Chapter 19: The Thyroid Gland

After studying this chapter, you should be able to:

• Describe the structure of the thyroid gland and how it relates to its function.

• Define the chemical nature of the thyroid hormones and how they are synthesized.

• Understand the critical role of iodine in the thyroid gland and how its transport is controlled.

• Describe the role of protein binding in the transport of thyroid hormones and peripheral metabolism.

• Identify the role of the hypothalamus and pituitary in regulating thyroid function.

• Define the effects of the thyroid hormones in homeostasis and development.

• Understand the basis of conditions where thyroid function is abnormal and how they can be treated.

The thyroid gland is one of the larger endocrine glands of the body. The gland has two primary functions. The first is to secrete the thyroid hormones, which maintain the level of metabolism in the tissues that is optimal for their normal function. Thyroid hormones stimulate O₂ consumption by most of the cells in the body, help regulate lipid and carbohydrate metabolism, and thereby influence body mass and mentation. Consequences of thyroid gland dysfunction depend on the life stage at which they occur. The thyroid is not essential for life, but its absence or hypofunction during fetal and neonatal life results in severe mental retardation and dwarfism. In adults, hypothyroidism is accompanied by mental and physical slowing and poor resistance to cold. Conversely, excess thyroid secretion leads to body wasting, nervousness, tachycardia, tremor, and excess heat production. Thyroid function is controlled by the thyroid-stimulating hormone (TSH, thyrotropin) of the anterior pituitary. The secretion of this hormone is in turn increased by thyrotropin-releasing hormone (TRH) from the hypothalamus and is also subject to negative feedback control by high circulating levels of thyroid hormones acting on the anterior pituitary and the hypothalamus.

The second function of the thyroid gland is to secrete calcitonin, a hormone that regulates circulating levels of calcium. This function of the thyroid gland is discussed in Chapter 21 in the broader context of whole body calcium homeostasis.

The thyroid is a butterfly-shaped gland that straddles the trachea in the front of the neck. It develops from an evagination of the floor of the pharynx, and a thyroglossal duct marking the path of the thyroid from the tongue to the neck sometimes persists in the adult. The two lobes of the human thyroid are connected by a bridge of tissue, the thyroid isthmus, and there is sometimes a pyramidal lobe arising from the isthmus in front of the larynx (Figure 19–1). The gland is well vascularized, and the thyroid has one of the highest rates of blood flow per gram of tissue of any organ in the body.

The portion of the thyroid concerned with the production of thyroid hormone consists of multiple acini (follicles). Each spherical follicle is surrounded by a single layer of polarized epithelial cells and filled with pink-staining proteinaceous material called colloid. Colloid consists predominantly of the glycoprotein, thyroglobulin. When the gland is inactive, the colloid is abundant, the follicles are large, and the cells lining them are flat. When the gland is active, the follicles are small, the cells are cuboid or columnar, and areas where the colloid is being actively reabsorbed into the thyrocytes are visible as “reabsorption lacunae” (Figure 19–2).

Microvilli project into the colloid from the apexes of the thyroid cells and canaliculi extend into them. The endoplasmic reticulum is prominent, a feature common to most glandular cells, and secretory granules containing thyroglobulin are seen (Figure 19–3). The individual thyroid cells rest on a basal lamina that separates them from the adjacent capillaries. The capillaries are fenestrated, like those of other endocrine glands (see Chapter 31).

CHEMISTRY

The primary hormone secreted by the thyroid is thyroxine (T₄), along with much lesser amounts of triiodothyronine (T₃). T₃ has much greater biologic activity than T₄ and is specifically generated at its site of action in peripheral tissues by deiodination of T₄ (see below). Both hormones are iodine-containing amino acids (Figure 19–4). Small amounts of reverse triiodothyronine (3,3′,5′-triiodothyronine, RT₃) and other compounds are also found in thyroid venous blood. Whether RT₃ is biologically active remains unclear.

