Thyroid Diseases
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Iodine and Thyroid Disease Kenneth A. Woeber, MD, FACP, FRCPE*
Iodine is a requisite substrate for the synthesis of the thyroid hormones L-thyroxine (T4) and L-triiodothyronine (T3)' The minimum daily requirement of iodine is generally considered to be about 50 f-Lg, but we may take in many times this quantity depending upon its availability in the environment, principally in the diet or in pharmaceuticals. Thus, we would be at the mercy of our iodine intake (in certain circumstances, this is indeed the case) were it not for the existence of regulatory mechanisms. These mechanisms serve to defend the near constancy of the rate of hormone synthesis and therefore of secretion in the face of wide fluctuations over the short term in the supply of iodine. However, when the supply of iodine falls below the minimum over the long term, the adaptation provided by regulatory mechanisms will not suffice and the pathologic consequences of iodine deficiency may ensue. Conversely, when the supply of iodine is excessive over the long term, especially when it is superimposed on the background of an intrinsic thyroid disorder, thyroid dysfunction may again result.
REGULATION OF THYROID FUNCTION The thyroid gland is virtually unique in possessing two regulatory mechanisms that are distinct yet operate in concert. First, the thyroid participates in a classic feedback system with the pituitary wherein the thyroid hormones regulate in a negative-feedback manner the secretion by the pituitary of thyroid-stimulating hormone (TSH). Triiodothyronine generated within the pituitary through monodeiodination of T4 arriving via the blood, as well as the T3 arriving directly via the blood, is the principal arbiter of this negative-feedback action. Thyrotropin-releasing hormone (TRH) of the hypothalamus appears to set the threshold of feedback control, but its regulation per se has not been fully defined, although the thyroid hormones may play some role in modulating its secretion. *Professor and Chief of Medicine, Mount Zion Medical Center of the University of California San Francisco, San Francisco, California
Medical Clinics of North America-Vo!' 75, No. 1, January 1991
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The second regulatory mechanism resides within the thyroid gland itself and is termed autoregulation. Autoregulation serves to maintain a pool of organic iodine, i. e., principally the thyroid hormones and their immediate precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT), within the thyroid. This is accomplished through a negative-feedback relationship existing between the size of the organic iodine pool and both the activity of the iodide transport mechanism and the sensitivity of the gland to TSH. Thus, autoregulation serves as the first line of defense against fluctuations in the supply of iodine. When autoregulation is no longer able to defend a normal rate of hormone synthesis and secretion in the face of a deficiency of iodine, activation of the hypothalamic-pituitary axis will ensue. Finally, autoregulation permits escape from the inhibition of hormone synthesis that a very large quantity of iodine induces (Wolff-Chaikoff effect and escape therefrom), thereby forestalling the development of goiter and hypothyroidism (vide infra).
IODINE DEFICIENCY Environmental iodine deficiency continues to be a major public health problem worldwide. lo Although it has been largely eradicated in Europe through the implementation of iodization programs and diversification of the diet, it is still prevalent in underdeveloped areas of South America, Asia, Africa, and Oceania. Iodine-deficient soil is encountered in high mountainous areas, such as the Andes and Himalayas, because of the washing away of iodine that occurs through glacial action. It is also encountered in valleys, such as the Ganges valley of India, where high rainfall and flooding are frequent. Staple foods as well as pastures cultivated in such soil are deficient in iodine and result in iodine deficiency in the indigenous population. Iodine intake can be estimated from the rate of urinary iodine excretion because iodine is virtually completely absorbed from the alimentary tract and cleared principally by renal excretion. When urinary iodine is less than 25 j-Lg/day, go iter is endemic in the community and the other consequences of iodine deficiency are present (Table 1). In some regions, such as Zaire, environmental iodine deficiency is aggravated by other dietary goitrogens; for example, certain staple foods, such as cassava, contain cyanoglucosides that are transformed to thiocyanate, a potent goitrogen, after absorption. Endemic goiter represents an adaptation to iodine deficiency that is brought about both by autoregulation and by an increase in TSH. These regulatory responses lead to increased iodide transport and to a disproportionate synthesis of T3 relative to T4 • This latter alteration reflects a more efficient utilization of the available iodine because T3 possesses only 75% as much iodine as T4 yet is approximately threefold more potent. Consequently, many inhabitants will not display clinical hypothyroidism, and laboratory testing will disclose essentially normal values for serum T 3 concentration despite subnormal values for serum T4 and increased values for serum TSH. As would be predicted, the thyroid uptake of radioiodine is increased, reflecting both the contraction of the body iodide pool and
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Table 1. Pathologic Consequences of Iodine Deficiency Endemic goiter ± hypothyroidism Neurologic endemic cretinism Myxedematous endemic cretinism Increased prevalence of cognitive and neuromotor disabilities Increased fetal and infant mortality
the effects of autoregulation and hyperstimulation by TSH. In older adults, the chronic hyperstimulation by TSH may ultimately result in the development of autonomous foci within the thyroid and set the stage for the emergence of iodine-induced thyrotoxicosis (Jod-Basedow disease) when ample quantities of iodine are provided (vide infra). From a public health standpoint, however, the major impact by far of iodine deficiency is upon fetal and childhood development. In its most extreme form, it results in endemic cretinism. Nonetheless, even in the absence of cretinism, the prevalence of intellectual and neuromotor disabilities is increased in the inhabitants of iodine-deficient areas,17 perpetuating the socioeconomic underdevelopment of the community. Endemic cretinism may take several forms-neurologic endemic cretinism, myxedematous endemic cretinism, and a mixed form depending on the timing and duration of severe iodine deficiency. Severe maternal iodine deficiency that is limited to early gestation during a critical phase of fetal development is thought to be responsible for the irreversible mental deficiency, deaf mutism, and spastic pareses that characterize neurologic endemic cretinism. On the other hand, severe iodine deficiency dating from early infancy results in myxedematous endemic cretinism, which is characterized by mental deficiency and growth retardation, but without the neurologic sequelae cited previously. In many older endemic cretins, goiter is lacking, and on necropsy examination, the thyroid is atrophic. The mechanism underlying this so-called exhaustion atrophy has not been elucidated, but it accounts for the reported failure of iodine supplementation to reverse the thyroid hormone deficiency in children who are older than 4 years of age. 3 The implementation of an iodization program has been shown to prevent endemic cretinism. 