Thyroid hormone synthesis and physiology

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Thyroid hormone synthesis and physiology

Author Douglas S Ross, MD Section Editor David S Cooper, MD Deputy Editor Kathryn A Martin, MD

Last literature review version 17.1: January 2009 | This topic last updated: September 16, 2008 (More) INTRODUCTION Thyroid hormones are critical determinants of brain and somatic development in infants and of metabolic activity in adults; they also affect the function of virtually every organ system. Thyroid hormones must be constantly available to perform these functions. To maintain their availability there are large stores of thyroid hormone in the circulation and in the thyroid gland. Furthermore, thyroid hormone biosynthesis and secretion are maintained within narrow limits by a regulatory mechanism that is very sensitive to small changes in circulating hormone concentrations. The processes of thyroid hormone synthesis, transport, and metabolism, and the regulation of thyroid secretion will be reviewed here. The actions of thyroid hormone are discussed elsewhere. ( See "Thyroid hormone action"). ANATOMY The thyroid gland weighs 10 to 20 grams in normal adults in the United States [ 1] . Thyroid volume measured by ultrasonography is slightly greater in men than women, increases with age and body weight, and decreases with increasing iodine intake [ 2] . Microscopically, the thyroid is composed of spherical follicles, each composed of a single layer of follicular cells surrounding a lumen filled with colloid (mostly thyroglobulin). When stimulated, the follicular cells become columnar and the lumen is depleted of colloid; when suppressed, the follicular cells become flat and colloid accumulates in the lumen. THYROID HORMONE BIOSYNTHESIS There are two biologically active thyroid hormones: thyroxine (T4) and 3,5,3'-triiodothyronine (T3) ( show figure 1). They are composed of a phenyl ring attached via an ether linkage to a tyrosine molecule. Both have two iodine atoms on their tyrosine (inner) ring. They differ in that T4 has two iodine atoms on its phenyl (outer) ring, whereas T3 has only one. The compound formed if an iodine atom is removed from the inner ring of T4 is 3,3',5'-triiodothyronine (reverse T3, rT3), which has no biological activity. T4 is solely a product of the thyroid gland, whereas T3 is a product of the thyroid and of many other tissues, in which it is produced by deiodination of T4. The thyroid gland contains

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large quantities of T4 and T3 incorporated in thyroglobulin, the protein within which the hormones are both synthesized and stored. Being stored in this way, T4 and T3 can be secreted more quickly than if they had to be synthesized. Iodine economy Iodine is essential for normal thyroid function, and it can be obtained only by consumption of foods that contain it or to which it is added.
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Foods rich in iodine include seafood, seaweed, kelp, dairy products, and some vegetables. Sea salt contains some iodine, and iodized salt is widely available (iodized salt in the US contains 45 to 80 mcg/g). Salt iodination is legally mandated in many countries (although not in the US). ( See "Iodide and thyroid function").

Dietary iodine is absorbed as iodide and rapidly distributed in the extracellular fluid, which also contains iodide released from the thyroid and by extrathyroidal deiodination of the iodothyronines. Iodide leaves this pool by transport into the thyroid and excretion into the urine.

The recommended daily iodine intake (Food and Nutrition Council, Institute of Medicine) is: infants 0 to 6 months, 110 mcg; infants 7 to 12 months, 130 mcg; children 1 to 8 years, 90 mcg; children 9 to 13 years, 120 mcg; adolescents and adults, 150 mcg; pregnant women, 220 mcg; lactating women, 290 mcg.

Iodine deficiency is defined by urinary iodine excretion, as follows: mild iodine deficiency, 50 to 99 mcg/L; moderate iodine deficiency, 20 to 49 mcg/L, and severe iodine deficiency, <20 mcg/L (urinary values are approximately 70 to 80 percent of intake). Severe iodine deficiency in fetuses and infants results in severe mental and growth retardation, and even mild iodine deficiency is associated with thyroid enlargement and learning disabilities in children. ( See "Iodine deficiency disorders").

