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 to 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.
FIGURE 19–1 The human thyroid.
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).
FIGURE 19–2 Thyroid histology. The appearance of the gland when it is inactive (left) and actively secreting (right) is shown. Note the small, punched-out “reabsorption lacunae” in the colloid next to the cells in the active gland.
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).
FIGURE 19–3 Thyroid cell. Left: Normal pattern. Right: After TSH stimulation. The arrows on the right show the secretion of thyroglobulin into the colloid. On the right, endocytosis of the colloid and merging of a colloid-containing vacuole with a lysosome are also shown. The cell rests on a capillary with gaps (fenestrations) in the endothelial wall.
FORMATION & SECRETION OF THYROID HORMONES
The primary hormone secreted by the thyroid is thyroxine (T4), along with much lesser amounts of triiodothyronine (T3). T3 has much greater biological 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. RT3 is not biologically active.
FIGURE 19–4 Thyroid hormones. The numbers in the rings in the T4 formula indicate the number of positions in the molecule. RT3 is 3,3′,5′-triiodothyronine.
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/d. 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/d enter the thyroid at normal rates of thyroid hormone synthesis and secretion. The thyroid secretes 80 μg/d in the form of T3 and T4, while 40 μg/d 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/d. The total amount of I– entering the ECF is thus 500 + 40 + 60, or 600 μg/d; 20% of this I– enters the thyroid, whereas 80% is excreted in the urine.
FIGURE 19–5 Iodine metabolism. The figure shows the movement of iodide amongst various body compartments on a daily basis.
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, whose patients suffer from 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.
FIGURE 19–6 Outline of thyroid hormone biosynthesis. Iodide is transported from the plasma across the cells of the thyroid gland by both secondary active and passive transport. The iodide is converted to iodine, which reacts with tyrosine residues exposed on the surface of thyroglobulin molecules resident in the colloid. Iodination of tyrosine takes place at the apical border of the thyroid cells while the molecules are bound in peptide linkage in thyroglobulin.
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.
FIGURE 19–7 Secretion and interconversion of thyroid hormones in normal adult humans. Figures are in micrograms per day. Note that most of the T3 and RT3 are formed from T4 deiodination in the tissues and only small amounts are secreted by the thyroid. T4 is also conjugated for subsequent excretion from the body.
TRANSPORT & METABOLISM OF THYROID HORMONES
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 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.
FIGURE 19–8 Regulation of thyroid hormone synthesis. T4 is secreted by the thyroid in response to TSH. Free T4 secreted by the thyroid into the circulation is in equilibrium with T4 bound to both plasma and tissue proteins. Free T4 also feeds back to inhibit TSH secretion by the pituitary.
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 T4under 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.
TABLE 19–1 Binding of thyroid hormones to plasma proteins in normal adult humans.
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 hyper- 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 anti-convulsant 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.
TABLE 19–2 Effect of variations in the concentrations of thyroid hormone-binding proteins in the plasma on various parameters of thyroid function after equilibrium has been reached.
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 physiological 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, renal failure, myocardial infarction, and febrile states. The low-T3state 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 T4levels 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.
FIGURE 19–9 Effect of starvation on plasma levels of T4, T3, and RT3in humans. The scale for T3 and RT3 is on the left and the scale for T4 is on the right. The most pronounced effect is a reduction in T3 levels with a reciprocal rise in RT3. The changes, which conserve calories by reducing tissue metabolism, are reversed promptly by re-feeding. Similar changes occur in wasting diseases. (Reproduced with permission from Burger AG: New aspects of the peripheral action of thyroid hormones. Triangle 1983;22:175. Copyright © 1983 Sandoz Ltd., Basel, Switzerland.)
REGULATION OF THYROID SECRETION
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 fashion 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 LH, FSH, and hCG-α (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/d. 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 thyroid receptors (TR) 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 chronic 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.
The TSH receptor is a typical G protein-coupled, seven-transmembrane receptor that activates adenylyl cyclase through Gs. 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), 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.
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 (see Clinical Boxes 19–1 and 19–2).
CLINICAL BOX 19–1
Reduced Thyroid Function
The syndrome of adult hypothyroidism is generally called myxedema, although this term is also used to refer specifically to the skin changes in the syndrome. Hypothyroidism may be the end result of a number of diseases of the thyroid gland, or it may be secondary to pituitary or hypothalamic failure. In the latter two conditions, the thyroid remains able to respond to TSH. Thyroid function may be reduced by a number of conditions (Table 19–3). For example, when the dietary iodine intake falls below 50 μg/d, thyroid hormone synthesis is inadequate and secretion declines. As a result of increased TSH secretion, the thyroid hypertrophies, producing an iodine deficiency goiterthat may become very large. Such “endemic goiters” have been substantially reduced by the practice of adding iodide to table salt. Drugs may also inhibit thyroid function. Most do so either by interfering with the iodide-trapping mechanism or by blocking the organic binding of iodine. In either case, TSH secretion is stimulated by the decline in circulating thyroid hormones, and a goiter is produced. Paradoxically, another substance that inhibits thyroid function under certain conditions is iodide itself. In normal individuals, large doses of iodide act directly on the thyroid to produce a mild and transient inhibition of organic binding of iodide and hence of hormone synthesis. This inhibition is known as the Wolff–Chaikoff effect.