14 It has also been shown to reduce fetal and infant mortality in the community. A single intramuscular injection of iodized oil will provide a source of iodine for up to 5 years, during which time an iodized salt program can be implemented in the community. Iodized oil should be avoided in inhabitants who are older than 45 years of age because it is in this group that thyroid autonomy is likely to be present, with the resulting risk of Jod-Basedow disease (vide infra).13 On the other hand, correction of iodine deficiency in younger inhabitants may forestall the development of thyroid autonomy, even though it may not fully reverse thyroid hormone deficiency after early childhood. With respect to the treatment of spontaneous hyperthyroidism, iodine deficiency has a salutary effect. Patients residing in an iodine-deficient area display a more rapid return to a euthyroid state with thionamide drug therapy than do patients residing in an iodine-sufficient area. 1 Moreover,
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Table 2. Common Iodine-Containing Preparations PREPARATIOI>
IODINE CONTEI>T
Oral Iodinated glycerol (Organidin) SSKI LugoJ's solution Amiodarone
25 47 7.8 75
mg/mL mg/drop mg/drop mg/200-mg tablet
Radiographic Diatrizoate (Renografin-60) Iopanoate (Telepaque) Iothalamate (Angioconray) Iopamidol (Isovue-370)
290 335 480 370
mg/mL mg/500-mg tablet mg/mL mg/mL
Topical Clioquinol (Vioform) Povidone-iodine (Betadine) Tincture of iodine
12.5 mg/g 10 mg/mL 20 mg/mL
they may be more likely to enjoy a long-term remission after the thionamide drug has been withdrawn. 16
IODINE EXCESS In developed societies, excessive quantities of iodine are encountered principally in medicinal preparations or in radiographic contrast media. Table 2 lists the iodine content of preparations that are commonly used in the United States. Most of the preparations listed are water soluble, with the result that the iodine is cleared rapidly by renal excretion. Consequently, pathologic consequences will not generally occur unless the preparation is administered on an ongoing basis and, as we shall see, unless there is disordered autoregulation as well. The route of administration is not important, because the pathologic effects of iodine excess have been observed following vaginal douching with povidone-iodine 7 as well as following the oral administration of iodinated glycerol as a mucolytic agent. 9 The iodine-containing cardiac drug amiodarone, whose chemical structure is depicted in Figure 1, is deserving of special mention. In common with the non-water-soluble contrast media iopanoate and ipodate,21 amiodarone inhibits the peripheral conversion of T4 to T3. 6 With the chronic administration of amiodarone, the iodine released during its degradation leads to a state of iodine excess. 11. 12 Furthermore, because amiodarone is stored in adipose tissue, its metabolic disposition is slow, with the result that the release of iodine will continue for up to several months after it has
Figure 1. Chemical structure of amiodarone. This drug contains about 37% by weight of iodine, is stored in adipose tissue, and may require up to 3 months for its metabolic disposition.
IODINE AND THYROID DISEASE
173
been withdrawn. Consequently, its role in the induction of thyroid dysfunction may be overlooked. Exposure to large, i. e., many milligram, quantities of iodine does not ordinarily lead to sustained thyroid dysfunction. Transport into the thyroid of large quantities of iodide is followed by an abrupt cessation of hormone synthesis, a phenomenon termed the Wolff-Chaikoff effect. 19 The mechanism responsible for this phenomenon has not been defined. Analysis of such thyroids discloses that although organic iodine content is greatly increased, the organic iodine is comprised principally of MIT, with marked reductions in the proportions present as DIT and iodothyronines. It has been suggested that the transport into the thyroid of large quantities of iodide results in the formation of a different species of iodine that is less effective in iodinating reactions. In any event, the overall expansion of the organic iodine pool ultimately leads to autoregulatory inhibition of iodide transport, with the result that the intrathyroid iodide content falls and the inhibition of iodothyronine synthesis abates. This latter phenomenon has come to be termed escape from the W olff-Chaikoff effect20 and can be viewed as an extension of physiologic autoregulation. In addition to its effects on hormone synthesis, the presence in the thyroid of large quantities of iodide retards the rate of hormone secretion through an inhibition of the proteolytic release of iodothyronines from thyroglobulin. As in the case of the Wolff-Chaikoff effect, escape from this effect also occurs when the intrathyroid iodide content falls as a result of autoregulatory inhibition of iodide transport. The pathologic consequences of iodine excess will ensue either because autoregulation is defective, in that escape from the Wolff-Chaikoff cannot occur, or because autoregulation is absent (Table 3). In the first circumstance, failure of "escape" leads to sustained inhibition of hormone synthesis and, subsequently, hormone secretion. Activation of the hypothalamicpituitary axis ensues, and the resulting increase in TSH promotes goiter and further enhances thyroid iodide transport, establishing a vicious cycle that serves to perpetuate the inhibition of hormone synthesis with goiter and often hypothyroidism as the end result. Failure of escape is confined to certain thyroid states. These include the fetal and neonatal thyroid, in which circumstance provision of large quantities of iodine to the mother may lead to goiter in the child with or without hypothyroidism. 7 Immaturity of the organic binding mechanism may account for the susceptibility of the fetal and neonatal thyroid to iodine. Other states characterized by defective organic binding of iodine are also susceptible to the induction of goiter Table 3. Pathologic Consequences of Iodine Excess With Defective Autoregulation: Iodide Goiter ± Hypothyroidism Fetal and neonatal thyroid Hashimoto's thyroiditis Radioiodine or surgically treated Graves' hyperthyroidism Associated with cystic fibrosis Drug-induced-lithium, phenazone, sulfonamides With Absent Autoregulation: Jod-Basedow Disease Longstanding goiter
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r,=:"":==="-"--,
SEM* T. 1,.,100.11
A
WEEKS
300
WEEKS
IODIDE AOIIIIISTRATlOII
1 _ WITIC_AI.