Thyroid hormones are synthesized in the thyroid gland via the following steps ( show figure 2) [ 3] : Thyroid iodide transport Iodide is transported into thyroid follicular cells against a chemical and electrical gradient. Iodide transport is linked to transport of sodium, is energydependent and saturable, and requires oxidative metabolism. The sodium iodine transporter is an intrinsic transmembrane protein located on the basolateral membrane of the thyroid follicular cells [ 4] . Other ions such as perchlorate and pertechnetate also are transported into the thyroid by the same mechanism, and therefore are competitive inhibitors of iodide transport. Tyrosyl iodination In thyroid follicular cells, iodide rapidly diffuses to the apical surface of the cells, where it is transported by pendrin, a membrane iodide-chloride transporter, to exocytotic vesicles fused with the apical cell membrane [ 4] . In these vesicles the iodide is rapidly oxidized and covalently bound (organified) to a few of the tyrosyl residues of
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thyroglobulin. The oxidation of iodide is catalyzed by thyroid peroxidase in a reaction that requires hydrogen peroxide. This enzyme catalyzes iodination of about 10 percent of the tyrosine residues of thyroglobulin. Coupling of iodotyrosyl residues of thyroglobulin T4 is formed by coupling of two diiodotyrosine residues and T3 by coupling of one monoiodotyrosine and one diiodotyrosine within a thyroglobulin molecule. These reactions also are catalyzed by thyroid peroxidase. Thyroglobulin synthesis Thyroglobulin is a 660 kilodalton (kd) glycoprotein composed of two identical noncovalently linked subunits. It is found mostly in the lumen of thyroid follicles [ 5] . It is synthesized and glycosylated in the rough endoplasmic reticulum, and then incorporated into exocytotic vesicles that fuse with the apical cell membrane. Only then are tyrosine residues iodinated and coupled to form T4 and T3. The coupling process is not random. T4 and T3 are formed in regions of the thyroglobulin molecule with unique amino-acid sequences [ 6] . Normal thyroglobulin contains about six molecules of monoiodotyrosine, four of diiodotyrosine, two of T4, and 0.2 of T3 per molecule. Endocytosis of colloid and hormone release To liberate T4 and T3, thyroglobulin is resorbed into the thyroid follicular cells in the form of colloid droplets. The droplets fuse with lysosomes to form phagolysosomes, in which the thyroglobulin is hydrolyzed to T4, T3, and its other constituent amino acids, and some T4 is converted to T3. The hormones are then secreted into the extracellular fluid and enter the circulation. Recycling of iodide The iodotyrosines liberated from thyroglobulin are deiodinated by iodotyrosine deiodinase. Most of the iodide is then recycled for thyroid hormone synthesis. Homozygous mutations in DEHAL1, the gene that encodes iodotyrosine deiodinase [ 7] , results in iodotyrosine deiodinase deficiency with hereditary, and sometimes, severe hypothyroidism and goiter [ 8] . ( See "Clinical features and detection of congenital hypothyroidism", section on Disorders of thyroid hormone synthesis and secretion). Thyroglobulin secretion About 100 g of thyroglobulin is released from the thyroid each day. This is a tiny fraction of the 25 mg that must be hydrolyzed to yield the 100 g (130 nmoles) of T4 that is secreted each day [ 6] . Extrathyroidal T3 production Approximately 80 percent of the T3 produced is formed by 5'-deiodination (outer-ring deiodination) of T4 in extrathyroidal tissue. This reaction is catalyzed by two T4-5'-deiodinases (type I and type II), which are, respectively, plasma membrane and microsomal enzymes that require reduced sulfhydryl groups as a cofactor. The liver and kidney contain abundant deiodinase activity [ 9,10] . These organs are the major sources of serum T3, but some T3 is produced in most if not all tissues. The two types of T4-5'-deiodinase (types I and II) are distinguished by their location, biochemical properties, and responses to physiologic stimuli [ 9] .
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Type I T4-5'-deiodinase is the predominant deiodinating enzyme in the liver, kidney, and thyroid. It has a high Km for T4, is propylthiouracil (PTU)-sensitive, and deiodinates in the following order: rT3>T4>T3.

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Type II T4-5'-deiodinase is the predominant deiodinating enzyme in muscle, brain, pituitary, skin, and placenta. It has a low Km for T4, is not inhibited by PTU, and deiodinates T4>rT3.