IODINE HOMEOSTASIS

Iodine is an essential raw material for thyroid hormone synthesis. Dietary iodide is absorbed by the intestine and enters the circulation; its subsequent fate is summarized in Figure 19–5. The minimum daily iodine intake that will maintain normal thyroid function is 150 μg in adults. In most developed countries, supplementation of table salt means that the average dietary intake is approximately 500 μg/day. The principal organs that take up circulating I^– are the thyroid, which uses it to make thyroid hormones, and the kidneys, which excrete it in the urine. About 120 μg/day enter the thyroid at normal rates of thyroid hormone synthesis and secretion. The thyroid secretes 80 μg/day in the form of T₃ and T₄, while 40 μg/day diffuses back into the extracellular fluid (ECF). Circulating T₃ and T₄ are metabolized in the liver and other tissues, with the release of a further 60 μg of I^– per day into the ECF. Some thyroid hormone derivatives are excreted in the bile, and some of the iodine in them is reabsorbed (enterohepatic circulation), but there is a net loss of I^– in the stool of approximately 20 μg/day. The total amount of I^– entering the ECF is thus 500 + 40 + 60, or 600 μg/day; 20% of this I^– enters the thyroid, whereas 80% is excreted in the urine.

IODIDE TRANSPORT ACROSS THYROCYTES

The basolateral membranes of thyrocytes facing the capillaries contain a symporter that transports two Na⁺ ions and one I^– ion into the cell with each cycle, against the electrochemical gradient for I^–. This Na⁺/I^– symporter (NIS) is capable of producing intracellular I^– concentrations that are 20–40 times as great as the concentration in plasma. The process involved is secondary active transport (see Chapter 2), with the energy provided by active transport of Na⁺ out of thyroid cells by Na, K ATPase. NIS is regulated both by transcriptional means and by active trafficking into and out of the thyrocyte basolateral membrane; in particular, thyroid-stimulating hormone (TSH; see below) induces both NIS expression and the retention of NIS in the basolateral membrane, where it can mediate sustained iodide uptake.

Iodide must also exit the thyrocyte across the apical membrane to access the colloid, where the initial steps of thyroid hormone synthesis occur. This transport step is believed to be mediated, at least in part, by a Cl^–/I^– exchanger known as pendrin. This protein was first identified as the product of the gene responsible for the Pendred syndrome, which causes thyroid dysfunction and deafness. Pendrin (SLC26A4) is one member of the larger family of SLC26 anion exchangers.

The relation of thyroid function to iodide is unique. As discussed in more detail below, iodide is essential for normal thyroid function, but iodide deficiency and iodide excess both inhibit thyroid function.

The salivary glands, the gastric mucosa, the placenta, the ciliary body of the eye, the choroid plexus, the mammary glands, and certain cancers derived from these tissues also express NIS and can transport iodide against a concentration gradient, but the transporter in these tissues is not affected by TSH. The physiologic significance of all these extrathyroidal iodide-concentrating mechanisms is obscure, but they may provide pathways for radioablation of NIS-expressing cancer cells using iodide radioisotopes. This approach is also useful for the ablation of thyroid cancers.

THYROID HORMONE SYNTHESIS & SECRETION

At the interface between the thyrocyte and the colloid, iodide undergoes a process referred to as organification. First, it is oxidized to iodine, and then incorporated into the carbon 3 position of tyrosine residues that are part of the thyroglobulin molecule in the colloid (Figure 19–6). Thyroglobulin is a glycoprotein made up of two subunits and has a molecular weight of 660 kDa. It contains 10% carbohydrate by weight. It also contains 123 tyrosine residues, but only 4–8 of these are normally incorporated into thyroid hormones. Thyroglobulin is synthesized in the thyroid cells and secreted into the colloid by exocytosis of granules. The oxidation and reaction of iodide with the secreted thyroglobulin is mediated by thyroid peroxidase, a membrane-bound enzyme found in the thyrocyte apical membrane. The thyroid hormones so produced remain part of the thyroglobulin molecule until needed. As such, colloid represents a reservoir of thyroid hormones, and humans can ingest a diet completely devoid of iodide for up to 2 months before a decline in circulating thyroid hormone levels is seen. When there is a need for thyroid hormone secretion, colloid is internalized by the thyrocytes by endocytosis, and directed toward lysosomal degradation. Thus, the peptide bonds of thyroglobulin are hydrolyzed, and free T₄ and T₃ are discharged into cytosol and thence to the capillaries (see below). Thyrocytes thus have four functions: They collect and transport iodine, they synthesize thyroglobulin and secrete it into the colloid, they fix iodine to the thyroglobulin to generate thyroid hormones, and they remove the thyroid hormones from thyroglobulin and secrete them into the circulation.

