Neurologic Effects

Congenital thyroid hormone deficiency results in cretinism (severe mental retardation) if not treated. This effect is prevented by thyroid hormone replacement early in life. Newborn screening for thyroid deficiency was initiated in Quebec in 1974. Intellectual development is normal in children with congenital hypothyroidism who are treated early and aggressively and is significantly better in those treated early (by 7 days of age) and with higher thyroid hormone doses (12 µg/kg per day) than in those started on therapy later or treated with lower doses.¹³

The degree of mental retardation in cretinism is related to the severity and duration of the hypothyroid state of the infant. The brain is susceptible to a lack of thyroid hormone during its rapid growth and maturation. Defective growth and permanent damage do not occur if hypothyroidism begins after morphologic maturation of the brain is completed (i.e., after a postnatal age of 3 years).

Thyroid hormone also affects peripheral nerves. In hypothyroidism, the relaxation phase of the ankle and knee-jerk reflexes is prolonged; in hyperthyroidism, the sympathetic and autonomic responses may be exaggerated.

Prenatal and postnatal maturation of the brain, retina, and cochlea is thyroid hormone dependent.³⁷ Thyroid hormone modulates expression of thyroid hormone–responsive target genes at precise times during development, controlled by an interplay of deiodinases, thyroid receptor expression, transporters, cofactors, and transcription factors.^4,12,33,89 T₃ promotes the neural differentiation of embryonic stem cells at a dendritic level.¹⁴ T₃ and T₄ have an important impact on vascular development in the brain.⁹⁸ Genes involved in neural migration are also regulated by thyroid hormone.¹² Animal models have been developed for further study of thyroid effects on brain development.^6,71

Cellular Metabolism

One of the principal actions of thyroid hormone is to stimulate rate of cellular oxidation in a large variety of tissues, leading to increased oxygen consumption, liberation of carbon dioxide, and production of heat. In hypothyroidism, the basal metabolic rate is reduced, but in hyperthyroidism, it is increased. The action of thyroid hormone may be mediated through increased protein synthesis. T₃ binds to the thyroid response element in the cell nucleus, leading to enhancement of polymerase activity, which in turn leads to increased cellular messenger RNA (mRNA) and corresponding proteins.⁴ Synthesis of membranous sodium-potassium adenosine triphosphatase (ATPase) is enhanced by this mechanism. A large portion of oxygen consumption depends on sodium pump activity. T₃ has direct effects on the mitochondria in vitro and probably in vivo.⁹⁶ T₄ in cell culture induces phosphorylation of mitogen-activated protein kinase. Thyroid hormone enhances response of beta-receptors to catecholamines without increasing the number of receptors.

Clinically, the calorigenic action of thyroid hormone affects circulation by increasing heart rate, stroke volume, and cardiac output. The pulse pressure is widened mainly by a decrease in the diastolic pressure and by some elevation in the systolic pressure. Circulation time is shortened. In hypothyroidism, the electrocardiogram (ECG) may show decreased voltage for all complexes, prolongation of the PR interval, and depression or inversion of the T wave. However, effects on the ECG may be secondary to myxedema of the myocardium.

Protein and Lipid Metabolism

Negative nitrogen balance occurs in hyperthyroidism unless the patient is protected by adequate caloric intake to provide for the increased energy requirements. In severe hypothyroidism, there is deposition of a mucoprotein containing hyaluronic acid in extracellular myxedematous fluid. Thyroid hormone influences the incorporation of creatinine into the phosphocreatine cycle. In hypothyroidism, there is an excessive storage of creatine, whereas in hyperthyroidism, the urinary excretion of creatine is increased. However, the total excretion of creatine and creatinine is not affected by thyroid hormone. Therefore thyroid hormone changes the urinary creatine-creatinine balance; creatine accounts for 10% to 30% in the normal child, 0% to 10% in those with hypothyroidism, and 25% to 65% in those with hyperthyroidism.

Effects of thyroid hormone on lipid metabolism are seen in the increased serum total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations in hypothyroidism. The total neutral fats, fatty acids, apolipoprotein B, and phospholipids of the serum are also increased in hypothyroidism.⁴³

Carbohydrates, Calcium, Vitamin D, Water Balance, and Liver Function

The rate of glucose absorption and use is increased by thyroid hormone. In hypothyroidism, hypercalcemia may occur, the serum carotene level may be high, and the glucuronic acid conjugation mechanism of the liver may be impaired. In infants, hyperbilirubinemia associated with primary hypothyroidism is almost entirely indirect; in hypothalamic-pituitary hypothyroidism, it is both direct and indirect. Retention of water in the extracellular compartment occurs in hypothyroidism, producing the myxedematous fluid.

