses of PTU may be given twice daily. MMI may be administered once daily. Usually patients can be followed every 4-6 months once thyroid function has normalized. The optimum duration of therapy is unknown. Approximately 50% of children will go into long term remission within 4 years, with a continuing remission rate of 25% every 2 years for up to 6 years of treatment (225). In patients treated with antithyroid drugs alone, a small drug requirement, small goiter, lack of orbitopathy and lower initial degree of hyperthyroxinemia (T4 <20 mg/dL (257.4 nmol/L); T3:T4 ratio <20) are favorable indicators that drug therapy can be tapered gradually and withdrawn. Recently, body mass index (BMI) <-0.5% and older age (pubertal versus prepubertal age) have also been associated with an increased likelihood of permanent remission (226). Persistance of TSH receptor antibodies, on the other hand, indicates a high likelihood of relapse. Initial studies suggesting that combined therapy (i.e., antithyroid drug plus l-T4) might be associated with an improved rate of remission (227) have not been confirmed (228).
Toxic drug reactions (erythematous rashes, urticaria, arthralgias, transient granulocytopenia, (<1500 granulocytes/mm3), have been reported in 5% to 14% of children. Rarely, more severe sequelae, such as hepatitis, a lupus like syndrome, thrombocytopenia, and agranulocytosis, (<250 granulocytes/mm3)) may occur. Most reactions are mild and do not contraindicate continued use. In more severe cases, switching to the other thioamide frequently is effective. The risk of hepatitis and agranulocytosis appear to be greater within the first 3 months of therapy and there is evidence that close monitoring of the white blood cell (wbc) count during this initial time period may be useful in identifying agranulocytosis prior to the development of a fever and infection (229). Many authors recommend also checking the wbc count and liver function tests prior to therapy because Graves' disease itself can be associated with abnormalities in these parameters. It is important to caution all patients to stop their medication immediately and consult their physician should they develop unexplained fever, sore throat, gingival sores, or jaundice. Approximately 10% of children treated medically will develop long term hypothyroidism, a consequence of coincident cell and cytokine-mediated destruction and/or the development of TSH receptor blocking antibodies.
Definitive therapy with either medical (radioactive iodine) or surgical thyroid ablation usually is usually reserved for patients who have failed drug therapy, developed a toxic drug reaction, or are noncompliant. In recent years, however, radioactive iodine is being favored increasingly, even as the initial approach to therapy. The advantages are the relative ease of administration, the reduced need for medical follow up and the lack of demonstrable long term adverse effects (224,230). Although a dose of 50 to 200 Ci of 131I/estimated gram of thyroid tissue has been used, the higher dosage is recommended, particularly in younger children, in order to completely ablate the thyroid gland and thereby reduce the risk of future neoplasia. The size of the thyroid gland is estimated, based on the assumption that the normal gland is 0.5-1.0 gms/year of age, maximum 15-20gms. The formula used is:
Estimated thyroid weight in grams X 50-200 µCi 131I
fractional 131I 24 hour uptake
Radioactive iodine therapy should be used with caution in children <10 years of age and particularly in those <5 years of age because of the increased susceptibility of the thyroid gland in the young to the proliferative effects of ionizing radiation. For example, the increased incidence of papillary thyroid cancer after the Chernobyl disaster was restricted to those <10 years of age, and greatest in children <5 years of age or in utero at the time of the reactor malfunction (231). Also, the risk of benign thyroid nodules following radioactive iodine therapy for Graves' disease decreases with each decade of life (231). Pretreatment with antithyroid drugs prior to RAI therapy is not necessary as long as the hyperthyroidism is not too severe.
Thyroid hormone concentrations may rise transiently 4 to 10 days after RAI administration due to the release of preformed hormone from the damaged gland. Beta blockers may be useful during this time period. Similarly, analgesics may be employed if there is mild discomfort due to radiation thyroiditis. Other acute complications of RAI therapy (nausea, significant neck swelling) are rare. One usually sees a therapeutic effect within 6 weeks to 3 months. Worsening of ophthalmopathy, described in adults after RAI does not appear to be common in childhood. However, if significant ophthalmopathy is present RAI therapy should be used with caution and pretreatment with steroids may be effective. Alternately, another permanent treatment modality (surgery) should be considered. In approximately 1000 children with Graves' disease treated with RAI and followed for <5 to >20 years to date, there does not appear to be any increased rate of congenital anomalies in offspring nor in thyroid cancer. However, long term follow up data in a larger cohort are still lacking.
Surgery, the third therapeutic modality, is performed less frequently now than in the past. An advantage of this form of therapy is the rapid resolution of the hyperthyroidism. Near-total thyroidectomy is the procedure of choice in order to minimize the risk of recurrence. Surgery usually is reserved for patients who have failed medical management, who have a markedly enlarged thyroid, who refuse radioactive iodine therapy, and for the rare patient with significant orbitopathy in whom radioactive iodine therapy is contraindicated. The reported rates of complications are: transient hypocalcemia (10%), recurrent laryngeal nerve paralysis (1.2%), hypoparathyroidism (2%), and, rarely (0.1%), death, but complications vary greatly from center to center. Therefore, this therapy should be performed only by an experienced pediatric thyroid surgeon. Occasionally (1.7%) unsightly keloid formation occurs at the site of the scar. Prior to surgery, it is important to treat with antithyroid medication in order to render the child euthyroid and prevent thyroid storm. Iodides (Lugol's solution, 5 to 10 drops tid or potasium iodide, 2 to 10 drops daily or Na ipodate, 0.5-1 gm every 3 days) are added for 7 to 14 days prior to surgery in order to decrease the vascularity of the gland.
