Заболевания щитовидной железы

During embryogenesis, epithelial cells on the pharyngeal floor thicken to form a diverticulum. This diverticulum elongates, and the primordial thyroid cells migrate caudally until they fuse with the ventral aspect of the fourth pharyngeal pouch, at about the fourth gestational week.

Two lobes connected by an isthmus are typically located approximately anterior to the third tracheal cartilage. The thyroglossal duct that results from the migration normally involutes. Retention and growth of thyroid tissue at the lower end of the duct occasionally results in a pyramidal lobe.

Thyroglobulin is produced by the eighth gestational week; trapping of iodine occurs by week 10, followed by iodination of tyrosine. Colloid formation and pituitary thyroid-stimulating hormone (TSH) secretion occur by week 12. Fetal thyroid development is completely independent of the mother's pituitary-thyroid axis, since negligible amounts of maternal thyroid-stimulating hormone or thyroxine ([T.sub.4]) cross the placenta.

Normal Thyroid Physiology

Secretion of [T.sub.4] is controlled by TSH secreted by the pituitary gland. TSH secretion, in turn, is controlled by thyrotropin-releasing hormone (TRH) produced in the hypothalamus. Both TSH and TRH secretion are moderated by serum [T.sub.4] levels, by means of a negative feedback loop.

Circulating [T.sub.4] is predominantly bound by thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin. [T.sub.4] is deiodinated in peripheral tissues to the more bioactive hormone triiodothyronine ([T.sub.3]). [T.sub.3] affects almost every tissue in the body. [T.sub.3] binds to its receptors in the nucleus, and this complex then alters gene transcription, leading to increased oxygen consumption and adenosine triphosphate (ATP) formation, and cellular cyclic adenosine monophosphate (AMP) concentration.

Within 30 minutes after delivery, TSH levels in the normal neonate rapidly rise to about 80 [micro] U per mL (80 mU per L) and then slowly decline over the next three days. In response, [T.sub.4] and [T.sub.3] levels rise dramatically by 24 hours of age, then slowly decline over the next few weeks.

Congenital Hypothyroidism

It has long been known that mental development of children with congenital hypothyroidism is related to adequacy of treatment.2 Beginning treatment before three months of age improves the prognosis for mental development in these children.3 However, early diagnosis and treatment were often delayed because of the paucity of early signs and symptoms in infants (Table 1).

TABLE 1

Signs and Symptoms of Congenital Hypothyroidism at Age Five Weeks

Sign or symptom Percentage of patients
Prolonged jaundice 31
Umbilical hernia 23
Constipation 21
Macroglossia 21
Feeding problems 19
Distended abdomen 16
Hypotonia 16
Hoarse cry 16
Large posterior fontanelle 13
Dry skin 10
Hypothermia 5
Goiter 2

In Quebec, population screening for congenital hypothyroidism began in 1974, using a newly developed technique, [T.sub.4] radioimmunoassay of blood spots on filter paper. This screening was combined with screening for phenylketonuria.[4] Refinements in the Quebec screening program developed rapidly, and most industrialized nations now have such screening programs.

Newborn screening programs in North America measure total [T.sub.4] levels in all newborns. Generally, in neonates whose [T.sub.4] level falls within the lowest 10th percentile, both [T.sub.4] and TSH are reassayed.

Newborn screening programs detect about one infant with congenital hypothyroidism for every 4,000 five births. Up to five false-positive screenings may occur for every one confirmed case of congenital hypothyroidism. However, statistically, congenital hypothyroidism may be missed by newborn screening programs in about three infants for every 100,000 live births (about 12 percent of an infants with congenital hypothyroidism).

Of infants with congenital hypothyroidism, 75 percent have sporadic thyroid dysgenesis, 10 percent have thyroid enzyme defects, 5 percent have hypothalamic-pituitary hypothyroidism and 10 percent have transient hypothyroidism. Thyroid enzyme defects are inherited in an autosomal recessive pattern.