24. SERUM ISH I,Utol)
11. 12. I.
B
1-' '-1 lEEKS
?-I
1-'
...
?-I
WE£KS
Figure 2. Response of serum T4 (A) and TSH (8) concentrations to SSKI, five drops daily, in patients with Graves' hyperthyroidism who had been treated with radioiodine 6 months to 3 years earlier. (From Braverman LE, Woeber KA, Ingbar SH: Induction of myxedema by iodide in patients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. N Engl J Med 281:816, 1969; with permission.)
with or without hypothyroidism. They include Hashmoto's thyroiditis 4 and the thyroid gland of Graves' disease after radioiodine or, to a lesser extent, surgical treatment (Fig. 2).5 Moreover, certain chemical compounds such as lithium, 15 phenazone, and possibly sulfonamides that are weak inhibitors of the organic binding of iodine render the thyroid susceptible to iodine. On the other hand, the potent inhibitors of organic binding, propylthiouracil and methimazole, do not display this influence. Finally, the thyroid of patients with cystic fibrosis, for unknown reasons, is peculiarly susceptible to iodine. 2 Accordingly, it is imperative that iodine-containing expectorants be avoided in these patients. Iodide goiter and hypothyroidism are selflimited and will subside when the provision of excess iodine ceases. The second circumstance in which iodine excess will lead to a pathologic consequence is that characterized by absent autoregulation. In this circumstance, the excess iodine leads to a sustained increase in hormone synthesis and secretion, with thyrotoxicosis as the end result (Jod-Basedow disease*). *Jod is the German word for iodine. Karl von Basedow was the first to describe thyrotoxicosis in continental Europe.
IODINE AND THYROID DISEASE
175
Owing to expansion of the body iodide pool, the thyroid uptake of radioiodine is characteristically subnormal, differentiating this form of thyrotoxicosis from spontaneous hyperthyroidism. Furthermore, this form of thyrotoxicosis, unlike the spontaneous form, is not characterized by a disproportionate increase in the serum concentration of T3 relative to that of T4. 13 Loss of the normal autoregulatory mechanism is present in thyroids that are the seat of autonomous foci. They include longstanding multinodular goiters in both iodine-deficient and iodine-sufficient areas. The obvious clinical implication of the foregoing is the avoidance of iodine-containing preparations in patients with multinodular goiter unless absolutely indicated diagnostically or therapeutically. Jod-Basedow disease will resolve when the source of excess iodine has been dissipated. However, it can be rapidly alleviated by the administration of potassium perchlorate, an inhibitor of iodide transport. 11 A rare effect of iodine excess is the rapid induction of a painful and enlarged thyroid gland, which subsides promptly after iodine has been withdrawn. 8 This acute thyroiditis is reminiscent of the acute sialadenitis that iodine sometimes induces.
THERAPEUTIC USES OF IODINE Apart from its being the cornerstone of the treatment of endemic goiter and cretinism, iodine has an important role as adjunctive therapy for hyperthyroidism. Its principal therapeutic use resides in its ability to inhibit the proteolytic release of iodothyronines from thyroglobulin. This inhibition results in a slowing of thyroid hormone secretion, which is more easily demonstrable in the hyperfunctioning thyroid than in the normal thyroid. 18 This effect of iodine occurs within a couple of days and therefore is much more rapid than the slowing of thyroid hormone secretion that results from thionamide drug inhibition of new hormone synthesis, because, unlike the latter effect, it does not depend on depletion of the preexisting hormone store. The mechanism underlying the inhibition by iodine of thyroglobulin proteolysis is not known, but it may require that the iodine undergo organic binding within the thyroid. The foregoing effect of iodine is exploited when rapid alleviation of hyperthyroidism is desired, such as in the circumstance of thyrotoxic crisis or severe thyrocardiac disease. The iodine can be administered orally as Lugol's solution, five drops every 8 hours, or intravenously as Lugol's solution, 500 mg/day. Alternatively, the iodine can be administered in the form of a non-water-soluble contrast medium, such as iopanoate or ipodate, which has the additional advantage of inhibiting the peripheral conversion of T4 to T3. 21 Within a day following the institution of therapy with iodine, thionamide therapy must be begun; this is important because escape from the effect of iodine on hormone secretion will occur after 10 days or so, with consequent aggravation of the thyrotoxic state by an iodine-enriched thyroid gland, unless hormone synthesis has been suppressed. On the other hand, the thionamide therapy should not be instituted before iodine
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because, by inhibiting organic binding, it may interfere with the effect of iodine that is being sought. A second consequence of the inhibition by iodine of thyroglobulin proteolysis is the accumulation of colloid within the thyroid follicles. This colloid enrichment is accompanied by decreased cellularity and decreased vascularity, resulting in a firmer thyroid gland. This overall effect of iodine on glandular structure is exploited in the clinical setting in the preparation of the hyperthyroid patient for thyroidectomy because it facilitates the surgeon's task. When employed in this setting, iodine is administered as Lugol's solution, five drops every 8 hours, after the patient has been rendered euthyroid with a thionamide drug. The iodine is given along with the thionamide in maintenance dosage for 7 to 10 days, at which time surgery is performed. A final therapeutic role of iodine is in the management of Graves' hyperthyroidism shortly after treatment with radioiodine. 5 This use of iodine exploits the failure of escape from the Wolff-Chaikoff effect (vide supra) that characterizes this particular clinical circumstance and may permit attainment of a euthyroid state while awaiting the therapeutic effect of the radioiodine. However, therapy with either a thionamide drug or a betaadrenergic blocker may be preferable unless contraindications to the use of these drugs exist.