TABLE 19–3 Causes of congenital hypothyroidism.
In completely athyreotic adults, the BMR falls to about 40%. The hair is coarse and sparse, the skin is dry and yellowish (carotenemia), and cold is poorly tolerated. Mentation is slow, memory is poor, and in some patients there are severe mental symptoms (“myxedema madness”). Plasma cholesterol is elevated. Children who are hypothyroid from birth or before are called cretins. They are dwarfed and mentally retarded. Worldwide, congenital hypothyroidism is one of the most common causes of preventable mental retardation. The main causes are included in Table 19–3. They include not only maternal iodine deficiency and various congenital abnormalities of the fetal hypothalamo–pituitary–thyroid axis, but also maternal antithyroid antibodies that cross the placenta and damage the fetal thyroid. T4 crosses the placenta, and unless the mother is hypothyroid, growth and development are normal until birth. If treatment is started at birth, the prognosis for normal growth and development is good, and mental retardation can generally be avoided; for this reason, screening tests for congenital hypothyroidism are becoming routine. When the mother is hypothyroid as well, as in the case of iodine deficiency, the mental deficiency is more severe and less responsive to treatment after birth. It has been estimated that 20 million people in the world now have various degrees of brain damage caused by iodine deficiency in utero.
Uptake of tracer doses of radioactive iodine can be used to assess thyroid function (contrast this with the use of large doses to ablate thyroid tissue in cases of hyperthyroidism (Clinical Box 19–2).
The treatment of hypothyroidism depends on the underlying mechanisms. Iodide deficiency can be addressed by adding it to the diet, as is done routinely in developed countries with the use of iodized salt. In congenital hypothyroidism, levothyroxine—a synthetic form of the thyroid hormone T4—can be given. It is important that this take place as soon as possible after birth, with levels regularly monitored, to minimize long-term adverse effects.
CLINICAL BOX 19–2
The symptoms of an overactive thyroid gland follow logically from the actions of thyroid hormone discussed in this chapter. Thus, hyperthyroidism is characterized by nervousness; weight loss; hyperphagia; heat intolerance; increased pulse pressure; a fine tremor of the outstretched fingers; warm, soft skin; sweating; and a BMR from +10 to as high as +100. It has various causes (Table 19–4); however, the most common cause is Graves disease (Graves hyperthyroidism), which accounts for 60–80% of the cases. This is an autoimmune disease, more common in women, in which antibodies to the TSH receptor stimulate the receptor. This produces marked T4 and T3 secretion and enlargement of the thyroid gland (goiter). However, due to the feedback effects of T4 and T3, plasma TSH is low, not high. Another hallmark of Graves disease is the occurrence of swelling of tissues in the orbits, producing protrusion of the eyeballs (exophthalmos). This occurs in 50% of patients and often precedes the development of obvious hyperthyroidism. Other antithyroid antibodies are present in Graves disease, including antibodies to thyroglobulin and thyroid peroxidase. In Hashimoto thyroiditis, autoimmune antibodies and infiltrating cytotoxic T cells ultimately destroy the thyroid, but during the early stage the inflammation of the gland causes excess thyroid hormone secretion and thyrotoxicosis similar to that seen in Graves disease.
TABLE 19–4 Causes of hyperthyroidism.
Some of the symptoms of hyperthyroidism can be controlled by the thioureylenes. These are a group of compounds related to thiourea, which inhibit the iodination of monoiodotyrosine and block the coupling reaction. The two used clinically are propylthiouracil and methimazole. Iodination of tyrosine is inhibited because propylthiouracil and methimazole compete with tyrosine residues for iodine and become iodinated. In addition, propylthiouracil but not methimazole inhibits D2 deiodinase, reducing the conversion of T4 to T3 in many extrathyroidal tissues. In severe cases, hyperthyroidism can also be treated by the infusion of radioactive iodine, which accumulates in the gland and then partially destroys it. Surgery is also considered if the thyroid becomes so large that it affects swallowing and/or breathing.
EFFECTS OF THYROID HORMONES
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).
TABLE 19–5 Physiologic effects of thyroid hormones.
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 (see Clinical Box 19–3).
FIGURE 19–10 Calorigenic responses of thyroidectomized rats to subcutaneous injections of T4and T3. Note the substantially greater potency of T3. (Redrawn and reproduced with permission from Barker SB: Peripheral actions of thyroid hormones. Fed Proc 1962;21:635.)
