Medical Physiology, 3rd Edition

Action of Thyroid Hormones

Thyroid hormones act through nuclear receptors in target tissues

Thyroid hormones act on many body tissues to exert both metabolic and developmental effects. Once T4 and T3 leave the plasma, they enter the cell either by diffusing through the lipid of the cell membrane or by carrier-mediated transport (Fig. 49-5). Most, but not all, of the actions of thyroid hormones occur as thyroid hormones bind to and activate nuclear receptors (see pp. 71–72). The multitude of thyroid hormone actions is mirrored by the ubiquitous expression of thyroid hormone receptors (TRs) throughout the body's tissues. There are actually two TR genes—α (chromosome 17) and β (chromosome 3)—and at least two isoforms of TRβ. The expression of these receptor genes is tissue specific and varies with time of development. The liver expresses TRβ, whereas TRα predominates in the brain. During development, the amount of α expressed may vary 10-fold or more. Both receptors bind to DNA response elements, predominately as heterodimers in association with the retinoid X receptor (RXR), and alter the transcription of specific genes.

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FIGURE 49-5 Action of thyroid hormones on target cells. Free extracellular T4 and T3 enter the target cell via facilitated diffusion. Once T4 is inside the cell, a cytoplasmic 5′/3′-monodeiodinase converts much of the T4 to T3, so that the cytoplasmic levels of T4 and T3 are about equal. T3 or T4 activates thyroid hormone receptors—already bound to nuclear DNA at thyroid response elements in the promoter region of certain genes—and thereby regulates the transcription of these genes. Of the total thyroid hormone bound to receptor, ~90% is T3. The receptor that binds to the DNA is preferentially a heterodimer of the thyroid hormone receptor and retinoid X receptor. MCT8, monocarboxylate transporter 8.

Biologically, T3 is much more important than T4. This statement may be surprising inasmuch as the total concentration of T4 in the circulation is ~50-fold higher than that of total T3. Nevertheless, T3 has greater biological activity for three reasons. First, T4 is bound (only 0.01 to 0.02% is free) more tightly to plasma proteins than is T3 (0.50% is free). The net effect is that the amounts of free T4 and free T3 in the circulation are comparable. Second, because the target cell converts some T4—once it has entered the cell—to T3, it turns out that T4 and T3 are present at similar concentrations in the cytoplasm of target cells. Third, the TR in the nucleus has ~10-fold greater affinity for T3 than for T4, so that T3 is more potent on a molar basis. As a result, T3 is responsible for ~90% of the occupancy of TRs in the euthyroid state. imageN49-3

N49-3

Sick Euthyroid Syndrome

Contributed by Eugene Barrett

Many hospitalized patients who are extremely ill exhibit abnormal results on thyroid function tests. However, the thyroid activity of most of these patients is actually appropriate and needs no correction. Many of these patients are in an intensive care unit (ICU) setting, and it is extremely important to distinguish true thyroid disease from this so-called sick euthyroid syndrome.

Sick euthyroid syndrome can take many forms, but the most common is a low or lower-than-normal total T4 level and a low T3 level. In true hypothyroidism, the diminished levels of thyroid hormones decrease feedback inhibition on the pituitary gland and lead to increased levels of TSH (see p. 1014). In sick euthyroid syndrome, the TSH level is usually normal. Although the reasons for this situation are not completely understood, at least one explanation may lie in the distinction between type 1 deiodinase, which is found in the periphery, and type 2 deiodinase, which is present in the pituitary. In sick euthyroid syndrome, the activity of type 1 or peripheral 5′/3′ deiodinase decreases, so that there is less conversion of peripheral T4 to T3, but more conversion to rT3. As a result, peripheral T3 levels fall. However, as was described in the main text with regard to starvation, type 2 deiodinase is not affected by stress nearly as much as is type 1 deiodinase; therefore, the pituitary gland continues to sense normal levels of T3, and it responds to what it perceives as normal levels of feedback inhibition from local T3 on the production and release of TSH. However, other factors must also be involved, inasmuch as this mechanism does not adequately account for the decrease in total T4.