SUMMARY Iodine is a requisite substrate for the synthesis of the thyroid hormones, the minimum daily requirement being about 50 j.Lg. An autoregulatory mechanism within the thyroid serves as the first line of defense against fluctuations in the supply of iodine and also permits escape from the inhibition of hormone synthesis that a very large quantity of iodine induces (Wolff-Chaikoff effect and escape therefrom). Environmental iodine deficiency continues to be a significant public health problem worldwide, compounded in some geographic regions by the presence of other goitrogens in some staple foods. The pathologic consequences of severe iodine defiCiency include endemic goiter, endemic cretinism, increased fetal and infant mortality, and an increased prevalence in the community of cognitive and neuromotor disabilities. The implementation of an iodization program prevents endemic cretinism and reduces the frequency of the other pathologic consequences of iodine deficiency. Iodine excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media. The pathologic consequences of iodine excess will ensue only when thyroid autoregulation is defective, in that escape from the Wolff-Chaikoff effect cannot occur, or when autoregulation is absent. Defective autoregulation characterizes the fetal and neonatal thyroid, Hashimoto's thyroiditis, radioiodine or surgically treated Graves' hyperthyroidism, the thyroid of patients with cystic fibrosis, and the thyroid that has been exposed to weak inhibitors of the organic binding of iodine. In these circumstances, the provision of excess iodine
177
IODINE AND THYROID DISEASE
may lead to iodide go iter with or without hypothyroidism. Absent autoregulation may be a feature of longstanding multinodular goiter, and the provision of excess iodine in this circumstance may induce thyrotoxicosis Ood-Basedow disease). The pathologic consequences of iodine excess will resolve when the source of iodine has been dissipated. In addition to its role in reversing iodine deficiency, iodine is used as adjunctive therapy for hyperthyroidism. By inhibiting the proteolytic release of iodothyronines from thyroglobulin, it induces a prompt slowing of thyroid hormone secretion. This effect is exploited in the treatment of thyrotoxic crisis or severe thyrocardiac disease. Iodine also reduces thyroid cellularity and vascularity and therefore is used in the preparation of the patient for thyroidectomy. Finally, by exploiting the failure of escape from the Wolff-Chaikoff effect, iodine may also be used in the early management of radioiodine-treated Graves' hyperthyroidism.
REFERENCES 1. Azizi F: Environmental iodine intake affects the response to methimazole in patients with diffuse toxic goiter. J Clin Endocrinol Metab 61:374, 1985 2. Azizi F, Bentley D, Vagenakis A, et al: Abnormal thyroid function and response to iodides in patients with cystic fibrosis. Trans Assoc Am Physicians 87:111, 1974 3. Boyages SC, Halpern J-p, Maberly GF, et al: Supplementary iodine fails to reverse hypothyroidism in adolescents and adults with endemic cretinism. J Clin Endocrinol Metab 70:336, 1990 4. Braverman LE, Ingbar SH, Vagenakis AG, et al: Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 32:515, 1971 5. Braverman LE, Woeber KA, Ingbar SH: Induction of myxedema by iodide in patients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. N Engl J Med 281:816, 1969 6. Burger A, Dinichert D, Nicod P, et al: Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxine, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones. J Clin Invest 58:255, 1976 7. Delange F, Chanoine JP, Abrassart C, et al: Topical iodine, breastfeeding, and neonatal hypothyroidism. Arch Dis Child 63:106, 1988 8. Edmunds HT: Acute thyroiditis from potassium iodide. Br Med J 1:354, 1955 9. Gomolin IH: More on the toxicity of iodinated glycerol. J Am Geriatr Soc 37:486, 1989 10. Hetzel BS, Dunn JT: The iodine deficiency disorders: Their nature and prevention. Annu Rev Nutr 9:21, 1989 11. Martino E, Aghini-Lombardi F, Mariotti S, et al: Amiodarone: A common source of iodine-induced thyrotoxicosis. Hormone Res 26:158, 1987 12. Martino E, Safran M, Aghini-Lombardi F, et al: Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 101:28, 1984 13. Martins MC, Lima N, Knobel M, et al: Natural course of iodine-induced thyrotoxicosis (Jod Basedow) in endemic goiter area: A 5-year follow-up. J Endocrinol Invest 12:239, 1989 14. Pharoah POD, Connolly KJ: A controlled trial of iodinated oil for the prevention of endemic cretinism: A long-term follow-up. Int J EpidemioI16:68, 1987 15. Shopsin B, Shenkman L, Blum M, et al: Iodine and lithium-induced hypothyroidism: Documentation of synergism. Am J Med 55:695, 1973 16. Solomon BL, Evaul JE, Burman KD, et al: Remission rates with antithyroid drug therapy: Continuing influence of iodine intake? Ann Intern Med 107:510, 1987 17. Vermiglio F, Sidoti M, Finocchiaro D, et al: Defective neuromotor and cognitive ability in iodine-deficient school children of an endemic goiter region in Sicily. J Clin Endocrinol Metab 70:379, 1990
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18. Wartofsky L, Ransil BJ, Ingbar SH: Inhibition by iodine of the release of thyroxine from the thyroid glands of patients with thyrotoxicosis. J Clin Invest 49:78, 1970 19. Wolff I, Chaikoff IL: Plasma inorganic iodide as homeostatic regulator of thyroid function. J Bioi Chem 174:555, 1948 20. Wolff J, Chaikoff IL, Goldberg RC, et al: The temporary nature of the inhibitory action of excess iodide on organic synthesis in the normal thyroid. Endocrinology 45:504, 1949 21. Wu S-Y, Shyh T-P, Chopra IJ, et al: Comparison of sodium ipodate (Oragrafin) and propylthiouracil in early treatment of hyperthyroidism. J Cl in Endocrinol Metab 54:630, 1982
Address reprint requests to Kenneth A. Woeber, MD, FACP, FRCPE Mount Zion Medical Center of the University 1600 Divisadero Street San Francisco, CA 94115
0025--7125/91 $0.00
+
.20
Iodine and Thyroid Disease Kenneth A. Woeber, MD, FACP, FRCPE*
Iodine is a requisite substrate for the synthesis of the thyroid hormones L-thyroxine (T4) and L-triiodothyronine (T3)' The minimum daily requirement of iodine is generally considered to be about 50 f-Lg, but we may take in many times this quantity depending upon its availability in the environment, principally in the diet or in pharmaceuticals. Thus, we would be at the mercy of our iodine intake (in certain circumstances, this is indeed the case) were it not for the existence of regulatory mechanisms. These mechanisms serve to defend the near constancy of the rate of hormone synthesis and therefore of secretion in the face of wide fluctuations over the short term in the supply of iodine. However, when the supply of iodine falls below the minimum over the long term, the adaptation provided by regulatory mechanisms will not suffice and the pathologic consequences of iodine deficiency may ensue. Conversely, when the supply of iodine is excessive over the long term, especially when it is superimposed on the background of an intrinsic thyroid disorder, thyroid dysfunction may again result.