Once an infant with congenital hypothyroidism has been identified by a state screening program, the physician should immediately examine that infant for signs of congenital hypothyroidism and obtain serum free and TSH levels for confirmation Infants who have TBG deficiency are also identified by state screening programs but, on confirmation testing, their free [T.sub.4] levels are found to be normal. Infants of mothers receiving antithyroid medication may have abnormal screening test results.

Therapy with levothyroxine (Levothroid, Levoxine, Synthroid) should begin without delay after the confirmatory blood tests, before results are obtained. If confirmatory tests show normal thyroid function, therapy is discontinued.The starting daily dosage of levothyroxine is 10 [micro] g per kg, which is usually the equivalent of 0.025 mg, 0.0325 mg or 0.05 mg per day.

Once treatment has been initiated, [T.sub.4] and TSH levels should be followed monthly during the first year of life, every other month during the second year, quarterly during the third year and biannually thereafter.

Dosage increases of 0.0125 mg (one-half of a 0.025 mg tablet) should be initiated when indicated, and repeat measurements of [T.sub.4] and TSH should be obtained one month after the increase. The tablets are easily crushed and can be added to formula or stirred into cereal.

Since the half-life of [T.sub.4] is about six days, four weeks are required for serum [T.sub.4] values to reach a steady state. Suppression of elevated TSH levels may take even longer.

Even with adequate diagnosis and therapy, some children with congenital hypothyroidism have IQ values that are lower than predicted. Factors that may contribute to this lower IQ include a markedly low [T.sub.4] value at birth, a markedly delayed bone age at birth, a delay in treatment, or a serum [T.sub.4] value less than 8 [micro] g per dL (103 nmol per L) during the first year of therapy.

Sometimes infants are identified by a state screening program as having congenital hypothyroidism, but the confirmatory test shows a normal [T.sub.4] value and a TSH value greater than 20 [micro] U per ML (20 mU per L). In these cases, a thyroid scan may show an ectopic gland. A normal thyroid scan in such an infant indicates the presence of impaired thyroid hormone synthesis, which may be caused by an enzyme defect. A cautious approach is to treat these infants with levothyroxine until after two years of age. At this time, therapy may be stopped for six weeks and repeat [T.sub.4] and TSH levels obtained. Some pediatric endocrinologists may choose to follow these infants carefully and treat them if the TSH levels increase over time.

Acquired Hypothyroidism

A common cause of acquired hypothyroidism in children is autoimmune thyroiditis, which occurs in genetically predisposed persons. Clinical disease is triggered or aggravated by unidentified factors. The thyroid gland becomes enlarged, but is usually not painful. Histologic changes include lymphocytic infiltration, formation of lymphoid follicles and follicular cell hyperplasia. Antibodies to thyroid peroxidase (so-called microsomal antibodies) are characteristic of Hashimoto's (chronic lymphocytic) thyroiditis. However, these antibodies are not responsible for the actual thyroid cell destruction, which is probably caused by cytotoxic lymphocytes.

Other causes of primary hypothyroidism in children include drug-induced hypothyroidism (e.g., lithium, amiodarone [Cordarone]), endemic goiter due to nutritional iodide deficiency, irradiation of the thyroid and surgical excision of the thyroid.

Hypothyroid children may have weakness, lethargy, decreased appetite, cold intolerance, constipation, dry skin and mild obesity. Common signs of childhood hypothyroidism are listed in Table 2.

TABLE 2

Signs of Acquired Hypothyroidism in Children

Goiter
Growth retardation
Delayed dentition
Delayed or precocious puberty
Galactorrhea
Carotenemia
Pale, dry skin
Myopathy and muscular hypertrophy
Derived from Dallas and Foley.

Once hypothyroidism is suspected in a child, serum [T.sub.4] and TSH levels should be measured. If the [T.sub.4] level is low and the TSH level is high, the diagnosis of hypothyroidism is confirmed, and levothyroxine therapy should be started. Measuring thyroid antibodies is unnecessary since the result of this test does not alter the treatment regimen.

In children with goiter and normal [T.sub.4] and TSH levels, positive titers of microsomal thyroid antibodies confirm a diagnosis of Hashimoto's thyroiditis, explaining the thyromegaly. If the child or adolescent with Hashimoto's thyroiditis has a noticeable goiter, treatment with levothyroxine may cause some reduction in the size of the goiter but does not usually lead to complete reduction in size.