In hyperthyroidism, calcium balance tends to be negative; urinary and fecal calcium excretion is enhanced. Demineralization of bone occurs, and efflux of calcium from the bones leads to higher plasma ionized calcium and phosphate and lower circulating 1,25(OH)₂D₃, which in turn results in decreased calcium absorption from the intestine.

Growth and Development

A principal action of thyroid hormone is its effect on growth and development. These effects may be tissue specific and synergistic with other hormones. Prenatal growth is highly dependent on nutrition and insulin secretion. Postnatal linear growth is dependent on thyroid hormone and growth hormone (GH), which are mediated through insulin-like growth factor type 1 and its receptor. Similar synergistic effects between thyroid hormone and growth hormone can be observed in skeletal maturation. Thyroid hormone exerts its effects together with multiple hormones and growth factors. When primary hypothyroidism occurs, dental eruption, linear growth, and skeletal maturation are retarded. Retardation of skeletal maturation may be severe and is associated with immature skeletal proportions and facial contours, which contribute to the characteristic body configuration of hypothyroidism (long torso compared to short length of arms and legs) that is different from that seen in stunted growth caused by isolated GH deficiency. Ossification of cartilage is also disturbed in hypothyroidism, leading to epiphyseal dysgenesis in radiographs of the ossifying epiphyseal centers (Figure 97-1). Growth rate and adult height are normal in children with congenital hypothyroidism in whom thyroid hormone therapy is consistently maintained.⁶¹

Calcitonin

In addition to the classic thyroid hormones (T₄ and T₃), a calcium-lowering hormone, thyrocalcitonin (i.e., calcitonin), is secreted by the parafollicular cells of the thyroid. Although calcitonin has hypocalcemic and hypophosphatemic actions when administered to humans, its physiologic role is not yet clearly understood. In normal newborn infants, a physiologic nadir in serum calcium concentration occurs at 24 to 48 hours of age, potentially related to delayed responsiveness of calcitonin. Thyroidectomy does not lead to hypercalcemia because there is secretion of calcitonin from extrathyroidal organs such as the brain, thymus, lung, gastrointestinal tract, and bladder.

Iodine Metabolism

Iodine is supplied to the body mainly through dietary intake, but it can be absorbed readily from the skin, lungs, and mucous membranes. Application of iodine-containing ointment or lotion to the skin, common during procedures with premature or sick infants, causes very high levels of iodide in circulation and promptly blocks thyroid hormone release from the thyroid gland. Although some organic iodine compounds, including T₄ and T₃, can be absorbed unchanged from the gastrointestinal tract, most are reduced and absorbed as inorganic iodide. One fourth to one third of ingested iodide is taken up by the thyroid; this is the basis for radioiodine uptake studies.

This iodide-trapping mechanism involves an active transport process (an iodide pump [iodide symporter]) that requires oxidative phosphorylation. The iodide pump is a major rate-limiting step in thyroid hormone biosynthesis, and when it is defective, it is a rare cause of congenital goitrous hypothyroidism.²⁵ The iodide pump is present at both the basal and apical surfaces of follicular cells. At the basal cell surface, the pump concentrates iodide in the cells by transporting them from the extracellular space. At the apical cell surface, the pump pushes iodide into the follicular lumen as a secondary reservoir. The mechanism is capable of maintaining intrathyroidal iodide concentration at a 20- to 100-fold higher level than that of serum. Some anions—bromide (Br²⁻), nitrate (NO₂²⁻), thiocyanate (SCN²⁻), perchlorate (ClO₄²⁻), and technetium pertechnetate (TcO₄²⁻)—are capable of competitively inhibiting iodide transport.

Iodide is immediately oxidized to an active form for iodination of thyroglobulin (TG) by a peroxidase enzyme system.²⁵ Thyroglobulin, a glycoprotein, is synthesized by the ribosomes of the follicular cells. Iodination of TG (organification) appears to occur at the cell colloid-lumen interface. Almost all the iodine taken up by the thyroid is rapidly incorporated into the 3 and the 5 positions of the many tyrosyl residues of TG to form monoiodothyronine (MIT) and diiodothyronine (DIT). Once it is organically bound to tyrosyl residues, iodine can no longer be readily released from the thyroid. Defects in iodide oxidation or organification can be seen in several types of goitrous cretinism.