REGULATION OF THYROID FUNCTION The thyroid gland is virtually unique in possessing two regulatory mechanisms that are distinct yet operate in concert. First, the thyroid participates in a classic feedback system with the pituitary wherein the thyroid hormones regulate in a negative-feedback manner the secretion by the pituitary of thyroid-stimulating hormone (TSH). Triiodothyronine generated within the pituitary through monodeiodination of T4 arriving via the blood, as well as the T3 arriving directly via the blood, is the principal arbiter of this negative-feedback action. Thyrotropin-releasing hormone (TRH) of the hypothalamus appears to set the threshold of feedback control, but its regulation per se has not been fully defined, although the thyroid hormones may play some role in modulating its secretion. *Professor and Chief of Medicine, Mount Zion Medical Center of the University of California San Francisco, San Francisco, California
Medical Clinics of North America-Vo!' 75, No. 1, January 1991
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The second regulatory mechanism resides within the thyroid gland itself and is termed autoregulation. Autoregulation serves to maintain a pool of organic iodine, i. e., principally the thyroid hormones and their immediate precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT), within the thyroid. This is accomplished through a negative-feedback relationship existing between the size of the organic iodine pool and both the activity of the iodide transport mechanism and the sensitivity of the gland to TSH. Thus, autoregulation serves as the first line of defense against fluctuations in the supply of iodine. When autoregulation is no longer able to defend a normal rate of hormone synthesis and secretion in the face of a deficiency of iodine, activation of the hypothalamic-pituitary axis will ensue. Finally, autoregulation permits escape from the inhibition of hormone synthesis that a very large quantity of iodine induces (Wolff-Chaikoff effect and escape therefrom), thereby forestalling the development of goiter and hypothyroidism (vide infra).
IODINE DEFICIENCY Environmental iodine deficiency continues to be a major public health problem worldwide. lo Although it has been largely eradicated in Europe through the implementation of iodization programs and diversification of the diet, it is still prevalent in underdeveloped areas of South America, Asia, Africa, and Oceania. Iodine-deficient soil is encountered in high mountainous areas, such as the Andes and Himalayas, because of the washing away of iodine that occurs through glacial action. It is also encountered in valleys, such as the Ganges valley of India, where high rainfall and flooding are frequent. Staple foods as well as pastures cultivated in such soil are deficient in iodine and result in iodine deficiency in the indigenous population. Iodine intake can be estimated from the rate of urinary iodine excretion because iodine is virtually completely absorbed from the alimentary tract and cleared principally by renal excretion. When urinary iodine is less than 25 j-Lg/day, go iter is endemic in the community and the other consequences of iodine deficiency are present (Table 1). In some regions, such as Zaire, environmental iodine deficiency is aggravated by other dietary goitrogens; for example, certain staple foods, such as cassava, contain cyanoglucosides that are transformed to thiocyanate, a potent goitrogen, after absorption. Endemic goiter represents an adaptation to iodine deficiency that is brought about both by autoregulation and by an increase in TSH. These regulatory responses lead to increased iodide transport and to a disproportionate synthesis of T3 relative to T4 • This latter alteration reflects a more efficient utilization of the available iodine because T3 possesses only 75% as much iodine as T4 yet is approximately threefold more potent. Consequently, many inhabitants will not display clinical hypothyroidism, and laboratory testing will disclose essentially normal values for serum T 3 concentration despite subnormal values for serum T4 and increased values for serum TSH. As would be predicted, the thyroid uptake of radioiodine is increased, reflecting both the contraction of the body iodide pool and
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Table 1. Pathologic Consequences of Iodine Deficiency Endemic goiter ± hypothyroidism Neurologic endemic cretinism Myxedematous endemic cretinism Increased prevalence of cognitive and neuromotor disabilities Increased fetal and infant mortality
the effects of autoregulation and hyperstimulation by TSH. In older adults, the chronic hyperstimulation by TSH may ultimately result in the development of autonomous foci within the thyroid and set the stage for the emergence of iodine-induced thyrotoxicosis (Jod-Basedow disease) when ample quantities of iodine are provided (vide infra). From a public health standpoint, however, the major impact by far of iodine deficiency is upon fetal and childhood development. In its most extreme form, it results in endemic cretinism. Nonetheless, even in the absence of cretinism, the prevalence of intellectual and neuromotor disabilities is increased in the inhabitants of iodine-deficient areas,17 perpetuating the socioeconomic underdevelopment of the community. Endemic cretinism may take several forms-neurologic endemic cretinism, myxedematous endemic cretinism, and a mixed form depending on the timing and duration of severe iodine deficiency. Severe maternal iodine deficiency that is limited to early gestation during a critical phase of fetal development is thought to be responsible for the irreversible mental deficiency, deaf mutism, and spastic pareses that characterize neurologic endemic cretinism. On the other hand, severe iodine deficiency dating from early infancy results in myxedematous endemic cretinism, which is characterized by mental deficiency and growth retardation, but without the neurologic sequelae cited previously. In many older endemic cretins, goiter is lacking, and on necropsy examination, the thyroid is atrophic. The mechanism underlying this so-called exhaustion atrophy has not been elucidated, but it accounts for the reported failure of iodine supplementation to reverse the thyroid hormone deficiency in children who are older than 4 years of age. 3 The implementation of an iodization program has been shown to prevent endemic cretinism. 14 It has also been shown to reduce fetal and infant mortality in the community. A single intramuscular injection of iodized oil will provide a source of iodine for up to 5 years, during which time an iodized salt program can be implemented in the community. Iodized oil should be avoided in inhabitants who are older than 45 years of age because it is in this group that thyroid autonomy is likely to be present, with the resulting risk of Jod-Basedow disease (vide infra).13 On the other hand, correction of iodine deficiency in younger inhabitants may forestall the development of thyroid autonomy, even though it may not fully reverse thyroid hormone deficiency after early childhood. With respect to the treatment of spontaneous hyperthyroidism, iodine deficiency has a salutary effect. Patients residing in an iodine-deficient area display a more rapid return to a euthyroid state with thionamide drug therapy than do patients residing in an iodine-sufficient area. 1 Moreover,
