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2 The Thyroid and Disruption of Thyroid Function in Humans THYROID hormones are critical determinants of growth and development in infants and of metabolic activity in infants and adults. They affect the functions of virtually every organ system, and they must be constantly available to carry out these functions. A steady supply of thyroid hormones is provided by large reservoirs in the circulation and the thyroid gland. Thyroid hormone biosynthesis and secretion are normally maintained within narrow limits by regulatory mechanisms that are sensitive to small changes in the circulating hormone concentrations. The regulatory mecha- nisms protect against both hypothyroidism (deficient thyroid hormone production) and hyperthyroidism (excess thyroid hormone production). There are two thyroid hormones, thyroxine (T4) and triiodothyronine (T3).1 All the circulating T4 and about 20% of the T3 are produced in the thyroid gland; the remaining 80% of the T3 is produced from T4 in most tissues of the body. Through a process known as deiodination, enzymes called deiodinases remove a single iodine atom from the T4 molecule to produce the more active hormone T3. Most of the effects of thyroid hor- mones in individual cells of the body are exerted by T3, acting to regulate thyroid hormone-responsive expression of genes that code for many cellular proteins that regulate development, growth, and metabolism. Topics discussed in this chapter include the production of T4 and T3, the 1 A third hormone of thyroid origin, calcitonin, is produced by different cells within the thyroid gland. It affects calcium metabolism but has no effects on iodide metabolism or T4 or T3 production or action and is not discussed further in this report. 35
36 Health Implications of Perchlorate Ingestion regulation of thyroid hormone production, the actions of the thyroid hor- mones, the development of thyroid function during fetal life, and the effects of perchlorate when given deliberately to humans. The effects of environ- mental exposure to perchlorate are summarized in Chapter 3. ANATOMY The thyroid is a butterfly-shaped gland in the front of the neck. It weighs about 1-1.5 g at birth and 10-20 g in healthy adults in the United States. It contains millions of spherical follicles, each composed of a single layer of cells known as thyroid follicular cells surrounding a space, or lumen, filled with fluid known as colloid (Figure 2-1). Thyroid follicles are the functional units of the thyroid gland. The colloid consists mostly of thyroglobulin, a thyroid protein that serves as the framework for production of T4 and T3 and as the storage form of the two hormones. THYROID HORMONE PRODUCTION, TRANSPORT, AND ACTION T4 and T3 are the only biologically active substances that contain iodine. They are similar in that each has two six-member ringsâan inner and an outer ring (Figure 2-2)âconnected by an ether linkage. Their inner rings have two iodine atoms; T4 has two iodine atoms in its 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), which has no biologic activity. Production of Thyroxine and Triiodothyronine in the Thyroid Gland Transport of Iodide into Thyroid Cells Iodine is an intrinsic component of T4 and T3. Transfer of iodide from the circulation into the thyroid gland is therefore an essential step in the synthesis of the two hormones.2 Iodide is transported from the bloodstream 2 Iodide is the negatively charged ion of iodine and is the form of iodine that is found in foods and in the circulation in humans.
The Thyroid and Disruption of Thyroid Function in Humans 37 Thyroid follicular cells Thyroid follicle Lumen Lumen Extracellular fluid Tg NIS - - T4 I- I I Tg 2 Na + 2 Na + T3 T4 T4 Tg T3 T3 Tg Apical membrane Basolateral membrane FIGURE 2-1 Diagram of thyroid cells and a thyroid follicle, showing key steps in thyroxine (T4) and triiodothyronine (T3) synthesis and secretion. A follicle consists of a single layer of thyroid follicular cells surrounding a lumen, which is filled with thyroglobulin (Tg). Iodide (I!) and sodium (Na+) ions are transported into cells via the sodium (Na+)/iodide (I!) symporter (NIS) in the basolateral membrane of the cells. Iodide diffuses to the luminal side of the cell and is transported into the lumen of the follicle, where it is oxidized and then used to form T4 and T3 (within Tg). Tg is taken up by cells and broken down, freeing its constituent T4 and T3 molecules, which then diffuse out of the cell and into the bloodstream. into thyroid cells against a chemical and electric gradient. It diffuses rapidly across the cells and is transported into the lumen of thyroid follicles, where T4 and T3 are produced (Figure 2-1). Iodide transport into the cells is mediated by a specific protein molecule, the sodium (Na+)/iodide (I6) symporter (NIS) (Dohan et al. 2003). The symporter is also present in substantial quantities in the salivary glands, stomach, and mammary glands; the iodide that is transported into these tissues is not further metabolized, as it is in the thyroid gland, but instead is secreted unchanged into saliva, gastric juice, or milk. Very small amounts of the symporter have been found in other tissues (see the last section of this chapter and Chapter 4).
38 Health Implications of Perchlorate Ingestion I I NH2 HO O CH2 CH COOH I I T h yro x in e I- I- I I NH2 NH2 HO O CH2 CH HO O CH2 CH COOH COOH I I I I 3 ,5 ,3 â-T riio d o th yro n in e 3 ,3 â,5 â-T riio d o th yro n in e FIGURE 2-2 Structures of thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (reverse T3). Note that T3 is missing an iodine atom on its outer ring and reverse T3 is missing an iodine atom on its inner ring. T3 is most potent thyroid hormone. T4 is active only after conversion to T3, and reverse T3 has no biologic activity. The NIS is a glycoprotein composed of 643 amino acids and a small amount of carbohydrate. It is in the outer (plasma) membrane at the baso- lateral surface of the thyroid follicular cells (Figure 2-1). It is not present in the membrane at the apical surface of the cell, the part of the cell that is adjacent to the lumen of the thyroid follicle. The symporter uses the inward movement of sodium ions to transport iodide into the cells; two sodium ions are transported for each iodide ion. NIS has a very high affinity for iodide, which allows transport of iodide into the cells against a high concentration gradient. It also transports other ions with a similar shape and electric charge, such as perchlorate and thiocyanate. The affinity of NIS for those substances is higher than its affinity for iodide, so they can block iodide transport into thyroid cells, which can result in a decrease in the iodide concentration in the cells and therefore in a decrease in the availability of iodide for synthesis of T4 and T3. Among those substances, perchlorate is the best studied. It is a true competitive inhibitor of iodide transport: it blocks iodide transport through the symporter in a dose-dependent manner. Conversely, iodide blocks
The Thyroid and Disruption of Thyroid Function in Humans 39 perchlorate transport in a similar manner. Whether perchlorate itself is transported into the thyroid gland is debated (Dohan et al. 2003; Van Sande et al. 2003). Thyrotropin (thyroid-stimulating hormone, TSH) is produced by the anterior pituitary gland that stimulates all aspects of thyroid function, including the production of symporter molecules and therefore iodide transport. T4, T3, and cytokines (molecules that mediate inflammatory reactions) inhibit TSH secretion, thereby decreasing the production of symporter molecules. Iodide deficiency results in an increase in production of symporter molecules independently of TSH. A few patients have had mutations in the gene for the NIS. Because their thyroid follicular cells cannot transport iodide, they are unable to synthesize T4 or T3, and conse- quently they have hypothyroidism. Synthesis and Secretion of Thyroxine and Triiodothyronine in the Thyroid Gland After passage through the symporter into thyroid follicular cells, iodide rapidly diffuses to the apical surface of the cells (Figure 2-1). There, it is transported across the apical membrane into the lumen of the follicles by pendrin, a membrane iodide-chloride transporter. It is then rapidly oxidized and covalently bound (âorganifiedâ) to specific tyrosine residues of thyro- globulin; some tyrosine residues gain one iodine atom (forming monoiodo- tyrosine), and others gain two iodine atoms (forming diiodotyrosine). These oxidation and binding reactions are catalyzed by the enzyme thyroid peroxidase in a reaction that requires hydrogen peroxide (Taurog 2000). Thyroglobulin is a large protein that serves as the site of thyroid hor- mone synthesis. It is synthesized by the thyroid follicular cells and then carried to the follicular lumen. Within the thyroglobulin molecule, T4 is formed by the coupling of two diiodotyrosine residues, and T3 is formed by the coupling of one monoiodotyrosine residue to one diiodotyrosine residue. Those reactions also are catalyzed by thyroid peroxidase. The coupling process is not random; T4 and T3 are formed in regions of the thyroglobulin molecule that have unique amino acid sequences (Dunn and Dunn 2000). A normal thyroglobulin molecule contains about six molecules of monoiodotyrosine, four of diiodotyrosine, and two of T4 or T3. To liberate T4 and T3, thyroglobulin is taken up from the lumen of the thyroid follicles into the thyroid follicular cells (Figure 2-1). It is then broken down into T4, T3, and its constituent amino acids. The hormones are then released into the circulation.