Thyroid hormone synthesis is a multistep process. Thyroid peroxidase generates reactive iodine species that can attack thyroglobulin. The first product is monoiodotyrosine (MIT). MIT is next iodinated on the carbon 5 position to form diiodotyrosine (DIT). Two DIT molecules then undergo an oxidative condensation to form T₄ with the elimination of the alanine side chain from the molecule that forms the outer ring. There are two theories of how this coupling reaction occurs. One holds that the coupling occurs with both DIT molecules attached to thyroglobulin (intramolecular coupling). The other holds that the DIT that forms the outer ring is first detached from thyroglobulin (intermolecular coupling). In either case, thyroid peroxidase is involved in coupling as well as iodination. T₃ is formed by condensation of MIT with DIT. A small amount of RT₃ is also formed, probably by condensation of DIT with MIT. In the normal human thyroid, the average distribution of iodinated compounds is 3% MIT, 33% DIT, 35% T₄, and 7% T₃. Only traces of RT₃ and other components are present.

The human thyroid secretes about 80 μg (103 nmol) of T₄, 4 μg (7 nmol) of T₃, and 2 μg (3.5 nmol) of RT₃ per day (Figure 19–7). MIT and DIT are not secreted. These iodinated tyrosines are deiodinated by a microsomal iodotyrosine deiodinase. This represents a mechanism to recover iodine and bound tyrosines and recycle them for additional rounds of hormone synthesis. The iodine liberated by deiodination of MIT and DIT is reutilized in the gland and normally provides about twice as much iodide for hormone synthesis as NIS does. In patients with congenital absence of the iodotyrosine deiodinase, MIT and DIT appear in the urine and there are symptoms of iodine deficiency (see below). Iodinated thyronines are resistant to the activity of iodotyrosine deiodinase, thus allowing T₄ and T₃ to pass into the circulation.

PROTEIN BINDING

The normal total plasma T₄ level in adults is approximately 8 μg/dL (103 nmol/L), and the plasma T₃ level is approximately 0.15 μg/dL (2.3 nmol/L). T₄ and T₃ are relatively lipophilic; thus, their free forms in plasma are in equilibrium with a much larger pool of protein-bound thyroid hormones in plasma and in tissues. Free thyroid hormones are added to the circulating pool by the thyroid. It is the free thyroid hormones in plasma that are physiologically active and that feed back to inhibit pituitary secretion of TSH (Figure 19–8). The function of protein-binding appears to be the maintenance of a large pool of hormone that can readily be mobilized as needed. In addition, at least for T₃, hormone binding prevents excess uptake by the first cells encountered and promotes uniform tissue distribution. Total T₄ and T₃ can both be measured by radioimmunoassay. There are also direct assays that specifically measure only the free forms of the hormones. The latter are the more clinically relevant measures given that these are the active forms, and also due to both acquired and congenital variations in the concentrations of binding proteins between individuals.

The plasma proteins that bind thyroid hormones are albumin, a prealbumin called transthyretin (formerly called thyroxine-binding prealbumin), and a globulin known as thyroxine-binding globulin (TBG). Of the three proteins, albumin has the largest capacity to bind T₄ (ie, it can bind the most T₄ before becoming saturated) and TBG has the smallest capacity. However, the affinities of the proteins for T₄ (ie, the avidity with which they bind T₄ under physiologic conditions) are such that most of the circulating T₄ is bound to TBG (Table 19–1), with over a third of the binding sites on the protein occupied. Smaller amounts of T₄ are bound to transthyretin and albumin. The half-life of transthyretin is 2 days, that of TBG is 5 days, and that of albumin is 13 days.

Normally, 99.98% of the T₄ in plasma is bound; the free T₄ level is only about 2 ng/dL. There is very little T₄ in the urine. Its biologic half-life is long (about 6–7 days), and its volume of distribution is less than that of ECF (10 L, or about 15% of body weight). All of these properties are characteristic of a substance that is strongly bound to protein.

T₃ is not bound to quite as great an extent; of the 0.15 μg/dL normally found in plasma, 0.2% (0.3 ng/dL) is free. The remaining 99.8% is protein-bound, 46% to TBG and most of the remainder to albumin, with very little binding to transthyretin (Table 19–1). The lesser binding of T₃ correlates with the facts that T₃ has a shorter half-life than T₄ and that its action on the tissues is much more rapid. RT₃ also binds to TBG.