Patients with sick euthyroid syndrome may appear profoundly hypothyroid, exhibiting hypothermia and a sluggish sensorium, but they are not hypothyroid, and they should not receive thyroid hormone replacement. In fact, treating sick euthyroid patients with thyroid hormone yields either no improvement or a worse outcome.

When T3 or T4 binds to the TR in the nucleus, the hormone-bound receptor either activates or represses the transcription of specific genes. As discussed above, TR preferentially binds to DNA as a heterodimer of TR and RXR (see Table 3-6). TR belongs to the superfamily of nuclear receptors that may contain domains A through F (see Fig. 3-14). Three regions are especially important for TR: (1) The amino-terminal A/B region contains the first of two transactivation domains, which are responsible for transducing receptor binding into a conformational change in the DNA and thereby initiating transcription. (2) The middle or C region is responsible for DNA binding through two zinc fingers (see p. 82) as well as dimerization between receptors. (3) the E region, toward the carboxyl terminus, is responsible for binding the ligand (T3 or T4), and also for dimerization.

Thyroid hormones can also act by nongenomic pathways

In addition to binding to receptors in the nucleus, T4 and T3 bind to sites in the cytosol, microsomes, and mitochondria. This observation has raised the issue of whether thyroid hormones exert actions through mechanisms not involving transcriptional regulation. Nongenomic actions of thyroid hormones have been observed in several tissues, including heart, muscle, fat, and pituitary. Thyroid hormones can act via nongenomic pathways to enhance mitochondrial oxidative phosphorylation—or at least energy expenditure as measured by O2 consumption. Nongenomic targets of thyroid hormones include ion channels, second messengers, and protein kinases. It is less clear whether these actions occur via TRα or TRβ—similar to the nongenomic actions of estrogens, which involve the estradiol receptor (see p. 989)—or whether other high-affinity thyroid-binding proteins are involved.

Thyroid hormones increase basal metabolic rate by stimulating futile cycles of catabolism and anabolism

Investigators have long observed that excess thyroid hormone raises the basal metabolic rate (BMR) as measured by either heat production (direct calorimetry) or O2 consumption (indirect calorimetry). Conversely, thyroid hormone deficiency is accompanied by a decrease in BMR. Figure 49-6 illustrates the effect of thyroid hormone levels on BMR, and Table 49-1 summarizes the effect of the thyroid hormones on several parameters. Thyroid hormones increase the BMR by stimulating both catabolic and anabolic reactions in pathways affecting fats, carbohydrates, and proteins.

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FIGURE 49-6 Effect of thyroid hormone on BMR. This graph shows the dependence of BMR on the daily rate of thyroid hormone secretion (T4 and T3). We use the secretion rate because it is difficult to know whether to use free T4 or free T3. Thus, the secretion rate is a crude measure of effective thyroid hormone levels. (Data from Guyton AC, Hall JE: Textbook of Medical Physiology, 9th ed. Philadelphia, WB Saunders, 1996.)

TABLE 49-1

Physiological Effects of the Thyroid Hormones (T3 and T4)

PARAMETER

LOW LEVEL OF THYROID HORMONES (HYPOTHYROID)

HIGH LEVEL OF THYROID HORMONES (HYPERTHYROID)

Basal metabolic rate

Carbohydrate metabolism

↓ Gluconeogenesis
↓ Glycogenolysis
Normal serum [glucose]

↑ Gluconeogenesis
↑ Glycogenolysis
Normal serum [glucose]

Protein metabolism

↓ Synthesis
↓ Proteolysis

↑ Synthesis
↑ Proteolysis
Muscle wasting

Lipid metabolism

↓ Lipogenesis
↓ Lipolysis
↑ Serum [cholesterol]

↑ Lipogenesis
↑ Lipolysis
↓ Serum [cholesterol]

