Etiology and Pathogenesis

Congenital hypothyroidism (CH) is one of the most common causes of preventable mental retardation (Figure 68-2). Fortunately, early identification and rapid treatment lead to normal neurocognitive development. Although approximately 10% of cases of CH are transient and caused by factors such as iodine exposure, prematurity, or maternal transfer of antithyroid antibodies, in most cases, hypothyroidism is permanent. Worldwide, iodine deficiency is the most common cause of CH. However, in areas of the world where iodine deficiency is uncommon, CH most commonly results from thyroid dysgenesis (≈75% of cases); thyroid dyshormonogenesis (≈10%), TSH deficiency (5%), and genetic defects in the TSH receptor are much less common. The incidence of CH is approximately one in 3000 to 4000 births. In most cases, CH is sporadic, but mutations in genes encoding transcription factors that are required for normal development of the thyroid gland are present in about 10% to 15% of cases. Circulating levels of TSH are elevated and thyroid hormone levels are low in those with CH.

Figure 68-2 Congenital hypothyroidism.

A clinical picture that is similar to CH can occur in children who have genetic defects in the thyroid hormone receptor or in the MCT8 protein required to transport thyroid hormone into cells. Unlike CH, however, these patients have elevated serum levels of both TSH and thyroid hormones.

Clinical Presentation

Although there may be few obvious symptoms of CH in the first few weeks of life, a prolonged period of hypothyroidism during infancy can have profound neurocognitive consequences. Therefore, newborn screening (NBS) programs have been established in many countries to identify newborns with CH who require prompt treatment. Infants with untreated CH have an enlarged posterior fontanelle, prolonged jaundice, macroglossia, hoarse cry, distended abdomen, umbilical hernia, hypotonia, poor growth, weight gain, pericardial edema, or delayed development.

Long-term studies in adults with a history of CH indicate that when treatment is initiated before 2 months of age, there are only minor differences in intelligence, school achievement, and performance on neuropsychologic tests by comparison with control groups of classmates and siblings. Residual deficits in these patients may include visuospatial processing, selective memory, and sensorimotor defects. The prognosis for mental and neurologic performance in children with CH identified after 2 months of age is uncertain. Infants with CH who were not identified by the NBS but whose treatment was initiated between 2 and 3 months of age may manifest nonspecific developmental delays, including impaired arithmetic ability, speech, or fine motor coordination later in life. Long-term untreated CH can result in severe mental retardation and impaired growth.

Evaluation (Figure 68-3)

NBS for CH is based on collection of a blood sample from the newborn between 48 hours and 4 days of life. Earlier measurement may lead to erroneous results because of the normal physiologic surge in TSH that occurs soon after birth. NBS programs use blood spots collected on filter paper and use one of two strategies to identify infants with CH: a primary TSH with backup T4 or a primary T4 with a backup TSH method. An abnormal result should be further evaluated immediately using serum-based assays for TSH and T4 or free T4. Premature or ill infants may have false-negative or false-positive results and should be retested by 7 days of age. Any infant with a TSH level above 40 mU/L with low T4 is considered to have primary hypothyroidism. In addition to T4 and TSH measurements, a thyroglobulin (TG) level may be helpful because elevation suggests dyshormonogenesis.

Figure 68-3 Evaluation of congenital hypothyroidism.

AB, antibody; CH, congenital hypothyroidism; TBG, thyroid-binding globulin; TH, thyroid hormone; TSH, thyroid-stimulating hormone.

When there is history of maternal autoimmune thyroid disease, measurement of TSH–receptor binding antibodies in the infant or the mother may identify transient CH. Other diagnostic tests include thyroid ultrasonography and technetium or iodine (I-123) scans to identify functional thyroid tissue, as well as the perchlorate washout test to detect iodine organification defects that might indicate Pendred’s syndrome. Treatment with levothyroxine (L-T4) should not be delayed to perform imaging.

