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Appendix A Thyroid Function in Health and Disease THE HUMAN THYROID The discussion that follows describes in technical terms the role and function of the thyroid gland in health and disease, and provides a brief description of racial differences that have been observed. The purpose is to put into perspective why the thyroid was a likely study candidate in the 1950s for research in accInnatization to cold in the AAL thyroid study (Rodah! and Bang, 1957) and why radioactive iodine was utilized. The thyroid gland is one of several glands in the body that makes and secretes hormones necessary for life. The hormones entering the bloodstream have biochemical effects on certain targeted body tissues. In humans the thyroid consists of two lobes in the lower part of the neck, on either side of the windpipe (trachea). These are the left and right lobes, which in turn are connected by a thin strand of thyroid called an isthmus that is located at or near the Adam's apple in the neck (cricoid cartilage). The level and activity of the thyroid is regulated by thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland, a peanut- sized organ located just beneath the brain that regulates various aspects of the body's growth, development, and functioning. The thyroid hormones, thyroxine (T4) arid 3,5 ,3'-triiodothyronine (T3), are important to growth and development of the fetus and child, and they regulate metabolic processes in essentially all tissues throughout life. The thyroid gland) is the only known source of T4. T4 is also metabolized in some peripheral tissues to a more active hormone, 3,5,3'-T3 by one enzyme or to a less active substance, 3,3',5'-T3 (reverse T3, rT3) by the action of a different enzyme (Chopra, 19911. 75 iThe thyroid gland also produces some T3, but the bulk (~75 percent) of T3 is produced outside of the thyroid in extrathyroidal tissues (e.g., liver and kidney) by enzymatic conversion of T4 to T3. T3 is some three to five times more active than T4 in two important effects of thyroid hormones: increase of oxygen consumption and suppression of TSH secretion by the anterior pituitary gland. Reverse T3 is only 1 percent as active as T4 in these two actions; its biological significance is not well understood at this time.

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defect in TBG synthesis. 76 The ALL Thyroid Function Study ROLE OF IODINE IN THYROID FUNCTION AND DIAGNOSTIC TESTS Iodine is a critical element in the normal production of thyroid hormones. The iodine is derived from iodide included in the diet. A typical dietary intake of iodide in the United States is approximately 500 micrograms (,ug) per day' 200-300 ,ug in the eastern states and 500- 750 fig in California. The main sources of iodide are water, bread, salt, kelp seaweed, and certain medicines. Iodide is nearly completely absorbed from the gastrointestinal tract and enters the inorganic pool in the extracellular fluid. The thyroid gland picks up some 75 fig of iodide per day for synthesis of thyroid hormones, and the rest is cleared (excreted) by the kidneys. When the dietary intake of iodide is reduced, the thyroid increases its uptake of iodide in the extracellular fluid, and vice versa. This is done in order to maintain normal amounts of thyroid hormone synthesized by the thyroid. Understanding this important concept of the regulation of thyroidal uptake of iodide became the basis for using thyroidal uptake of radioactive iodine (radioiodide) as an index measurement of thyroidal function. Since the dietary intake of iodide by Americans has increased from approximately 150-200 ,ug/day in 1950 to 200-750 ,ug/day after the 1970s, mainly from increased content of iodide in bread, the normal 24-hour thyroidal radioiodine uptake has decreased from 20-50 percent to 10-25 percent. Thyroidal uptake of radioactive iodine is typically increased in the condition known as hyperthyroidism. In this condition, the thyroid gland becomes overactive and produces large quantities of thyroxin, which in turn speeds up all chemical reactions in the body. Radioactive iodine uptake in the thyroid is typically decreased in a condition known as hypothyroidism, but there are some exceptions to this rule. In hypothyroidism, the thyroid produces only small amounts of thyroid hormone, and the body's chemical processes slow down (Greenspan and Rapoport, 1983~. The thyroid secretes ~75 fig of organic (hormonal) iodine daily, mainly as T4 and a small amount as T3 or rT3. Secreted thyroid hormones circulate bound tightly to three blood serum proteins: thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA, transthyretin) and albumin. Only a small proportion of T4 (~0.03 percent) and T4 (~0.3 percent) is free, and it is this small fraction of total thyroid hormones that constitutes the biologically active thyroid hormone (Chopra and Solomon, 1979~. At the present tune, blood serum total T4 concentration is generally measured by a sensitive radioimmunoassay. Radioimmunoassay is the measurement by radioactive detectors of concentrations of radioactive tracer substances in body organs, tissues, or serum. The normal serum T4 ranges between 5 and 12 micrograms per deciliter (pg/dl). Serum To concentration is increased in hyperthyroidism and decreased in hypothyroidism. It is also increased when serum concentration of TBG, the most avid T4-binding protein, is increased, and vice versa. Serum TBG is commonly increased in patients taking the hormone estrogen. On the other hand, serum TBG concentration is decreased during treatment with the hormone androgen, or by a congenital Like T4 serum, T3 concentration can also be measured by a radioimmunoassay. Serum T3 concentration normally approximates one-seventieth that of T4 (70-200 ng/dl) in serum. T3 is increased in hyperthyroidism and is normal or decreased in hypothyroidism (Greenspan and Rapoport, 1983). In the 1950s, the above-mentioned sensitive and specific measurements of thyroid hormones were not available. Instead, circulating thyroid hormone level was estimated from the measurement of protein-bound iodine (PBl). This.measurement took advantage of two . . J J .,