Thermogenesis

Autonomic nervous system

Normal levels of serum catecholamines

↑ Expression of β adrenoceptors (increased sensitivity to catecholamines, which remain at normal levels)

Carbohydrate Metabolism

Thyroid hormones raise the rate of hepatic glucose production, principally by increasing hepatic gluconeogenic activity (see p. 1176). This effect generally does not result in increases in plasma [glucose], provided the pancreas responds by augmenting insulin secretion. Thyroid hormones also enhance the availability of the starting materials required for increased gluconeogenic activity (i.e., amino acids and glycerol), and they specifically induce the expression of several key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase, pyruvate carboxylase, and glucose 6-phosphatase.

Protein Metabolism

The amino acids required for increased hepatic gluconeogenesis stimulated by thyroid hormones come from increased proteolysis, predominantly in muscle. Thyroid hormones also increase protein synthesis. Because the increases in protein degradation usually outweigh the increases in synthesis, a net loss of muscle protein occurs. The catabolic effect is exaggerated when T3 is present in great excess, so that muscle wasting and weakness, as well as increased nitrogen loss in the urine as urea (see pp. 770–772 and 965), can be prominent features of clinical thyrotoxicosis (hyperthyroidism).

Lipid Metabolism

Thyroid hormones increase the degradation of stored triacylglycerols in adipose tissue, releasing fatty acids (FAs) and glycerol. The FAs provide fuel for the liver to support the energy demand of gluconeogenesis, and the glycerol provides some of the starting material for gluconeogenesis. Thyroid hormones not only increase lipolysis but also enhance lipogenesis. Indeed, modest amounts of thyroid hormones are needed for the normal synthesis of FAs by liver. Very high levels of T3 shift the balance in favor of lipolysis, with resulting generalized fat mobilization and loss of body fat stores.

By accelerating the rates of glucose production, protein synthesis and degradation, as well as lipogenesis and lipolysis, the thyroid hormones stimulate energy consumption. Therefore, to the extent that thyroid hormones stimulate both synthesis and degradation, they promote futile cycles that contribute significantly to the increased O2 consumption seen in thyrotoxicosis (hyperthyroidism).

How, at the molecular level, thyroid hormones affect the BMR in states of both spontaneous and experimentally induced thyroid hormone excess or deficiency has been a difficult question to answer. The changes in metabolic rate do not appear to be determined by changes in the expression of a single gene. Several specific examples of the effects of thyroid hormones on target tissues serve to illustrate their general mechanism of action.

Na-K Pump Activity

In muscle, liver, and kidney, thyroid hormone–induced increases in oxygen consumption are paralleled by increases in the activity of the Na-K pump in the plasma membrane (see pp. 115–117). This increase in transport is the result, at least in part, of an increase in the synthesis of new transporter units that are inserted into the plasma membrane. At least in some tissues, the blockade of the increases in Na-K pump activity with ouabain also blocks the increase in O2 consumption. T3 stimulates the transcription of the genes for both the α and β subunits of the Na-K pump. In addition, T3 increases translation by stabilizing the mRNA that encodes the Na-K pump. Increases in pump activity consume additional ATP, which results in increased O2 consumption and heat generation. Inasmuch as states of thyroid hormone excess are not accompanied by any noticeable derangement of plasma electrolyte levels, presumably the increase in Na-K pump activity is compensated in some manner by a leak of Na+ and K+, although such pathways have not yet been defined. Overall, the increased activity of the Na-K pump (with an accompanying cation leak) would result in a futile cycle in which energy was consumed without useful work.

Thermogenesis

In rodents, thyroid hormones may affect metabolic rate and thermogenesis through another futile cycle mechanism. Brown fat in these animals expresses a mitochondrial uncoupling protein (UCP), or thermogenin, that dissociates oxidative phosphorylation from ATP generation. Thus, mitochondria consume O2 and produce heat without generating ATP. Both T3 and β-adrenergic stimulation (acting through the β3 receptor) enhance respiration in brown adipose tissue by stimulating this uncoupling mechanism. We discuss thermogenin—and the vital role it plays in helping to keep newborn humans warm—on page 1166.