40 Health Implications of Perchlorate Ingestion Extrathyroid Production of Thyroid Hormones About 80% of the T3 produced each day is formed by removal of one iodine atom from the outer ring of T4 (outer-ring deiodination) in tissues outside the thyroid gland, such as the liver, kidneys, muscle, and nervous system. The deiodination reaction is stimulated (catalyzed) by enzymes called deiodinases. Two deiodinasesâtype 1 and type 2âcatalyze the conversion of T4 to T3. Type 3 deiodinase catalyzes the conversion of T4 to reverse T3 and of T3 to 3,3â-diiodothyronine (inner-ring deiodination); neither reverse T3 nor 3,3â-diiodothyronine has biologic activity (Bianco et al. 2002). The three deiodinases differ in tissue distribution and regulation. Type 1 deiodinase is the predominant deiodinating enzyme in the liver, kidneys, and thyroid. Type 2 is the predominant deiodinating enzyme in the brain, pituitary gland, heart, and muscle. Type 3 is prominent in the skin, brain, uterus, and placenta. Thyroid Hormone Production Rate There are major quantitative and qualitative differences between T4 and T3 in production and metabolism. In healthy adults, the production rate of T4 is 80-100 :g per day, all of which is produced in the thyroid gland. T4 is degraded at about 10% per day, mostly by deiodination to form T3 or inactive reverse T3. The production rate of T3 is 30-40 :g per day, of which about 20% is produced in the thyroid gland and 80% by the extrathyroid deiodination of T4. T3 is degraded about 75% per day, mostly by deiodin- ation. Most or all of the biologic activity of thyroid hormones is exerted by T3, whether produced in the thyroid or from T4 in other tissues. T4 is largely a prohormone, with little, if any, intrinsic biologic activity, and its conversion to T3 in effect produces the active thyroid hormone. The conversion pro- cess in extrathyroidal tissues is regulated, so production of T3 may change independently of changes in the function of the thyroid gland itself. Transport of Thyroid Hormones in Serum The thyroid hormones circulate in the bloodstream in two forms: some as the free (unbound) hormone and most bound to protein. Some 99.97% of the T4 and 99.7% of the T3 are protein-bound. The serum proteins that
The Thyroid and Disruption of Thyroid Function in Humans 41 bind the hormones are thyroxine-binding globulin (TBG), transthyretin, albumin, and lipoproteins. TBG is the most important: it carries 75-85% of the T4 and T3 in serum. As a result of the binding of T4 and T3 to those proteins, clearance of the hormones from the circulation is slow; the serum half-life of T4 is 5-7 days, and that of T3 is about 20 hours (hr). Thus, even when release of T4 and T3 from the thyroid gland abruptly ceasesâfor example, when the thyroid gland is surgically removedâthe serum concen- trations of the two hormones fall slowly. The fall is considerably smaller and slower when T4 and T3 production is only partially reduced. The binding of T4 and T3 to the serum proteins is not a determinant of the actions of the hormones in tissues. People with no TBG (a rare disorder caused by a mutation of the gene for TBG) or with twice the normal amount (caused by pregnancy, treatment with estrogen, or a duplication of the gene for TBG) have normal thyroid function. They have, respectively, low or high serum total T4 and total T3 concentrations but normal serum free (unbound) T4 and T3 concentrations. Those findings establish that it is the serum free T4 and T3 concentrations that determine the hormonesâ biologic activity and ultimately the clinical status of people. The binding proteins maintain the serum free T4 and T3 concentrations within narrow limits and ensure not only that the hormones are continuously available to tissues but also that more free hormone can be made available almost instantly from the large amounts bound to the proteins in the serum if a sudden need arises. Because T4 and T3 bind to the proteins so well, tissues are protected from surges in T4 or T3 in the circulation. The proteins thus have both storage and buffering functions. Cellular Uptake and Actions of Thyroid Hormones in Tissues Free T4 and free T3 in serum are available for uptake into cells at any time. They are carried into cells primarily by transporter molecules in the cell membranes (Hennemann et al. 2001). There are several transporters, with different affinity for T4 and T3, and some hormone may enter cells by passive diffusion. T3 is also available to cells because it is produced from T4 in them (Figure 2-3). Some of the T3 produced in the cells returns to the circulation, and some remains in the cells. Indeed, locally produced T3 provides most of the T3 found in the nuclei of the cells in many tissues. Thus, there are two sources of T3 in cells: some enters the cells from the circulation, and
42 Health Implications of Perchlorate Ingestion Extracellular fluid Cell Nucleus of cell T4 T4 Tissue proteins Gene transcription T3 T3 T3 +R T3R mRNA Secreted proteins T3 Enzymes FIGURE 2-3 Diagram of a cell showing pathways of thyroxine (T4) and triiodo- thyronine (T3) metabolism. T4 and T3 are transported into cells, after which T4 is converted to T3 by action of deiodinases, thereby increasing the pool of T3 in the cell. Some T3 enters the nucleus of the cell, where it binds to specific T3 receptors (R). Hormone-receptor complexes then bind to DNA and alter gene transcription and therefore synthesis of many proteins, including tissue proteins, proteins that are secreted for action elsewhere, and enzymes that regulate metabolic activity. Some T3 also leaves the cell and enters the bloodstream. Source: American Heritage 2003. DNA illustration by Carlyn Iverson. Reprinted by permission of American Heritage Children's Science Dictionary, copyright 2003. some is produced in the cells by deiodination of T4. The relative contribu- tions of the two sources to the T3 that is bound to its receptors in the nuclei of cells vary substantially from tissue to tissue (Bianco et al. 2002). In cells, T3 diffuses into the nuclei, where it binds to specific nuclear receptors (Figure 2-3). The T3-receptor complexes then bind to the regula- tory regions of many different DNA molecules (genes). The interaction of the genes with the receptor-hormone complexes alters the rate at which the genes synthesize molecules of messenger RNA, and thus leads to changes in the rate of synthesis of thyroid hormone-dependent proteins (Mariash et
The Thyroid and Disruption of Thyroid Function in Humans 43 al. 2000). T3 may also have some actions at other sites of cells, such as the cell membrane, but the biologic importance of these actions is not known. Some biologic responses to T3 are stimulatory, and others inhibitory. By stimulating the production of several proteins in the heart, T3 increases heart rate and contractility. In the liver, it stimulates the synthesis of many different proteins required for growth, metabolism, and energy production. It also stimulates the production of proteins in the brain, most obviously during development. In contrast, in the pituitary gland, T3 inhibits the production of TSH, a process termed negative feedback, which ultimately leads to a decrease in hormone synthesis by the thyroid gland. REGULATION OF THYROID HORMONE PRODUCTION Thyroid hormone production is regulated in two ways: â¢ Regulation of thyroid gland synthesis and secretion of T4 and T3 by TSH. Pituitary secretion of TSH is inhibited by T4 and T3 and stimulated by a decrease in T4 and T3. TSH secretion is also stimulated by thyrotropin- releasing hormone, produced in the hypothalamus. â¢ Regulation of extrathyroid conversion of T4 to T3 by several hor- mones, including T4 and T3 themselves, and by nutritional and illness- related factors. The effect of those factors differs in different tissues; for example, starvation results in a decrease in conversion in the liver, but not in the brain. The first mechanism provides a sensitive defense against increases and especially decreases in thyroid hormone production. The second mechanism provides for rapid changes in the availability of T3 in different tissues, especially in response to illness or starvation. Thyrotropin-Releasing Hormone Thyrotropin-releasing hormone is distributed throughout the nervous system and elsewhere, where it is thought to modulate transmission of nerve impulses. Its content is highest in the hypothalamus, and the thyrotropin- releasing hormone produced in this region is an important regulator of TSH secretion and therefore of T4 and T3 production by the thyroid gland (Figure 2-4). The production and secretion of thyrotropin-releasing hormone in the
44 Health Implications of Perchlorate Ingestion Hypothalamus TRH (-) (-) (+) Pituitary (-) Gland (-) TSH T 3, T 4 (+) Thyroid T3 Gland T4 I- I- Liver and Other Organs Extrathyroid Conversion of T4 to T3 FIGURE 2-4 Diagram of the hypothalamic-pituitary-thyroid system. All thyrox- ine (T4) and some triiodothyronine (T3) are produced by the thyroid gland, and their production there is stimulated by thyroid-stimulating hormone (TSH, thyrotropin), a product of the anterior pituitary gland. Some T4 is converted to T3 in other tissues, including the pituitary gland and the hypothalamus. T3 inhibits pituitary secretion of TSH, and hypothalamic secretion of thyrotropin-releasing hormone (TRH), which stimulates TSH secretion. The interplay between T3 and TSH maintains thyroid hormone production within a narrow range. (+), stimulation; (!), inhibition. Sources: Liver illustration reprinted by permission of Media Lab, University of Wisconsin-Madison (2004), copyright 2003; thyroid illustration in Yale New Haven Health (2004) reprinted by permission of Nucleus Medical Art, copyright 2005. All rights reserved. www.nucleusinc.com.