Synthesis of Triiodothyronine and Thyroxine

The synthesis of T₃ requires the coupling of an MIT and a DIT molecule, accompanied by elimination of an alanine residue. T₄ is formed by the coupling of two DIT molecules. These reactions occur within the structure of TG and involve oxidative processes, probably catalyzed by thyroid peroxidase as well.

Secretion of Triiodothyronine and Thyroxine

Secretion of T₄ and T₃ into the circulation requires the liberation of these moieties from TG.⁸⁰ Thyroglobulin molecules pass from the lumen of the follicles into the follicular cells (endocytosis), where colloid droplets are ingested by lysosomes and undergo proteolysis. Congenital hypothyroidism may result from abnormal TG synthesis or metabolism. Of the about 125 tyrosyl residues in TG, only about 10 form iodothyronines, and another 20 consist of MIT and DIT. After proteolysis of TG, the freed MIT and DIT are deiodinated by iodotyrosine deiodinase, and the liberated iodide is recycled by the thyroid for reiodination of new TG. A defect in the deiodination mechanism of freed iodotyrosines results in depletion of iodine by release from the thyroid gland into the circulation and then excretion into the urine, resulting in goitrous cretinism.

Serum Protein Binding or Transport

The thyroid is the only source of T₄, and its blood concentration is 50 to 100 times greater than that of T₃. T₄ and T₃ secreted into the circulation are transported by loose attachment, through noncovalent bonds, to the plasma proteins. Three proteins play a role in the transport system. More than 75% of T₄ is normally bound to thyroxine-binding globulin (TBG). A second carrier protein is transthyretin (TTR); about 15% of T₄ is bound to TTR. A third protein is serum albumin, a high-capacity, low-affinity, iodothyronine-binding protein that usually transports less than 10% of the circulating T₄. Although T₄ binds with all three proteins, T₃ binds only with TBG and albumin, and its binding affinity is much less than that of T₄. The free T₄ (FT₄) concentration more accurately indicates the metabolic status of the individual than total T₄ or T₃ does because only the free hormones can enter the cells to exert their effects. If the capacity of TBG is increased, a rise in the concentration of total hormones will follow, and the concentration of free hormones will be maintained without significant change.

Monodeiodination of Thyroxine

Monodeiodination of T₄ occurs in many tissues through the action of three distinct deiodinase enzymes. Type I deiodinase, or 5′-monodeiodinase, is found in peripheral tissues such as the liver and kidney. Deiodination at the 5′ position of T₄ in peripheral tissues generates T₃, the iodothyronine that mediates the metabolic effects of thyroid hormone. Eighty percent of circulating T₃ is produced by the monodeiodination of T₄. However, the relative serum levels of T₄ and T₃ do not reflect the intracellular proportions of the hormones. The tissue distribution of T₃ may differ greatly from that of T₄ from tissue to tissue. The plasma half-life of T₃ is 1 day, compared with 6.9 days for T₄. However, the plasma half-life of T₄ is much shorter (3.6 days) in neonates. Most T₃ is localized in cells, whereas T₄ is found mainly in the extracellular space. The metabolic effects of T₃ are mediated through binding to specific receptors in the DNA response element that regulates transcription. It also interacts with membranous, mitochondrial, and cytosolic binding sites. The direct binding of T₄ in fetal neural tissue may be important in early neural development to permit intracellular deiodination to T₃.

Neural tissue requires FT₄ (and does not bind T₃). Intracellularly, the FT₄ is converted to FT₃ by type II deiodinase. Type II deiodinase regulates T₃ production from T₄ in the pituitary, neuroglial cells, and astrocytes and is involved in the control of thyrotropin (TSH) secretion from the pituitary gland.⁷⁷ Type III deiodinase, or 5-deiodinase, regulates peripheral deiodination of T₄ at the 5 position on the thyronine molecule instead of 5′ and generates reverse T₃ (rT₃). Serum rT₃ concentration parallels that of T₃ in normal circumstances but not in fetal life, starvation, or patients with severe nonthyroidal illnesses (e.g., euthyroid sick syndrome, non-thyroidal illness syndrome). Reverse T₃ is generally metabolically inactive, although weak nuclear binding activity has been reported.

