Chapter 528. Acquired Hypothyroidism

Hypothyroidism can develop at any age among previously healthy children, although it is more common among girls. Growth retardation is an early sign. Iodine deficiency remains a major cause of hypothyroidism, but the worldwide incidence is decreasing. A high proportion of patients have circulating antithyroid antibodies characterizing an autoimmune process (Hashimoto thyroiditis). Among others, acquired juvenile hypothyroidism can be caused by exposure to goitrogenic agents, thyroid dysgenesis, late onset of hypothyroidism caused by an inborn error of thyroidal biosynthesis, acquired hypothalamic or pituitary hypothyroidism, or endemic factors.1-6 As part of the clinical history, the physician should inquire about potential intake, or contact through environmental or familial occupational” sources, with the known potential goitrogens listed in Table 527-2.

Iodine deficiency remains the leading cause of hypothyroidism worldwide.7-16 During the past 40 years, major efforts to supplement iodine intake in endemic deficiency areas have been highly successful, and the geographic distribution of severe endemic iodine deficiency has been markedly reduced. Residual areas of deficiency include Africa; Southeast Asia; the Western Pacific; and some areas of Europe, the Eastern Mediterranean, and the more isolated mountainous areas of the Americas. It is estimated that some 2 billion individuals remain at risk, with 740 million affected by iodine-deficient goiter and 43 million believed to be mentally disabled as the result of iodine deficiency.16

In Europe from 1989 to 1995, clinically euthyroid schoolchildren in iodine-deficient areas were reported to have subtle or overt neuropsychointellectual deficits compared to iodine-sufficient children in the same areas. This is believed to result from transient hypothyroidism during the critical fetal-postnatal period of brain development. Similar studies have not been conducted in the Americas. Cretinism and severe iodine deficiency are now largely restricted to remote areas of developing countries. However, some 40 million individuals in the Americas and 130 million in Europe are exposed to mild-moderate iodine deficiency, largely in more isolated mountainous areas.

Environmental iodine deficiency leads to a series of thyroid system abnormalities, including increased thyroid-stimulating hormone (TSH) secretion, increased iodide uptake, reduced thyroglobulin iodination, increased thyroglobulin production and turnover, thyroid colloid depletion, and thyroid gland hypertrophy and hyperplasia.16Iodine deficiency results in poorly iodinated tyrosine and iodothyronine residueswithin stored thyroglobulin, resulting in increased (MIT/DIT) and T3/T4 ratios. As a result, the thyroid T3/T4 secretion ratio is increased and serum T3 levels are relatively increased while serum T4 concentrations fall. T4-to-T3 conversion within the thyroid gland and in peripheral tissues also increases. The result of these changes is a circumstance of compensated euthyroidism manifest by a modest increase in serum TSH, a high normal or increased serum T3 level, a low normal or decreased serum T4 concentration, and thyroidal hyperplasia and hyperactivity.

The increased T3/T4 secretion ratio allows a degree of adaptation to iodine deficiency because T3 possesses four times the metabolic potency of T4, while requiring only 75% as much iodine for synthesis. With severe iodine deficiency, however, such compensation may be inadequate, leading to hypothyroidism of varying degree. In severe endemic goiter areas, goiter and cretinism, decreased fertility, increase perinatal death, increased infant mortality, and varying degrees of mental retardation are observed. In areas of moderate iodine deficiency (< 100 μg iodine intake daily) in the absence of overt endemic goiter, thyroid function in adults is normal, but the prevalence of transient neonatal hypothyroidism is increased and mental development in euthyroid schoolchildren has been shown to be impaired.

Ectopic thyroid glands in children first come to attention during childhood because of the presence of an enlarging mass at the base of the tongue or along the course of the thyroglossal duct. Usually only one sibling is affected, but rare familial instances have been reported. The enlargement can occur at any age; it usually accelerates a short time before adolescence. Degrees of hypothyroidism range from barely detectable to severe. Children with unilateral thyroid aplasia have a functional hemithyroid gland. Such patients usually do not have hypothyroidism.7They may be given the mistaken diagnosis of a functioning thyroid nodule.

Complete substitution treatment usually reduces the thyroid tissue enlargement, so surgery can be avoided in patients with hemithyroid hypertrophy. Full substitution must be continued for life. Severe hypothyroidism occasionally follows surgical removal of what has been presumed to be a thyroglossal duct cyst. As with lingual thyroid, masses high in the neck may prove to be the only functional thyroid tissue present. In some patients, enlargement of the mass is correlated with failing thyroid function before surgery.

The spectrum of autoimmune thyroid disease in children includes euthyroid goiter, hypothyroid goiter, Graves disease, hashitoxicosis, nodular goiter, thyroid antigen-antibody nephritis, and multiple endocrine deficiency disease.11-13 The last includes diabetes mellitus, adrenal insufficiency, hypoparathyroidism, moniliasis, and, less commonly, pernicious anemia and thrombocytopenia. The most common clinical association is Hashimoto thyroiditis and diabetes mellitus with or without adrenal cortical insufficiency (Schmidt syndrome).