CLINICAL BOX 19–3
Thyroid Hormone Resistance
Some mutations in the gene that codes for TRβ are associated with resistance to the effects of T3 and T4. Most commonly, there is resistance to thyroid hormones in the peripheral tissues and the anterior pituitary gland. Patients with this abnormality are usually not clinically hypothyroid, because they maintain plasma levels of T3 and T4 that are high enough to overcome the resistance, and hTRα is unaffected. However, plasma TSH is inappropriately high relative to the high circulating T3 and T4 levels and is difficult to suppress with exogenous thyroid hormone. Some patients have thyroid hormone resistance only in the pituitary. They have hypermetabolism and elevated plasma T3and T4 levels with normal, nonsuppressible levels of TSH. A few patients apparently have peripheral resistance with normal pituitary sensitivity. They have hypometabolism despite normal plasma levels of T3, T4, and TSH An interesting finding is that attention deficit hyperactivity disorder, a condition frequently diagnosed in children who are overactive and impulsive, is much more common in individuals with thyroid hormone resistance than in the general population. This suggests that hTRβ may play a special role in brain development.
Most patients remain euthyroid in this condition, even in the face of a goiter. It is important to consider thyroid hormone resistance in the differential diagnosis of Graves disease to avoid the inappropriate use of antithyroid medications or even thyroid ablation. Isolated peripheral resistance to thyroid hormones can be treated by supplying large doses of synthetic T4 exogenously. These are sufficient to overcome the resistance and increase the metabolic rate.
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 hypo-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 pathological settings, arises from their overlapping biological 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 under- 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.
For all questions, select the single best answer unless otherwise directed.
1. A 40-year-old woman comes to her primary care physician complaining of nervousness and an unexplained weight loss of 20 pounds over the past 3 months despite her impression that she is eating all the time. On physical examination, her eyes are found to be protruding, her skin is moist and warm, and her fingers have a slight tremor. Compared to a normal individual, a biopsy of her thyroid gland would most likely reveal which of the following:
A. Decreased numbers of reabsorption lacunae
B. Decreased evidence of endocytosis
C. A decrease in the cross-sectional area occupied by colloid
D. Increased levels of NIS in the basolateral membrane of thyrocytes
E. Decreased evidence of lysosomal activity
2. Which of the following is not essential for normal biosynthesis of thyroid hormones?
D. Protein synthesis
3. Increasing intracellular I– due to the action of NIS is an example of
B. Passive diffusion
C. Na+ and K+ cotransport
D. Primary active transport
E. Secondary active transport
4. The metabolic rate is least affected by an increase in the plasma level of
D. Free T4
E. Free T3
5. In which of the following conditions is it most likely that the TSH response to TRH will be reduced?
A. Hypothyroidism due to tissue resistance to thyroid hormone
B. Hypothyroidism due to disease destroying the thyroid gland
C. Hyperthyroidism due to circulating antithyroid antibodies with TSH activity
D. Hyperthyroidism due to diffuse hyperplasia of thyrotropes of the anterior pituitary
E. Iodine deficiency
6. Hypothyroidism due to disease of the thyroid gland is associated with increased plasma levels of
7. A young woman has puffy skin and a hoarse voice. Her plasma TSH concentration is low but increases markedly when she is given TRH. She probably has
A. hyperthyroidism due to a thyroid tumor.
B. hypothyroidism due to a primary abnormality in the thyroid gland.
C. hypothyroidism due to a primary abnormality in the pituitary gland.
D. hypothyroidism due to a primary abnormality in the hypothalamus.
E. hyperthyroidism due to a primary abnormality in the hypothalamus.
8. The enzyme primarily responsible for the conversion of T4 to T3 in the periphery is
A. D1 thyroid deiodinase
B. D2 thyroid deiodinase
C. D3 thyroid deiodinase
D. Thyroid peroxidase
E. None of the above
9. Which of the following would be least affected by injections of TSH?
A. Thyroidal uptake of iodine
B. Synthesis of thyroglobulin
C. Cyclic adenosine monophosphate (AMP) in thyroid cells
D. Cyclic guanosine monophosphate (GMP) in thyroid cells
E. Size of the thyroid
10. Thyroid hormone receptors bind to DNA in which of the following forms?
A. A heterodimer with the prolactin receptor
B. A heterodimer with the growth hormone receptor
C. A heterodimer with the retinoid X receptor
D. A heterodimer with the insulin receptor
E. A heterodimer with the progesterone receptor
Brent GA: Graves’ disease. N Engl J Med 2008;358:2594.
Dohan O, Carrasco N: Advances in Na+/I– symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol 2003;213:59.
Glaser B: Pendred syndrome. Pediatr Endocrinol Rev 2003;1(Suppl 2):199.
Peeters RP, van der Deure WM, Visser TJ: Genetic variation in thyroid hormone pathway genes: Polymorphisms in the TSH receptor and the iodothyronine deiodinases. Eur J Endocrinol 2006;155:655.