The Thyroid and Disruption of Thyroid Function in Humans 45 hypothalamus are inhibited by T4 and T3 and stimulated in their absence. People with thyrotropin-releasing hormone deficiency have hypothyroidism because they have TSH deficiency. Thyrotropin TSH (thyrotropin) is synthesized and secreted by specific cells (thyro- troph cells) of the anterior pituitary gland (Figure 2-4). It stimulates virtu- ally every step of T4 and T3 synthesis and secretion by the thyroid gland, including NIS activity, synthesis of thyroglobulin, formation of T4 and T3 in thyroglobulin, and breakdown of thyroglobulin and release of T4 and T3 into the bloodstream. It also stimulates the blood supply and growth of the thyroid gland. The secretion of TSH is inhibited by small increases in serum T4 and T3 concentrations, and it increases in response to small decreases in serum T4 and T3 concentrations. This tight control of TSH secretion results in main- tenance of T4 and T3 production and secretion by the thyroid gland within very narrow limits. Thyroid gland function decreases in people with TSH deficiency, as a result of a pituitary gland disorder, just as it does in people with thyroid disease. Regulation of Extrathyroid Production of Triiodothyronine The tissue distribution and regulation of the deiodinases that catalyze the conversion of T4 to T3, the conversion of T4 to reverse T3, and the conversion of T3 to 3,3â-diiodothyronine differ (Bianco et al. 2002). The activity of type 1 deiodinase, the predominant deiodinating enzyme in the liver and kidney, is decreased by thyroid hormone deficiency (hypo- thyroidism) and increased by thyroid hormone excess (hyperthyroidism). The activity of type 2 deiodinaseâthe predominant deiodinating enzyme in the brain, pituitary, and muscleâis increased by thyroid hormone defi- ciency and decreased by thyroid hormone excess. The activity of those deiodinases is also altered by nonthyroid illness, caloric deprivation, other hormones, and drugs, and it differs between fetuses and adults. IODIDE NUTRITION AND METABOLISM Iodide is essential for the production of T4 and T3 by the thyroid gland. It can be obtained only by ingestion of foods that naturally contain it or of
46 Health Implications of Perchlorate Ingestion foods to which iodide is added during processing (iodization). Foods rich in iodide include seafood and sea products (kelp and seaweed), dairy products, eggs, commercial bakery products, and some vegetables. Sea salt also contains iodide, and iodized salt is widely available (and mandated by law in many countries). Dietary iodide is absorbed and distributed rapidly (as iodide) in the extracellular fluid, which also contains iodide released from the thyroid gland during hormone secretion and from extrathyroid deiodination of T4 and T3. T4 and T3 are eventually completely deiodinated, and the iodide returned to the circulation. Iodide leaves the circulation by transport into the thyroid or by excretion in the urine. In healthy adults in the United States, serum inorganic iodide concentrations range from 1 to 2 :g per deciliter (dL). The World Health Organization (WHO) recommends a dietary intake of 150 :g per day for adults, 200 :g per day for pregnant women, 90-120 :g per day for children 2-11 years old, and 50 :g per day for infants less than 2 years old (WHO 1996). The Institute of Medicine of the National Academies recommends a slightly higher intake, 220 :g per day, for preg- nant women (IOM 2000). At those intakes there are no clinical or biochemical manifestations of thyroid dysfunction. Lower intakes are associated with increasing fre- quency of thyroid enlargement (goiter), biochemical evidence of thyroid hormone deficiency, and ultimately, in people with severe iodide defi- ciency, hypothyroidism. WHO considers people whose iodide intake ranges from 50 to 99 :g per day to have mild iodide deficiency, those whose intake ranges from 20 to 49 :g per day to have moderate iodide deficiency, and those whose intake is less than 20 :g per day to have severe iodide deficiency. (In studies of iodide nutrition, iodide intake is not measured directly but is usually estimated as the amount of iodide in a liter of urine, because excretion of iodide by the kidneys is by far the most important route of loss of iodide from the body.) From 1988 to 1994, iodide intake in the United States averaged about 150 :g per day on the basis of single spot (untimed) measurements of urinary iodide excretion in 20,369 people 6-74 years old (median urinary iodide excretion, 145 :g/L) (Hollowell et al. 1998); the median value was about 50% lower than the value in 1971-1974. The value was less than 50 :g per day in 12% of adults (15% of women of childbearing age and 7% of pregnant women). It should be noted that the distribution of iodide values measured in spot urine samples is broader than values measured repeatedly in individual subjects (Andersen et al. 2001); this leads to overestimation of the number of subjects with both low and high values. Furthermore, among people 15-44 years old, including pregnant women, there were no
The Thyroid and Disruption of Thyroid Function in Humans 47 differences in serum TSH and T4 concentrations between those with urinary iodide values less than 50 :g/L and those with higher values (Soldin et al. 2005); apparently, the iodide intake in the former group was not low enough to cause a fall in T4 secretion. The reasons for the decrease in iodide intake in the United States between 1971-1974 and 1988-1994 are not known precisely, but they include lower salt intake (iodized salt contains iodide at 76 :g/g), less use of iodide in the baking and dairy industries, and a decrease in the addition of iodide to animal feed. More recent data suggest that the decline has ceased; in a national survey in 2000, the median value was 161 :g/L as compared with 145 :g/L in 1988-1994 (NCHS 2002). Iodide deficiency is more prevalent in many other countries but can be largely ameliorated by salt iodization. So far as the committee is aware, there are no reports of perchlorate exposure in areas of iodide deficiency. PERTURBATIONS OF THYROID HORMONE PRODUCTION Severe iodide deficiency is one of many conditions that can reduce T4 and T3 production (and is the most common worldwide). Others include iodide excess, various drugs, congenital abnormalities of development of the thyroid gland, congenital deficiencies of the components of the T4 and T3 synthesis pathway, and many diseases that damage the thyroid gland. The range of thyroid hormone deficiency that occurs in those conditions varies greatly, from almost clinically undetectable and fully compensated by the mechanism described below to severe hypothyroidism. Among infants, hypothyroidism can result in severe abnormalities in neural and skeletal development; in adults, it can result in substantial disability and rarely hypothyroid coma. When thyroid gland synthesis and secretion of T4 and T3 fall as a result of iodide deficiency or any other cause, the serum concentrations of the hormones fall. That results in a prompt increase in TSH secretion. If the thyroid is severely damaged or has been removed surgically or if the dose of an offending drug is high enough to block synthesis and secretion of the hormones completely, TSH has little effect. Serum T4 and T3 concentra- tions continue to fall, and although TSH secretion increases further, severe hypothyroidism occurs. If the problem is iodide deficiency or if thyroid damage or drug blockade of T4 and T3 synthesis and secretion is incomplete, the initial increase in serum TSH concentrations stimulates synthesis and secretion of the two thyroid hormones enough to raise their serum concen- trations to normal or near normal. The rise in turn lowers TSH secretion to,
48 Health Implications of Perchlorate Ingestion or almost to, its original level. The person has few, if any, symptoms or signs of hypothyroidism, although the thyroid gland may enlarge. Indeed, thyroid enlargement may be the only evidence that T4 and T3 production was low and TSH secretion was high at an earlier time. In summary, there is a potent mechanismâincreased TSH secretion by the pituitary glandâto compensate for thyroid hormone deficiency. The mechanism is activated by small decreases in T4 and T3 production. It effectively restores thyroid hormone production to normal or near normal even when the initial insult is substantial, for example, a large fall in iodide intake (see next section). There is another compensatory mechanismâthe effect of hypothy- roidism to increase conversion of T4 to the more active T3 in some tissues, especially the brain. The role of that intracellular compensatory mechanism is hard to measure, but it almost certainly contributes to the apparent nor- mality of people, including infants, with decreased T4 production. Iodide Deficiency and Other Perturbations The varied effects of iodide deficiency, depending on its severity, provide an example of the compensatory mechanism. People with mild iodide deficiency, as defined above, have normal serum T4 and TSH con- centrations, but about 5-10% have some thyroid enlargement. People with moderate iodide deficiency also have normal serum T4 and TSH concentra- tions, but about 20-30% have thyroid enlargement. And people with severe iodide deficiency may have slightly low serum T4 concentrations and high serum TSH concentrations, and over 30% have thyroid enlargement; overt hypothyroidism occurs only if iodide intake is below about 5-10 :g per day (Delange 2000). As iodide intake declines, thyroid uptake of iodide in- creases because of an increase in the number of NIS molecules. Those changes are intrinsic parts of the compensatory response; they are facilitated by an increase in TSH secretion but probably can occur in the absence of an increase. In addition, there is a shift to production of T3, which contains less iodide but is more active than T4. In summary, there is remarkable compensation for the effects of iodide deficiency so that even in the pres- ence of very low iodide intake normal or near-normal thyroid hormone production and TSH production are maintained. However, severe defi- ciency in iodide intake (below 20 :g per day) in pregnant women may result in major neurodevelopmental deficits and goiter in their offspring. Similar iodide deficiency in infants and children may result in smaller but still important neurodevelopmental deficits (Delange 2000).
