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THYROID PHYSIOLOGY

This chapter provides background information on thyroid function, physiological need for and sources of iodine, benefits and harms of radioiodine, and benefits of and risks posed by potassium iodide administration.

Overview of Thyroid Function

The iodine-rich thyroid hormones thyroxine (T4) and triiodothyronine (T3) are necessary for growth and development and they stimulate all aspects of cell metabolism, including protein synthesis and oxygen consumption. The synthesis of T4 and T3 takes place through a complex series of enzymatic steps on the interface between the thyroid follicular cell and the large protein thyroglobulin. Thyroid peroxidase is the major enzyme responsible for the oxidation (organification) of the iodine actively transported from the blood into the thyroid by the sodium-iodide symporter (NIS), the addition of the



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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident 2 THYROID PHYSIOLOGY This chapter provides background information on thyroid function, physiological need for and sources of iodine, benefits and harms of radioiodine, and benefits of and risks posed by potassium iodide administration. Overview of Thyroid Function The iodine-rich thyroid hormones thyroxine (T4) and triiodothyronine (T3) are necessary for growth and development and they stimulate all aspects of cell metabolism, including protein synthesis and oxygen consumption. The synthesis of T4 and T3 takes place through a complex series of enzymatic steps on the interface between the thyroid follicular cell and the large protein thyroglobulin. Thyroid peroxidase is the major enzyme responsible for the oxidation (organification) of the iodine actively transported from the blood into the thyroid by the sodium-iodide symporter (NIS), the addition of the

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident oxidized iodine to the amino acid tyrosine to generate mono- and diiodotyrosine (MIT and DIT, respectively), and the coupling of a MIT and a DIT to generate T3, and two DITs to generate T4. T4 and T3 are then secreted into the peripheral circulation where they are tightly bound to plasma proteins, primarily the thyroid-hormone binding globulin (TBG), an inter alpha globulin. Very small fractions of the circulating hormones are not bound to TBG, and these free or unbound hormones are available to enter all peripheral cells. It is generally recognized that T3, not T4, is the bioactive hormone and that the major source of T3 is not the thyroid but, in the peripheral tissues, the removal of an iodine from the outer or phenolic ring of T4 by a selenoenzyme, 5'-deiodinase. T3 binds to T3 nuclear receptors in the cells of the peripheral tissues and stimulates a wide variety of genomic events that result in enhanced protein synthesis and increased metabolism. Central nervous system control of thyroid function resides in the anterior hypothalamus, which synthesizes and secretes a tripeptide, thyrotropin-releasing hormone (TRH), into the hypothalamic-pituitary portal circulation. TRH binds to the TRH receptor on the beta cells of the anterior pituitary to stimulate and release into the peripheral circulation the glycoprotein, thyroid-stimulating hormone (thyrotropin or TSH), which consists of an alpha (α) subunit and a beta (β) subunit. The β subunit binds to the TSH receptor on the basal cell surface of the thyroid cell, stimulates the synthesis of the iodine-rich thyroid hormones, T4 and T3, and releases them into the peripheral circulation. It is evident that to maintain normal thyroid function (euthyroidism), the synthesis of the thyroid hormones and their release from the thyroid must be under tight control. That is accomplished by the classical negative-feedback system so typical of endocrine systems. Thus, a small rise in the circulating free thyroid hormones results in a decrease in the release of TSH from the anterior pituitary and, less so, TRH from the hypothalamus, thereby decreasing T4 and T3 synthesis and their release from the thyroid and maintaining euthyroidism. In contrast, a small decrease in circulating T4 and T3 concentrations enhances the release of TSH from the anterior pituitary and, less so, TRH from the anterior hypothalamus