Levothyroxine treatment should be started with a dosage of 0.05 mg per day, which is lower than the dosage required to attain euthyroidism. Initial treatment with larger doses of levothyroxine may cause headaches and abrupt personality changes.

[T.sub.4] and TSH levels should be determined no sooner than one month after a dosage change. TSH levels in the normal range are desirable, while a TSH level below normal indicates over-treatment.

Parents and teachers should be warned that the previously quiet, docile child will soon be more active and even rambunctious. The dramatic change in personality that occurs after therapy is initiated may be more than teachers, and even some parents, can readily accommodate.

Euthyroid Sick Syndrome

[T.sub.4] is converted in peripheral tissues to bioactive [T.sub.3] by the 5'-deiodinase enzyme. This enzyme is also responsible for clearing the small amounts of inactive reverse [T.sub.3] that are a byproduct of [T.sub.4] metabolism. During acute or chronic severe illnesses, surgery, trauma or malnutrition, activity of the deiodinase enzyme is decreased, thus decreasing the amount of [T.sub.3] produced and causing a build-up of reverse [T.sub.3]. TSH secretion is also decreased and does not respond to falling levels of [T.sub.4]. Low levels of [T.sub.4] and [T.sub.3], as well as normal to low levels of TSH, are common in stressed persons. These sick euthyroid patients do not need to be treated with thyroid hormone replacement.

Hyperthyroidism

Children with hyperthyroidism can be divided into two broad groups: those with an increased production of thyroid hormone and those with only an increased release of thyroid hormone (Table 3). A radioactive iodine uptake scan will clearly differentiate between these two causes of hyperthyroidism. In cases of excess thyroid hormone production, the scan shows increased uptake. In cases of increased release only, the scan reveals decreased uptake.

TABLE 3

Causes of Hyperthyroidism

Excess production of [T.sub.4]
Graves' disease
Toxic adenoma
McCune-Albright syndrome
TSH-producing pituitary tumor
Pituitary resistance to thyroid hormone

Excess release of [T.sub.4]
Subacute thyroiditis
Hashimoto's toxic thyroiditis
Iodine-induced hyperthyroidism
[T.sub.4] = thyroxine, TSH = thyroid-stimulating hormone.

Graves' disease is an autoimmune disorder in which the patient develops antibodies that stimulate the TSH receptor, thus stimulating the production of [T.sub.4].

Hyperthyroid children may note tiredness or easy fatigability. Hyperthyroidism in children can easily be mistaken for an anxiety disorder, anorexia nervosa or a psychiatric illness. Common symptoms and signs of Graves' disease in adolescents are presented in Table 4.

TABLE 4

Prevalence of Signs and Symptoms of Graves' Disease in Adolescents

Sign or symptom Percentage of patients

Goiter 98
Tachycardia 82
Nervousness 82
Increased pulse pressure 80
Proptosis 65
Increased appetite 60
Tremor 52
Weight loss 50
Heat intolerance 30

The diagnosis of Graves' disease can often be made clinically in the presence of goiter, exophthalmos, weight loss or tachycardia. The diagnosis may be documented by an elevated free [T.sub.4] level and a low TSH level. TSH assays are now capable of differentiating low levels from normal levels. In less obvious cases, a radioactive iodine uptake scan is helpful in determining the presence and etiology of hyperthyroidism (increased uptake in cases of Graves' disease).

Treatment of Graves' disease may be initiated with antithyroid medications, radioactive iodine ablation or surgical excision of the thyroid. Administration of beta blockers such as propranolol (Inderal), 10 to 20 mg every eight hours, stops many of the symptoms of hyperthyroidism and may make patients more comfortable.

Propylthiouracil and methimazole (Tapazole) interfere with several steps in thyroid hormone synthesis. Propylthiouracil also blocks the peripheral conversion of [T.sub.4] to [T.sub.3]. Propylthiouracil, at a dosage of 5 to 10 mg per kg per day, is given every eight hours. Methimazole, at a dosage of 0.5 mg per kg per day, may be given once daily.