FLUCTUATIONS IN BINDING

When a sudden, sustained increase in the concentration of thyroid-binding proteins in the plasma takes place, the concentration of free thyroid hormones falls. This change is temporary, however, because the decrease in the concentration of free thyroid hormones in the circulation stimulates TSH secretion, which in turn causes an increase in the production of free thyroid hormones. A new equilibrium is eventually reached at which the total quantity of thyroid hormones in the blood is elevated but the concentration of free hormones, the rate of their metabolism, and the rate of TSH secretion are normal. Corresponding changes in the opposite direction occur when the concentration of thyroid-binding protein is reduced. Consequently, patients with elevated or decreased concentrations of binding proteins, particularly TBG, are typically neither hyperthyroid nor hypothyroid; that is, they are euthyroid.

TBG levels are elevated in estrogen-treated patients and during pregnancy, as well as after treatment with various drugs (Table 19–2). They are depressed by glucocorticoids, androgens, the weak androgen danazol, and the cancer chemotherapeutic agent L-asparaginase. A number of other drugs, including salicylates, the anticonvulsant phenytoin, and the cancer chemotherapeutic agents mitotane (o, p′-DDD) and 5-fluorouracil inhibit binding of T₄ and T₃ to TBG and consequently produce changes similar to those produced by a decrease in TBG concentration. Changes in total plasma T₄ and T₃ can also be produced by changes in plasma concentrations of albumin and prealbumin.

METABOLISM OF THYROID HORMONES

T₄ and T₃ are deiodinated in the liver, the kidneys, and many other tissues. These deiodination reactions serve not only to catabolize the hormones, but also to provide a local supply specifically of T₃, which is believed to be the primary mediator of the physiologic effects of thyroid secretion. One third of the circulating T₄ is normally converted to T₃ in adult humans, and 45% is converted to RT₃. As shown in Figure 19–7, only about 13% of the circulating T₃ is secreted by the thyroid while 87% is formed by deiodination of T₄; similarly, only 5% of the circulating RT₃ is secreted by the thyroid and 95% is formed by deiodination of T₄. It should be noted as well that marked differences in the ratio of T₃ to T₄ occur in various tissues. Two tissues that have very high T₃/T₄ ratios are the pituitary and the cerebral cortex, due to the expression of specific deiodinases, as discussed below.

Three different deiodinases act on thyroid hormones: D₁, D₂, and D₃. All are unique in that they contain the rare amino acid selenocysteine, with selenium in place of sulfur, which is essential for their enzymatic activity. D₁ is present in high concentrations in the liver, kidneys, thyroid, and pituitary. It appears primarily to be responsible for maintaining the formation of T₃ from T₄ in the periphery. D₂ is present in the brain, pituitary, and brown fat. It also contributes to the formation of T₃. In the brain, it is located in astroglia and produces a supply of T₃ to neurons. D₃ is also present in the brain and in reproductive tissues. It acts only on the 5 position of T₄ and T₃ and is probably the main source of RT₃ in the blood and tissues. Overall, the deiodinases appear to be responsible for maintaining differences in T₃/T₄ ratios in the various tissues in the body. In the brain, in particular, high levels of deiodinase activity ensure an ample supply of active T₃.

Some of the T₄ and T₃ is further converted to deiodotyrosines by deiodinases. T₄ and T₃ are also conjugated in the liver to form sulfates and glucuronides. These conjugates enter the bile and pass into the intestine. The thyroid conjugates are hydrolyzed, and some are thereafter reabsorbed (enterohepatic circulation), but others are excreted in the stool. In addition, some T₄ and T₃ passes directly from the circulation to the intestinal lumen. The iodide lost by these routes amounts to about 4% of the total daily iodide loss.

FLUCTUATIONS IN DEIODINATION

Much more RT₃ and much less T₃ are formed during fetal life, and the ratio shifts to that of adults about 6 weeks after birth. Various drugs inhibit deiodinases, producing a fall in plasma T₃ levels and a reciprocal rise in RT₃. Selenium deficiency has the same effect. A wide variety of nonthyroidal illnesses also suppress deiodinases. These include burns, trauma, advanced cancer, cirrhosis, chronic kidney disease, myocardial infarction, and febrile states. The low-T₃ state produced by these conditions disappears with recovery. It is difficult to decide whether individuals with the low-T₃ state produced by drugs and illness have mild hypothyroidism.