The Thyroid and Disruption of Thyroid Function in Humans 49 Iodide excess and therapy with lithium carbonate provide additional examples of the compensatory mechanism. When ingested at 1 mg per day (1,000 :g per day) or more, iodide has an antithyroid action in healthy subjects. In 1-2 weeks, serum T4 and T3 concentrations fall by 10-15% and serum TSH concentrations increase by about 50% (Roti and Vagenakis 2000). Those changes persist, but do not worsen, if intake of excess iodide is continued. A similar pattern of changes in serum T4, T3, and TSH con- centrations occurs in people with psychiatric disease who are treated with lithium carbonate, a drug with antithyroid actions. The same pattern of changes in serum T4, T3, and TSH concentrations may be found in people with many thyroid disorders, including autoimmune thyroiditis, in which the thyroid is damaged by immune mechanisms; tumors of the head and neck regions that have been treated with radiation; hyperthyroidism that has been treated with radioactive iodide; and surgical removal of one side of the thyroid gland. In summary, many substances and conditions lower T4 and T3 secretion and result in a rise in TSH secretion. If the thyroid gland is not seriously damaged, serum T4 and T3 concentrations may return to normal, or so near to normal that there are few or no consequences. Clinical Consequences of Perturbations of Thyroid Hormone Production Compensation for iodide deficiency or other perturbations in thyroid hormone production, as described above, is the rule. In those cases, adults have no clinical consequences; they have normal serum T4 and TSH con- centrations and no clinical abnormalities. If the perturbation is greater, hypothyroidism occurs. Multiple terms are used to describe hypothyroidism, according to its severity, causes, duration, and the affected persons. They include the following: â¢ Subclinical hypothyroidism is defined as high serum TSH concen- tration and normal serum T4 concentration. â¢ Overt hypothyroidism is defined as high serum TSH concentration and low serum T4 concentration. â¢ Primary hypothyroidism is hypothyroidism resulting from thyroid disease or a condition (iodide deficiency) or drug that decreases thyroid hormone production. â¢ Central (or pituitary) hypothyroidism is hypothyroidism resulting from deficiency of TSH or thyrotropin-releasing hormone.
50 Health Implications of Perchlorate Ingestion â¢ Hypothyroidism may be permanent or transientâlasting a few weeks or months or until reversal of the causative condition, for example, by treatment of iodide deficiency or disappearance of antibodies that block the action of TSH. â¢ Hypothyroidism may be congenital (present at birth) or acquired later in life. In the United States, subclinical hypothyroidism is found in 4-8.5% of adults (Surks et al. 2004) and 2.5% of pregnant women (Klein et al. 1991); the frequency is higher in parts of the world that have severe iodide defi- ciency. People with subclinical hypothyroidism have few or no symptoms of hypothyroidism (Surks et al. 2004). They may have mild hypercholester- olemia and small decreases in cardiovascular function (Biondi et al. 2002), but overall cardiovascular-disease morbidity and mortality are not increased (Vanderpump et al. 1996; Parle et al. 2001). However, people with sub- clinical hypothyroidism caused by autoimmune thyroiditis have progression to overt hypothyroidism at a rate of 2-4% per year (Vanderpump et al. 1995). There is general agreement among endocrinologists that women with subclinical hypothyroidism who are pregnant or planning pregnancy should be treated with T4 but little agreement regarding treatment of others with the disorder. Thyroid hormone production must fall substantially and, more impor- tant, must remain low for a prolonged period for adverse effects to occur (see section Maternal Hypothyroidism for discussion of effects in pregnant women). Removal of half a personâs thyroid is not associated with symp- toms, because the resulting thyroid deficiency is not prolonged (Matte et al. 1981). The minimum extent and duration of the fall in thyroid hormone production that has adverse effects are not known. It is known that thyroid hormone production can fall enough to increase TSH secretion yet remain within the normal range (subclinical hypothyroidism, as defined above). Some of the people in whom that happens have slightly high serum TSH concentrations (4.6 to10 milliunits [mU] per liter; normal range, 0.5 to 4.5) but no symptoms or other manifestations of hypothyroidism (Surks et al. 2004). Among people with overt hypothyroidism, there is a moderate inverse correlation between serum T4 concentration and severity of symp- toms, increase in serum TSH concentration, and degree of abnormality of several physiologic and biochemical measures of thyroid hormone action (for example, reflex time and serum cholesterol concentration) (Staub et al. 1992). In studies of people being treated for hypothyroidism, changes in
The Thyroid and Disruption of Thyroid Function in Humans 51 the daily dose of T4 of 25 :g (about one quarter of daily production in healthy adults) have small effects not only on TSH secretion but also on well-being (Carr et al. 1988) and resting metabolic rate (Al-Adsani et al. 1997). Factors Affecting Susceptibility to Substances with Antithyroid Activity People who have a condition that reduces T4 and T3 production by the thyroid would be expected to be more sensitive to any additional factor that might further reduce production of the two hormones. The additional factor might be another thyroid disorder or treatment with a drug or other sub- stance that has antithyroid activity. Autoimmune thyroiditis is the most common thyroid disorder in the United States, and people who have it are known to be more vulnerable to the antithyroid activity of iodide or lithium carbonate (Roti and Vagenakis 2000). People who have iodide deficiency would also be expected to be more susceptible to antithyroid substances. For example, in some regions of the world (notably Africa) where iodide intake is low, a high dietary intake of cassava, which contains thiocyanate, accentuates the iodide deficiency (Delange 2000). Perchlorate, if present in sufficient concentrations, might have the same effect, although an inter- action between iodide deficiency and perchlorate has not been documented. Thyroid Overactivity The converse sequence of changes occurs when serum T4 and T3 con- centrations rise, whether because of thyroid inflammation and release of thyroid hormones stored in the thyroid gland; because of a thyroid disorder, such as a nodular goiter, that results in secretion of thyroid hormones independently of TSH; because of Graves disease, in which the thyroid gland is stimulated by antibodies that act like TSH; or because of ingestion of T4 or T3 tablets. When serum T4 and T3 concentrations rise, TSH secre- tion decreases. T4 and T3 production by any normal thyroid tissue then falls. Thus, the person is to some extent protected against hyperthyroidism by the normal negative feedback mechanism.
52 Health Implications of Perchlorate Ingestion HYPOTHALAMIC-PITUITARY-THYROID DEVELOPMENT AND FUNCTION IN FETUSES AND INFANTS Development of the Hypothalamic-Pituitary-Thyroid System in Fetuses Before the onset of human fetal thyroid function at 10-12 weeks of gestation, T4, presumably of maternal origin, can be detected in the coelom- ic fluid of 6-week-old embryos (Calvo et al. 2002). It can also be detected in the brains of 10-week-old fetuses, as can deiodinases and T3 receptors (Kilby et al. 2000). That maternally derived T4 is probably essential for normal early development. The thyroid gland, pituitary, and hypothalamus form during the first trimester of gestation (Fisher and Brown 2000). The thyroid gland is derived from cells that originate in the floor of the primitive pharynx and then descend into the neck, where they divide and move laterally, forming the two lobes of the thyroid. Formation of the precursors of the thyroid follicular cells and the growth and descent of these precursor cells into the neck result from the coordinate action of multiple transcription factors (molecules that regulate gene function), hormones, and growth factors. Primitive thyroid follicles, iodide uptake, and thyroglobulin are first de- tected at 10-12 weeks of fetal life. Low concentrations of T4 and T3 can be detected in fetal serum soon thereafter. The iodide needed for fetal thyroid hormone synthesis must be provided by the mother. Placental tissue contains a small amount of the NIS, but its importance in maternal-to-fetal transfer of iodide is probably small. That women who have mutations in the NIS can have normal children suggests that absence of transporters in tissue of maternal origin does not limit the transfer of iodide from mother to fetus (Kosugi et al. 2002). The anterior pituitary gland, site of production of TSH, develops from the floor of the primitive forebrain and an outgrowth of the primitive oral cavity (Rathkeâs pouch). Although the structures are visible by 5 weeks, a morphologically mature pituitary gland and its vascular connections with the hypothalamus above it are not identifiable until 14 weeks. Low concen- trations of TSH can be detected in fetal serum from 12 weeks to about 18- 20 weeks, after which they rise substantially. The hypothalamic centers that produce thyrotropin-releasing hormone and the hormone itself are not identifiable until 15-18 weeks.
