Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

75C. Hypothyroidism in Infants, Children, and Adolescents: Acquired Hypothyroidism

Guy van Vliet

The unique feature of hypothyroidism in infants, children, or adolescents is that, if diagnosis is delayed, the condition may have a profound impact on skeletal growth and maturation, pubertal development, and adult height. When it occurs before birth, hypothyroidism may retard skeletal maturation, but it does not result in stunted intrauterine growth. However, starting immediately after birth (1), and until epiphyseal fusion, longitudinal bone growth is exquisitely sensitive to thyroid hormone deficiency. Thus, slowing of linear growth is the most sensitive clinical indicator of hypothyroidism in children. On the other hand, hypothyroidism in children 3 years of age or older does not have the same dramatic potential consequence of irreversible brain damage as when it is present at birth or soon thereafter. However, the initiation of treatment of severe hypothyroidism acquired during childhood and adolescence may transiently decrease learning ability and alter behavior, sometimes dramatically.

EPIDEMIOLOGY AND CAUSES OF ACQUIRED HYPOTHYROIDISM IN CHILDREN

The causes of acquired hypothyroidism in children and adolescents are shown in Table 75C.1. In addition to these disorders, in some infants with congenital hypothyroidism the onset of symptoms and signs of hypothyroidism may be delayed, and affected children may therefore present as if they have acquired hypothyroidism. This is most common in children with inborn errors of thyroid hormone biosynthesis (see Chapter 48), but the mechanism of the delayed expression of the gene defect is unknown (2). On the other hand, children with central hypothyroidism caused by mutations in the β-subunit of thyrotropin (TSH) are missed by TSH-based neonatal screening programs and may only be recognized later.

TABLE 75C.1. CAUSES OF ACQUIRED HYPOTHYROIDISM IN CHILDREN AND ADOLESCENTS

 

Primary hypothyroidism

   Hashimoto's thyroiditis (goitrous and atrophic forms)

   Irradiation of the thyroid

External irradiation for head and neck tumors

Radioactive iodine treatment for hyperthyroidism

    Thyroidectomy

   Drug-induced (interferon-α, lithium, iodine-containing drugs)

    Consumptive (liver or skin hemangiomas)

    Iodine deficiency

Central hypothyroidism

   Tumors or infiltrative diseases of the hypothalamo-pituitary area

   Part of evolving hypopituitarism associated with:

Developmental defects (e.g., pituitary stalk interruption)

Pituitary transcription factor mutations

 

Although the prevalence of congenital hypothyroidism is well known and varies little from country to country, there are relatively few studies of the prevalence of acquired hypothyroidism in children. In a recent study of 103,500 people aged 0 to 22 years in Scotland, 140 patients (0.14%) had received prescriptions for thyroxine (T4) on a regular basis (2a). The male to female ratio was 1:2.8. A review of these patients' charts revealed that 75% had acquired hypothyroidism. The vast majority had primary hypothyroidism and evidence of autoimmune thyroid disease, 3.5% had type 1 diabetes mellitus, 2% had juvenile rheumatoid arthritis, and 1.5% had Down's syndrome. Geographic variations in the prevalence of hypothyroidism caused by autoimmune thyroid disease suggest that iodine deficiency may be protective (3). Hashimoto's thyroiditis is a common diagnosis in pediatric endocrine clinics in iodine-replete North America, but is much rarer in European countries such as Belgium, in which iodine intake is marginal.

Much less common than hypothyroidism due to autoimmune thyroid disease is radiation-induced hypothyroidism. This may occur as a result of external radiation therapy for tumors of the head and neck, or after radioiodine therapy for thyrotoxicosis (see Chapter 76) (4). Hypothyroidism after thyroidectomy is rare in children, because few children undergo thyroid surgery. Hypothyroidism due to drugs is also rare. Interferon-α, lithium, and iodine-containing drugs can cause hypothyroidism in children, as in adults, primarily in children with preexisting chronic autoimmune thyroiditis.