Overall, in normal subjects, about 65 percent of the extrathyroidally produced T3 in serum is probably contributed by type II deiodinase and 35 percent by type I deiodinase. The proportion contributed by the type II enzyme is higher in hypothyroidism and lower in hyperthyroidism [ 11] . Identification of polymorphisms in the deiodinase genes may ultimately prove to have clinical importance. For example, a single nucleotide polymorphism in the type I deiodinase (rs2235544) appears to increase deiodinase function, resulting in higher ratios of free T3/free T4 in patients, including those taking levothyroxine [ 12] . Reverse T3 is produced at extrathyroidal sites by 5-deiodination (inner ring deiodination) of T4 (type III T4-5-deiodinase). This enzyme is widely distributed throughout the body, and its properties are very similar to those of type I T4-5'-deiodinase. THYROID HORMONE METABOLISM There are major differences in the production and metabolism of T4 and T3, both quantitatively and qualitatively: Thyroxine The production rate of T4 is 80 to 100 g (100 to 130 nmoles) per day, all of which is produced in the thyroid [ 13] . The extrathyroidal pool of T4 contains 800 to 1,000 g (1000 to 1300 nmoles), most of which is extracellular. T4 is degraded at a rate of about 10 percent per day. Approximately 80 percent is deiodinated, 40 percent to form T3 and 40 percent to form rT3. The remaining 20 percent is conjugated with glucuronide and sulfate, deaminated and decarboxylated to form tetraiodothyroacetic acid (tetrac), or cleaved between the two rings [ 13] . Deiodination of T4 to T3 leads to increased biologic activity, but the other metabolites of T4 are biologically inactive. The conversion of T4 to T3 in extrathyroidal tissues is regulated (see below), so that production of T3 may change independently of changes in pituitary-thyroid function. Triiodothyronine Most T3 (80 percent) is produced by extrathyroidal deiodination of T4 and the rest by the thyroid [ 13] . The total production rate is 30 to 40 g (45 to 60 nmoles) per day. The extrathyroidal T3 pool contains about 50 g (75 nmoles), most of which is intracellular. T3 is degraded, mostly by deiodination, much more rapidly than T4 (about 75 percent per day). Reverse triiodothyronine The production rate of rT3 is 30 to 40 g (45 to 60 nmoles) daily, nearly all by extrathyroidal deiodination of T4 [ 13] . rT3 is degraded even more rapidly than is T3, mostly by deiodination. SERUM BINDING PROTEINS More than 99.95 percent of the T4 and 99.5 percent of the T3 in serum are bound to several serum proteins, thyroxine-binding globulin (TBG), transthyretin (TTR, formerly called thyroxine-binding prealbumin [TBPA]), albumin, and
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lipoproteins ( show figure 3) [ 14,15] .

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For T4, approximately 75 percent is bound to TBG, 10 percent to TTR, 12 percent to albumin and 3 percent to lipoproteins. Approximately 0.02 percent, or 2 ng/dL (25 pmol/L), of the T4 in serum is free.

For T3, approximately 80 percent is bound to TBG, 5 percent to TTR, and 15 percent to albumin and lipoproteins. Approximately 0.5 percent, or 0.4 ng/dL (6 pmol/L), is free.

Because nearly all of the T4 and T3 in serum is bound, changes in the serum concentrations of binding proteins, especially TBG, have a large effect on serum total T4 and T3 concentrations and the fractional metabolism of T4 and T3. They do not, however, alter free hormone concentrations or the absolute rates of metabolism of T4 and T3. ( See "Euthyroid hyperthyroxinemia and hypothyroxinemia"). General functions It is the serum free T4 and T3 concentrations that determine the hormones' biological activity. The binding proteins serve to maintain the serum free T4 and T3 concentrations within narrow limits, yet ensure that T4 and T3 are immediately and continuously available to tissues. These proteins, therefore, have both storage and buffer functions. The storage function also facilitates uniform distribution of T4 and T3 within tissues, particularly large solid organs [ 16] . In the longer term, if thyroid secretion ceases, the T4 stored in serum serves to delay the onset of hypothyroidism. In contrast, the supply would be exhausted within hours if only free T4 were available. The binding proteins also protect tissues from sudden increases in thyroid secretion or extrathyroidal T3 production. Thyroxine-binding globulin TBG is a 54-kd glycoprotein synthesized in the liver that has one binding site for T4. The affinity of TBG for T4 is very high; that for T3 is lower [ 14,15] . The serum TBG concentration in normal subjects is about 1.5 mg/dL (0.27 mol/L), an amount capable of binding about 20 g of T4 (26 nmoles). Only about one-third of the TBG in serum normally contains T4. Transthyretin TTR is a 55-kd tetrameric protein composed of four identical subunits that is synthesized in the liver. Each TTR molecule has two T4 binding sites; however, occupation of one site decreases the affinity of the second site for T4. The affinity of TTR for T4 (and T3) is less than that of TBG [ 14,15] . The serum TTR concentration is about 25 mg/dL (4.6 mol/ L), an amount that can bind up to 200 g of T4 (260 nmoles). Albumin Albumin has one strong and several weaker binding sites for T4. There are four T4-binding albumin isoforms, with varying affinity for T4 and T3 [ 14,15] . Because only about 12 percent of the T4 in serum is bound to albumin, changes in serum albumin concentrations have little effect on serum T4 concentrations. Lipoproteins Lipoproteins, primarily the apoprotein A-I component of high-density lipoproteins, bind a small amount of the T4 and T3 in serum [ 14] .