Treatment

To avoid neurocognitive deficit, newborns with CH must be treated promptly with L-T4 and monitored closely by a pediatric endocrinologist. L-T4 is instituted at a dosage of 10 to 17 µg/kg/d initially, with a goal to normalize the serum T4 level within 2 weeks (fT4 >2 ng/dL) and serum TSH by 1 month of age. There are no suitable liquid preparations of L-T4, so tablets must be used. Tablets should be crushed and mixed with a few milliliters of formula, breast milk, or water. Soy-based formula, fiber, or iron may reduce absorption of L-T4 and should be given separately.

Serum levels of T4, T4 index or free T4, and TSH should be measured every 1 to 2 months during the first 6 months of life, every 3 to 4 months until 3 years of age, and then every 6 to 12 months until growth is complete. The half-life of T4 in the circulation is 1 week, so levels of TSH and T4 should be repeated 4 to 5 weeks after dose changes to ensure appropriate steady-state levels. An appropriately treated child will have serum T4 levels that are at or above the upper limit of normal with a serum TSH level of 1 to 2 mU/mL. The serum TSH level is not a reliable indicator of euthyroidism in children with pituitary or hypothalamic disorders, and in these patients, the T4 level should be maintained at the upper limit of the assay’s normal range. Infants with suspected transient hypothyroidism should continue L-T4 therapy until at least age 2 years, when thyroid-dependent CNS myelinization is complete.

Etiology and Pathogenesis

Hypothyroidism is defined as a deficiency in thyroid hormone and in most cases is associated with an elevated TSH level. Hypothyroidism is more common in females than males and has an increased incidence in adolescents. The most common cause of hypothyroidism is chronic lymphocytic (Hashimoto’s) thyroiditis, which results in autoimmune destruction of the thyroid gland. Goiter, caused by lymphocytic infiltration of thyroid tissue, and circulating antithyroid antibodies (antitissue peroxidase and anti-TG) are common but are not universally present. Hashimoto’s thyroiditis is common in children who have the type 2 autoimmune polyglandular syndrome, which includes Addison’s disease of the adrenal gland, pernicious anemia, celiac disease, type 1 diabetes mellitus, and juvenile rheumatoid arthritis. Children with chromosomal defects, such as trisomy 21, Turner’s syndrome, 22q11 deletion syndrome, and Klinefelter’s syndrome, have an increased incidence of autoimmune diseases, including autoimmune thyroid disease.

Other causes of hypothyroidism include chronic iodine deficiency, excessive iodine exposure, hypothalamic–pituitary dysfunction, acute infection, and medications. Excessive iodine exposure may lead to acute blockage of thyroid hormone release or thyroid hormone synthesis, known as the Wolff-Chaikoff effect. Children with CNS disease are at risk of central hypothyroidism. Medications such as amiodarone, antiepileptics, nitroprusside, and lithium can all affect thyroid hormone production or metabolism; dopamine can reduce TSH secretion.

Clinical Presentation (Figure 68-4)

Symptoms of hypothyroidism include dry skin, constipation, cold intolerance, and a decreased energy level. Severe thyroxine deficiency is associated with linear growth failure and delayed bone age, coarse hair, myxedema, galactorrhea, delayed or rarely precocious puberty, bradycardia, depressed reflexes, pallor, and hyperlipidemia. Carotenemia is more common in children than adults with hypothyroidism. Children with weight gain are often referred for evaluation of hypothyroidism. Although weight gain can occur in children with hypothyroidism, height is reduced, which is in contrast to exogenous obesity, in which height is often increased. On examination, the thyroid gland may be enlarged, asymmetric, and/or bosselated. In severe hypothyroidism, the gland may be atrophic. Reflexes are often slowed, the heart rate may be reduced, and the pulse pressure can be decreased. There is a family history of thyroid disease in 30% to 40% of patients.

Figure 68-4 Clinical features of hypothyroidism and hyperthyroidism.