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Table 2. Common Iodine-Containing Preparations PREPARATIOI>
IODINE CONTEI>T
Oral Iodinated glycerol (Organidin) SSKI LugoJ's solution Amiodarone
25 47 7.8 75
mg/mL mg/drop mg/drop mg/200-mg tablet
Radiographic Diatrizoate (Renografin-60) Iopanoate (Telepaque) Iothalamate (Angioconray) Iopamidol (Isovue-370)
290 335 480 370
mg/mL mg/500-mg tablet mg/mL mg/mL
Topical Clioquinol (Vioform) Povidone-iodine (Betadine) Tincture of iodine
12.5 mg/g 10 mg/mL 20 mg/mL
they may be more likely to enjoy a long-term remission after the thionamide drug has been withdrawn. 16
IODINE EXCESS In developed societies, excessive quantities of iodine are encountered principally in medicinal preparations or in radiographic contrast media. Table 2 lists the iodine content of preparations that are commonly used in the United States. Most of the preparations listed are water soluble, with the result that the iodine is cleared rapidly by renal excretion. Consequently, pathologic consequences will not generally occur unless the preparation is administered on an ongoing basis and, as we shall see, unless there is disordered autoregulation as well. The route of administration is not important, because the pathologic effects of iodine excess have been observed following vaginal douching with povidone-iodine 7 as well as following the oral administration of iodinated glycerol as a mucolytic agent. 9 The iodine-containing cardiac drug amiodarone, whose chemical structure is depicted in Figure 1, is deserving of special mention. In common with the non-water-soluble contrast media iopanoate and ipodate,21 amiodarone inhibits the peripheral conversion of T4 to T3. 6 With the chronic administration of amiodarone, the iodine released during its degradation leads to a state of iodine excess. 11. 12 Furthermore, because amiodarone is stored in adipose tissue, its metabolic disposition is slow, with the result that the release of iodine will continue for up to several months after it has
Figure 1. Chemical structure of amiodarone. This drug contains about 37% by weight of iodine, is stored in adipose tissue, and may require up to 3 months for its metabolic disposition.
IODINE AND THYROID DISEASE
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been withdrawn. Consequently, its role in the induction of thyroid dysfunction may be overlooked. Exposure to large, i. e., many milligram, quantities of iodine does not ordinarily lead to sustained thyroid dysfunction. Transport into the thyroid of large quantities of iodide is followed by an abrupt cessation of hormone synthesis, a phenomenon termed the Wolff-Chaikoff effect. 19 The mechanism responsible for this phenomenon has not been defined. Analysis of such thyroids discloses that although organic iodine content is greatly increased, the organic iodine is comprised principally of MIT, with marked reductions in the proportions present as DIT and iodothyronines. It has been suggested that the transport into the thyroid of large quantities of iodide results in the formation of a different species of iodine that is less effective in iodinating reactions. In any event, the overall expansion of the organic iodine pool ultimately leads to autoregulatory inhibition of iodide transport, with the result that the intrathyroid iodide content falls and the inhibition of iodothyronine synthesis abates. This latter phenomenon has come to be termed escape from the W olff-Chaikoff effect20 and can be viewed as an extension of physiologic autoregulation. In addition to its effects on hormone synthesis, the presence in the thyroid of large quantities of iodide retards the rate of hormone secretion through an inhibition of the proteolytic release of iodothyronines from thyroglobulin. As in the case of the Wolff-Chaikoff effect, escape from this effect also occurs when the intrathyroid iodide content falls as a result of autoregulatory inhibition of iodide transport. The pathologic consequences of iodine excess will ensue either because autoregulation is defective, in that escape from the Wolff-Chaikoff cannot occur, or because autoregulation is absent (Table 3). In the first circumstance, failure of "escape" leads to sustained inhibition of hormone synthesis and, subsequently, hormone secretion. Activation of the hypothalamicpituitary axis ensues, and the resulting increase in TSH promotes goiter and further enhances thyroid iodide transport, establishing a vicious cycle that serves to perpetuate the inhibition of hormone synthesis with goiter and often hypothyroidism as the end result. Failure of escape is confined to certain thyroid states. These include the fetal and neonatal thyroid, in which circumstance provision of large quantities of iodine to the mother may lead to goiter in the child with or without hypothyroidism. 7 Immaturity of the organic binding mechanism may account for the susceptibility of the fetal and neonatal thyroid to iodine. Other states characterized by defective organic binding of iodine are also susceptible to the induction of goiter Table 3. Pathologic Consequences of Iodine Excess With Defective Autoregulation: Iodide Goiter ± Hypothyroidism Fetal and neonatal thyroid Hashimoto's thyroiditis Radioiodine or surgically treated Graves' hyperthyroidism Associated with cystic fibrosis Drug-induced-lithium, phenazone, sulfonamides With Absent Autoregulation: Jod-Basedow Disease Longstanding goiter
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r,=:"":==="-"--,
SEM* T. 1,.,100.11
A
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300
WEEKS
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Figure 2. Response of serum T4 (A) and TSH (8) concentrations to SSKI, five drops daily, in patients with Graves' hyperthyroidism who had been treated with radioiodine 6 months to 3 years earlier. (From Braverman LE, Woeber KA, Ingbar SH: Induction of myxedema by iodide in patients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. N Engl J Med 281:816, 1969; with permission.)