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CELLULAR HORMONE ENTRY AND BINDING Serum free T4 and T3 are available for cellular uptake at any instant in time. In addition, T4 and T3 dissociate from the binding proteins so rapidly that more free T4 and T3 can become available almost instantaneously. T4 and T3 enter the cells of most organs by carrier-mediated transport and perhaps also by diffusion [ 17] . T3 is also available to cells because it is produced from T4 within them. Some of the locally produced T3 must leave the cells, as evidenced by the observation that serum free (and total) T3 concentrations are normal in hypothyroid patients taking T4 in doses that raise their serum T4 concentrations to normal. However, some of the T3 does not leave, and local production of T3 provides much of the T3 that is bound to T3-nuclear receptors in many tissues. Overall, approximately 90 percent of the extrathyroidal T3 pool of 50 g (75 nmoles) is intracellular. The fraction of T3 that is produced locally from T4 and the contribution of locally produced T3 to the amount of T3 bound to its receptors vary substantially from tissue to tissue. In rats, as an example, locally produced T3 accounts for about 20 percent of the nuclear T3 in the liver, 50 percent in the pituitary, 80 percent in the cerebral cortex, and less than 10 percent in other tissues [ 18] . T3-nuclear receptors Nuclear receptors mediate most if not all of the physiologic actions of thyroid hormone [ 19] . Cytosolic T3 diffuses or is transported into nuclei, and then binds to the chromatin-localized receptors. Some characteristics of the receptors are:
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Affinity for T4 and T3 The nuclear receptors bind T3 much more avidly than T4, and in vivo virtually all of the nuclear-bound hormone is T3. T4 is therefore largely a prohormone, with little if any intrinsic biologic activity.

Types of receptors There are two T3-nuclear receptors, alpha and beta, both of which are linear proteins ( show figure 4). The mRNAs for each receptor can be spliced in several ways, so that there are at least three forms of alpha receptors and two forms of beta receptors. The receptors differ in the structure of their amino- and carboxyl-terminal regions, but the DNA- and T3-binding regions are highly conserved, and each receptor binds to DNA in the absence of T3.

Tissue distribution of the receptors Beta-1 and beta-2 receptors are concentrated, respectively, in brain, heart, liver, and kidney and in pituitary and hypothalamic tissue [ 19] .

Variability in tissue action There is a variable tissue response to occupation of the nuclear receptors. In the pituitary and heart, there is a linear correlation between increasing occupancy of nuclear sites by T3 and the response, while in other tissues increasing receptor occupancy results in nonlinear, amplified responses. As an example of the latter, an increase in T3-receptor occupancy from 50 to 100 percent in the liver

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results in a 10-fold increase in the rate of synthesis of some enzymes. These differences can be explained by the diversity of the T3-nuclear receptors, the variations in their distribution among different tissues, the fact that receptors containing T3 and not containing T3 are biologically active, and variations in the tissue content of other transcription-regulating factors. Those tissues most responsive to T3, such as the pituitary and liver, contain more T3-nuclear receptors than do less responsive tissues, such as the spleen and testes. Furthermore, T3 regulates the production of the mRNAs for the different forms of the nuclear receptor in some tissues. In animals, hepatic T3-nuclear receptor content is reduced by starvation, diabetes, uremia, and partial hepatectomy [ 20,21] . Such changes, if they occurred in humans, would limit the impact of T3 in patients with nonthyroidal illness. REGULATION OF THYROID HORMONE PRODUCTION Thyroid hormone production is regulated in two ways ( show figure 5):
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Regulation of thyroidal biosynthesis and secretion of T4 and T3 by thyrotropin (thyroidstimulating hormone, TSH). The secretion of TSH is inhibited by T4 and T3 and is stimulated by thyrotropin-releasing hormone (TRH).

Regulation of extrathyroidal conversion of T4 to T3 by nutritional, hormonal, and illness-related factors. The effect of these factors differs in different tissues.