Occasionally, patients with Hashimoto’s thyroiditis present with elevations in T4 levels and suppressed TSH, mimicking Graves’ disease, but without the eye symptoms. This is termed Hashitoxicosis, and it may occur because of excessive release of thyroid hormone from thyroid destruction. Patients with Hashimoto’s thyroiditis can have TG antibodies or blocking TSH-receptor antibodies, both of which are known to destroy thyroid cells. TG antibodies are seen in Hashimoto’s thyroiditis, and blocking TSH-receptor antibodies are seen in patients with atrophic thyroiditis. In addition, patients typically have thyroid peroxidase (TPO) antibodies, which are considered markers of inflammation. TPO antibodies also cause thyroid inflammation and thyroid disease to persist, interfering with the healing process. Patients with Hashitoxicosis can also have stimulating TSH-receptor antibodies, although their levels may not reach the high levels that cause hyperthyroidism in patients with Graves’ disease.

In some ways, these patients can be described as having both Hashimoto’s thyroiditis and Graves’ disease because the antibodies associated with both diseases are often present. Thyroid uptake scans can differentiate between Hashitoxicosis with decreased uptake and true Graves’ disease with increased uptake.

Evaluation

Typically, patients with hypothyroidism present with elevated TSH, low T4, and elevated TPO or TG antibodies. In the euthyroid state, TSH, T4, and T3 levels are in equilibrium. Decreased thyroid hormone production in hypothyroidism leads to negative feedback on the pituitary, with a concomitant increase in TSH levels. If the gland is unable to respond with an increase in T4 production, the TSH continues to increase, and there will be very low levels of T4, fT4, and T3.

Children with suspected hypothalamic or pituitary abnormalities should have yearly assessment of pituitary function, including thyroid tests (T4, fT4, or both). Affected children have low fT4 levels; low-normal T4 levels; and normal, low, or mildly elevated TSH levels. In the case of central hypothyroidism, fT4 levels are monitored instead of TSH.

Children with slight elevations in TSH (<10 mIU/L) and normal T4 or fT4 levels, with or without antibodies, are considered to have subclinical hypothyroidism. In this scenario, treatment may be delayed unless the child has symptoms of hypothyroidism, a goiter, or increasing levels of TSH.

Treatment

Children with confirmed hypothyroidism should be treated with daily L-T4 with a therapeutic target of normalizing serum levels of T4 (or fT4) and achieving a TSH level of 1 to 2 mIU/L. When there is evidence of longstanding hypothyroidism, L-T4 may be started at a low dose and slowly increased to full replacement over several weeks. Serum levels of L-T4 and TSH should be measured 4 to 6 weeks after initiation of therapy or change of L-T4 dosage to ensure that the expected steady-state levels are achieved. In general, T4 and TSH levels should be tracked every 3 to 6 months as part of routine monitoring.

When used appropriately, L-T4 is a very safe medication, and the principal adverse effects are caused by overtreatment or undertreatment. In treatment of severe hypothyroidism, bone age may advance rapidly, which can impair ultimate height.

Etiology and Pathogenesis (Box 68-1)

Graves’ disease accounts for over 90% of hyperthyroidism in children. Other less common etiologies include a hyperfunctioning toxic (“hot”) nodule, transient hyperthyroidism as an early phase of chronic lymphocytic thyroiditis (Hashitoxicosis), and the hyperthyroid phase of subacute thyroiditis. Amiodarone, which contains 37% iodine by weight, causes hyperthyroidism in up to 12% of patients on long-term therapy. It has been suggested that amiodarone-induced myxedema predominates in areas in which the soil is iodide replete and that thyrotoxicosis occurs in areas of iodide deficiency.

Clinical Presentation (see Figure 68-4)

Children with hyperthyroidism often have hyperactivity with periods of fatigue and poor sleeping habits. Emotional lability, poor concentration, and a marked decrease in school performance are common. Children often come to medical attention because of cardiovascular complaints such as persistent tachycardia, palpitations, or syncopal episodes. Heat intolerance, weight loss, tremors, and diaphoresis are seen regularly. Although many children with hyperthyroidism indeed lose weight, paradoxical weight gain is common. Hyperthyroidism will also result in an increased appetite, and in some patients, an increased appetite and increased food intake may lead to weight gain despite the increase in metabolic rate that usually accompanies hyperthyroidism.