An exceptional cause of hypothyroidism is consumptive hypothyroidism, resulting from the overexpression of type 3 deiodinase (see Chapter 7) by large liver or cutaneous hemangiomas (5). Although some of these infants have hypothyroidism at birth (6), most presented in the first few months of life, when hemangiomas are typically at their maximal size. One young adult with this syndrome has also been reported (7). Importantly, severe primary hypothyroidism requiring a high dose of T4 was the presenting manifestation of multiple hepatic hemangiomas in one child, suggesting that a search for these tumors should be undertaken in any child with unexplained primary hypothyroidism who requires a high dose of T4 (8).

Lastly, iodine deficiency remains an important cause of hypothyroidism worldwide (see section on iodine deficiency in Chapter 11 and Chapter 49). Although acquired hypothyroidism due to iodine deficiency is rare in North America and other countries where iodized salt is available, it can occur in children whose diets are severely restricted in salt and iodine-containing foods (9).

Acquired central hypothyroidism is typically associated with other pituitary hormone deficiencies. It is rarely the first or presenting manifestation of hypothalamic or pituitary disease, including tumors and infiltrative diseases such as histiocytosis, or of developmental defects with delayed expression.

CLINICAL PRESENTATION

The symptoms and signs of acquired hypothyroidism in children and adolescents depend on its severity and duration. Some patients present with a relatively short history of fatigue, constipation, dry skin, and cold intolerance, without a change in their growth pattern and without retardation of bone maturation, reflecting a sudden onset of hypothyroidism. However, in the vast majority of patients, assessment of growth reveals long-standing hypothyroidism. Typically, there is a rather abrupt deceleration in height gain at some time in the more or less distant past, whereas weight gain is relatively preserved. Thus, the patients present with short stature and relative weight excess, but they are seldom obese (Fig. 75C.1). The effect of hypothyroidism on bone maturation is even more pronounced than its effect on linear growth, so that the bone age is often younger than the height age (i.e., the age at which the child's height corresponds to the 50th percentile). Tooth eruption is also delayed. Other skeletal effects of hypothyroidism in children include stippling of the epiphyses and a slipped capital femoral epiphysis (see Chapter 62) (10).

FIGURE 75C.1. Stature and weight curves of a girl with long-standing severe primary hypothyroidism caused by Hashimoto's thyroiditis. Her height and weight increased normally until she was about 7 years old (left picture), when height gain started to decrease while weight gain accelerated. At age 11.25 years, she had no fatigue, constipation, or cold intolerance, but her facial appearance had changed (right picture). Physical examination at that time revealed facial puffiness, very dry skin, and a small goiter. Her serum TSH concentration was 695 mU/L, her serum free thyroxine (T4) concentration was 0.2 ng/dL (2.6 p), and her serum titer of antithyroid peroxidase antibodies was 1:1,600. Bone age was 7.5 years ( on left). During the first months of TMopen circle4 therapy (), she lost weight. This was followed by catch-up growth, progressive breast development, and rapid progression of bone maturation [bone age 11 years at chronological age 12 years ( on right)]. Despite treatment with a long-acting gonadotropin-releasing hormone agonist (GnRH-A) from age 12 to age 16 years to slow maturation (), her adult height is below her target height ().left vertical arrowopen circleright vertical arrowright horizontal arrow Because long-standing hypothyroidism retards bone maturation, it is often assumed that it invariably retards pubertal development. However, pubertal development may occur at a normal age. In some children, the effect of sex steroids on bone maturation seems to override that of hypothyroidism, resulting in an adult height below genetic potential. Rare children with severe primary hypothyroidism have sexual precocity (11): this appears to result from activation of follicle-stimulating hormone receptors by very high serum TSH concentrations. Accordingly, affected boys have testicular enlargement without excess testosterone secretion (12,13), and affected girls have functional ovarian cysts with vaginal bleeding, either with no other signs of puberty (14) or with breast development and galactorrhea but no pubic hair (11).