with or without hypothyroidism. They include Hashmoto's thyroiditis 4 and the thyroid gland of Graves' disease after radioiodine or, to a lesser extent, surgical treatment (Fig. 2).5 Moreover, certain chemical compounds such as lithium, 15 phenazone, and possibly sulfonamides that are weak inhibitors of the organic binding of iodine render the thyroid susceptible to iodine. On the other hand, the potent inhibitors of organic binding, propylthiouracil and methimazole, do not display this influence. Finally, the thyroid of patients with cystic fibrosis, for unknown reasons, is peculiarly susceptible to iodine. 2 Accordingly, it is imperative that iodine-containing expectorants be avoided in these patients. Iodide goiter and hypothyroidism are selflimited and will subside when the provision of excess iodine ceases. The second circumstance in which iodine excess will lead to a pathologic consequence is that characterized by absent autoregulation. In this circumstance, the excess iodine leads to a sustained increase in hormone synthesis and secretion, with thyrotoxicosis as the end result (Jod-Basedow disease*). *Jod is the German word for iodine. Karl von Basedow was the first to describe thyrotoxicosis in continental Europe.
IODINE AND THYROID DISEASE
175
Owing to expansion of the body iodide pool, the thyroid uptake of radioiodine is characteristically subnormal, differentiating this form of thyrotoxicosis from spontaneous hyperthyroidism. Furthermore, this form of thyrotoxicosis, unlike the spontaneous form, is not characterized by a disproportionate increase in the serum concentration of T3 relative to that of T4. 13 Loss of the normal autoregulatory mechanism is present in thyroids that are the seat of autonomous foci. They include longstanding multinodular goiters in both iodine-deficient and iodine-sufficient areas. The obvious clinical implication of the foregoing is the avoidance of iodine-containing preparations in patients with multinodular goiter unless absolutely indicated diagnostically or therapeutically. Jod-Basedow disease will resolve when the source of excess iodine has been dissipated. However, it can be rapidly alleviated by the administration of potassium perchlorate, an inhibitor of iodide transport. 11 A rare effect of iodine excess is the rapid induction of a painful and enlarged thyroid gland, which subsides promptly after iodine has been withdrawn. 8 This acute thyroiditis is reminiscent of the acute sialadenitis that iodine sometimes induces.
THERAPEUTIC USES OF IODINE Apart from its being the cornerstone of the treatment of endemic goiter and cretinism, iodine has an important role as adjunctive therapy for hyperthyroidism. Its principal therapeutic use resides in its ability to inhibit the proteolytic release of iodothyronines from thyroglobulin. This inhibition results in a slowing of thyroid hormone secretion, which is more easily demonstrable in the hyperfunctioning thyroid than in the normal thyroid. 18 This effect of iodine occurs within a couple of days and therefore is much more rapid than the slowing of thyroid hormone secretion that results from thionamide drug inhibition of new hormone synthesis, because, unlike the latter effect, it does not depend on depletion of the preexisting hormone store. The mechanism underlying the inhibition by iodine of thyroglobulin proteolysis is not known, but it may require that the iodine undergo organic binding within the thyroid. The foregoing effect of iodine is exploited when rapid alleviation of hyperthyroidism is desired, such as in the circumstance of thyrotoxic crisis or severe thyrocardiac disease. The iodine can be administered orally as Lugol's solution, five drops every 8 hours, or intravenously as Lugol's solution, 500 mg/day. Alternatively, the iodine can be administered in the form of a non-water-soluble contrast medium, such as iopanoate or ipodate, which has the additional advantage of inhibiting the peripheral conversion of T4 to T3. 21 Within a day following the institution of therapy with iodine, thionamide therapy must be begun; this is important because escape from the effect of iodine on hormone secretion will occur after 10 days or so, with consequent aggravation of the thyrotoxic state by an iodine-enriched thyroid gland, unless hormone synthesis has been suppressed. On the other hand, the thionamide therapy should not be instituted before iodine
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because, by inhibiting organic binding, it may interfere with the effect of iodine that is being sought. A second consequence of the inhibition by iodine of thyroglobulin proteolysis is the accumulation of colloid within the thyroid follicles. This colloid enrichment is accompanied by decreased cellularity and decreased vascularity, resulting in a firmer thyroid gland. This overall effect of iodine on glandular structure is exploited in the clinical setting in the preparation of the hyperthyroid patient for thyroidectomy because it facilitates the surgeon's task. When employed in this setting, iodine is administered as Lugol's solution, five drops every 8 hours, after the patient has been rendered euthyroid with a thionamide drug. The iodine is given along with the thionamide in maintenance dosage for 7 to 10 days, at which time surgery is performed. A final therapeutic role of iodine is in the management of Graves' hyperthyroidism shortly after treatment with radioiodine. 5 This use of iodine exploits the failure of escape from the Wolff-Chaikoff effect (vide supra) that characterizes this particular clinical circumstance and may permit attainment of a euthyroid state while awaiting the therapeutic effect of the radioiodine. However, therapy with either a thionamide drug or a betaadrenergic blocker may be preferable unless contraindications to the use of these drugs exist.