The first mechanism provides a very sensitive defense against alterations in thyroid secretion, and the second provides for rapid changes in tissue thyroid hormone availability in response to nonthyroidal illness. ( See "Thyroid function in nonthyroidal illness"). Thyrotropin TSH is a 28-kd glycoprotein that is synthesized and secreted by the thyrotrophs of the anterior pituitary. It is composed of noncovalently bound alpha and beta subunits, and contains about 15 percent carbohydrate [ 22] . The alpha subunit is the same as that of luteinizing hormone, follicle-stimulating hormone, and chorionic gonadotropin. In contrast, the beta subunit is unique and therefore determines the hormone's biologic specificity. The TSH secretion rate in normal subjects ranges from 75 to 150 mU/day (15 to 30 g/day, 0.5 to 1 nmol/day). TSH secretion is pulsatile, and serum TSH concentrations are 50 to 100 percent higher in the late evening than during the day. Thyroid hormone regulation of TSH secretion TSH secretion is inhibited by very small increases in serum T4 and T3 concentrations, and it increases in response to very small decreases in serum T4 and T3 concentrations. As a result of this very "tight" control of TSH secretion, thyroid hormone secretion is maintained within very narrow limits. An important exception is that the decrease in serum T3 concentrations that occurs in patients with nonthyroidal illness has little effect on TSH secretion, probably because serum T4 contributes more to the nuclear T3 content of the hypothalamus and pituitary than it does in many other

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tissues [ 9,18] . T4 and T3 inhibit the synthesis and release of both TSH, and TRH [ 23,24] . The inhibition of TSH synthesis is achieved primarily by inhibition of transcription of the TSH subunit genes. The rate and extent of T4- and T3-induced inhibition of TSH secretion are dependent upon the initial serum TSH concentration, the particular hormone given, and its dose. Serum TSH concentrations decline within hours after administration of single 400 to 500 g doses of T3 or T4 to hypothyroid patients; the action of lower doses is considerably slower. The maximum inhibition of TSH secretion occurs later than the peak serum T4 or T3 concentrations. In usual doses, T3 decreases serum TSH to normal in hypothyroid patients in approximately one week, but the response to T4 is slower. When given chronically, the potency of T3 as an inhibitor of TSH secretion is about three times greater than that of T4 [ 25] . Conversely, serum TSH concentrations become supranormal in 10 to 14 days after cessation of T4 or T3 therapy in patients with hypthyroidism [ 26] . Thyrotropin-releasing hormone TRH is the tripeptide pyroglutamyl-histidylprolineamide. It is distributed throughout the hypothalamus, but its content is highest in the median eminence and paraventricular nuclei [ 27] . Small amounts of TRH are found elsewhere in the central nervous system and in the pituitary gland, gastrointestinal tract, pancreatic islets, and reproductive tract. The function of TRH in these sites is unknown. TRH is synthesized as a 26-kd protein (proTRH) containing five copies of the molecule. It is formed from proTRH by the action of peptidases and then cyclization of the glutamine residue to form a pyroglutamyl residue [ 28] . The production of proTRH mRNA and its translation in the paraventricular nuclei are increased by hypothyroidism and decreased by local or systemic injection of T4 or T3 [ 24] . TRH is metabolized very rapidly, its plasma half-life being about three minutes. TRH stimulates TSH secretion via receptor-mediated activation of the phospholipase Cphosphoinositide pathway, which stimulates mobilization of calcium from intracellular storage sites. Chronic TRH stimulation also increases the synthesis and glycosylation of TSH; the latter action increases the biologic activity of TSH [ 22] . TRH secretion is probably pulsatile, accounting for pulsatile TSH secretion. Hypothyroidism ensues when TRH is absent. ( See "Disorders that cause hypothyroidism"). The physiologic role of TRH is to determine the set-point of thyroid hormone regulation of TSH secretion. In animals or humans with hypothalamic lesions, thyroidectomy results in smaller increases in TSH secretion and less T4 and T3 is needed to inhibit TSH secretion than in normal subjects or animals. Exogenous administration of TRH causes a dose-dependent increase in serum TSH concentrations in normal subjects. The response is increased in hypothyroid patients and decreased in hyperthyroid patients. Exogenous TRH administration also stimulates prolactin release in normal subjects and most patients with hyperprolactinemia, and it stimulates growth hormone secretion in normal elderly subjects and patients with acromegaly, chronic liver disease, and diabetes mellitus.

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Other factors altering TSH secretion Other factors that affect TSH secretion include somatostatin, dopamine, and glucocorticoids.
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Infusions of somatostatin and its long-acting analog octreotide reduce serum TSH concentrations, but not as much as they reduce growth hormone secretion; patients receiving long-term treatment with octreotide do not become hypothyroid [ 29] . In animals with hypothalamic lesions that reduce somatostatin content, TSH secretion is increased, suggesting that somatostatin may be a physiologically important inhibitor of TSH secretion.

Infusions of dopamine, in doses of 1 g/kg per min or more, cause a rapid decrease in serum TSH concentrations; thus, serum TSH concentrations are often low in intensive care-unit patients receiving dopamine. ( See "Drug interactions with thyroid hormones"). Conversely, serum TSH concentrations rise after the administration of dopamine antagonists such as metoclopramide. These actions are exerted on the pituitary, not the hypothalamus [ 30] . Like somatostatin, dopamine may be a physiologically important inhibitor of TSH secretion.