The Thyroid and Disruption of Thyroid Function in Humans 53 Maturation of the Hypothalamic-Pituitary-Thyroid Axis At 18-20 weeks, fetal serum TSH concentration begins to rise, and then serum total and free T4 concentrations rise progressively (Fisher and Brown 2000). The progressive increase in serum total T4 concentration is due to a concomitant rise in serum TBG concentration, caused by an increase in production of the protein by the fetal liver and by increased thyroid produc- tion of T4. The increase in TSH secretion is caused by rising thyrotropin- releasing hormone secretion from the maturing hypothalamus and is re- quired to stimulate the fetal thyroid gland to produce the increasing amounts of T4 needed to sustain the rise in serum total and free T4 concentrations. The progressive maturation of thyrotropin-releasing hormone and TSH secretion during the latter part of gestation and early postnatal life results in an increasing capacity to respond to both decreases and increases in serum T4 concentrations. Thus, as in adults, TSH secretion in fetuses increases if fetal thyroid secretion is inhibited as a result of a thyroid disor- der or iodide deficiency or the transfer of a substance that has antithyroid activity. Conversely, fetal TSH secretion is inhibited if serum T4 concentra- tion increases. Fetal T3 and reverse T3 metabolism is different from that in adults. Fetal serum T3 concentrations are low until about 32 weeks and thereafter rise slowly until birth. Conversely, serum reverse T3 concentrations are high and decline near birth. Fetal serum T3 concentrations are low because fetal tissues and the placenta have low type 1 deiodinase activity (which converts T4 to T3) and high type 3 deiodinase activity (which converts T3 to diiodothyronine) (Bianco et al. 2002). The fetal hypothalamic-pituitary-thyroid system does not function completely independently of that of the mother. Thyrotropin-releasing hormone and TSH do not cross the placenta in appreciable amounts, but T4 and T3 do cross the placenta, as noted above. In infants who cannot synthe- size any T4 or T3, serum T4 concentrations at birth are 20-40% of those of healthy infants (Vulsma et al. 1989). Maternal T4 and T3 undoubtedly contribute to the serum concentrations of the two hormones in healthy fetuses but not as much as in fetuses that are unable to produce the hor- mones themselves. Development of Tissue Deiodinases and Triiodothyronine-Nuclear Receptors The tissue distribution and activity of the deiodinase enzymes in fetuses differ from those in adults. Studies in humans are very limited but show
54 Health Implications of Perchlorate Ingestion that type 3 deiodinase, which inactivates T4 and T3, can be detected in fetal liver and brain in 10-week-old fetuses. Its content in the liver decreases progressively thereafter during fetal life, and it decreases further in the first weeks after birth (Fisher and Brown 2000). Type 1 deiodinase activity has been detected in the liver of 20-week-old fetuses, and its activity gradually increases thereafter, not only during gestation but also after birth. The high fetal type 3 deiodinase activity, with high placental type 3 deiodinase activity, explains why fetal serum T3 concentrations are low early in gesta- tion, increase only slowly until birth, and then increase rapidly (and why fetal serum reverse T3 concentrations change in the opposite way) (Bianco et al. 2002). Type 2 deiodinase is present in fetal tissues, and its content, at least in animals, increases during gestation and after birth. Indeed, in animals, the patterns of deiodinase activity differ in different tissues, even in different regions of tissues, such as the brain, at different times during development. Those findings indicate that there are variations in local production of T3 at different times during normal development and that correct timing of the changes is critical for normal development. The tissue distribution and timing of appearance of T3-nuclear receptors in fetuses also differs from those in adults. T3 receptors can be detected in embryonic animal stem cells; in the brains of 10- to 11-week-old human fetuses, probably before the fetal thyroid begins to secrete T4 (Kilby et al. 2000); and in the liver, heart, and lungs of 16- to 18-week-old fetuses. Thyroid Function in Infants Term Infants At birth, there is a dramatic increase in TSH secretion in healthy term infants, a consequence of the relative hypothermia of the extrauterine environment. Serum TSH concentrations rise abruptly, from 3 to 8 mU/L at delivery to 50 to 70 mU/L in 30-60 minutes (min) (Fisher and Brown 2000). The concentrations then fall rapidly for 24 hr, and more slowly thereafter, to less than about 10-12 mU/L at the end of the first week of life. The thyroid stimulation that results from the surge in TSH secretion raises serum T4 concentrations by about 50% in 24 hr, after which they gradually decline. Serum T3 concentrations increase by 300-400% in 24 hr, not only because of the increase in TSH secretion but also because of an increase in type 1 deiodinase activity and a decrease in type 3 deiodinase activity in the infantsâ tissues. Serum T4 and T3 concentrations gradually fall in the first 4 weeks of life to values that are slightly higher than those in adults.
The Thyroid and Disruption of Thyroid Function in Humans 55 Preterm Infants At birth, the functioning of the hypothalamic-pituitary-thyroid system is slightly lower in preterm infants than in term infants, but for the most part it is appropriate for their gestational age. Their serum free T4 concentra- tions are slightly lower than those of fetuses of comparable age in utero. After delivery, serum TSH and T4 concentrations increase, as in infants born at term, but the increases are slightly smaller. In very premature infants (less than 32 weeks of gestation), there is no surge of TSH secretion after birth, and serum T4 concentrations fall during the first week of life, the degree of decline reflecting the degree of prematurity (Oden and Freemark 2002). Even more premature infants (less than 30 weeks) may have very low serum T4 concentrations at birth and no postnatal rise. Their serum total T4 concentrations tend to be more abnormal than their serum free T4 concentrations. The difference is indicative of decreased production of TBG or other binding proteins as a consequence of immature liver function. In infants who are healthy and grow well, serum T4 concentrations gradu- ally increase to values similar to or higher than those at birth in 4-6 weeks. In addition to the aforementioned changes in serum TSH and T4 con- centrations, preterm infants have low serum T3 concentrations. That is due to immaturity of type 1 deiodinase, inhibition of the activity of this enzyme by nonthyroid illness (for example, the respiratory distress syndrome), or both. The causes for the postnatal fall in serum T4 concentrations in very premature infants include clearance of maternal T4, decreased serum bind- ing of T4, and immaturity of the hypothalamic-pituitary-thyroid system. In those infants, TSH secretion does not increase as much in response to low serum T4 concentrations as it does in more mature infants. Furthermore, preterm infants are more likely to suffer from systemic illness, such as the respiratory distress syndrome, and to be treated with medications, such as glucocorticoids, that reduce TSH or thyroid hormones. All those situations tend to reduce serum TSH and T4 concentrations. In addition, preterm infants are more sensitive to the effects of iodide deficiency and iodide excess, and the incidence of transient hypothyroidism with high serum TSH is increased (Frank et al. 1996). In view of the critical dependence of brain maturation on thyroid hormone at this age, any period of low serum free T4 concentrations could impair neurologic or neuropsychologic development. However, in most preterm infants, the hormonal abnormalities are transient, and the infants do not benefit from T4 therapyâas assessed by mental development, neurologic function, or growthâcompared with placebo (van Wassenaer et al. 1997; Oden and Freemark 2002).
56 Health Implications of Perchlorate Ingestion Thyroid Hormone Actions in Developing Fetuses and Newborn Infants T3 is required for normal development of the central nervous system. Its actions include stimulation of the development and growth of neurons (nerve cells) and supporting (glial) cells, the formation of connections (synapses) between neurons, the formation of the myelin sheaths that surround neuronal processes, and the development of the neurotransmitters that transmit signals from one nerve cell to another (Fisher and Brown 2000). T3 stimulates the transcription of several genes whose products are important for neural development, including the genes for myelin basic protein, a cerebellar Purkinje-cell protein, a calcium-binding protein, and neurogranin (Oppenheimer and Schwartz 1997). In hypothyroid animals, the expression of those genes is delayed, but most are ultimately expressed to the same extent as in normal animals. The resulting abnormalities in neurologic and neuropsychologic development, although variable and determined at least in part by when the deficiency occurred, are permanent; this indicates that the correct timing of the expression of those and other genes in the brain during development is critical. However, the linkage between the biochemical abnormalities in the brain and the developmental abnormalities is far from clear. T4 and T3 also are required for normal skeletal development and growth. Bone cells have T3 receptors, and T3 stimulates bone formation and the appearance of the epiphyseal centers that are needed for normal growth of long bones. T3 also stimulates the production of pituitary growth hormone and insulin-like growth factor. Treatment with T4 leads to resumption of bone growth and skeletal maturation, but severely affected infants are unlikely to have normal stature. Effects of Perturbations of Maternal, Fetal, and Child Thyroid Function on Fetal and Child Development The clinical manifestations of hypothyroidism in infants vary widely, according to whether the mother, the fetus, or both have hypothyroidism and how long it persists after birth. The abnormalities are greatest when both mother and fetus are affected; this is most likely to occur in regions of severe iodide deficiency. The consequences of severe combined maternal and fetal hypothyroidism during fetal life and in newborn infants include microcephaly (small brain), mental retardation, deaf-mutism, paraplegia or quadriplegia, and movement disorders. Those abnormalities are not revers-