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident and results in stimulation of the thyroid to maintain serum T4 and T3 concentrations in the normal, euthyroid range. Changes in circulating T4 and T3 concentrations will result in far greater changes in the serum TSH concentration; this emphasizes the sensitivity of TSH secretion in maintaining euthyroidism. Overt hyperthyroidism is associated with increases in the serum free T4 and T3 concentrations and suppression of the serum TSH concentration. In contrast, overt hypothyroidism will result in decreases in the serum free T4 and T3 concentrations and an increase in the serum TSH concentration. Abnormalities in thyroid function may be mild and are usually diagnosed on the basis of low or high serum TSH and normal circulating free T4 and T3 concentrations; again, this emphasizes the use of serum TSH in diagnosing thyroid dysfunction. Physiologic Need for Iodine and Sources of Iodine It has been recognized for more than 50 years that iodine is an essential component of the thyroid hormones, T4 and T3, and that severe iodine deficiency (less than 50 μg iodine intakes daily) is the major cause of mental retardation and endemic goiter and cretinism worldwide. Major efforts have been made over the last decade to eradicate iodine deficiency, and remarkable success has been achieved. However, much work remains, and careful continued monitoring of populations is necessary to confirm that proper iodine intake continues. The major and most efficient method to provide iodine to a population is the dietary use of iodized salt, but production and stability pose problems in many areas of the world. Other methods include the ingestion of iodized oil (lasts for about a year after a single dosage), iodination of the central water system (which is also antimicrobial), use of iodinated water to irrigate crops, and addition of iodine to animal feed. In the United States and other countries, dairy products, especially milk, are important sources of iodine because of the use of iodophors in the dairy industry. Fish is also an important dietary source of iodine. Daily average iodine intake in the United States decreased from about 300 μg in 1971-1974 to about 150 μg in 1988-1994

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident (Hollowell et al., 1998). Preliminary data from the current National Health and Nutrition Examination Survey (NHANES IV) suggests that daily iodine intake remains about 150 μg. This amount of iodine is appropriate for normal adult thyroid function, except for pregnant and lactating nursing women in whom 220 μg and 290 μg iodine daily, respectively, is recommended. The thyroid responds to dietary iodine deficiency by enlarging and more actively transporting iodine from the blood, thereby concentrating sufficient iodine to maintain normal function. In contrast, when iodine ingestion is excessive, the thyroid decreases the transport of iodine from the blood into the thyroid. The mechanism responsible for the adaptation of the thyroid to excess iodine is described below. It has been recognized since the 1940s that excess iodine exposure causes a transient decrease in thyroid-hormone synthesis for about 48 hours—called the acute Wolff-Chaikoff (W-C) effect (Wolff et al., 1944)—and that normal thyroid-hormone synthesis resumes shortly thereafter despite continued ingestion of excess iodine (adaptation to or escape from the acute W-C effect) (Wolff et al., 1949). The transient inhibition of hormone synthesis is most likely due to the generation of an iodinated lipid or an iodolactone that inhibits thyroid peroxidase activity and the oxidation of iodine, iodination of tyrosines, and the coupling of the iodinated tyrosines MIT and DIT to generate T4 and T3 (Pisarev and Gartner, 2000). The escape from the acute W-C effect was postulated to be due to a decrease in the active transport of iodine from the blood to the thyroid that decreased intrathyroidal iodine and allowed normal thyroid hormone synthesis to resume (Braverman and Ingbar, 1963). The cloning of the NIS in 1996 by Dai et al. (1996) provided a unique opportunity to restudy the W-C effect in the rat. In 1999, Eng et al. (1999) reported that during the first 24 - 48 hours of excess iodine ingestion, there was a marked reduction in thyroid NIS mRNA and NIS protein that persisted during continued ingestion of iodinated water. Thus, escape from the acute W-C effect is due at least partially to the decrease in NIS and the iodine trap and later decrease in intrathyroidal iodine. Excess iodine ingestion by healthy subjects may slightly decrease the secretion of T4 and T3 from the thyroid