Glucocorticoids also inhibit TSH secretion [ 31] . They mostly decrease pulsatile TSH secretion, indicating that they inhibit TRH secretion. However, serum TSH responses to exogenous TRH are also decreased, suggesting a direct effect on the pituitary. In contrast, decreases in cortisol production result in a transient increase in serum TSH concentrations.

The overall impact of the inhibitory actions of somatostatin, dopamine, and glucocorticoids on TSH secretion is probably small. While increases in endogenous dopamine, somatostatin, or glucocorticoid secretion may transiently decrease TSH secretion, sustained increases in their production do not lead to sustained decreases in TSH secretion (and hypothyroidism). Once serum T4 and T3 concentrations fall, the ensuing stimulation of TSH secretion overcomes the inhibition. Mechanism of action of TSH TSH stimulates every step in thyroid hormone synthesis and secretion by the thyroid ( show figure 2) [ 3,32] . It also stimulates intermediary metabolism and the expression of many genes in thyroid tissue, and causes thyroid hyperplasia and hypertrophy. The actions of TSH are initiated by its binding to specific plasma membrane receptors. The receptor is an 85-kd glycoprotein with an extracellular domain of approximately 400 amino acids, seven transmembrane domains of about 250 amino acids, and an intracytoplasmic domain of about 100 amino acids [ 32] . The binding of TSH to its receptors activates adenylyl cyclase, increasing cyclic AMP formation, which then activates several protein kinases. How these steps are linked to the specific steps of thyroid hormone synthesis and secretion or to other thyroid metabolic processes is not known. TSH also stimulates phospholipase C activity in thyroid tissue, via the same receptor, thereby increasing
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phosphoinositide turnover, intracellular calcium ion concentrations, and protein kinase C activity. Other thyroid-stimulating substances Other factors that may be involved in thyroid growth (goiter formation) include insulin-like growth factor-I and epidermal growth factor. Thyroid cells produce and have receptors for these substances. Regulation of extrathyroidal T3 production The activity of the extrathyroidal T4-5'deiodinases that catalyze the conversion of T4 to T3 is altered by many factors. The activity of type I T4-5'-deiodinase, the enzyme that predominates in liver and kidney, is decreased in tissues from fetal animals and animals that are starved, hypothyroid, diabetic, uremic, or have other nonthyroidal illnesses ( show table 1) [ 9,10,18,20,33] . Propylthiouracil, glucocorticoids, beta blockers, and various iodothyronine analogues, notably rT3, also decrease the activity of this enzyme. On the other hand, type I T4-5'-deiodinase activity is increased by hyperthyroidism, glucose plus insulin, and a high caloric intake [ 34] . The biochemical mechanisms that might cause alterations in tissue T4-5'-deiodinase activity include alterations in substrate (T4) production, transport of T4 into cells, intracellular distribution of T4, enzyme activity or mass, and cofactor availability. The drugs that reduce T4-5'-deiodinase activity bind to the enzyme, whereas starvation may decrease hepatic T3 production by decreasing T4 uptake into the liver [ 35] . In other situations, alterations of enzyme mass or activity are the likely cause(s) of decreased T3 production, but the specific nutritional, hormonal, or toxic factors or cytokines that cause these changes are not known. The regulation of the type II T4-5'-deiodinase that predominates in brain, pituitary, and muscle is different ( show table 1). Its activity is increased by thyroid deficiency, little affected by nutritional deficiency and PTU, and decreased by hyperthyroidism [ 9,10,18,33,36] . Such regulation serves to reduce the impact of systemic thyroid deficiency in these tissues by increasing the availability of T3 for maintenance of neural growth and function and pituitary function. The increase in pituitary T4-5'-deiodinase activity that occurs in thyroid deficiency and the decrease that occurs with thyroid hormone excess probably do not include the thyrotrophs, because alterations in T3 production in these cells would blunt the changes in TSH secretion needed to defend against changes in thyroidal T4 and T3 secretion. Overall, these findings indicate that the production of T3 in different tissues is regulated in different ways, and that changes in thyroidal or extrathyroidal thyroid hormone production, as manifested by their circulating concentrations, are not the only, and perhaps not the major, determinants of intracellular T3 availability. Local regulation of T3 production may be particularly important in reducing the impact of thyroid deficiency in tissues such as the brain and pituitary, and this local regulation undoubtedly leads to differences in T3 content in different tissues in patients with nonthyroidal illness. ACKNOWLEDGMENT The author and UpToDate would like to acknowledge Robert D Utiger, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Subscription and License Agreement.
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REFERENCES 1. Pankow, BG, Michalak, J, McGee, MK. Adult human thyroid weight. Health Phys 1985; 49:1097. 2. Hegedus, L. Thyroid size determined by ultrasound. Influence of physiological factors and non-thyroidal disease. Dan Med Bull 1990; 37:249. 3. Kopp, P. Thyroid hormone synthesis. In: The Thyroid: Fundamental and Clinical Text, 9th ed, Braverman, LE, Utiger, RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p. 52. 4. Spitzweg, C, Heufelder, AE, Morris, JC. Thyroid iodine transport. Thyroid 2000; 10:321. 5. Arvan, P, Di Jeso, B. Thyroglobulin structure, function, and biosynthsesis. In: The Thyroid: Fundamental and Clinical Text, 9th ed, Braverman, LE, Utiger, RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p. 77. 6. Van Herle, AJ, Vassart, G, Dumont, JE. Control of thyroglobulin synthesis and secretion. N Engl J Med 1979; 301:239. 7. Moreno, JC. Identification of novel genes involved in congenital hypothyroidism using serial analysis of gene expression. Horm Res 2003; 60 Suppl 3:96. 8. Moreno, JC, Klootwijk, W, van Toor, H, et al. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med 2008; 358:1811. 9. Bianco, AC, Larsen, PR. Intracellular pathways of iodothyronine metabolism. In: The Thyroid: Fundamental and Clinical Text, 9th ed, Braverman, LE, Utiger, RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p. 109. 10. Bianco, AC, Kim, BW. Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 2006; 116:2571. 11. Maia, AL, Kim, BW, Huang, SA, et al. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 2005; 115:2524. 12. Panicker, V, Cluett, C, Shields, B, et al. A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. J Clin Endocrinol Metab 2008; 93:3075. 13. Engler, D, Burger, AG. The deiodination of the iodothyronines and of their derivatives in man. Endocr Rev 1984; 5:151. 14. Benvenga, S. Thyroid hormone transport proteins and the physiology of hormone binding. In: The Thyroid: Fundamental and Clinical Text, 9th ed, Braverman, LE, Utiger, RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p. 97. 15. Bartalena, L. Recent achievements in studies on thyroid hormone-binding proteins. Endocr Rev 1990; 11:47. 16. Mendel, CR, Weisiger, RA, Jones, AL, et al. Thyroid hormone-binding proteins in plasma facilitate uniform distribution of thyroxine within tissues: A perfused rat liver study. Endocrinology 1987; 120:1742.