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Appendix A 77 characteristics of thyroid hormones: (~) they circulate predominantly (greater than 99 percent) bound to serum--proteins; and (2) iodine constitutes the bulk of the weight of thyroid hormone (65 percent in the case of T4 and 59 percent in the case of T31. Serum PBI level is increased in hyperthyroidism and decreased in hypothyroidism. Contamination with iodide frequently caused a (misleading) elevation of PBI as a test of thyroid function (Quimby et al., 1958; BlahU, 19651. Besides the measurement of serum thyroid radioactive iodide uptake (RAlU), radioiodine was used to estunate thyroidal activity by measurement of other parameters in the AAL thyroid study. These parameters included urinary excretion of radioiodine (~3~), ratio of salivary excretion of IN to total DIasma Till and plasma PBli3~. conversion ratio. and plasma levels of PA. The tests are discussed below because they are pertinent to the study under examination; a more detailed description of the methodology is available elsewhere (Chopra and Solomon, 1979; Quimby et al., 19581. Such tests are not employed for evaluation of thyroid function today because better methods are now available. URINARY AND SALIVARY EXCRETION STUDIES Since iodide circulating in the body is ultimately disposed of by two competing mechanisms, thyroidal uptake and urinary excretion, urinary excretion bears a reciprocal relationship to thyroidal uptake and is an indirect measure of thyroid function. Thus, a higher amount of excreted iodide in the urine is an indication of reduced uptake in the thyroid. Urinary excretion of less than 30 percent of the tracer dose (5 to 50 microcuries [,uCi] of lit) in 24 hours suggests hyperthyroidism because the thyroid may be harboring more of the iodide for production of thyroid hormones. Excretions in excess of 40 percent are usually associated with normal or decreased thyroid function. There is a significant degree of overlap in test results between normal subjects and hyperthyroid or hypothyroid patients. Salivary }~3{ and ratio of salivary ll31 to total plasma }~3} and plasma PB! salivas iodide reflect the level of plasma inorganic iodide. When radioiodine is administered to hyperthyroid patients, plasma is rapidly cleared of inorganic iodide and therefore the concentration of radioiodine is decreased in the saliva. In hypothyroidism, radioiodine persists in the plasma and therefore the salivary excretion of radioiodine is increased (Chopra and Solomon, 1979; Quimby et al., 19581. CONVERSION RATIO AND PLASMA LEVELS OF PBli3~ These tests depend on the conversion of iodide trapped by the thyroid to organically bound thyroid hormone, and the secretion of this hormone into the circulation of the bloodstream. There, as noted previously, it is bound by serum proteins and can therefore be separated from iodide by a variety of methods. The conversion ratio is determined at a fixed tune, usually 24 hours, after oral administration of a tracer dose ~ ~ 50 loci) of radioiodine. It is expressed as a ratio (in percent) of protein-bound radioiodine in the plasma to the total plasma radioiodine. The ratio is increased in hyperthyroidism and decreased in hypothyroidism. Renal (kidney) insufficiency and congestive heart failure reduce renal clearance of radioiodine and

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The ALL Thyroid Function Study would diminish the diagnostic value of this test in hyperthyroidism. Plasma levels of PBI~3~ are measured typically at about 72 hours after oral administration of ~25 ,uCi of radioiodine Ilk. Levels are expressed as a percentage of the administered dose per liter of plasma. PBIi3i is elevated in hyperthyroidism and diminished in hypothyroidism. RACIAL DIFFERENCES IN THYROID FUNCTION The effect of race has been examined carefully only in a limited number of studies. While in a very few instances variations have been found on the basis of racial differences, other causes may play a role. In one large study of 1,020 men and 575 women in Jerusalem, serum To was higher in females than in males. Similarly, serum To was higher in 17-year-old boys than in adult men. Serum T4 was also higher in Israelis originating from Asian and Middle Eastern countries than in those immigrating from Western countries (Slater et al., 1984). In a second study, serum TSH level was found to be lower in American blacks than in whites after adjustment for age and sex, and the difference explained ~ 6.5 percent of the variation in TSH levels (Schect~nan et al., 1991). In a third study, prevalence of hypothyroidism was greater in whites than in blacks, in women, and in subjects over 75 years of age (compared with the 55-64-year-old age group (Bagchi, et al., 1990). Thyroid hormone and/or TSH levels are altered in subjects in some regions because of an effect of prevalent iodine deficiency (Cooper et al., 1993) or abnormalities in serum thyroid hormone-binding proteins (Dick and Watson, 1980). Thus, serum concentration of TBG is much lower in Aborigines in western Australia than in white Australians, and this is associated with decreased serum concentration of total thyroid hormone levels. The AAL, study by Rodahl and his Air Force colleagues (Rodahl and Bang, 1957) did not demonstrate a significant clear difference in thyroidal RAIN, salivary or urinary excretion of radioiodine, or the conversion ratio and PBI~3i of coastal Inupiats and Athabascan Indians compared with white soldiers and airmen. The RAID was elevated in inland Inupiats and mountain Athabascan Indians, and this was attributed to decreased intake of iodide in these populations. Rodahl did not observe a significant effect of seasons on thyroid function parameters. More recently, Tkachev and colleagues (1991) have studied the effect of daylight duration on serum TSH and thyroid hormone levels in polar inhabitants. They noted that serum TSH and T3 increased and serum T4 and cholesterol decreased with the lengthening of daylight duration. Reed, Brice, and colleagues (199Oa) have recently described increased serum binding, yet the increased metabolic clearance rate and daily production rate of T3 increased in white men who lived in Antarctica for more than five continuous months; the authors named this change the "polar T3 syndrome" (Reed et al., 19901. UTILIZATION OF li3} AS A DIAGNOSTIC TOOL IN was the first radioiodine to be employed in clinical studies and has a half-life of only 12.6 hours. It was followed by the use of {~3i' with a half-life of eight days, which could be