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident with a small compensatory rise in the serum TSH to maintain the serum T4 and T3 concentrations well within the normal range. Thus, many studies have reported that pharmacologic quantities of iodine given to healthy volunteers (without underlying thyroid disease) will induce small decreases in serum T4 and a compensatory small rise in serum TSH; both remain well within the normal range. Those findings indicate that healthy subjects can ingest excessive quantities of iodine for a long period of time, i.e. escape from the acute W-C effect, and maintain the euthyroid state. Radioactive Iodine Medical Uses Radioactive iodine plays an important role in the diagnosis and treatment of various thyroid disorders. The two iodine isotopes used for those purposes are 123I, primarily a gamma-emitter with a short physical half-life of 13 hours, and 131I, a beta- and gamma-emitter with a longer physical half-life of 8 days. Since greater cellular damage or cell death is produced by the higher energy beta emissions of 131I than by the gamma emissions of either isotope, 123I is now the preferred choice for diagnostic studies of the thyroid. Its short half-life and its mainly gamma emission reduce potential radiation effects on the thyroid. The ability of the thyroid to concentrate iodine permits the use of radioiodine to quantify the iodine-concentration activity of the thyroid because the isotope equilibrates with blood iodine and reflects the uptake of stable (nonradioactive) iodine into the thyroid. Thyroid radioiodine uptake is elevated in patients with hyperthyroidism, is usually low in hypothyroid patients, and varies inversely with iodine intake. Thus, the radioiodine uptake will be higher than normal in subjects with low iodine intake and lower in subjects with high iodine intake. The former probably occurred in Chornobyl because of dietary iodine deficiency, and the latter would occur in Japan, where iodine intake is high. The ability of the thyroid to concentrate radioiodine also permits visualization of the thyroid with appropriate

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident imaging instruments to determine its location, configuration, and the functional status of thyroid nodules if they are present. Radioiodine concentrated by the thyroid in large amounts can cause cell death primarily because of 131I’s beta radiation. Large doses of 131I are, therefore, given to treat patients with hyperthyroidism; those who have large nodular goiters that are causing local compressive symptoms on the trachea and esophagus, and those who cannot tolerate thyroid surgery; and to ablate functioning residual normal or malignant thyroid tissue after definitive surgery for thyroid cancer. The very large doses used to treat thyroid cancer occasionally lead to radiation-induced salivary gland inflammation and loss of taste because iodine is also concentrated by the salivary glands. Harmful Effects A large amount of 131I delivered to the thyroid almost always leads to hypothyroidism because of permanent radiation-induced destruction of thyroid cells. Therefore, with a smaller population of vulnerable thyroid cells remaining, these large radiation doses from 131I are much less likely to cause thyroid cancer. In contrast, a surprising number of children exposed to a relatively low radiation dose from 131I and possibly other shorter-lived isotopes of iodine after the 1986 Chornobyl accident developed thyroid cancer within a few years. There are several potential reasons for the differences between the medical use of radioactive iodine and exposure to radiation fallout in causing thyroid cancer. As noted above, large amounts of 131I can result in thyroid-cell death. In contrast, low-dose exposure damages but does not kill thyroid cells and can induce nuclear damage and mutations, which can result in thyroid cancer. Radioiodine released to the atmosphere may likely include a number of shorter-lived isotopes of iodine in addition to 131I, which are also potentially carcinogenic.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Because their thyroid-cells divide more frequently than in adults, children are at far greater risk of nuclear mutations and thyroid cancer when exposed to low level radiation to the thyroid. As noted earlier, the presumed low dietary iodine intake in the Chornobyl area probably resulted in an increased uptake of radioactive iodines. How KI Works Under normal circumstances, excess iodine decreases NIS on the thyroid-cell surface, thereby inhibiting the further entrance of iodine into the thyroid. Excess iodide administration at the appropriate time decreases the thyroid radioactive iodine uptake (RAIU) by decreasing NIS and by increasing the amount of nonradioactive iodine available for binding to thyroid cells. In the event of release of radioiodine from a nuclear incident, a marked decrease in thyroid RAIU could be achieved by the timely administration of stable iodine that would be extremely useful in reducing internal radiation to the thyroid caused by exposure to iodine radioisotopes from inhalation or by consumption of radioiodine-contaminated foods, especially milk, other dairy products, and leafy vegetables. In healthy volunteers, thyroid uptake of radioactive iodine has been reported to be essentially blocked for at least 24 hours by administration of 30-200 mg of stable iodine, administered in the form of KI, just before and minutes after exposure. If KI is given one to three hours after exposure to radioactive iodine, further thyroid radioiodine uptake (that is, beyond what is already in the thyroid) is blocked for at least 24 hours. The inhibitory effect on the thyroid RAIU of a single dosage of 130 mg of iodine as KI lasts for about 48 hours. Even if KI is given 8 hours after exposure to radioiodine, the normal uptake of 28% of the radioiodine would be reduced by about 40% to an uptake of about 16% (see Table 2.1). However, it should be noted that if KI is given first 2 to 3 days after 131I exposure, there is some concern that the retention of the 131I would be slightly