Epidemiology

Hashimoto thyroiditis is the most common thyroid disorder in children, with a marked predilection for females. Chronic thyroiditis is the most common cause of goiter and hypothyroidism among children older than 6 years in North America. It occurs in a genetically predisposed population8-10; 30% to 40% of patients have a family history of thyroid disease.

Pathophysiology

Circulating thymus-dependent (T) lymphocytes sensitized against the particulate portion of thyroid cells (microsomes and cell membranes) are found in almost all patients with Hashimoto thyroiditis and Graves disease.8 A genetically determined defect in the immune surveillance system has been postulated. Both T lymphocytes sensitized against thyroidal components and humoral antibodies directed at various thyroidal components produce the thyroid abnormality. The latter antibodies are produced by B rather than T lymphocytes. It is known that the interaction of T and B lymphocytes plays a crucial role in the elaboration of immunoglobulins by B lymphocytes.

Age-specific incidence rates for Graves disease and Hashimoto thyroiditis show an increasing rate of onset through the fifth decade and a decline thereafter. This has been interpreted as suggesting the existence of a subpopulation of subjects with genetic predisposition who develop thyroid autoimmune disease with increasing exposure to potentiating environmental factors. A genetic predisposition to thyroid autoimmunity is also suggested by observations in twins. There is an approximately 50% concordance for Graves disease in monozygotic twins, as contrasted with a 5% concordance rate in fraternal twins. There are several reports of monozygotic twins pairs in which one twin manifested Graves disease and the other Hashimoto thyroiditis. Moreover, thyroid autoantibodies have been reported in some 50% of siblings of patients with Graves disease.

An increased prevalence of HLA-B8, HLA-DR3, and DQA1-0501 transplantation antigens has been reported in Caucasian patients with Graves disease. The association has been HLA-DR5 antigen in Japanese patients and HLA-DR9 in Chinese patients with the disorder, but these associations carry a risk ratio of only 3:5. Associations have been observed between HLA-DR3, DR4, or DR5 and Hashimoto thyroiditis. Linkage to the HLA genes is weak, however, and linkage with other loci on the X chromosome and on chromosomes 14 and 20 have been reported. Responsible genes have not been identified, and multiple genetic factors may be involved. More recently, an association with CTLA-4 has been described.

Clinical Features and Diagnosis

Disease onset is usually insidious, starting with an euthyroid goiter or a goiter with mild hypothyroidism. The thyroid gland is usually irregularly enlarged and firm with accentuation of the normal lobular architecture (bosselated). The goiter occasionally gives rise to the sensation of local pressure and difficulty in swallowing. If the patient is not treated, the course of Hashimoto thyroiditis is variable. The gland may undergo progressive atrophy, and the patient develops hypothyroidism without a recognized period of compensatory hypertrophy. Spontaneous remission can occur in 30% of adolescent patients.

Most patients have detectable levels of circulating antithyroid antibodies, including antibodies against thyroglobulin, against a colloid component other than thyroglobulin, against the peroxidase enzyme, against the sodium-iodide symporter protein, against thyroid nuclei, and against thyroid-stimulating hormone (TSH) receptors.8Antithyroglobulin and antiperoxidase antibodies are most prevalent, and these are the antibodies that have been most useful in diagnosis (eFig. 528.1).

Antithyroid antibodies are not pathognomonic of Hashimoto thyroiditis because positive titers are found in 15% to 20% of adults without thyroiditis. Antithyroid antibodies are also present in patients with untreated Graves disease. The familial prevalence of antithyroid antibody helps identify the familial predisposition to autoimmune thyroid disease.

Compensated or Partially Compensated Defect in Thyroid Hormone Biosynthesis

An occasional infant with a compensated thyroid hormone biosynthetic defect and normal T4 values can escape detection in a neonatal T4 screening program. The appearance of goiter among these patients can be delayed. Some patients have a goiter and compensated hypothyroidism, as well as apparent acquired hypothyroidism. The goiter in these patients, including those with peripheral resistance to T3, is diffuse, soft, and variable in size. The Hashimoto gland, in contrast, tends to be firm, bosselated, and only moderately enlarged.

Acquired Hypothalamic-Pituitary Hypothyroidism

Hypothalamic or pituitary disorders may be acquired secondary to head trauma, tumors including craniopharyngiomas, granulomatous disease, and meningitis. However, the most frequent causes are irradiation of the neurocranium and chemotherapy in the treatment of malignant disorders, especially brain tumors, as described in Chapter 523.