The Thyroid and Disruption of Thyroid Function in Humans 57 ible by treatment with T4 (Foley 2000). However, the abnormalities can be largely prevented by administration of iodide to the mothers before or during the first trimester and early part of the second trimester of pregnancy (Pharoah 1993; Cao et al. 1994). That finding underlies the importance of the availability of T4 from the mother before fetal thyroid secretion begins, as noted above. The infants of mothers who have mild iodide deficiency have larger thyroid glands and higher serum TSH or thyroglobulin concentrations at birth than do infants of mothers whose iodide intake is higher (Glinoer et al. 1995; Kung et al. 2000). Otherwise, they appear to be neurologically and physically normal. Newborn infants who have hypothyroidism may have other abnormali- ties, including lethargy, poor muscle tone, poor feeding, constipation, and persistent jaundice, if not at birth then thereafter. The changes are similar to those which occur in older children and adults who have hypothyroidism, and, in contrast with the neurologic abnormalities, they are reversible with adequate T4 treatment. Maternal Hypothyroidism Pregnant women who have overt hypothyroidism and are adequately treated have normal pregnancies, and their infants develop normally (Liu et al. 1994). Pregnant women who have subclinical hypothyroidism or overt hypothyroidism and are inadequately treated or not treated at all have an increased risk of fetal loss (Allan et al. 2000; Abalovich et al. 2002). The infants of those mothers who do not miscarry have normal thyroid function at birth and thereafter, but their neurodevelopment may be slightly impaired. A prospective study of seven infants born to mothers who had subclinical hypothyroidism during pregnancy and six infants born to moth- ers who had normal thyroid function found that the former had lower scores on the Bayley Mental Developmental Index at the ages of 6 and 12 months but not at 24 months; the scores on the Bayley Psychomotor Development Index were similar at all three times (Smit et al. 2000). Another study compared 7- to 9-year-old children born to 62 women who had subclinical hypothyroidism during the second trimester of pregnancy with 124 children born to women who had normal thyroid function (Haddow et al. 1999). The mean full-scale IQ score was 4 points lower in the former group, and 15% had scores of 85 or lower, compared with 5% of the control children. The infants of mothers who have low serum free T4 concentrations early in pregnancy also may have slightly impaired neurodevelopment. Among
58 Health Implications of Perchlorate Ingestion 220 infants tested with the Bayley Scales of Infant Development at the age of 10 months, the 22 infants whose mothers had serum free T4 concentra- tions in the lowest 10th percentile (but normal serum TSH concentrations) at 12 weeks of gestation scored lower on the Psychomotor Development Index (by 7 points, 93% vs 100%) but not the Mental Developmental Index (Pop et al. 1999). In a second study, 57 infants whose mothers had serum free T4 values in the lowest 10th percentile and 58 infants whose mothers had serum free T4 values in the 50th to 90th percentile were tested in the same way at the ages of 1 and 2 years. The scores on both indexes were slightly but statistically significantly lower (mean differences ranged from 4 to 6 points of 100 points) at both times in the infants of the mothers who had low serum free T4 values (Pop et al. 2003). Those studies, although not definitive, suggest an effect on develop- ment in infants whose mothers had subclinical hypothyroidism or low- normal serum free T4 concentrations during pregnancy, but they have limitations. The differences in test scores were small, and the scores could be confounded by socioeconomic, educational, and other differences be- tween the study groups. Moreover, the results contrast with the normal development of the infants of mothers who had overt hypothyroidism (Liu et al. 1994). Nonetheless, if confirmed, they emphasize the potential vulnerability of fetuses to decreases in maternal thyroid function. Fetal and Neonatal Hypothyroidism Infants who have congenital hypothyroidism usually appear normal at birth (Foley 2000). Their serum T4 concentrations are low, but not very low and indicate that some maternal T4 crossed the placenta. Their serum TSH concentrations are high and rise further soon after birth as the maternally derived T4 is metabolized and its concentration in the infantsâ serum falls. Those infants can be identified as having hypothyroidism if screened by measurements of TSH or T4 in blood collected 24-96 hr after birth; such screening has been in place in the United States for about 25 years. Infants so identified by neonatal screening have normal neural development and growth if aggressive T4 treatment is started within the first 2 or 3 weeks after birth. After birth, not only maternal T4 and T3 but also other maternal factors that might have affected fetal thyroid secretion are cleared from the infantâs circulation. Whether those substances alter a newborn infantâs thyroid function depends on the dose and rate of clearance of the substance and the prematurity of the infant. The efficacy of prompt T4 treatment of newborn
The Thyroid and Disruption of Thyroid Function in Humans 59 infants found by screening to have hypothyroidism makes it highly unlikely that any rapidly cleared substance that reached the fetus from the mother and reduced thyroid secretion in the fetus in utero but no longer reached the infant after birth could cause postnatal hypothyroidism of sufficient severity to cause permanent developmental delay. That conclusion is born out by the uncommon clinical situation described below. Hyperthyroidism occurs in about one in 2,000 pregnant women. Some of the affected women require treatment with an antithyroid drug through- out their pregnancies. The antithyroid drugs propylthiouracil and methima- zole may cross the placenta in sufficient quantities to cause transient fetal hypothyroidism. After birth, no more drug reaches the infants, the hor- monal changes that can be detected in utero disappear rapidly, and the infants develop normally (Eisenstein et al. 1992). Years ago, some preg- nant women who had hyperthyroidism were treated successfully with potassium perchlorate. Most of the infants were normal, but one had slight thyroid enlargement that disappeared soon after birth. No other abnormali- ties at birth were reported, and the infants were not followed thereafter (Crooks and Wayne 1960). Iodide Nutrition in Childhood Adequate iodide intake during infancy and childhood is also important; children with moderate iodide deficiency have learning disabilities and do less well on tests of mental and psychomotor performance than do children with adequate iodide intake (Tiwari et al. 1996; van den Briel et al. 2000; Santiago-Fernandez et al. 2004). In the most extensive study of this topic, of 1,221 Spanish children (mean age, 10.8 years), 30% of children with urinary iodide excretion less than 25 :g/L had an IQ at or below the 25th percentile, compared with 16% of children with urinary iodide excretion of more than 150 :g/L (Santiago-Fernandez et al. 2004). However, urinary iodide values were positively correlated with serum TSH values and not correlated with serum free T4 and free T3 values, and the results were not adjusted for parental socioeconomic or educational status. PERCHLORATE AND THE THYROID Perchlorate potentially can affect thyroid function because of its ability to block the transport of iodide into thyroid follicular cells. As noted above, it does so by competitively inhibiting iodide transport by the NIS in the
60 Health Implications of Perchlorate Ingestion plasma membrane of these cells. The fact that the inhibition is competitive means that it can be overcome by higher concentrations of iodide, and, in laboratory studies, perchlorate did not inhibit uptake of iodide by thyroid tissue when high concentrations of iodide were present (Wolff 1998). After recognition in the 1950s of the ability of perchlorate to block uptake of iodide in animal and then human thyroid tissue (Stanbury and Wyngaarden 1952), it was given on a long-term basis to patients who had hyperthyroidism, with the goal of reducing synthesis and secretion of T4 and T3. The effects of perchlorate therapy in hyperthyroid patients and of perchlorate given prospectively to healthy subjects are reviewed in the following sections. Therapeutic Uses of Perchlorate The medical literature of the 1960s contains reports of successful treatment with potassium perchlorate of more than 1,000 patients who had hyperthyroidism caused by Graves disease or nodular goiter. The potas- sium perchlorate was given in doses of 400-2,000 mg per day for many weeks or months (Crooks and Wayne 1960; Morgans and Trotter 1960; summarized in Wolff 1998 and Soldin et al. 2001). One patient was treated for 22 years at 200 mg per day (Connell 1981). The patients included 12 pregnant women who were treated with 600-1,000 mg per day. The only adverse effect was slight thyroid enlargement in one infant, which de- creased soon after birth, as noted above (Crooks and Wayne 1960). Potassium perchlorate treatment of hyperthyroid patients was for the most part safe, although some had nausea and vomiting (gastric inflamma- tion), skin rashes, fever, lymph node enlargement, and kidney dysfunction. The frequency of those side effects was dose-dependent; they occurred in 3-4% of patients taking 400-600 mg per day, and in 16-18% of patients taking 1,000-2,000 mg per day (Crooks and Wayne 1960; Morgans and Trotter 1960). Thirteen patients who had taken 400-1,000 mg per day for 2-20 weeks developed aplastic anemia or agranulocytosis (cessation of production of red blood cells or white blood cells, respectively), and seven of them died (summarized in Soldin et al. 2001). As a result of the latter events, and perhaps also because of the contemporaneous development of other antithyroid drugs, the use of perchlorate to treat patients for hyper- thyroidism largely ceased by the middle to late 1960s. The most recent report of long-term potassium perchlorate treatment of patients for hyperthyroidism caused by Graves disease was in 1984. In that