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Appendix A 79 produced relatively inexpensively in large quantities; its useful gamma radiation made it the isotope most commonly used in clinical investigation in the 1950s. li25 was tested in thyroid studies in the 1960s; its lower radiation energy caused less radiation exposure to the patient than |~3i, even though }~25 has a much longer half-life (60 days as opposed to ~ days). However, absorption and retention of l]25 by overlying tissue was its major disadvantage over the use of ~3~. }~3{ has now been replaced for clinical use by }~23. This radioisotope causes much less radon exposure tO the patient because it has a short half-life (13 hours) and it emits very few or no beta particles during that tune. The dn.se of Ti3i used for thvrnidal radioactive in~lirle Intake v~ri~1 with the ~.n~itivi~v _ ~! ~^ ~-^ ~ of detecting equipment. Approximately 50-250 ,uCi was employed when Geiger-Muller tubes were used as detectors. With the availability of efficient scintillation systems with wide-angle amiable radiation collection systems and markedly enhanced sensitivity, it became possible to reduce the dose of ii3{ needed for thyroid uptake to about 5 loci. The dose of li3] recommended for measurement of salivary ~3i excretion, conversion ratio and PBli3i approximated 50 psi, and this dose was used in the AAL thyroid experiments. }~3{ has also been used for scanning of the thyroid to examine the morphology of the thyroid, and also to evaluate the relative function of different portions of the thyroid. The dose recommended for this purpose approximated 300 ,uCi (Quimby et al., 1958; Bauer et al., 1953~. CONTRAINDICATIONS TO TO USE OF }~3} Pregnancy and lactation have been considered absolute contraindications for the use of |~31 in treatment of hypothyroidism (Edmonds and Smith, 19861. No such guidelines are described for diagnostic use of microcurie quantities of ]~31 in pregnant and lactating women. However, most medical centers have avoided use of Ti3i in pregnant and lactating women, and this was also the practice during the period of the 1950s AAL study. Literature review suggests that 400 reds or more of radiation dose is required to cause significant oocyte loss from the gonads (Baker, 19711. This degree of radiation exposure occurs only after therapeutic doses of {~3], not at the levels recorded in the ML experiments. Interestingly, fertility has been observed to remain normal even after therapeutic dosage treatments (Edmonds and Smith, 19861. One case has been described in a woman who was administered li31 at therapeutic levels inadvertently during the first week of pregnancy and a high concentration of radioactivity was observed in the pregnant uterus (Cox et al., 19901. Exposure to radiation was considered to be a factor involved in the occurrence of abortion, in this case, at eight weeks of gestation (Romney et al., 19891. Radioiodide is transported freely across the placenta into the fetus. Administration of millicurie doses of li31 during pregnancy can adversely affect and even ablate the fetal thyroid after 10 weeks of gestation, when the fetal thyroid becomes capable of accumulating iodine (Green et al., 1971; Shepard, 19671. In men, a high dose of }~3} (~350 mCi), as needed for treatment of thyroid cancer, was reported to have been followed by occurrence of testicular failure in one case (Ahmed and Shalet, 19851. Radioiodide is concentrated in the breast tissue, especially during lactation (BauemIer, 1986; Dydeck and Blue, 1988; Hedrick et al., 1987; Lawes, 1992; Romney et al.; 1989), and therefore it has been recommended that a mother stop breastfeeding up to 14 days after

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80 The A~4L Thyroid Function Study radioiodide has been administered to her (Lawes, 1992; Romney et al., 1989). Some suggest that no radioiodine studies should be done in women who wish to continue breastfeeding (Dydeck and Blue, 19881.