Thyroxine

The plasma pool of T₄ constitutes a large protein-bound reservoir; this pool turns over slowly. Therefore, T₄ measurement usually reflects the adequacy of the hormonal supply. The normal level of T₄ is age dependent in infancy and childhood, particularly during the neonatal period. T₄ reaches a peak concentration shortly after birth and declines slowly, gradually approaching the adult normal range in puberty.²⁷ The range of normal levels for each age group is also wide (Figure 97-2). However, it should be kept in mind that more than 99% of circulating T₄ is bound to serum thyroid hormone–binding proteins. Any change or abnormality in the concentration of these proteins, particularly TBG, can affect the T₄ level. Several clinical situations and pharmacologic agents can alter the levels of TBG or TTR.

Drug Effects on Thyroid Concentrations

Certain anticonvulsants not only bind competitively to TBG but also interfere with T₄ assays, without greatly influencing the TSH level in a person with an otherwise normal thyroid reserve. These drugs include phenytoin, valproate, primidone, and carbamazepine. As much as twice the dose of drugs such as carbamazepine may be required in a patient receiving T₄ therapy. In addition, T₄ dose requirement may double in a patient receiving carbamazepine. Other drugs, such as furosemide, salicylate, and L-asparaginase, compete with thyroid hormone for binding with plasma proteins and can alter the levels of T₄, T₃, FT₄, and FT₃. Phenobarbital increases hepatic binding of T₄ and its disposal without altering circulating levels of thyroid hormone. Propylthiouracil (PTU), propranolol, dexamethasone, and some cholecystographic dyes inhibit peripheral conversion of T₄ to T₃. This effect of PTU is separate from its action on thyroid hormone biosynthesis by the thyroid gland. Administration of T₃ results in a decrease in T₄ because it suppresses endogenous T₄ secretion.

Amiodarone, an antiarrhythmic drug, contains covalently bound iodine and can alter thyroid test results.¹⁰ It inhibits the hepatic conversion of T₄ to T₃ and decreases the clearance of T₄. FT₄ and rT₃ are increased, and T₃ and FT₃ are decreased. Because of its high content of iodine, amiodarone can also result in either hypothyroidism or hyperthyroidism and may cause congenital goitrous hypothyroidism when it is administered to pregnant women. This effect is analogous to direct exposure of the fetus or infant to high doses of iodine.

Triiodothyronine

When TSH becomes elevated, the percentage of T₃ produced by the thyroid gland is increased. Serum concentration of T₃ can vary from day to day. Because of the overall small quantity of T₃ in serum, its level may not fall below the normal range until T₄ is critically low. Therefore, serum T₃ is not very useful in evaluation of patients for possible hypothyroidism. T₃ is physiologically low in the fetus and cord blood, but rises promptly after birth to levels greater than those in older children and adults. T₃ and FT₃ are also low during nonthyroidal illness. Normal serum T₃ concentrations vary among laboratories, but generally range from about 100 to 220 ng/dL in children and 80 to 200 ng/dL in adults.⁸

Reverse Triiodothyronine

Most hormonally inactive rT₃ is derived from deiodination of T₄ and represents a deiodination rate similar to that of T₄-to-T₃ conversion in normal adults. Serum half-life is very short, less than one half that of T₃. Concentration of rT₃ usually parallels that of T₃. However, rT₃ is disproportionately high in the fetus, in the early neonatal period, and in severe nonthyroidal illness, probably reflecting altered tissue metabolism of T₄.⁸ Normal adult serum level of rT₃ is 30 to 80 ng/dL.

Free Hormones

FT₄ in serum can be estimated by direct dialysis. This method depends on the FT₄ concentration being governed by equilibrium in levels of binding proteins, protein-bound T₄, and FT₄, following the law of mass action. In clinical settings, FT₄ does not depend on the T₄-binding capacity as such because a change in such a capacity is soon compensated for by a change in the amount of T₄ released from the thyroid. To estimate FT₄, serum is placed in a dialysis cell on one side of a semipermeable dialysis membrane, with a buffer solution on the other side. T₄ equilibrates across the membrane. Bound T₄ remains with serum, and free T₄ crosses the membrane and enters the buffer solution. T₄ is measured in the buffer solution, and the amount corresponds to the level of endogenous FT₄. FT₃ levels in the serum can be measured in the same dialysate as that used for FT₄. FT₄ by dialysis may be artifactually elevated in familial dysalbuminemic hyperthyroxinemia.³⁹