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident prolonged, theoretically enhancing the radiation effect of the retained 131I. Because of normal prolonged retention of radioiodine by the thyroid (half-life 80-120 days) further slowing of thyroid discharge by subsequent KI is likely to be small. If 131I continues to be detected in the air at concentration capable of producing a thyroid dose of 5 Gy (500 rad) or more, then KI should be given. Table 2.1 Percent Thyroid Protection from 131I after a Single 130 mg Dosage of KI Time of KI with Respect to 131I Exposure (hours) Protection Afforded KI Ingestion (% of control) -96 Very little -48 ~80 -1 ~100 0 98 2 80 3 60 8 40 24 16 a Data at 0 and 3 hours from experimental observations (Blum and Eisenbud, 1967, Sternthal et al., 1980, Ramsden et al., 1967); other data derived from models of iodine metabolism (Zanzonico and Becker, 2000). Why KI is Used KI is readily available, inexpensive, and stable, and it has a long shelf-life if tablets are stored in a blister package to prevent exposure to light and moisture. Although iodate is used in some European countries and is also stable, it has traditionally not been used as a blocking agent in the United States and is not as readily

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident available as is KI. KI tablets are the only form of iodine approved by the Food and Drug Administration (FDA) for use as a blocking agent. Other antithyroid drugs have been proposed to block the entrance of iodine into the thyroid, including thiocyanate and perchlorate. The former is too toxic, and the latter may not be acceptable due to concerns over the unproven adverse thyroid effects of the trace amounts of perchlorate that are in groundwater in at least 14 states (Engell and Lamm, 2003). Current Recommended Use of KI in the Event of a Nuclear Incident According to the WHO Guidelines for Stable Iodine Prophylaxis Following Nuclear Accidents, the uptake of radioiodine by the thyroid is effectively blocked by administration of 100 mg of stable iodine, corresponding to 130 mg of KI or 170 mg of potassium iodate, KIO3, in adults and adolescents. For children, the administered dosage of KI must be reduced. Table 2.2 summarizes single dosage of stable iodine for different age groups recommended by WHO in 1999. According to the IAEA International Basic Safety Standards, the generic optimized intervention level for iodine blockade is 100 mGy (10 rad) of avertable committed absorbed dose to the thyroid due to radioiodine. Iodine prophylaxis is recommended when this postulated dose is exceeded. The lifetime thyroid cancer risk to exposed children, the most vulnerable population, is estimated by WHO at 1% per Gy (1% per 100 rad) and the risk of severe side effects from a single administration of stable iodine at 10-7 (WHO, 1999). WHO recommends an age-specific intervention level for this group of 10 mGy (1 rad) of avertable dose to the thyroid (one-tenth of the IAEA generic optimized intervention level). WHO considers that justified because, even with the lower intervention level—some 2 to 5 extra thyroid cancer cases per 1,000,000 children exposed per year are expected, which is still several times higher than the generally encountered background incidence (WHO, 1999).