Diet also has a clear-cut effect on conversion of T₄ to T₃. In fasted individuals, plasma T₃ is reduced by 10–20% within 24 h and by about 50% in 3–7 days, with a corresponding rise in RT₃ (Figure 19–9). Free and bound T₄ levels remain essentially normal. During more prolonged starvation, RT₃ returns to normal but T₃ remains depressed. At the same time, the basal metabolic rate (BMR) falls and urinary nitrogen excretion, an index of protein breakdown, is decreased. Thus, the decline in T₃ conserves calories and protein. Conversely, overfeeding increases T₃ and reduces RT₃.

Thyroid function is regulated primarily by variations in the circulating level of pituitary TSH (Figure 19–8). TSH secretion is increased by the hypothalamic hormone TRH (see Chapter 17) and inhibited in a negative feedback manner by circulating free T₄ and T₃. The effect of T₄ is enhanced by production of T₃ in the cytoplasm of the pituitary cells by the 5′-D₂ they contain. TSH secretion is also inhibited by stress, and in experimental animals it is increased by cold and decreased by warmth.

CHEMISTRY & METABOLISM OF TSH

Human TSH is a glycoprotein that contains 211 amino acid residues. It is made up of two subunits, designated α and β. The α subunit is encoded by a gene on chromosome 6 and the β subunit by a gene on chromosome 1. The α and β subunits become noncovalently linked in the pituitary thyrotropes. TSH-α is identical to the α subunit of luteinizing hormone, follicle-stimulating hormone, and human chorionic gonadotropin (hCG) (see Chapters 18 and 22). The functional specificity of TSH is conferred by the β subunit. The structure of TSH varies from species to species, but other mammalian TSHs are biologically active in humans.

The biologic half-life of human TSH is about 60 min. TSH is degraded for the most part in the kidneys and to a lesser extent in the liver. Secretion is pulsatile, and mean output starts to rise at about 9:00 PM, peaks at midnight, and then declines during the day. The normal secretion rate is about 110 μg/day. The average plasma level is about 2 μg/mL.

Because the α subunit in hCG is the same as that in TSH, large amounts of hCG can activate TSH receptors nonspecifically. In some patients with benign or malignant tumors of placental origin, plasma hCG levels can rise so high that they produce mild hyperthyroidism.

EFFECTS OF TSH ON THE THYROID

When the pituitary is removed, thyroid function is depressed and the gland atrophies; when TSH is administered, thyroid function is stimulated. Within a few minutes after the injection of TSH, there are increases in iodide binding, synthesis of T₃, T₄, and iodotyrosines, secretion of thyroglobulin into the colloid, and endocytosis of colloid. Iodide trapping is increased in a few hours; blood flow increases; and, with long-term TSH treatment, the cells hypertrophy and the weight of the gland increases.

Whenever TSH stimulation is prolonged, the thyroid becomes detectably enlarged. Enlargement of the thyroid is called a goiter.

TSH RECEPTORS

The TSH receptor is a typical G-protein–coupled, seven-transmembrane receptor that activates adenylyl cyclase through G_s. It also activates phospholipase C (PLC). Like other glycoprotein hormone receptors, it has an extended, glycosylated extracellular domain.

OTHER FACTORS AFFECTING THYROID GROWTH

In addition to TSH receptors, thyrocytes express receptors for insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), and other growth factors. IGF-I and EGF promote growth, whereas interferon-γ and tumor necrosis factor-α inhibit growth. The exact physiologic role of these factors in the thyroid has not been established, but the effect of the cytokines implies that thyroid function might be inhibited in the setting of chronic inflammation, which could contribute to cachexia, or weight loss.

CONTROL MECHANISMS

The mechanisms regulating thyroid secretion are summarized in Figure 19–8. The negative feedback effect of thyroid hormones on TSH secretion is exerted in part at the hypothalamic level, but it is also due in large part to an action on the pituitary, since T₄ and T₃ block the increase in TSH secretion produced by TRH. Infusion of either T₄ or T₃ reduces the circulating level of TSH, which declines measurably within 1 h. In experimental animals, there is an initial rise in pituitary TSH content before the decline, indicating that thyroid hormones inhibit secretion before they inhibit synthesis. The day-to-day maintenance of thyroid secretion depends on the feedback interplay of thyroid hormones with TSH and TRH (Figure 19–8). The adjustments that appear to be mediated via TRH include the increased secretion of thyroid hormones produced by cold and, presumably, the decrease produced by heat. It is worth noting that although cold produces clear-cut increases in circulating TSH in experimental animals and human infants, the rise produced by cold in adult humans is negligible. Consequently, in adults, increased heat production due to increased thyroid hormone secretion (thyroid hormone thermogenesis) plays little if any role in the response to cold. Stress has an inhibitory effect on TRH secretion. Dopamine and somatostatin act at the pituitary level to inhibit TSH secretion, but it is not known whether they play a physiologic role in the regulation of TSH secretion. Glucocorticoids also inhibit TSH secretion.