The eyes may reveal a “lid lag” or prominent eyes, with or without proptosis (exophthalmos) in which the eyes are pushed forward (may be asymmetric). In Graves’ disease, the more severely hyperthyroid patients have the largest goiters (Figure 68-5). Mild polyuria may be seen. Frequent bowel movements, rather than diarrhea, are occasionally present.

Figure 68-5 Thyroid pathology in Graves’ disease.

Heart rate and blood pressure may be elevated with a widened pulse pressure. The degree of tachycardia parallels the severity of the hyperthyroidism. There may be normal to accelerated linear growth with concomitant weight loss. The skin is warm to the touch. The thyroid is smooth and diffusely enlarged, and there may be a palpable thrill or audible bruit caused by increased blood flow. Tremors and generalized restlessness are common. A change in mentation associated with hypertension and cardiovascular instability could indicate thyroid storm, which requires urgent hospitalization.

Subacute, or De Quervain’s, thyroiditis is thought to be viral in origin and lasts weeks to months. In the first few months, hyperthyroidism may be seen because of leakage of thyroid hormone in a damaged gland. In time, hypothyroidism commonly develops.

Evaluation

After the diagnosis of hyperthyroidism has been established, it is important to establish the cause. Laboratory assessment of patients with hyperthyroidism should include measurement of total or free T4, T3, and TSH. In hyperthyroidism, TSH should be suppressed (<0.3 mIU/L on most assays). Because of intense stimulation of the gland by TSI, patients with Graves’ disease typically have a disproportionately greater increase in T3 compared with T4. The degree of hyperthyroidism is related to the degree of elevation of fT4 and T3.

Thyroid TPO and TG antibodies can be present in both Graves’ disease and chronic lymphocytic thyroiditis. Measuring TSI can be helpful when the diagnosis of Graves’ disease is uncertain in a child with hyperthyroidism. An I-123 scan will show diffusely high uptake of iodine in patients with Graves’ disease (see Figure 68-5) and patchy areas of uptake in those with chronic lymphocytic thyroiditis. The thyroid gland is hypervascular in Graves’ disease, and this increased blood flow can be assessed by color-flow Doppler ultrasonography.

Treatment

Treatment of children with hyperthyroidism should be made in collaboration with a pediatric endocrinologist. Families should be informed of three treatment modalities: medication, radioactive iodine (I-131) ablation, and surgery. Most endocrinologists believe that initial treatment with antithyroid medication is indicated, especially because approximately 20% of children may go into a remission within 2 years of starting pharmacologic therapy.

The two antithyroid medications that are available in the United States are propylthiouracil (PTU) and methimazole. Both of these agents block synthesis of thyroid hormone, but only PTU can also prevent conversion of T4 to T3. The dosing of PTU is commonly two to three times per day compared with once or twice daily with methimazole. Methimazole has emerged as the preferred treatment based on recent reports that PTU usage, particularly in children, is associated with the occasional development of severe liver failure that often requires transplantation. Side effects from both medications occur in 5% to 14% of children and include skin rash, arthralgia, arthritis, lupus-like reaction, thrombocytopenia, and agranulocytosis. A β-blocker is used in patients with more severe cardiovascular signs.

Radioactive iodine ablation of the thyroid is an effective therapy for destroying the thyroid, although it does not ameliorate proptosis of the eyes. The destruction of the thyroid occurs 2 to 4 months after therapy with I-131. Surgery is used occasionally to treat children with Graves’ disease, although complications include hypothyroidism, hypoparathyroidism, and damage to the laryngeal nerves.

Monitoring thyroid function frequently is particularly important in children with hyperthyroidism because of the fluctuating nature of the disease. Monthly laboratory assessments are common. An occasional complete blood count and chemistry panel, including hepatic function tests, may be useful to monitor for medication side effects.