SUMMARY Iodine is a requisite substrate for the synthesis of the thyroid hormones, the minimum daily requirement being about 50 j.Lg. An autoregulatory mechanism within the thyroid serves as the first line of defense against fluctuations in the supply of iodine and also permits escape from the inhibition of hormone synthesis that a very large quantity of iodine induces (Wolff-Chaikoff effect and escape therefrom). Environmental iodine deficiency continues to be a significant public health problem worldwide, compounded in some geographic regions by the presence of other goitrogens in some staple foods. The pathologic consequences of severe iodine defiCiency include endemic goiter, endemic cretinism, increased fetal and infant mortality, and an increased prevalence in the community of cognitive and neuromotor disabilities. The implementation of an iodization program prevents endemic cretinism and reduces the frequency of the other pathologic consequences of iodine deficiency. Iodine excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media. The pathologic consequences of iodine excess will ensue only when thyroid autoregulation is defective, in that escape from the Wolff-Chaikoff effect cannot occur, or when autoregulation is absent. Defective autoregulation characterizes the fetal and neonatal thyroid, Hashimoto's thyroiditis, radioiodine or surgically treated Graves' hyperthyroidism, the thyroid of patients with cystic fibrosis, and the thyroid that has been exposed to weak inhibitors of the organic binding of iodine. In these circumstances, the provision of excess iodine
177
IODINE AND THYROID DISEASE
may lead to iodide go iter with or without hypothyroidism. Absent autoregulation may be a feature of longstanding multinodular goiter, and the provision of excess iodine in this circumstance may induce thyrotoxicosis Ood-Basedow disease). The pathologic consequences of iodine excess will resolve when the source of iodine has been dissipated. In addition to its role in reversing iodine deficiency, iodine is used as adjunctive therapy for hyperthyroidism. By inhibiting the proteolytic release of iodothyronines from thyroglobulin, it induces a prompt slowing of thyroid hormone secretion. This effect is exploited in the treatment of thyrotoxic crisis or severe thyrocardiac disease. Iodine also reduces thyroid cellularity and vascularity and therefore is used in the preparation of the patient for thyroidectomy. Finally, by exploiting the failure of escape from the Wolff-Chaikoff effect, iodine may also be used in the early management of radioiodine-treated Graves' hyperthyroidism.
REFERENCES 1. Azizi F: Environmental iodine intake affects the response to methimazole in patients with diffuse toxic goiter. J Clin Endocrinol Metab 61:374, 1985 2. Azizi F, Bentley D, Vagenakis A, et al: Abnormal thyroid function and response to iodides in patients with cystic fibrosis. Trans Assoc Am Physicians 87:111, 1974 3. Boyages SC, Halpern J-p, Maberly GF, et al: Supplementary iodine fails to reverse hypothyroidism in adolescents and adults with endemic cretinism. J Clin Endocrinol Metab 70:336, 1990 4. Braverman LE, Ingbar SH, Vagenakis AG, et al: Enhanced susceptibility to iodide myxedema in patients with Hashimoto's disease. J Clin Endocrinol Metab 32:515, 1971 5. Braverman LE, Woeber KA, Ingbar SH: Induction of myxedema by iodide in patients euthyroid after radioiodine or surgical treatment of diffuse toxic goiter. N Engl J Med 281:816, 1969 6. Burger A, Dinichert D, Nicod P, et al: Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxine, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones. J Clin Invest 58:255, 1976 7. Delange F, Chanoine JP, Abrassart C, et al: Topical iodine, breastfeeding, and neonatal hypothyroidism. Arch Dis Child 63:106, 1988 8. Edmunds HT: Acute thyroiditis from potassium iodide. Br Med J 1:354, 1955 9. Gomolin IH: More on the toxicity of iodinated glycerol. J Am Geriatr Soc 37:486, 1989 10. Hetzel BS, Dunn JT: The iodine deficiency disorders: Their nature and prevention. Annu Rev Nutr 9:21, 1989 11. Martino E, Aghini-Lombardi F, Mariotti S, et al: Amiodarone: A common source of iodine-induced thyrotoxicosis. Hormone Res 26:158, 1987 12. Martino E, Safran M, Aghini-Lombardi F, et al: Environmental iodine intake and thyroid dysfunction during chronic amiodarone therapy. Ann Intern Med 101:28, 1984 13. Martins MC, Lima N, Knobel M, et al: Natural course of iodine-induced thyrotoxicosis (Jod Basedow) in endemic goiter area: A 5-year follow-up. J Endocrinol Invest 12:239, 1989 14. Pharoah POD, Connolly KJ: A controlled trial of iodinated oil for the prevention of endemic cretinism: A long-term follow-up. Int J EpidemioI16:68, 1987 15. Shopsin B, Shenkman L, Blum M, et al: Iodine and lithium-induced hypothyroidism: Documentation of synergism. Am J Med 55:695, 1973 16. Solomon BL, Evaul JE, Burman KD, et al: Remission rates with antithyroid drug therapy: Continuing influence of iodine intake? Ann Intern Med 107:510, 1987 17. Vermiglio F, Sidoti M, Finocchiaro D, et al: Defective neuromotor and cognitive ability in iodine-deficient school children of an endemic goiter region in Sicily. J Clin Endocrinol Metab 70:379, 1990
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18. Wartofsky L, Ransil BJ, Ingbar SH: Inhibition by iodine of the release of thyroxine from the thyroid glands of patients with thyrotoxicosis. J Clin Invest 49:78, 1970 19. Wolff I, Chaikoff IL: Plasma inorganic iodide as homeostatic regulator of thyroid function. J Bioi Chem 174:555, 1948 20. Wolff J, Chaikoff IL, Goldberg RC, et al: The temporary nature of the inhibitory action of excess iodide on organic synthesis in the normal thyroid. Endocrinology 45:504, 1949 21. Wu S-Y, Shyh T-P, Chopra IJ, et al: Comparison of sodium ipodate (Oragrafin) and propylthiouracil in early treatment of hyperthyroidism. J Cl in Endocrinol Metab 54:630, 1982
Address reprint requests to Kenneth A. Woeber, MD, FACP, FRCPE Mount Zion Medical Center of the University 1600 Divisadero Street San Francisco, CA 94115