The principle of analogue methods is that the rate of binding of labeled hormones to antibodies depends on the FT₄ concentration during a timed incubation. Analogue methods are less expensive, can be performed more rapidly than the direct dialysis method, and are acceptable for routine testing in children. However, FT₄ analogue methods may not provide an accurate assessment of FT₄ in some neonates, patients receiving medications that interfere with T₄ binding, chronically or critically ill neonates or children, or patients with very low levels of TBG.⁹⁴

When hypothalamic or pituitary hypothyroidism is suspected, the definitive test to measure the FT₄ is by direct dialysis. This test is readily available in specialized commercial laboratories. Because there is a delay in obtaining results, the specimen should be collected and T₄ therapy started. If there is an associated ACTH or cortisol deficiency, hydrocortisone therapy should be started at least 6 to 8 hours before T₄ therapy is initiated.⁴⁵

Measurement of FT₃ is not currently part of standard care. In the future, FT₃ measurements may be shown to be useful in assessing hypothyroidism. Currently, FT₃ may be useful when the diagnosis of thyrotoxicosis is suspected and TSH is suppressed but values for T₄, T₃, or both are normal. The approximate serum values for normal adults are 1.0 to 2.4 ng/dL for FT₄ and 240 to 620 pg/dL for FT₃. The range of normal values for infants and young children is probably higher than that for adults, but exact ranges have not been established.

Proteins That Bind to Thyroid Hormones

Because concentrations of T₄ and T₃ are affected by those of thyroid hormone–binding proteins and by the degree of their saturation at the binding site, T₄ must be interpreted with a simultaneous evaluation of these proteins. The simplest approach is to measure TSH and FT₄ (by dialysis or analogue methods) and not measure T₄ at all, avoiding the issue of changes in levels of thyroid hormone–binding proteins.

The alternative approach is to determine T₃U, which is a rapid, indirect assessment of the binding proteins. However, it may not be accurate in the same clinical conditions as those described previously for the FT₄ analogue methods. The T₃U value is then multiplied by the total T₄ value to give the FT₄ index, which is essentially a mathematically corrected T₄ value for the degree of saturation of the thyroid hormone–binding proteins. Direct dialysis is the best FT₄ method, especially in infants. Analogue methods are very cost effective in measuring FT₄ and will probably replace methods that measure the FT₄ index.

In general, when TBG is increased in a euthyroid individual, T₄ is elevated and T₃U is low, but FT₄ is about normal. The reverse situation is observed in individuals with low TBG, but again FT₄ is normal. The administration of a drug that competes with T₄ for TBG-binding sites results in low T₄ and high T₃U but normal FT₄.

Serum TBG is determined by radioimmunoassay in commercial laboratories, and its measurement is useful in the quantitation of abnormal levels of TBG. Because most T₄ is bound to TBG, these measurements give a good approximation of the T₄-binding protein capacity. The binding capacity of TBG is increased in many clinical situations, including those during pregnancy and in neonates. It may also be increased in patients with hypothyroidism, liver disease, porphyria, or human immunodeficiency virus.

Pharmacologic agents that increase TBG levels include estrogens, methadone, and heroin. The concentration of TBG may be decreased in preterm infants and in hyperthyroidism, hypercortisolism, acromegaly, diabetic ketoacidosis, chronic hepatic diseases, alcoholism, nephrotic syndrome, other chronic renal diseases, and protein-calorie malnutrition. Drugs that decrease TBG levels include androgens, anabolic steroids, danazol, glucocorticoids, and l-asparaginase. Pharmacologic agents that compete with T₄ for TBG-binding sites include salicylates, phenytoin, and possibly other anticonvulsants, hypolipemic agents, sulfonylureas, diazepam, heparin, and fenclofenac. These agents give falsely low T₄ and falsely high T₃U values. TSH and FT₄ determinations by direct dialysis method are usually normal. The normal value for TBG in adults is about 1.2 to 2.8 mg/dL.