The Thyroid and Disruption of Thyroid Function in Humans 61 study, 18 patients were treated initially with 900 mg per day (Wenzel and Lente 1984). As serum thyroid hormone concentrations declined, the dose of potassium perchlorate was reduced to an average of 93 mg per day at 12 months. Thereafter, the patients received 40-120 mg per day (perchlorate at 0.41-1.2 mg/kg of body weight per day for a 70-kg person) for 12 months. During that 12-month period, all the patients had normal serum T4 and T3 concentrations, and the majority had normal serum concentrations of TSH-receptor stimulating antibodies, the cause of hyperthyroidism in patients who had Graves disease; this indicated that they no longer had Graves disease. There is no mention of side effects in the report, but all the patients treated with perchlorate completed the study. Given that most of the patients did not have high serum concentrations of TSH-receptor stimulating antibodies during the second year of perchlorate therapy, the results strongly suggest that moderate doses of perchlorate given chron- ically do not cause hypothyroidism. Potassium perchlorate treatment has been revived in recent years as a treatment for patients who have a type of hyperthyroidism caused by amiodarone, an iodinated drug used to treat patients for abnormal cardiac rhythms. Amiodarone can cause two types of hyperthyroidism: one from the excess iodide and the other from thyroid inflammation. The iodide- induced type of hyperthyroidism usually occurs in patients who have a pre- existing nodular goiter, and it has proved difficult to treat with standard antithyroid drugs. Cessation of amiodarone is not helpful, because the drug is not completely excreted for many months. In affected patients, perchlo- rate therapy can be helpful because of its ability to prevent iodide uptake by thyroid tissue. Potassium perchlorate at 200-1,000 mg per day has been given for several weeks or months. There have been no reports of adverse effects, and in some of the studies blood counts and kidney function were monitored and remained normal (Martino et al. 1986; Newnham et al. 1988; Reichert and de Rooy 1989; Bartalena et al. 1996). Most patients were treated simultaneously with a standard antithyroid drug (methimazole or propylthiouracil), so the benefit cannot be ascribed to perchlorate alone. Perchlorate has also been given prophylactically to patients who have multinodular goiter to prevent iodide-induced hyperthyroidism. They were patients who were to receive an iodinated contrast agent, which, like amiodarone, contains large amounts of iodide, to visualize blood vessels as part of radiographic or computed-tomography studies. In a study in which 51 patients who had multinodular goiter were randomly assigned to receive no treatment or methimazole or sodium perchlorate (900 mg per day) for 14 days starting on the day of a radiographic study, two patients in the control
62 Health Implications of Perchlorate Ingestion group became hyperthyroid, compared with one patient in each treatment group (Nolte et al. 1996). There were no side effects of the sodium per- chlorate. There are no reports of the appearance of a new thyroid disorder, thyroid nodules, or thyroid carcinoma in any patient treated with potassium perchlorate for hyperthyroidism. Iodide deficiency in the thyroid gland, a possible consequence of perchlorate administration or exposure, is not associated with an increase in thyroid cancer (Schlumberger 1998). In hyperthyroid patients treated with antithyroid drugs, there was no increase in thyroid cancer mortality (Ron et al. 1998). Clinical Pharmacology and Effects of Perchlorate in Healthy Humans Perchlorate is usually administered as potassium perchlorate. It is rapidly absorbed after ingestion, and peak serum perchlorate concentrations are reached in 3 hr. Its half-life in serum is about 6-8 hr, and it is rapidly eliminated unchanged from the body, primarily in urine. Five studies have been conducted in which perchlorate was given to healthy subjects for various periods, and its effects on thyroid function were determined. In one study, five healthy men were given 200 :g of iodide daily for 4 weeks and then 900 mg of potassium perchlorate daily (perchlo- rate at about 9 mg/kg per day for a 70-kg person) for 4 weeks. At the end of each 4-week period, there were no differences in serum T4 and T3 con- centrations or thyroid volume. The mean 24-hr serum TSH concentrations (1.0 vs 1.8 mU/L), serum free T4 concentrations (14.3 vs 15.7 picomoles/L), and total thyroid iodide content (3.0 vs 4.0 millimoles/mL) were slightly lower at the end of the perchlorate period than at the end of the iodide period (Brabant et al. 1992). Note that the serum TSH values were lower at the end of the perchlorate period, indicating lack of an antithyroid effect. In the second study (Lawrence et al. 2000), nine healthy men 22-30 years old ingested 10 mg of potassium perchlorate (perchlorate at about 0.10 mg/kg per day for a 70-kg person) in 1 L of water daily for 14 days. Their serum perchlorate concentrations averaged 0.6 :g/mL, and the aver- age urinary perchlorate excretion was 7.7 mg per day. Urinary iodide values did not change (the mean baseline value was 254 :g per day). There were no changes in serum T4, T3, or TSH concentrations during the 14-day period of perchlorate ingestion. The 24-hr thyroid uptake of radioactive iodide (iodide-123) was measured three times. At baseline, the mean value was 23.6% of the administered dose; it decreased to 14.0% of the dose after
The Thyroid and Disruption of Thyroid Function in Humans 63 perchlorate ingestion for 14 daysâa 42% reduction that was statistically significant (p < 0.01). The uptake was 27.1% 14 days after cessation of perchlorate. Measurements of uptake at 4 and 8 hr revealed similar degrees of inhibition during ingestion of perchlorate and a similar return to baseline after it was stopped. In the third study, the same investigators then adminis- tered 3 mg of potassium perchlorate daily (perchlorate at about 0.03 mg/kg per day for a 70-kg person) to eight healthy men (ages not given) for 14 days (Lawrence et al. 2001). The mean 24-hr thyroid uptake of radioactive iodide was 16.1% at baseline and 14.5% during perchlorate ingestion, and the mean 8-hr uptake values were 13.8% and 11.8%, respectively; neither change was statistically significant. There were no changes in serum T4, T3, or TSH concentrations. In the fourth and most comprehensive study (Greer et al. 2002), 21 healthy women and 16 healthy men (mean age, 38 years; range, 18-57 years) were given potassium perchlorate in doses of perchlorate at 0.007-0.5 mg/kg of body weight per day for 14 days (the daily dose was given in 400 mL of water with instructions that 100 mL be consumed four times each day). The doses were chosen on the basis of the effects observed by Law- rence et al. (2000). Thyroid uptake of radioiodide was measured 8 and 24 hr after radioiodide administration at baseline, on days 2 and 14 days of perchlorate administration, and 15 days later. On day 14, the 24-hr radio- iodide uptake was 98.2% of the baseline value in the subjects given 0.007 mg/kg (Table 2-1), a 1.8%, and statistically insignificant, decrease, well within the variation of repeated measurements in healthy subjects. The day- 14 24-hr radioiodide uptake value was 83.6% of the baseline value (16.4% decrease) in the subjects given 0.02 mg/kg, 55.3% of the baseline value (44.7% decrease) in those given 0.1 mg/kg, and 32.9% of the baseline value (67.1% decrease) in those given 0.5 mg/kg. The results of thyroid radioiodide uptake measurements on day 2 of perchlorate administration were very similar to those on day 14 in the three higher dose groups (uptake was not measured on day 2 in the lowest dose group) (Table 2-1), indicating that the effect did not change with time. The 8-hr thyroid radioiodide uptake values, both as percentage of dose and as percentage of baseline, on days 2 and 14 were very similar to those at 24 hr (not shown). The thyroid uptake values 15 days after exposure were very similar to the baseline values, indicating rapid disappearance of inhibition when that had occurred. The results were similar in women and men. The investigators concluded that the no-observed-effect-level (NOEL) for perchlorate-induced inhibition of thyroid iodide uptake was 0.007 mg/kg per day. On the basis of the inhibition of uptake that occurred at higher doses of perchlorate and the potency of perchlorate as an inhibitor of iodide
64 Health Implications of Perchlorate Ingestion TABLE 2-1 24-Hour Thyroid Radioiodide Uptake in Healthy Subjects before, during, and after Oral Administration of Potassium Perchlorate for 14 Days 24-Hr Thyroid Uptake Uptake as % No. of (% of Dose) of Baseline P, Compared Subjects (Mean Â± SE) (Mean Â± SE) with Baseline 0.007 mg/kg-day Baseline 7 18.1 Â± 3.1 Day 14 7 16.5 Â± 1.6 98.2 Â± 8.3 Day 15 post- 7 17.3 Â± 2.5 100.3 Â± 8.4 exposure 0.02 mg/kg-day Baseline 10 18.4 Â± 1.2 Day 2 8 15.7 Â± 1.4 82.8 Â± 5.6 <0.05 Day 14 10 15.2 Â± 1.1 83.6 Â± 4.1 <0.005 Day 15 post- 10 19.1 Â± 1.3 105.3 Â± 5.5 exposure 0.1 mg/kg-day Baseline 10 19.9 Â± 2.1 Day 2 8 11.8 Â± 1.7 59.2 Â± 3.5 <0.005 Day 14 10 11.0 Â± 1.6 55.3 Â± 3.9 <0.005 Day 15 post- 10 20.8 Â± 2.2 106.6 Â± 9.1 exposure 0.5 mg/kg-day Baseline 10 21.6 Â± 2.0 Day 2 8 6.5 Â± 0.6 30.6 Â± 2.6 <0.005 Day 14 10 6.9 Â± 0.9 32.9 Â± 3.8 <0.005 Day 15 post- 10 21.7 Â± 2.0 104.6 Â± 9.4 exposure Source: Greer et al. 2002. uptake in vitro, they estimated that a daily intake of 150 :g of iodide would protect against the effects of a daily intake of 4 mg of perchlorate (0.06 mg/kg for a 70-kg person). Serum perchlorate concentrations ranged from 0.10 to 0.17 :g/mL during administration of 0.1 mg/kg per day and from 0.45 to 0.85 :g/mL during administration of 0.5 mg/kg per day. The serum perchlorate half-life after cessation of this dose averaged 8.1 hr (range, 6.0-9.3); the half-life in the other groups could not be measured, because the values were or became undetectable very soon after perchlorate administration was stopped.