Hypothyroidism acquired after 3 years of age (the critical period during which it has an irreversible effect on brain development) does not typically affect school performance and progression. If the hypothyroidism is severe and of long duration, the child may require more time to accomplish the assigned tasks, but will rarely be held back academically. In fact, more often, school performance deteriorates after treatment is started.

Aside from its effects on growth, maturation, and puberty, the symptoms and signs of acquired hypothyroidism in children and adolescents are similar to those in adults (see Chapters 46, and 52,53,54,55,56,57,58,59,60,61,62,63,64). Thus, a constellation of increasing fatigue, constipation, cold intolerance, and puffiness of the face should alert the clinician to the possibility of hypothyroidism. Hypothyroidism has also been reported in otherwise asymptomatic children with hypercholesterolemia, and serum TSH should be measured in children with any type of hyperlipidemia (15).

In children with any symptoms and signs of hypothyroidism, the size of the thyroid should be determined. The World Health Organization definition that a goiter is present when the thyroid lobes are larger than the distal phalanx of the thumb of the child may seem rather crude, but is useful in children given their greatly varying size (16). In iodine-sufficient areas, the most common cause of goiter associated with hypothyroidism is Hashimoto's thyroiditis, in which case both lobes of the thyroid are usually moderately enlarged, firm, and irregular (“pebbly”). Nodules greater than 1 cm in diameter are rare, but a “Delphian node” is a frequent finding (a lymph node sometimes as small as a grain of rice that can be palpated above the isthmus, close to the midline). A family history of autoimmune thyroid disease is often elicited. Although a goiter is usually present at the time of diagnosis of Hashimoto's thyroiditis, the gland will usually gradually atrophy later. Thyroid atrophy may be present at diagnosis at any age, but this appears to be more common in infants (17).

Imaging of the pituitary is often performed when growth decelerates. It is important to remember that children and adolescents, as well as adults, with long-standing primary hypothyroidism can have pituitary enlargement, caused by hypertrophy and hyperplasia of the thyrotrophs (see Chapter 3). The enlargement may mimic that of a pituitary tumor, but is reversed by T4 therapy (18). Thus, neuroradiologic studies should not be ordered in children with growth deceleration before serum TSH is measured. The shrinking of an enlarged pituitary may be responsible for the rare occurrence of transient growth hormone deficiency during the first years of T4 therapy in children with hypothyroidism (19).

DIAGNOSTIC EVALUATION

Primary Hypothyroidism

A clinical suspicion of hypothyroidism should always be confirmed by measurements of serum TSH and free T4. On the other hand, the serendipitous discovery of a high serum TSH concentration in a normally growing child or adolescent without any symptoms and signs of hypothyroidism should be verified before embarking on long-term treatment, because transient hypothyroidism may occur in autoimmune thyroiditis. If a diagnosis of primary hypothyroidism is confirmed, the next step is to determine its etiology. In infants, a radionuclide scan should be done to rule out a congenital cause that may have been missed on neonatal screening or if the onset of hypothyroidism was delayed. As stated above, most infants with congenital hypothyroidism in whom the onset of symptoms is delayed have some type of thyroid dyshormonogenesis (2,20), but one boy with normal blood-spot TSH and T4 values at neonatal screening who had severe hypothyroidism due to ectopic thyroid tissue documented by radionuclide imaging at age 3 years has been reported (21). Intense radionuclide uptake by a normal-sized or enlarged thyroid in an infant with acquired hypothyroidism may suggest the presence of consumptive hypothyroidism (8).

In older infants, children, and adolescents, serum antithyroid peroxidase antibodies should be measured. A high concentration confirms the diagnosis of chronic autoimmune thyroiditis, whether the patient has a goiter (Hashimoto's thyroiditis, goitrous autoimmune thyroiditis) or not (atrophic autoimmune thyroiditis). On radionuclide imaging studies, the size of the thyroid may vary from small to large, and the heterogeneous pattern of uptake often seen in adults, which probably results from areas of fibrosis, is rarely seen in children (22). On ultrasonography, heterogeneous echogenicity is usually present (see Chapter 16) (23). In fact, neither scintigraphy nor ultrasonography is necessary to establish the diagnosis of chronic autoimmune thyroiditis. Imaging should be restricted to those children with a palpable thyroid nodule.