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17. Hennemann, G, Docter, R, Friesema, EC, et al. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 2001; 22:451. 18. Larsen, PR, Silva, JE, Kaplan, MM. Relationships between circulating and intracellular thyroid hormones. Physiological and clinical implications. Endocr Rev 1981; 2:87. 19. Yen, PM. Genomic and nongenomic actions of thyroid hormones. In: The Thyroid: Fundamental and Clinical Text, 9th ed, Braverman, LE, Utiger, RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p. 135. 20. Lim, VS, Passo, C, Murata, Y, et al. Reduced triiodothyronine content in liver but not pituitary of the uremic rat model: Demonstration of changes compatible with thyroid hormone deficiency in liver only. Endocrinology 1984; 114:280. 21. Jolin, T. Diabetes decreases liver and kidney nuclear 3,5,3'-triiodothyronine receptors in rats. Endocrinology 1987; 120:2144. 22. Magner, JA. Thyroid-stimulating hormone: biosynthesis, cell biology, and bioactivity. Endocr Rev 1990; 11:354. 23. Shupnik, MA, Ridgway, EC, Chin, WW. Molecular biology of thyrotropin. Endocr Rev 1989; 10:459. 24. Dyess, EM, Segerson, TP, Liposits, Z, et al. Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus. Endocrinology 1988; 123:2291. 25. Sawin, CT, Hershman, JM, Chopra, IJ. The comparative effect of T4 and T3 on the TSH response to TRH in young adult men. J Clin Endocrinol Metab 1977; 44:273. 26. Leboeuf, R, Perron, P, Carpentier, AC, et al. L-T(3) preparation for whole-body scintigraphy: a randomized-controlled trial. Clin Endocrinol (Oxf) 2007; 67:839. 27. Jackson, IM. Thyrotropin-releasing hormone. N Engl J Med 1982; 306:145. 28. Wu, P, Lechan, RM, Jackson, IMD. Identification and characterization of thyrotropinreleasing hormone precursor peptides in rat brain. Endocrinology 1987; 121:108. 29. Williams, TC, Kelijman, M, Crelin, WC, et al. Differential effects of somatostatin (SRIH) and a SRIH analog, SMS 201-995, on the secretion of growth hormone and thyroidstimulating hormone in man. J Clin Endocrinol Metab 1988; 66:39. 30. Brabant, G, Prank, K, Hoang-Vu, C, et al. Hypothalamic regulation of pulsatile thyrotropin secretion. J Clin Endocrinol Metab 1991; 72:145. 31. Hollenberg, AN. Regulation of thyrotropin secretion. In: The Thyroid: Fundamental and Clinical Text, 9th ed, Braverman, LE, Utiger, RD (Eds), Lippincott Williams and Wilkins, Philadelphia 2005. p. 197. 32. Vassart, G, Dumont, JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992; 13:596. 33. Kaplan, MM, Utiger, RD. Iodothyronine metabolism in rat liver homogenates. J Clin Invest 1978; 61:459. 34. Danforth, E, Horton, ES, O'Connell, M, et al. Dietary-induced alterations in thyroid hormone metabolism during overnutrition. J Clin Invest 1979; 64:1336.