The amount of thyroid hormone necessary to maintain normal cellular function in thyroidectomized individuals used to be defined as the amount necessary to normalize the BMR, but it is now defined as the amount necessary to return plasma TSH to normal. Indeed, with the accuracy and sensitivity of modern assays for TSH and the marked inverse correlation between plasma free thyroid hormone levels and plasma TSH, measurement of TSH is now widely regarded as one of the best tests of thyroid function. The amount of T₄ that normalizes plasma TSH in athyreotic individuals averages 112 μg of T₄ by mouth per day in adults. About 80% of this dose is absorbed from the gastrointestinal tract. It produces a slightly greater than normal FT₄I but a normal FT₃I, indicating that in humans, unlike some experimental animals, it is circulating T₃ rather than T₄ that is the principal feedback regulator of TSH secretion (Clinical Boxes 19–1 and 19–2).

Some of the widespread effects of thyroid hormones in the body are secondary to stimulation of O₂ consumption (calorigenic action), although the hormones also affect growth and development in mammals, help regulate lipid metabolism, and increase the absorption of carbohydrates from the intestine (Table 19–5). They also increase the dissociation of oxygen from hemoglobin by increasing red cell 2,3-diphosphoglycerate (DPG) (see Chapter 35).

MECHANISM OF ACTION

Thyroid hormones enter cells and T₃ binds to TR in the nuclei. T₄ can also bind, but not as avidly. The hormone–receptor complex then binds to DNA via zinc fingers and increases (or in some cases, decreases) the expression of a variety of different genes that code for proteins that regulate cell function (see Chapters 1 and 16). Thus, the nuclear receptors for thyroid hormones are members of the superfamily of hormone-sensitive nuclear transcription factors.

There are two human TR genes: an α receptor gene on chromosome 17 and a β receptor gene on chromosome 3. By alternative splicing, each forms at least two different mRNAs and therefore two different receptor proteins. TRβ2 is found only in the brain, but TRα1, TRα2, and TRβ1 are widely distributed. TRα2 differs from the other three in that it does not bind T₃ and its function is not yet fully established. TRs bind to DNA as monomers, homodimers, and heterodimers with other nuclear receptors, particularly the retinoid X receptor (RXR). The TR/RXR heterodimer does not bind to 9-cis retinoic acid, the usual ligand for RXR, but TR binding to DNA is greatly enhanced in response to thyroid hormones when the receptor is in the form of this heterodimer. There are also coactivator and corepressor proteins that affect the actions of TRs. Presumably, this complexity underlies the ability of thyroid hormones to produce many different effects in the body.

In most of its actions, T₃ acts more rapidly and is three to five times more potent than T₄ (Figure 19–10). This is because T₃ is less tightly bound to plasma proteins than is T₄, but binds more avidly to thyroid hormone receptors. As previously noted, RT₃ is inert (Clinical Box 19–3).

CALORIGENIC ACTION

T₄ and T₃ increase the O₂ consumption of almost all metabolically active tissues. The exceptions are the adult brain, testes, uterus, lymph nodes, spleen, and anterior pituitary. T₄ actually depresses the O₂ consumption of the anterior pituitary, presumably because it inhibits TSH secretion. The increase in metabolic rate produced by a single dose of T₄ becomes measurable after a latent period of several hours and lasts 6 days or more.

Some of the calorigenic effect of thyroid hormones is due to metabolism of the fatty acids they mobilize. In addition, thyroid hormones increase the activity of the membrane-bound Na, K ATPase in many tissues.

Effects Secondary to Calorigenesis

When the metabolic rate is increased by T₄ and T₃ in adults, nitrogen excretion is increased; if food intake is not increased, endogenous protein and fat stores are catabolized and weight is lost. In hypothyroid children, small doses of thyroid hormones cause a positive nitrogen balance because they stimulate growth, but large doses cause protein catabolism similar to that produced in the adult. The potassium liberated during protein catabolism appears in the urine, and there is also an increase in urinary hexosamine and uric acid excretion.