The child's growth trajectory should be carefully reconstructed and analyzed. Even if previous growth data are unavailable, a radiograph of the left hand and wrist should be obtained if hypothyroidism is severe, because its duration can be estimated by the degree of retardation of bone maturation.

As mentioned above, chronic autoimmune thyroiditis is more prevalent in children with type 1 diabetes. It is also more prevalent in children with chromosomal disorders, principally aneuploidies [trisomy 21 (24) and Turner's syndrome (25); the evidence for an association with Klinefelter's syndrome is less clear (26)]. Hypothyroidism is seldom the presenting feature of the polyglandular autoimmune syndromes.

Central Hypothyroidism

Central hypothyroidism is much less common than primary hypothyroidism in children and adolescents, and it is harder to diagnose. The symptoms and signs of hypothyroidism are usually more subtle, although slow growth and delayed bone maturation remain the most common presenting problems (27). Once a diagnosis of central hypothyroidism has been documented by measurements of serum free T
4 (low) and TSH (low, normal, or only slightly high) (see Chapter 51), other pituitary functions should be evaluated and neuroradiologic studies, preferably magnetic resonance imaging, should be performed. Most patients with central hypothyroidism have other pituitary hormone deficiencies, especially growth hormone deficiency, and TSH deficiency is seldom the first deficiency to be identified.

Some children with growth hormone deficiency may develop central hypothyroidism when they are treated with growth hormone, and hypothyroidism is one reason for a poor therapeutic response to growth hormone. This central hypothyroidism is generally due to evolving hypothalamic or pituitary disease. It should be distinguished from the decrease in serum free T4 concentrations that occurs consistently during the first few months of growth hormone treatment in both growth hormone–deficient (28) and–sufficient humans (29), and which appears to be due mainly to increased conversion of T4 to T3. On the other hand, an increase in hypothalamic somatostatin secretion during growth hormone treatment may induce a decrease in serum TSH concentrations and true central hypothyroidism (30). However, treatment of growth hormone–deficient children with T4 may result in a greater acceleration of bone maturation than of linear growth (31), and should therefore not be undertaken lightly. Despite these diagnostic difficulties, children who have a suboptimal response to growth hormone therapy, coupled with symptoms and signs of hypothyroidism and unequivocally low serum free T4 concentrations, should be treated with T4. This occurs mainly in children with organic hypopituitarism (32).

Whether a thyrotropin-releasing hormone (TRH) stimulation test should be performed before treatment is controversial (33). In children and adolescents with central hypothyroidism, administration of TRH typically induces an ample and sustained serum TSH response, with a peak serum TSH concentration at 60 minutes or later. This response suggests that the pituitary thyrotrophs are not only present but also store rather than secrete TSH because of lack of stimulation from endogenous TRH (34). The TSH produced in these patients has low bioactivity (35). Imaging studies usually reveal an interrupted pituitary stalk, often associated with other developmental defects such as an ectopic posterior pituitary gland (36). This type of hypothyroidism is caused by a disconnection between the hypothalamic TRH neurons and the pituitary thyrotrophs.

In the rare cases of central hypothyroidism resulting from pituitary transcription factor mutations, the serum TSH response to TRH is blunted or absent, and the pituitary stalk is normal on imaging (37). Thus, aside from it being required in all patients with central hypothyroidism to rule out space-occupying lesions or infiltrative processes of the hypothalamic–pituitary area, imaging clarifies the developmental defects underlying many of the other cases.