Thyroid hormones also increase the BMR by increasing the thermogenic effects of other processes. An example is the effect of adrenergic stimulation on thermogenesis, discussed above. In humans, plasma concentrations of catecholamines are normal in states of both excess and deficient T3 and T4. However, excess thyroid hormone raises the sensitivity of tissues to the action of adrenergic hormones. In heart, skeletal muscle, and adipose tissue, this effect is the result, at least in part, of increased expression of β-adrenergic receptors by these tissues. In patients who are acutely thyrotoxic, treatment with β-receptor antagonists is one of the first priorities. This treatment blunts the hypersympathetic state induced by the excess of thyroid hormones. Thyroid hormones may also exert postreceptor effects that enhance adrenergic tone. In the heart, thyroid hormones also regulate the expression of specific forms of myosin heavy chain. Specifically, in rodents, thyroid hormone increases the expression of the myosin α chain, thereby favoring the α/α isoform of myosin heavy chain (see Table 9-1). This isoform is associated with greater activity of both actin and Ca2+-activated ATPase, faster fiber shortening, and greater contractility.

Thyroid hormones are essential for normal growth and development

In amphibians, thyroid hormone regulates the process of metamorphosis. Removing the thyroid gland from tadpoles causes development to arrest at the tadpole stage. Early administration of excess thyroid hormone can initiate premature metamorphosis. Iodothyronines are present even farther down the phylogenetic tree, at least as far as primitive chordates, although these animals lack a thyroid gland per se. However, the biological actions of iodothyronines in many species are not known.

Thyroid hormones are essential for normal human development as well, as starkly illustrated by the unfortunate condition of cretinism in regions of endemic iodine deficiency. Cretinism is characterized by profound mental retardation, short stature, delay in motor development, coarse hair, and a protuberant abdomen. Correction of iodine deficiency has essentially eliminated endemic cretinism in developed nations. Sporadic cases continue to occur, however, as a result of congenital defects in thyroid hormone synthesis. If hypothyroidism (Box 49-3) is recognized and corrected within 7 to 14 days after birth, development—including mental development—can proceed almost normally. Once the clinical signs of congenital hypothyroidism become apparent, the developmental abnormalities in the CNS are irreversible. For this reason, all U.S. states and territories conduct laboratory screening of newborns for hypothyroidism. This screening has shown that the overall rate of congenital hypothyroidism is ~0.3% and varies considerably across racial and ethnic groups, being lower in African Americans (~0.1%) and higher in Hispanic infants (~0.6%).

Box 49-3

Hypothyroidism

Hypothyroidism is one of the most common of all endocrine illnesses, affecting between 1% and 2% of all adults at some time in their lives. Women are much more commonly affected than men. Although hypothyroidism has several causes, the most common cause worldwide is iodine deficiency. In the United States, by far the most common cause is an autoimmune disorder called Hashimoto thyroiditis. Like Graves disease, Hashimoto thyroiditis is caused by an abnormal immune response that includes the production of antithyroid antibodies—in this case, antibodies against the thyroid follicular cells, microsomes, and TSH receptors. Unlike in Graves disease, the antibodies in Hashimoto thyroiditis are not stimulatory, but rather are part of an immune process that blocks and destroys thyroid function. The titers of these autoantibodies can reach colossal proportions.

Typically, hypothyroidism in Hashimoto thyroiditis is an insidious process that develops slowly; indeed, many patients are diagnosed long before striking clinical manifestations are apparent when routine blood tests reveal an elevated TSH level despite normal levels of T3 and T4. These individuals, although not yet clinically hypothyroid, are sometimes treated with thyroid hormone replacement, so the clinical manifestations of hypothyroidism are never given a chance to develop.