The Thyroid and Disruption of Thyroid Function in Humans 65 There were no changes in serum T4, T3, and TSH concentrations, which were measured repeatedly during the study in 24 subjects, except for a very small decrease in serum TSH concentrations in the subjects given 0.5 mg/kg per day (not an increase, as would be expected if thyroid secretion de- creased, and probably explicable on the basis of multiple measurements of TSH concentration, which varies over the course of a day). One woman had a slightly high serum TSH concentration at baseline (18 mU/L), and it was slightly lower (15 mU/L) on day 14 of perchlorate (0.007 mg/kg per day) administration. In the fifth study, the chronic effects of two doses of potassium per- chlorate were evaluated in a small study of 13 healthy subjects (Braverman et al. 2004). Four subjects were given placebo, five were given 0.5 mg of perchlorate daily, and four were given 3 mg of perchlorate daily for 6 months (these doses correspond to 0.007 and 0.04 mg/kg, respectively, for a 70-kg subject). Serum TSH, free T4 index, and T3 were measured at baseline, monthly during perchlorate administration, and 1 month after exposure. Thyroid radioiodide uptake was measured at baseline, at 3 and 6 months during perchlorate administration, and 1 month after exposure. There were no changes in any of the serum measurements or in thyroid radioiodide uptake, compared with baseline, at any time in either perchlo- rate group or in the placebo group. The results of the studies, in which thyroid function was assessed in several ways, are remarkably consistent. The study subjects were healthy men and women 18-57 years old; none was taking medications that might influence thyroid radioiodide independently of perchlorate. They were free- living, eating a self-selected diet. In the studies in which thyroid radioiodide uptake was measured, the baseline values varied somewhat among the subjects, but no more than expected in healthy people eating their usual diet. The normal range for 24-hr thyroid uptake of radioiodide in many places in the United States is 10-30%, also reflecting variation in dietary iodide intake. Although individual study groups were small, from four to 10 subjects in the studies of thyroid radioiodide uptake, the results were highly consistent within each treatment group in that the variance of the change, or lack of change, in thyroid radioiodide uptake during potassium perchlorate administration was similar to or less than the variance at base- line (Table 2-1). The effects of similar doses of potassium perchlorate on thyroid radioiodide uptake were very similar; a daily perchlorate dose of 0.007 mg/kg had no effect in two studies (Greer et al. 2002; Braverman et al. 2004), a daily dose of 0.02 mg/kg had a small effect (about 15% inhibi- tion of thyroid iodide uptake) in Greer et al. (2002), and daily doses of 0.03 and 0.04 mg/kg had no effect in two other studies (Lawrence et al. 2000;
66 Health Implications of Perchlorate Ingestion Braverman et al. 2004). Those results have been analyzed in multiple ways, but the experimental results are clear: in healthy subjects, a dose of per- chlorate of 0.007 mg/kg per day has no effect on thyroid radioiodide uptake or any other measure of thyroid function, and doses of 0.02-0.04 mg/kg per day have minimal or no effect on those measures. Summary of Potential Perchlorate-Induced Perturbations of Thyroid Function in Healthy Humans The duration of the studies of potassium perchlorate administration in healthy subjects varied from 2 weeks to 6 months. In all those studies, there were no changes in serum T4, T3, and TSH concentrations to suggest that there had been any decrease in thyroid hormone secretion. Some doses of perchlorate given for 2 weeks did inhibit thyroid uptake of radioiodide. A high dose given for 4 weeks lowered thyroid iodide content by 25%, indi- cating some decrease in iodide uptake (Brabant et al. 1992), and resulted in a very small fall in serum free T4 concentrations, but serum TSH concentra- tions were also lowerânot higher, as would occur if serum free T4 concen- trations decreased to an important extent. If inhibition of iodide uptake were prolonged, the result should be iodide deficiency in the thyroid, similar to that which occurs in dietary iodide deficiency and with the same consequences and compensation. Lack of iodide in the thyroid gland should cause a decrease in T4 and T3 synthesis and secretion and therefore a fall in serum T4 and T3 concentrations. TSH secretion would then increase, and, assuming an adequate iodide intake, iodide uptake and T4 and T3 synthesis and secretion would return toward normal. Thus, there should be complete compensation if the maximal effect of the dose of perchlorate was only partial inhibition of iodide uptake by the thyroid gland. Even if the block were more complete, substantial or com- plete compensation would be expected although the thyroid gland might enlarge. There is therefore little likelihood that the decreases in thyroid iodide uptake found in the short-term studies of perchlorate administration, even at the higher doses, would be sustained, and it is highly likely that iodide uptake would return to normal. Possible exceptions might occur if the dose of perchlorate were very high comparable to those given to patients with hyperthyroidism, or if the person had severe iodide deficiency. Given the compensation that is known to occur in people with iodide deficiency, as discussed earlier, it is highly likely that in people with a normal iodide intake the dose of perchlorate would have to reduce thyroid iodide uptake
The Thyroid and Disruption of Thyroid Function in Humans 67 by at least 75% for a sustained period (several months or longer) for iodide uptake and thyroid hormone production to decline enough to cause adverse health effects (equivalent to reducing dietary iodide intake by 75%). In adults, that is likely to require sustained exposure to more than 30 mg of perchlorate per day (0.4 mg/kg per day for a 70-kg person), on the basis of the clinical studies in healthy subjects and the studies of long-term treat- ment of hyperthyroidism, both described in this chapter, and the studies of environmental exposure, described in Chapter 3 (Gibbs et al. 1998; Lamm et al. 1999; Crump et al. 2000). In pregnant women, infants and children, and people who have a low iodide intake or pre-existing thyroid dysfunc- tion, the dose required to cause a decrease in thyroid hormone production may be lower. However, a dose that does not inhibit thyroid iodide uptake will not affect thyroid function, even in subjects with an abnormal thyroid gland or a very low iodide intake. NONTHYROID EFFECTS OF PERCHLORATE The NIS is present in the salivary glands; mammary glands, especially during lactation; stomach; choroid plexus of the brain; and ciliary body of the eye (Dohan et al. 2003). However, the iodide that is transported into those tissues is not further metabolized, as it is in the thyroid gland, but is rapidly returned to the circulation or secreted into the saliva or breast milk. Furthermore, iodide transport into these tissues is not known to be required for their normal function, with the possible exception of mammary tissue. TSH increases the content of the NIS only in thyroid tissue. Perchlorate acutely inhibits iodide transport in salivary and mammary tissue, but it does not appear to reduce the iodide content of breast milk (see Chapter 3). As noted above, very small amounts of the NIS have been detected in other tissues, including the heart, kidneys, lungs, and placenta. Perchlorate is not known to cause congenital malformations, but the relationship has not been well studied. The adverse effects of perchlorate given to hyperthyroid patients are described in the preceding section. Note that the effects occurred only in patients with hyperthyroidism given very high doses (many years ago) and that the effects have not been described in any of the more recent studies in which perchlorate was given to patients with hyperthyroidism in lower doses but for periods as long as 2 years. The possibility that perchlorate will adversely affect the immune system was raised by suggestions that some of the side effects of high doses of perchlorateârashes, aplastic anemia, or agranulocytosisâmight have been immunologic responses. Whether those effects were caused by a direct
68 Health Implications of Perchlorate Ingestion toxic effect of perchlorate itself or a contaminant of it or by an immunologic reaction to the drug or a contaminant is not known. The fact that the effects were dose-dependent argues for direct toxicity rather than an immunologic reaction. An immunologic effect of perchlorate might also be suggested by the finding that serum concentrations of the antibodies that stimulate thyroid secretion in patients who have hyperthyroidism caused by Graves disease decline during treatment with antithyroid drugs, including perchlorate (Wenzel and Lente 1984). However, the decline in serum concentrations of those antibodies follows, rather than precedes, the drug-induced decrease in thyroid hormone secretion, and declines also occur in patients treated with other drugs, radioiodide, or thyroidectomy. Regarding a possible immunologic effect of perchlorate, a letter to the editor in 1984 reported that incubation of perchlorate at 0.12 or 1.2 mg/mL with lymphocytes of healthy people for 10 days inhibited immunoglobulin production and lymphocyte transformation (Weetman et al. 1984). However, it is not possible to assess potential clinical effects from experiments in which high doses of perchlorate were added directly to immune cells in vitro. In summary, there is no evidence that regular ingestion of perchlorate in any dose causes immunologic abnormalities in humans. REFERENCES Abalovich, M., S. Gutierrez, G. Alcaraz, G. Maccallini, A. Garcia, and O. Levalle. 2002. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 12(1):63-68. al-Adsani, H., L.J. Hoffer, and J.E. Silva. 1997. Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replace- ment. J. Clin. Endcrinol. Metab. 82(4):1118-1125. Allan, W.C., J.E. Haddow, G.E. Palomaki, J.R. Williams, M.L. Mitchell, R.J. Hermos, J.D. Faix, and R.Z. Klein. 2000. Maternal thyroid deficiency and pregnant complications: Implications for population screening. J. Med. Screen. 7(3):127-130. American Heritage. 2003. Childrenâs Science Dictionary. Houghton-Mifflin Company. Andersen, S., K.M. Pedersen, I.B. Pedersen, and P. Laurberg. 2001. Variations in urinary iodine excretion and thyroid function. A 1-year study in healthy men. Eur. J. Endocrinol. 144(5):461-465. Bartalena, L., S. Brogioni, L. Grasso, F. Bogazzi, A. Burelli, and E. Martino. 1996. Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: Results of a prospective study. J. Clin. Endocrinol. Metab. 81(8):2930-2933.
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