Thyrotropin

Measurements of TSH and FT₄ are the most important tools for screening thyroid function. Serum TSH is measured by specific competitive-binding isotopic and nonisotopic methods, and values are expressed in milliunits per liter (mU/L) of an international reference standard. TSH is the most sensitive test for primary hypothyroidism at any age and is used in many neonatal thyroid screening programs. Serum TSH is also an indicator of the adequacy of thyroid hormone replacement therapy and is used in assessment of the hypothalamic-pituitary-thyroid axis by the TSH surge test and the TRH test (see Thyrotropin-Releasing Hormone). The normal adult value is 0.2 to 3.0 mU/L.⁸ TSH is elevated in primary hypothyroidism. A surge of TSH release also occurs at parturition and reaches a peak within 2 hours after birth. TSH in the cord serum and the infant’s serum after the first day of postnatal life is usually less than 20 mU/L. Therefore, TSH is the most important test to screen for primary congenital hypothyroidism. The target range for TSH during thyroid hormone therapy for primary hypothyroidism is 0.5 to 2 mU/L. The highly sensitive TSH assay can also be used in identifying individuals with thyrotoxicosis in whom TSH is suppressed to less than 0.01 mU/L.

Thyroid Autoantibodies

Numerous methods have been used for detection of a large variety of thyroid antibodies. Assays for thyroglobulin antibodies (TGAb) and thyroperoxidase (microsomal) antibodies (TPOAb) are widely available. These antibodies are found in Hashimoto thyroiditis and in about 2% of the adult population. TSH receptor stimulating and blocking antibodies may be detected in the sera of patients with autoimmune thyroid diseases and are known as TSH receptor antibodies (TRAb). TRAb that are stimulatory are found in the sera of patients with active Graves disease and are known as thyroid-stimulating immunoglobulins (TSI); TRAb that are inhibitory are called TBII.

Mothers with primary hypothyroidism and Hashimoto thyroiditis may have circulating serum TBII or antibodies that block the TSH receptor. These mothers give birth to children with a transient form of congenital hypothyroidism as a result of the transplacental transfer of TBII. The disease may recur in infants of subsequent pregnancies if the high-affinity antibody persists in the mother’s circulation. The half-life of immunoglobulins in the neonate is about 2 weeks, and TRAb usually disappear from the serum of affected infants by 6 to 8 weeks of age.

Mothers with Graves hyperthyroidism may have TBII but more commonly have TSI. These mothers give birth to children with a transient form of hyperthyroidism as a result of the transplacental transfer of TSI. This disease may also recur in infants of subsequent pregnancies if the high-affinity antibody persists in the maternal circulation. Hyperthyroidism in the affected infant may persist for 2 to 6 months.

Thyroglobulin

It was previously believed that TG was present only in the thyroid gland. With the development of radioimmunoassay for TG, it is now known that some of it appears in the circulation. The mean value of TG for normal adults is 5 ng/mL, with a range from less than 1 to about 30 ng/mL. The median value for preterm infants at birth is high (102 ng/mL), rapidly decreases during the first 30 days of life for reasons not yet understood, and further decreases during infancy and childhood to the adult mean value by 20 years of age.

In athyreotic cretinism, TG is not detectable. However, in the form of autoimmune congenital hypothyroidism caused by antibodies that block the TSH receptor, TG may be detectable even when the radioactive iodine scan suggests an absent thyroid gland. Ultrasound identifies the thyroid gland; TG levels may be elevated when the thyroid gland is hyperactive, as in endemic goiter, subacute thyroiditis, toxic nodular goiter, and Graves disease. TG cannot be reliably measured in Hashimoto thyroiditis because of the possible presence of TGAb. Thyroglobulin levels are often greatly increased in papillary-follicular carcinoma but not in medullary or anaplastic carcinoma of the thyroid. Thyroglobulin levels are useful not only in the differential diagnosis, but also in follow-up studies to monitor patients for recurrence of papillary-follicular carcinoma.

Thyroid Imaging

The development of sensitive and specific assays to quantitate thyroid hormone and TSH has largely obviated the need for radioiodine uptake studies in childhood. As a result, radioactive thyroid scans are rarely performed in infants and children. Measurement of TG concentration can identify the presence or absence of thyroid glandular tissue. Ultrasonography of the thyroid gland is useful for visualization of normal-sized glands and goiters. It is also used to distinguish solid and cystic nodules of the thyroid. Ultrasonography can identify dysgenetic thyroid glands.⁶⁸ Slower correction of TSH may be seen with dysgenetic glands than with eutopic glands. Ultrasonography should be used as the first imaging tool, with a scan performed to distinguish agenesis from ectopia. However, hypoplastic or ectopic glands may be missed by this technique. When a scan is necessary, ¹²³I or ^99mTc should be used to reduce radiation exposure to the child. The half-life of ¹²³I is 13.3 hours, compared with 8 days for ¹³¹I.