When the metabolic rate is increased, the need for all vitamins is increased and vitamin deficiency syndromes may be precipitated. Thyroid hormones are necessary for hepatic conversion of carotene to vitamin A, and the accumulation of carotene in the bloodstream (carotenemia) in hypothyroidism is responsible for the yellowish tint of the skin. Carotenemia can be distinguished from jaundice because in the former condition the sclera are not yellow.

The skin normally contains a variety of proteins combined with polysaccharides, hyaluronic acid, and chondroitin sulfuric acid. In hypothyroidism, these complexes accumulate, promoting water retention and the characteristic puffiness of the skin (myxedema). When thyroid hormones are administered, the proteins are metabolized, and diuresis continues until the myxedema is cleared.

Milk secretion is decreased in hypothyroidism and stimulated by thyroid hormones, a fact sometimes put to practical use in the dairy industry. Thyroid hormones do not stimulate the metabolism of the uterus but are essential for normal menstrual cycles and fertility.

EFFECTS ON THE CARDIOVASCULAR SYSTEM

Large doses of thyroid hormones cause enough extra heat production to lead to a slight rise in body temperatures (Chapter 17), which in turn activates heat-dissipating mechanisms. Peripheral resistance decreases because of cutaneous vasodilation, and this increases levels of renal Na⁺ and water absorption, expanding blood volume. Cardiac output is increased by the direct action of thyroid hormones, as well as that of catecholamines, on the heart, so that pulse pressure and cardiac rate are increased and circulation time is shortened.

T₃ is not formed from T₄ in cardiac myocytes to any degree, but circulatory T₃ enters the myocytes, combines with its receptors, and enters the nucleus, where it promotes the expression of some genes and inhibits the expression of others. Those that are enhanced include the genes for α-myosin heavy chain, sarcoplasmic reticulum Ca²⁺ ATPase, β-adrenergic receptors, G-proteins, Na, K ATPase, and certain K⁺ channels. Those that are inhibited include the genes for β-myosin heavy chain, phospholamban, two types of adenylyl cyclase, T₃ nuclear receptors, and NCX, the Na⁺–Ca²⁺ exchanger. The net result is increased heart rate and force of contraction.

The two myosin heavy chain (MHC) isoforms, α-MHC and β-MHC, produced by the heart are encoded by two highly homologous genes located on the short arm of chromosome 17. Each myosin molecule consists of two heavy chains and two pairs of light chains (see Chapter 5). The myosin containing β-MHC has less ATPase activity than the myosin containing α-MHC. α-MHC predominates in the atria in adults, and its level is increased by treatment with thyroid hormone. This increases the speed of cardiac contraction. Conversely, expression of the α-MHC gene is depressed and that of the β-MHC gene is enhanced in hypothyroidism.

EFFECTS ON THE NERVOUS SYSTEM

In hypothyroidism, mentation is slow and the cerebrospinal fluid (CSF) protein level is elevated. Thyroid hormones reverse these changes, and large doses cause rapid mentation, irritability, and restlessness. Overall, cerebral blood flow and glucose and O₂ consumption by the brain are normal in adult hypothyroidism and hyperthyroidism. However, thyroid hormones enter the brain in adults and are found in gray matter in numerous different locations. In addition, astrocytes in the brain convert T₄ to T₃, and there is a sharp increase in brain D₂ activity after thyroidectomy that is reversed within 4 h by a single intravenous dose of T₃. Some of the effects of thyroid hormones on the brain are probably secondary to increased responsiveness to catecholamines, with consequent increased activation of the reticular activating system (see Chapter 14). In addition, thyroid hormones have marked effects on brain development. The parts of the central nervous system (CNS) most affected are the cerebral cortex and the basal ganglia. In addition, the cochlea is also affected. Consequently, thyroid hormone deficiency during development causes mental retardation, motor rigidity, and deaf–mutism. Deficiencies in thyroid hormone synthesis secondary to a failure of thyrocytes to transport iodide presumably also contribute to deafness in Pendred syndrome, discussed above.

Thyroid hormones also exert effects on reflexes. The reaction time of stretch reflexes (see Chapter 12) is shortened in hyperthyroidism and prolonged in hypothyroidism. Measurement of the reaction time of the ankle jerk (Achilles reflex) has attracted attention as a clinical test for evaluating thyroid function, but this reaction time is also affected by other diseases and thus is not a specific assessment of thyroid activity.