TREATMENT

As in adults, the treatment of choice for children and adolescents with either primary or central hypothyroidism is the daily oral administration of T4. An anticipated full replacement dose may be prescribed from the outset in children and adolescents. A rapid return to the euthyroid state is occasionally accompanied by dramatic psychological changes; and a few adolescents have an acute (and transient) psychosis. However, such cases are exceptional, and some have occurred even after gradual dose escalation (38). Another rare side effect during the early phase of T4 therapy in children is benign intracranial hypertension; this, too, can occur despite gradual dose escalation (39). Thus, parents should be warned that dramatic behavioral changes may occur after therapy is begun, and that the onset of severe headaches should lead to prompt fundoscopic examination.

A full daily replacement dose of T4, expressed as µg/kg of body weight, is about 5 for children 1 to 5 years old, 4 for children 6 to 12 years old, and 3 for adolescents. These doses correspond to about 100 µg/m2 of body surface area (40). The needed dose is usually lower in patients with central hypothyroidism. However, there is substantial variation in the effect of T4 in different patients, so these estimates are only a rough guide for the dose likely to be needed for an individual patient. The dose appropriate for a patient with primary hypothyroidism should be adjusted so that the patient's serum TSH concentration is normal. Absorption may be better if T4 is administered 30 minutes or more before meals, and it may be decreased by the simultaneous intake of iron and calcium supplements (41,42).

After therapy is started, the appearance of children with severe long-standing hypothyroidism changes dramatically, and initially weight may be lost (Fig. 75C.1). Subsequently, catch-up growth in height with proportionate weight gain occurs. In prepubertal children with severe hypothyroidism, pubertal development and bone maturation should be monitored closely, because progression may be too rapid. When this occurs, administration of a gonadotropin-releasing hormone agonist to decrease sex steroid secretion and delay epiphyseal maturation may be considered, although the impact of combined T4 and agonist therapy on adult height is uncertain (43). Diagnosis of hypothyroidism before it has had an important impact on growth—which can be achieved if linear growth in children is followed longitudinally—is obviously preferable.

Because equilibration is slow, serum TSH should not be measured less than 6 weeks after therapy is started or changed. Once the patient's serum TSH concentration is normal, growth, pubertal development, and serum TSH should be monitored yearly.

T4 therapy in patients with central hypothyroidism should be monitored by measurements of serum free T4. In those patients in whom serum TSH concentrations were normal before therapy, undetectable values suggest overtreatment, even if their serum free T4 concentrations are in the normal range. This should be avoided because it may lead to accelerated bone maturation, and the dose should be the lowest possible for optimal growth and maturation.

PROGNOSIS

In peripubertal children with severe long-standing hypothyroidism, the prognosis regarding adult height should be guarded (44). On the other hand, hypothyroidism acquired after the critical period of brain development during infancy does not carry a risk for irreversible long-term effects on cognition. In most patients, and specifically those who have chronic autoimmune thyroiditis, hypothyroidism will likely be permanent. However, as in many other autoimmune diseases, there may be periods of remission. In particular, thyroid function may fluctuate, sometimes widely (45), and it may therefore be appropriate to withdraw T4 for 6 to 8 weeks every several years or at the end of growth. This is not necessary in patients who have high serum TSH concentrations while taking T4, or in those who had severe hypothyroidism with thyroid atrophy at the time of diagnosis.

Adolescent girls should be informed that they may need more T4 if they take an estrogen-containing oral contraceptive, although currently used oral contraceptives have only a minimal influence on thyroid function in normal women (46). More important, they should be advised that the adequacy of treatment should be determined before and as soon as possible after they become pregnant, because most pregnant women with hypothyroidism need a higher dose of T4 than when they are not pregnant (see Chapters 67 and 80). Among those with chronic autoimmune thyroiditis, serum TSH receptor–blocking antibodies may be present, but rarely in sufficient quantities to affect fetal thyroid function (47).

Other factors that may lead to the need for an increase in T4 include treatment with phenytoin, carbamazepine, or rifampin. These drugs increase the clearance of T4; unlike normal subjects, patients with hypothyroidism cannot increase T4 secretion to compensate for the increase in clearance. Other substances, for example, iron and calcium, can reduce intestinal absorption of T4, thereby necessitating an increase in T4 dose (see Chapter 67).

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