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Table 2.2 Recommended Single Dosage of Stable Iodine to Block Radioiodine Uptake According to Age Group Age group Mass of Iodine mg Mass of KI mg Mass of KIO3 mg Fraction of KI 130-mg Tablet Adults and adolescents (over 12 years old) 100 130 170 1 Children (3-12 years old) 50 65 85 ½ Infants (1 month to 3 years old) 25 32 42 ¼ Neonates (birth to 1 month old) 12.5 16 21 1/8   Source: WHO, 1999. Table 2.3 summarizes the reference levels for the implementation of iodine blockade recommended for different age groups by WHO in 1999. WHO recommends different intervention levels for different age groups and pregnant and lactating women. The intervention level for neonates, infants, children, and adolescents up to 18 years old and for pregnant and lactating women is, because of the higher radiation risks in this group, only one-tenth of that for adults up to 40 years old. But because the risk of thyroid cancer is very small in adults over 40, WHO recommended iodine blockade only in the case of very high exposure—more than 5 Gy (500 rad),

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident which may cause thyroid effects other than cancer (such as hypothyroidism). Table 2.3 WHO Reference Levels for the Implementation of Iodine Blockade for Different Age Groups Population Exposure Pathway To Be Considered Reference Level Neonates, infants, children, adolescents up to 18 years old and pregnant and lactating women Inhalation (and ingestionb) 10 mGyc avertable dose to thyroid Adults up to 40 years old Inhalation 100 mGyc avertable dose to thyroid Adults over 40 years old Inhalation 5 Gyd projected dose to thyroid aThese levels do not take into account the practicalities involved in planning to respond to an accident involving many radionuclides in unknown quantities in real time. For this reason, a generic intervention level of 100 mGy (10 rad) has been specified in the International Basic Safety Standards; but it does not obviate consideration of the IAEA practicality of planning to implement iodine prophylaxis for specific age groups. bIngestion of milk by infants where alternative supplies of milk cannot be made available. cAdherence to these values would ensure that doses for all age groups would be well below the threshold for deterministic effects. dIntervention undertaken to ensure prevention of deterministic effects in the thyroid. 5 Gy (500 rad) is recommended lower limit for deterministic effects given in International Basic Safety Standards. Source : WHO, 1999.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident On the basis of WHO, 1999 and FDA, 2001a guidelines, we recommend that dosage of stable iodine according to age groups be as follows (Table 2.4): Table 2.4 Predicted Thyroid Exposures to Radioactive Iodines and Recommended Dosages of KI for Different Risk Groups Group Predicted Thyroid Exposure (mGy)a KI Dosage (mg) No. of 130 mg KI Tablets (100 mg I) No. of 65 mg KI Tablets (50 mg I) No. of 32 mg KI Tablets (25 mg I) Adolescents and Adults 12 - 40 Years Old           Pregnant and Lactating Women ≥50 130 1 2 4 Children 3 - 11 Years Old   65 ½ 1 2 Infants 1 Month to 3 Years Old   32 ¼ ½ 1 Neonates Birth to 1 Month Old   16 1/8 ¼ ½ a50 mGy is equivalent to 5 rad. The single intervention level of 50 mGy (5 rad) for all exposed people under the age of 40 years was chosen based upon the FDA guidelines for pregnant women, infants, and children (FDA, 2001a). The KI dosage levels are based on recommendations accepted by many other bodies, including the WHO, and when taken appropriately, are levels known to block almost all the thyroid uptake of radioiodine. We also recommend that this threshold for intervention be kept under review as further information on the consequences of exposure to radiation from fallout from Chornobyl and from other radiation incidents becomes available.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Since infants and children are most vulnerable to the thyroid cancer producing effect of radioactive iodine, appropriate scored KI tablets should be made available. A 32 mg scored KI tablet would be preferable to the currently available 130 mg and 65 mg tablets to more efficaciously and conveniently deliver the recommended KI dosage to the very young. The highest KI dosage could still be easily achieved by the ingestion of multiple tablets. The lactating woman presents a unique situation since the breast removes iodine from the blood which is then transported into breast milk. Approximately ¼ of iodine ingested by the mother is secreted into breast milk. An excess of stable iodine can partially decrease the transport of radioiodine into the breast. Thus, the mother must minimize her potential thyroid exposure to radioiodine by taking the recommended adult dosage of KI and