Isolated central hypothyroidism (thyroid-stimulating hormone [TSH] deficiency) is an uncommon disorder associated with subclinical hypothyroidism and short stature in children.14,15In children presenting with these clinical symptoms, low free T4, and normal or low serum TSH without other evidence of pituitary disease, the diagnosis of central hypothyroidism is straightforward. In others, however, with a serum free T4 level in the lower half of the normal range and a normal TSH concentration, the diagnosis is difficult to confirm, even if suspected. These children manifest an abnormal circadian pattern of serum TSH concentration with absence or blunting of their nocturnal TSH surge. The diagnosis can be confirmed by measuring serum TSH hourly for 2 to 3 hours between 2 and 4 pm and between 10 pm and 2 am. Normally, the serum TSH level increases 50% to 300% during sleep. Blunting of the nocturnal surge should lead to a trial of thyroxine treatment in such children.

Consumptive Hypothyroidism

This rare syndrome, first described in 2000, is characterized by excessive ectopic inactivation of thyroid hormone by type 3 iodothyronine monodeiodinase (MDI-3).17 The syndrome has been associated with massive hemangiomas and hepatic hemangioendotheliomas in children, and by hemangioendothelioma and malignant fibrous tumors in adults. The hemangiomata and tumor tissues express high levels of MDI-3 activity, which inactivates thyroid hormones at a rate exceeding the production capacity of the thyroid gland. Thyroid-stimulating hormone (TSH) levels are increased, free T4 is decreased, and reverse T3 (rT3) concentrations are increased. The dosage of thyroxine to increase circulating free T4 levels to the normal range are increased severalfold. Treatment includes T4 therapy and management of the causative vascular malformation or tumor.

Other Disorders Associated with Hypothyroidism

About 30% of children with diabetes mellitus have thyroid autoantibodies and approximately 10% have elevated serum thyroid-stimulating hormone (TSH) levels. All children with diabetes mellitus need screening for autoimmune thyroid disease. Hypothyroidism appears to occur with increased frequency in association with several chromosomal disorders, including Turner syndrome, Down syndrome, and Klinefelter syndrome.18Autoimmune thyroiditis is more prevalent with these disorders. With Down syndrome, there is also an increased prevalence of thyroid dysgenesis. Compensated hypothyroidism occurs frequently and early among children with nephropathic cystinosis. Some children with the disorder have overt hypothyroidism. The thyroid gland displays extensive destruction and infiltration of the epithelium with cystine crystals.

Clinical Features

The most useful aid in recognizing acquired hypothyroidism among children is a serial record of growth. Considerable time usually elapses between the onset of hypothyroidism and the emergence of classic signs of myxedema. If growth records are available, however, the onset of hypothyroidism can be documented with a progressive downward deviation from previously normal growth (eFig. 528.2). Weight tends to increase. Retardation of bone age almost always equals or exceeds the retardation in linear growth, but delayed bone age is also present in other forms of dwarfism and is not pathognomonic of hypothyroidism. A patient with thyroid deficiency usually has slowing of the deep tendon reflexes with a delayed relaxation phase. Varying clinical manifestations of myxedema related to organ hypofunction (eg, cardiac, intestinal, skin, renal) occur with prolonged or severe hypothyroidism.

Sexual development of most children with hypothyroidism is delayed in approximate proportion to the retardation of skeletal maturation. However, some children with severe hypothyroidism are sexually precocious.19Girls have precocious menstruation, breast development, and galactorrhea. Among boys, this syndrome is associated with excessive enlargement of the penis and testes. Most of these patients lack sexual hair, and bone age is retarded in keeping with the duration of the hypothyroid state. Many have an enlarged sella turcica.

Serum levels of prolactin and follicle-stimulating hormone (FSH) may be elevated, but the mechanism is not clear. The increase in serum prolactin level can be explained by the fact that thyrotropin-releasing hormone (TRH) stimulates both thyroid-stimulating hormone (TSH) and prolactin release from the pituitary gland. A paracrine action on gonadotropes may explain the increased gonadotropin secretion. When the hypothyroid state is alleviated, the manifestations of sexual precocity regress, and normal puberty occurs when the general level of maturity has progressed appropriately.

Diagnostic Tests

The diagnosis of hypothyroidism always must be supported with tests of thyroid function before treatment is instituted. Minimal documentation includes serum T4 and/or free T4 and thyroid-stimulating hormone (TSH). If a goiter exists, antithyroid antibodies are measured. If not, a thyroid scan is useful to exclude thyroid dysgenesis. An elevated TSH level establishes that the disease originates in the thyroid rather than the pituitary gland. A low T4 (and free T4) level with a low serum TSH indicates hypothalamic or pituitary hypothyroidism. Whenever the latter is suspected, it is mandatory that other pituitary deficiencies be sought with an MRI of the hypothalamic-pituitary area and a complete set of pituitary function studies, including provocative tests of adrenocorticotrophic hormone (ACTH) and growth hormone secretion, and the response of TSH to administration of thyrotropin-releasing hormone (TRH).20

Treatment

Na-L-thyroxine is the treatment of choice for juvenile hypothyroidism. The initial dosage is based on age (see Table 527-3) and adjusted to maintain serum thyroid-stimulating hormone (TSH) in the normal range. In central hypothyroidism, serum TSH is not a reliable euthyroid marker, and serum T4 should be maintained in the upper half of the normal range for age.