Both propylthiouracil and methimazole are associated with side effects, including rash, arthritis, leukopenia and hepatic toxicity. These side effects require stopping the medication in about 5 percent of patients. Patients must be warned about these side effects and instructed to return to their physician for a complete blood count if they have a sore throat or a fever. Patients who develop jaundice must stop the medication immediately and contact their physician.

Forty-five percent of patients taking these drugs may experience a remission, as evidenced by goiter resolution, and no longer require antithyroid medication. If remission does not occur within three years of treatment initiation, radioactive ablation or subtotal thyroidectomy should be performed.

Radioactive iodine ablation does not increase the risk of future thyroid neoplasia, nor does it appear to have any teratogenic effects among the progeny of patients who receive it. Increased thyroid antibody titers occur after radioactive iodine ablation and may be responsible for the temporary worsening of Graves' eye disease that is sometimes observed after radioactive iodine ablation.[18] Besides leaving a scar, thyroidectomy may cause damage to the recurrent laryngeal nerve and hypoparathyroidism.

Neonatal Graves' Disease

Pregnant women with Graves' disease or a history of Graves' disease may transfer IgG thyroid-stimulating immunoglobulins (TSI) to the fetus. Affected infants may exhibit any of the signs listed in Table 5. An elevated free [T.sub.4] level, low TSH level and positive TSI test confirm the diagnosis.[19] Treatment with propylthiouracil, 5 to 10 mg per kg per day, or methimazole, 0.5 mg per kg per day, should be initiated in these children.

TABLE 5

Signs and Symptoms of Neonatal Graves' Disease

Premature birth
Low birth weight
Goiter
Restlessness and irritability
Fever, flushing
Tachycardia, cardiomegaly, heart failure
Lid retraction, proptosis, periorbital edema
Poor weight gain or weight loss
Increased gastrointestinal motility frequent, stooling
Derived from Dallas and Foley.[10]

In severely ill neonates, prednisone may be required to stabilize the infants while they are thyrotoxic. As [T.sub.4] levels become suppressed, levothyroxine should be given to maintain normal [T.sub.4] and TSH levels. After six months, the antithyroid medication and levothyroxine may be discontinued.

Subacute Thyroiditis

Painful enlargement of the thyroid gland that is associated with signs and symptoms of hyperthyroidism may occur as a postviral syndrome. The [T.sub.4] level is elevated, while the TSH level is suppressed. A radioactive iodine uptake scan reveals little uptake. Although no thyroid hormone production occurs, there is an increased dysfunctional release of the vast stores of thyroid hormone from the inflamed gland. Antithyroid medications such as propylthiouracil have no effect on subacute thyroiditis. Treatment is limited to administration of beta blockers, aspirin and, in extreme cases, glucocorticoids.

Thyroid Nodules

Thyroid nodules are uncommon in children, compared with a 5 percent prevalence in adults over 50 years of age. The risk of a solitary thyroid nodule being malignant in a child or an adolescent is approximately 33 percent.

In these children and young people, a history of endocrine tumors indicative of multiple endocrine neoplasia type II in any family members should be sought, as well as a history of previous radiation therapy to the head or neck.

Solid thyroid nodules in children should be surgically excised. Before excision, a l@31 thyroid scan may be obtained. "Hot" nodules are usually not malignant, but some exceptions have occurred.] Simple cysts are usually not malignant, but exceptions are also possible in these cases

Ultrasonographic examination of the thyroid is warranted for "cold" nodules. A cold nodule that is found to be solid, complex cystic or mixed on ultrasonography should be regarded as malignant until proved otherwise. Fine-needle biopsy of solitary thyroid nodules in adults has proved helpful; however, its efficacy has not yet been proved in children.

Thyroid surgery in children requires a pediatric anesthesiologist and a surgeon with ample experience in anterior neck surgery.

Final Comment

Acquired hypothyroidism in children can be diagnosed and treated by the family physician. Congenital hypothyroidism, Graves' disease, subacute thyroiditis and thyroid nodules are conditions that might best be referred to a pediatric endocrinologist, after appropriate laboratory evaluation and confirmation of the diagnosis.