Radioiodine uptake studies are invaluable for diagnosing certain inborn errors of thyroid hormone synthesis, such as the iodide-trapping defect and the iodide oxidation or organification defect. ^99mTc-pertechnetate can also be used for iodide-trapping studies because this anion is trapped by the thyroid in a manner similar to iodine, but is not organified and is, therefore, discharged early from the thyroid gland. In addition to the thyroid gland, the salivary glands, gastric mucosa, uterus, small intestine, mammary glands, and placenta are capable of concentrating iodine. In patients with goitrous cretinism caused by iodide-trapping defects, the ability of salivary glands to trap iodide can be exploited for diagnostic purposes. The trapping defect is shared by the thyroid and the salivary glands in these patients. The perchlorate discharge test is performed during the radioiodine uptake test to detect the presence of a defect in the oxidation of iodide to iodine.

Thyrotropin-Releasing Hormone

In 2002, the TRH test became commercially unavailable in the United States. Historically, TRH was the first identified hypothalamic neuropeptide and had been used in clinical assessment since the 1960s. The following section regarding the TRH test is retained in this chapter for reference in the event that the TRH test again becomes a tool available to the clinician.

Given current ultrasensitive TSH assays, the TRH test is required only when TSH is mildly elevated (4.5 to 10 mU/L) to help determine whether the child has mild primary hypothyroidism (as opposed to central hypothyroidism) or for the assessment of possible thyroid hormone resistance. A suppressed basal TSH value is significant and sufficient for the diagnosis of hyperthyroidism, and a basal TSH concentration higher than 10 mU/L (after the first week of age) is significant and sufficient for the diagnosis of primary hypothyroidism.

A bolus infusion of TRH (7 µg/kg of body weight) results in increased TSH that peaks at 20 to 30 minutes. A peak increment of 10 to 30 mU/L is seen in healthy children, with a decline to basal TSH levels by 2 to 3 hours. Serum T₃ levels peak at 3 to 4 hours and T₄ levels at 6 to 9 hours after TRH. Therefore, the TRH test can be used to examine responsiveness of both TSH to TRH and of thyroid gland to TSH when necessary. Patients with primary hypothyroidism have an exaggerated TSH response. Patients with hyperthyroidism and those receiving T₄ replacement do not respond to TRH stimulation because of chronic suppression of TSH by thyroid hormone.⁴⁵

The TRH test may be helpful in confirming central hypothyroidism (pituitary or hypothalamic) in some patients. Those with secondary (pituitary) hypothyroidism do not respond to TRH.⁴⁵ In some patients with tertiary hypothyroidism (hypothalamic TRH deficiency), a delayed response of TSH to TRH stimulation is seen, so TSH at 60 minutes is higher than at 20 to 30 minutes. However, many patients with tertiary hypothyroidism have a normal response to TRH.

AM to PM Thyroid-Stimulating Hormone Ratio, Thyroid-Stimulating Hormone Surge Test

Central hypothyroidism is diagnosed in infants who have low or low-normal FT₄, no TSH elevation, and other common features of hypopituitarism (e.g., hypoglycemia, microphallus). More subtle central hypothyroidism (FT₄ in the lowest third of the normal range) can be confirmed in children older than 1 year by the am to pm TSH ratio or the TSH surge test.77,78 This test is not useful in infants before development of the circadian pattern of TSH secretion.

The TSH surge test is performed by obtaining blood for TSH assay at the usual time of the nadir of the circadian variation of TSH (the mean of two or three samples between 10:00 am and 6:00 pm) and again at the usual time of peak TSH secretion (the mean of the three highest sequential samples between 10:00 pm and 4:00 am). The mean nadir and peak TSH values are calculated. Normal night-time (peak) TSH values are 50% to 300% higher than those (nadir) obtained during the day. Blunting or absence of this rise confirms central hypothyroidism.⁷⁷ At age older than 1 year, with FT4 less than 1.2 mg/dL, an 8 am to 4 pm TSH ratio less than 1.3 also confirms central hypothyroidism.⁷⁸