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35. Van der Heyden, JTM, Docter, R, van Toor, H, et al. Effects of caloric deprivation on thyroid hormone tissue uptake and generation of low-T3 syndrome. Am J Physiol 1986; 251:E156. 36. Silva, JE, Leonard, JL. Regulation of rat cerebrocortical and adenohypophyseal type II 5'-deiodinase by thyroxine, triiodothyronine and reverse triiodothyronine. Endocrinology 1985; 116:1627.

GRAPHICS

Structures of the thyroid hormones

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Thyroid hormone biosynthesis

Thyroid hormone synthesis includes the following steps: (1) iodide (I -) trapping by the thyroid follicular cells; (2) diffusion of iodide to the apex of the cells; (3) transport of iodide into the colloid; (4) oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid; (5) combination of two diiodotyrosine (DIT) molecules to form tetraiodothyronine (thyroxine, T4) or of monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3); (6) uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4, T3, DIT, and MIT; (7) release of T4 and T3 into the circulation; and (8) deiodination of DIT and MIT to yield tyrosine. T3 is also formed from monodeiodination of T4 in the thyroid and in peripheral tissues. Modified from Scientific American Medicine, Scientific American, New York, 1995.

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Transport and metabolism of thyroid hormones

Forms of T4 (thyroxine) and T3 (triiodothyronine) in serum and pathways of T4 and T3 production and degradation. TBG: thyroxine-binding globulin; TTR: transthyretin. Adapted from Utiger, RD. The Thyroid: Physiology, thyrotoxicosis, hypothyroidism, and the painful thyroid. In: Endocrinology and Metabolism, 3rd ed, Felig, R, Baxter, JD, Frohman, LA (Eds), McGraw-Hill, 1995.

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Thyroid hormone synthesis and physiology

Schematic representation of the structure of the T3 (triiodothyronine) nuclear receptor

The region labeled DNA is the portion of the receptor that binds to DNA, and the region labeled T3-binding is the region that binds T3. NH2 denotes the amino-terminal end of the receptor and COOH the carboxy-terminal end. Adapted from Utiger, RD. The thyroid: Physiology thyrotoxicosis, hypothyroidism, and the painful thyroid. In: Endocrinology and Metabolism, 3rd ed, Felig, R, Baxter, JD, Frohman, LA (Eds), McGraw-Hill, NY 1995.

Pathways of thyroid hormone metabolism

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Thyroid hormone synthesis and physiology

Thyrotropin-releasing hormone (TRH) increases the secretion of thyrotropin (TSH), which stimulates the synthesis and secretion of trioiodothyronine (T3) and thyroxine (T4) by the thyroid gland. T3 and T4 inhibit the secretion of TSH, both directly and indirectly by suppressing the release of TRH. T4 is converted to T3 in the liver and many other tissues by the action of T4 monodeiodinases. Some T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine. Some T4 and T3 formed in the intestine may be reabsorbed. Drug interactions may occur at any of these sites.

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Thyroid hormone synthesis and physiology

Conditions affecting thyroxine 5'-deiodinase activity Enzyme type affected* Condition

Fetus Hypothyroidism Hyperthyroidism Starvation Diabetes mellitus Uremia Propylthiouracil Amiodarone Propranolol Type 1 Decreased Decreased Increased Decreased Decreased Decreased Decreased Decreased Decreased Type 2 Decreased Increased Decreased Normal Normal Normal Normal Decreased ?

* Type 1 deiodinase predominates in the liver, kidneys, and thyroid; type 2 deiodinase in the brain, pituitary, and skin.

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