RELATION TO CATECHOLAMINES

The actions of thyroid hormones and the catecholamines norepinephrine and epinephrine are intimately interrelated. Epinephrine increases the metabolic rate, stimulates the nervous system, and produces cardiovascular effects similar to those of thyroid hormones, although the duration of these actions is brief. Norepinephrine has generally similar actions. The toxicity of the catecholamines is markedly increased in rats treated with T₄. Although plasma catecholamine levels are normal in hyperthyroidism, the cardiovascular effects, tremulousness, and sweating that are seen in the setting of excess thyroid hormones can be reduced or abolished by sympathectomy. They can also be reduced by drugs such as propranolol that block β-adrenergic receptors. Indeed, propranolol and other β-blockers are used extensively in the treatment of thyrotoxicosis and in the treatment of the severe exacerbations of hyperthyroidism called thyroid storms. However, even though β-blockers are weak inhibitors of extrathyroidal conversion of T₄ to T₃, and consequently may produce a small fall in plasma T₃, they have little effect on the other actions of thyroid hormones. Presumably, the functional synergism observed between catecholamines and thyroid hormones, particularly in pathologic settings, arises from their overlapping biologic functions as well as the ability of thyroid hormones to increase expression of catecholamine receptors and the signaling effectors to which they are linked.

EFFECTS ON SKELETAL MUSCLE

Muscle weakness occurs in most patients with hyperthyroidism (thyrotoxic myopathy), and when the hyperthyroidism is severe and prolonged, the myopathy may be severe. The muscle weakness may be due in part to increased protein catabolism. Thyroid hormones affect the expression of the MHC genes in skeletal as well as cardiac muscle (see Chapter 5). However, the effects produced are complex and their relation to the myopathy is not established. Hypothyroidism is also associated with muscle weakness, cramps, and stiffness.

EFFECTS ON CARBOHYDRATE METABOLISM

Thyroid hormones increase the rate of absorption of carbohydrates from the gastrointestinal tract, an action that is probably independent of their calorigenic action. In hyperthyroidism, therefore, the plasma glucose level rises rapidly after a carbohydrate meal, sometimes exceeding the renal threshold. However, it falls again at a rapid rate.

EFFECTS ON CHOLESTEROL METABOLISM

Thyroid hormones lower circulating cholesterol levels. The plasma cholesterol level drops before the metabolic rate rises, which indicates that this action is independent of the stimulation of O₂ consumption. The decrease in plasma cholesterol concentration is due to increased formation of low-density lipoprotein (LDL) receptors in the liver, resulting in increased hepatic removal of cholesterol from the circulation. Despite considerable effort, however, it has not been possible to produce a clinically useful thyroid hormone analog that lowers plasma cholesterol without increasing metabolism.

EFFECTS ON GROWTH

Thyroid hormones are essential for normal growth and skeletal maturation (see Chapter 21). In hypothyroid children, bone growth is slowed and epiphysial closure delayed. In the absence of thyroid hormones, growth hormone secretion is also depressed. This further impairs growth and development, since thyroid hormones normally potentiate the effect of growth hormone on tissues.

• The thyroid gland transports and fixes iodide to amino acids present in thyroglobulin to generate the thyroid hormones thyroxine (T₄) and triiodothyronine (T₃).

• Synthesis and secretion of thyroid hormones is stimulated by thyroid-stimulating hormone (TSH) from the pituitary, which in turn is released in response to thyrotropin-releasing hormone (TRH) from the hypothalamus. These releasing factors are controlled by changes in whole body status (eg, exposure to cold or stress).

• Thyroid hormones circulate in the plasma predominantly in protein-bound forms. Only the free hormones are biologically active, and both feed back to reduce secretion of TSH.

• Thyroid hormones exert their effects by entering cells and binding to thyroid receptors. The liganded forms of thyroid receptors are nuclear transcription factors that alter gene expression.

• Thyroid hormones stimulate metabolic rate, calorigenesis, cardiac function, and normal mentation, and interact synergistically with catecholamines. Thyroid hormones also play critical roles in development, particularly of the nervous system, and growth.

• Disease results with both underactivity and overactivity of the thyroid gland. Hypothyroidism is accompanied by mental and physical slowing in adults, and by mental retardation and dwarfism if it occurs in neonatal life. Overactivity of the thyroid gland, which most commonly is caused by autoantibodies that trigger secretion (Graves disease) results in body wasting, nervousness, and tachycardia.