ensure that the nursing infant be given KI as recommended for infants. Both mother and infant must take KI for both to be protected from thyroid radioiodine exposure. Adverse Effects of KI Few nonthyroidal side effects were observed after KI administration to a large population, including children, in Poland after the Chornobyl accident (Nauman and Wolff, 1993). Indeed, it would be difficult to attribute some reported effects, such as skin rashes and gastrointestinal symptoms, to a single administration of KI inasmuch as such mild events are common, especially in infants and children. Most of the potential nonthyroidal side effects reported although often unverified, are listed in Table 2.5. It should be understood that most of these are very rare. Extremely rare disorders reported to be aggravated by excess iodine ingestion include dermatitis herpetiformis Duhring, ioderma tuberosum, hypocomplementemia vasculitis, and myotonia congenita.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Table 2.5 Potential Nonthyroid Side Effects of KI Gastrointestinal Nausea, vomiting, diarrhea, and stomach pain Allergy-related Angioedema (generalized swelling) Arthralgia (joint pains) Eosinophilia (abnormal white blood cells) Lymphadenopathy (enlarged lymph nodes) Urticaria (itching) Skin Rashes People with underlying thyroid disease—such as autoimmune thyroiditis or nontoxic nodular goiter, both of which are more prevalent in the elderly and may occur in approximately 25 percent of older individuals, especially women—are at risk for iodine-induced thyroid dysfunction. People who develop iodine-induced hypothyroidism do not escape from the acute W-C effect described earlier under physiologic need for iodine and sources of iodine. Underlying thyroid disorders and other clinical situations that would predispose to iodine-induced thyroid dysfunction are listed in Tables 2.6 and 2.7 (Roti et al., 1997). People over 40 years old appear to be more resistant to the thyroid-cancer causing effects of 131I exposure as well as to the underlying thyroid disorders that predispose to iodine-induced thyroid dysfunction occur later in life. Therefore, people over 40 probably should not take KI tablets after a nuclear incident as they are at virtually no risk of developing thyroid cancer from the radiation, and are more likely than younger people to develop side effects from the KI. In contrast with iodine-induced hypothyroidism, excess iodine ingestion may induce hyperthyroidism or Iod Basedow disease, especially in regions of iodine deficiency, including many countries in Western Europe.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Table 2.6 Risk Groups for Iodine-Induced Hypothyroidism No underlying thyroid disease   Fetus and neonate, mostly preterm     Secondary to transplacental passage of iodine or exposure of neonate to topical or parenteral iodine-rich substances   Infant     Occasionally reported in infants drinking iodine-rich water   (China) Adult     In Japanese subjects with high iodine intake where Hashimoto’s thyroiditis has been excluded   Elderly     Reported in elderly subjects with and without possible defective organification and autoimmune thyroiditis   Chronic nonthyroidal illness     Cystic fibrosis Chronic lung disease (including Hashimoto’s thyroiditis) Chronic dialysis treatment Thalassemia major Anorexia nervosa Underlying thyroid disease   Hashimoto’s thyroiditis Euthyroid patients previously treated for Graves disease with 131I, thyroidectomy, or antithyroid drugs Subclinical hypothyroidism, especially in the elderly After transient postpartum thyroiditis After subacute painful thyroiditis After hemithyroidectomy for benign nodules Euthyroid patients with a previous episode of amiodarone-induced destructive thyrotoxicosis Euthyroid patients with a previous episode of interferon-alpha-induced thyroid disorders Patients receiving lithium therapy

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Table 2.7 Risk Groups for Iodine-Induced Hyperthyroidism Underlying thyroid disease Iodine supplementation for endemic iodine-deficiency goiter Iodine administration to patients with euthyroid Graves disease, especially those in remission after antithyroid drug therapy Nontoxic nodular goiter Autonomous nodules Nontoxic diffuse goiter No underlying thyroid disease Iodine administration to patients with no recognized underlying thyroid disease, especially in areas of mild to moderate iodine deficiency Iodine may also be useful in some clinical situations other than a need to prevent iodine deficiency (Table 2.8). Table 2.8 Medical Uses of Stable Iodine   Treatment and prevention of iodine deficiency goiter Thyroid storm Preoperative preparation of toxic goiter Post 131I therapy of Graves disease As sole therapy of Graves disease (when sensitive to antithyroid drugs)