Following both medical and surgical thyroid ablation most patients become hypothyroid and require lifelong thyroid replacement therapy. On the other hand, if therapy is inadequate, hyperthyroidism may recur. Therefore longterm followup is mandatory.
Thyroid nodules are rare in the first 2 decades of life, but when found, they are more likely to be carcinomatous than are similar masses in adults (232). Follicular adenomas and colloid cysts account for the majority of benign nodules. Other causes of nodular enlargement include CLT and embryological defects, such as intrathyroidal thyroglossal duct cysts or unilateral thyroid agenesis (232). Like in adults, the most common form of thyroid cancer in childhood and adolescence is papillary thyroid carcinoma, but other histological types found in the adult may also occur (233).
A high index of suspicion is necessary if the nodule is painless, of firm or hard consistency, if it is fixed to surrounding tissues or if there is a family history of thyroid cancer. Other worrisome findings include a history of rapid increase in size, associated cervical adenopathy, hoarseness or dysphagia. Even the findings of a cystic component or a “functioning” nodule, commonly used as favorable signs in adult patients, do not completely exclude the possibility of neoplasia (234). Occasionally, thyroid cancer presents in childhood as unexplained cervical adenopathy or neoplasia is found in patients who also have CLT (234). The possibility of a rare medullary thyroid carcinoma should be considered if there is a family history of thyroid cancer or pheochromocytoma or if the child has multiple mucosal neuromas and a marfanoid habitus, findings suggestive of multiple endocrine neoplasia (MEN) types 2A and/or 2B (235).
Children exposed previously to thyroid irradiation comprise a high-risk group. The increased risk of thyroid cancer in adults exposed during childhood to low levels of thyroid irradiation for benign conditions of the head and neck is well known (236). Formerly it was thought that high dose thyroid irradiation during childhood would not constitute an increased risk for thyroid neoplasia because the thyroid tissue would be destroyed. However, the increased incidence of both benign and carcinomatous nodules in patients with Hodgkin disease who had received radiotherapy to the neck during childhood is being documented increasingly (237, 238). Similarly, as noted previously, children exposed to high levels of radioactive iodine in the first decade of life or in utero, a consequence of the Chernobyl disaster, are at a markedly increased risk of developing papillary thyroid cancer. The risk of thyroid cancer is related to the dose of external irradiation and, unlike the 19 year average latency after low dose irradiation, the average latent period in survivors of Hodgkin disease appears to be only 9 years (237).
Initial investigation of a thyroid nodule includes evaluation of thyroid function and anti TPO and anti Tg Abs. A suppressed serum TSH concentration accompanied by an elevation in the circulating T4 and/or T3 suggests the possibility of a functioning nodule. The finding of positive Abs, on the other hand, indicates the presence of underlying CLT, although in some cases, positive Abs may simply constitute evidence of an immune response to the presence of neoplastic cells. Thyroid scintiscan can be used to provide information as to whether the nodule is ‘cold’, while thyroid ultrasound provides information about whether the nodule is solid or cystic. Fine-needle aspiration biopsy, popular in the investigation of thyroid carcinoma in adults, has been employed increasingly in older children (239). Unfortunately, false-negative results have occurred occasionally with this technique, leading some to continue to favor immediate open excisional biopsy for all solitary, solid thyroid nodules or goiter-associated lymphadenopathy in childhood and adolescence (234). Fine needle aspiration biopsy is less useful in patients with a history of thyroid irradiation in whom there is a high risk of multifocal disease (240).
There is an increased incidence of both cervical node involvement (233, 241 and of pulmonary metastases (233) at the time of diagnosis in children with thyroid carcinoma. Nonetheless, the long term cancer specific mortality rate is no greater in children than in adults <40 years of age (241). Thus, the approach to treatment is similar. (See Chapter 18). Excision of the tumor or lobe is the appropriate treatment for benign tumors and cysts, whereas total thyroidectomy with preservation of the parathyroid glands and recurrent laryngeal nerves is the initial therapy for malignant thyroid tumors. The latter procedure is followed by radioablation if there is evidence of residual gland or tumor after surgery. After radioiodine therapy, the dose of thyroxine is adjusted to keep the serum TSH concentration suppressed (between 0.05 mU/L and 0.1 mU/L in a sensitive assay). Measurement of serum Tg, a thyroid follicular cell-specific protein, is used to detect evidence of metastatic disease in differentiated forms of thyroid cancer, such as papillary or follicular carcinoma. This is best performed after a period (usually 6 weeks) of thyroxine withdrawal although it is likely that, like in adults, exogenous administration of recombinant TSH, too, will prove useful (242).
Measurement of circulating calcitonin is used as a tumor marker for medullary thyroid cancer (MTC), a C-cell derived malignancy (243). Mutations of the RET proto-oncogene, detectable in nearly all familial forms of MTC, is of value in screening family members (235, 243). In families affected with multiple endocrine neoplasia type 2, screening of children as young as 5 years followed by total thyroidectomy has been successful in curing patients with microscopic MTC, an otherwise highly malignant neoplasm with a poor prognosis (235).
Optimal monitoring of patients with a history of thyroid irradiation during childhood remains controversial (240). Because of the insensitivity of clinical palpation, regular assessment of thyroid function (TSH and, as necessary free T4) as well as ultrasound examinations should be performed. There is evidence that thyroid suppression is associated with a reduction in the development of new nodules after partial surgical resection of an irradiated thyroid gland (244) but whether it plays any role if the TSH is not elevated or in preventing neoplasia is unknown.