In patients in whom the disease does evolve, the classical presentation consists of painless goiter, skin changes, peripheral edema, constipation, headache, joint aches, fatigue, and, in women, anovulation. The TSH level should be checked in any female patient with secondary amenorrhea. A subset of these Hashimoto thyroiditis patients may also develop other autoimmune endocrine deficiency disorders. Those with multiple endocrine deficiency type 1 have insufficient production of parathyroid, adrenal, and thyroid hormones. Those with multiple endocrine deficiency type 2 have insufficiencies in pancreatic islet β-cell (i.e., insulin), adrenal, and thyroid hormones. Other nonendocrine autoimmune diseases (e.g., pernicious anemia, myasthenia gravis) also are associated with autoimmune thyroid disease.

Like patients with hyperthyroidism, who may be threatened by thyroid storm, those with hypothyroidism have their own severe, life-threatening variant, in this case called myxedema coma. This malady is quite rare and occurs most commonly in elderly patients with established hypothyroidism. Hypothermia and coma evolve slowly in these patients, and the usual causes are failure to take prescribed thyroid hormone replacement drugs, cold exposure, sepsis, heart failure, and alcohol abuse.

Typically overshadowed by the impaired cognitive development that occurs in cretinism is the dwarfism that results from the effects of thyroid hormone deficiency on human growth (Fig. 49-7). In children with normal thyroid function at birth, development of hypothyroidism at any time before the fusion of the epiphyses of the long bones leads to growth retardation or arrest. Much of the loss in height that occurs can be recovered after thyroid hormone treatment is begun, a phenomenon called catch-up growth. If the diagnosis and treatment of hypothyroidism are delayed, loss of potential growth may occur, as indicated in Figure 49-7. However, as noted above, mental development does not catch up unless the treatment is begun within 7 to 14 days of birth. In general, the longer the duration of congenital hypothyroidism, the more profound is the mental retardation. In rodents, thyroid hormone regulates the induction of expression of several neural proteins, including myelin basic protein (MBP; see Table 11-4). How deficiencies in these proteins result in the generalized cortical atrophy seen in human infantile hypothyroidism is not clear.

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FIGURE 49-7 Effect of thyroid hormone on growth and development. The graph shows developmental age—that is, the age that the child appears to be based on height, bone radiography, and mental function—versus chronological age. For a normal child, the relationship is the straight line (red), for which developmental and chronological age are identical. The three green curves are growth curves for a child with thyroid hormone deficiency. Notice that at age 4.5 years, before initiation of therapy, height age, bone age, and mental age are all substantially below normal. Initiating replacement therapy with thyroid hormone at age 4.5 causes a rapid increase in both height age and bone age (“catch-up”) but has no effect on mental age, which remains infantile. Treatment can help mental development only if the therapy is begun within a few days of birth. (Data from Wilkins L: The Diagnosis and Treatment of Endocrine Disorders of Childhood and Adolescence. Springfield, IL, Charles C Thomas, 1965.)

The growth curve (i.e., a plot of the child's height and weight versus age) can provide a particularly sensitive early indicator of hypothyroidism in children who develop hypothyroidism after the neonatal period. An overactive thyroid is much less a problem than is an underactive thyroid with regard to its effect on growth; other signs and symptoms of an overactive thyroid predominate.

Cellular explanations of the effects of thyroid hormones on human development are incomplete. In rats, thyroid hormone induces the secretion of pituitary growth hormone (GH); thus, the growth retardation in thyroid-deficient rats may be partly the result of decreased GH secretion. However, in humans, who have no thyroid hormone response element in the promoter region of the GH gene, plasma [GH] is normal in hypothyroidism. Thus, the growth failure of hypothyroid human infants is not as readily explained. In humans, changes in the growth of long bones are more or less characteristic of thyroid hormone deficiency. These changes include a delay in formation of centers of ossification at the growth plate, followed by the appearance of several ossification centers, which eventually merge. Short stature in human juvenile or infantile hypothyroidism may be in part related to these abnormalities of cartilage growth and development as well as to resistance to the normal action of GH to promote growth.