Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

11F.Effect of Excess Iodide: Clinical Aspects

Elio Roti

Apostolos G. Vagenakis

An adequate supply of dietary iodide is essential for synthesis of the thyroid hormones. Iodide deficiency results in endemic goiter in many geographic areas, including continental western Europe; in many other regions, however, dietary iodide intake has increased, such as in the United States, Great Britain and Scandinavia. The National Health and Nutrition Examination Survey III 1988–1994 (NHANES III) found in the US population a median urinary iodide excretion rate of 145 µg/L. This value was significantly lower than that of 321 µg/L measured in the 1971 to 1974 period. Furthermore, urinary iodide concentrations were low (< 50 µg/L) in 11.7% of the population, a 4.5-fold increase compared with that observed in 1971 to 1974. The proportion of women of childbearing age (15 to 47 years) and of pregnant women with low urinary iodide concentrations was 15% and 7%, 3.8 and 6.9 times the respective proportions in compared with the 1971 to 1974 survey (1). The decrement of iodide intake was probably due to the dairy industry's effort to reduce iodide in milk and a decrease in the use of iodide salts as the dough conditioner in commercial bread production (2). A recent survey of the iodide content in various brands of milk in Boston revealed a relatively high content of 116 µg iodide in 8 ounces of milk (2a). This trend in iodide consumption has also resulted in a decline in the percentage of the population with excessive iodide intake (>500 µg/L) from 27.8% in the 1971 to 1974 survey to 5.3% in the 1988 to 1994 survey. In a study in Denmark, urinary iodide excretion was extremely variable, dependent upon the iodide content in drinking water, which varied from < 1.0 to 139 µg/L, and variable intake from day to day (3,4).

Strong evidence indicates that excess iodide can induce thyroid dysfunction, and these iodide-induced abnormalities in thyroid function are the subject of this subchapter.


In animals and humans, the thyroid gland has intrinsic autoregulatory mechanisms to effectively handle excess iodide intake, probably involving the iodide transporter (the sodium iodide (Na+/I-) symporter; NIS) recently cloned by Dal and colleagues (5).

The acute, transient inhibitory effect of iodide excess on thyroid iodide organification, the Wolff-Chaikoff effect, and the escape phenomenon are discussed in Chapter 4. It has been suggested that adaptation to or escape from the acute Wolff-Chaikoff effect is due to a decrease in NIS messenger RNA (mRNA) and protein (6) and to increased NIS protein turnover (7), thereby lowering intrathyroidal iodide and permitting normal hormone synthesis to resume (6). The well-known but less understood effect of iodide on the release of thyroxine (T4) and triiodothyronine (T3) from the thyroid has been studied prospectively in humans. When normal subjects were given approximately 40 to 150 mg iodide for 1 to 3 weeks, a small but significant decrease in the serum concentrations of T4 and T3 occurred, with a small but significant compensatory increase in the serum thyroid-stimulating hormone (thyrotropin, TSH) concentration and an increased TSH response to thyrotropin-releasing hormone (TRH) (8,9,10). These alterations were all within the normal range for each parameter. In another study, daily mouth rinsing with polyvinylpyrrolidone iodide for 6 months for gingivitis resulted in the absorption of about 3 mg iodide daily and in small but significant increases in the serum TSH concentration (11). After iodide withdrawal, all values returned to baseline levels. In contrast to these findings, an acute increase in serum iodide concentrations, approximately 90-fold above baseline values, following endoscopic retrograde cholangiopancreaticography with iopamidol, a nonionic contrast agent, was not followed by significant changes of serum TSH, free T4, and free T3 concentrations (12). This is in contrast with another study of 70 patients in whom there was a persistent decrease in serum TSH, especially in those with nodular goiters. The serum T3 increased in all 70 patients and serum free T4 only in patients with nodular goiters. Symptoms of thyrotoxicosis were not present (13).

Smaller quantities of iodide (1,500 and 4,500 µg/day) administered to normal subjects who resided in iodide-replete areas resulted in significant decreases in serum T4 and free T4 but not in serum T3 concentrations. Serum TSH concentrations increased, as did the serum TSH response to TRH. The smallest quantity of iodide that did not affect thyroid function was 500 µg/day (14). In another study, however, this small quantity of iodide enhanced the TSH response to TRH (15) and in a few patients also increased the basal serum TSH concentration above the normal range. Thus, iodide supplements of about 500 µg/day above the normal diet in iodide-sufficient areas might cause subtle changes in thyroid function (16).

These subtle changes in thyroid function during iodide administration are accompanied by a small increase of thyroid volume determined by echography (17) and by a decrement of thyroid blood flow evaluated by echo color Doppler (18). The latter finding, however, was not related to serum TSH changes.


Various drugs and food preservatives contain a large quantity of iodide that is either absorbed directly or released after metabolism of the drug. Many vitamin preparations are supplemented with about 150 µg iodide, a quantity that is considered to be the physiologic daily requirement. Iodophors contain large quantities of iodide and are used as udder antiseptics in the dairy industry, resulting in increased content of iodide in cow's milk from local contamination and increased secretion into milk from absorbed iodide. Iodide is concentrated by the mammary gland and secreted into the milk and, therefore, may influence thyroid function in the newborn fed cow's milk. Recent evidence in Boston suggests that human breast milk may contain insufficient quantities of iodide to maintain adequate iodide nutrition in breast fed neonates (E Pearce and L Braverman, unpublished data). Many iodide-rich products, such as kelp, kombu, and dolts, are available in natural food stores. In some areas of Japan, bread is made exclusively from seaweed, exposing the population to large quantities of iodide.

Iodides are present in high concentration in various proprietary and prescribed expectorants, including iodinated glycerol, although iodide has been removed from this latter medication in the United States. Another potential source of excess iodide is the use of contrast media in radiologic studies. Preparations used for computed tomography, arteriography, or pyelography are cleared from the plasma relatively quickly, but the iodide released during these procedures affects thyroid function. However, a dye commonly used for arteriography, meglumine ioxaglate, did not affect serum T4, T3, or free T4 index up to 56 days after catheterization, but serum TSH was not measured (19). Coronary angiography performed in 788 unselected euthyroid patients, induced thyrotoxicosis in 2 patients within 12 weeks. The baseline serum TSH was normal and ultrasonography of the thyroid showed no abnormalities (20). Drugs used in the past for myelography, uterosalpingography, or bronchography were lipid soluble and cleared slowly, maintaining high plasma inorganic iodide concentrations for years. The newer water-soluble iodide-containing preparations, such as metrizamide, have markedly reduced this problem. Occasionally drinking water may be a source of excess iodide intake, such as in some Chinese counties where the drinking water has an iodide concentration of 300 to 462 µg/L. The population residing in those areas has a urinary iodide excretion rate as high as 900 µg/L (21,22,23,24). Also, iodide-based water purification systems may cause chronic excessive iodide intake. A group of American volunteers working in west Africa had a median urinary iodide excretion of 5,048 µg/L, due to a faulty iodination system, and some developed goiter and subclinical hypothyroidism (25). A partial list of medications and other preparations containing large quantities of iodide is given in Table 11F.1



Iodide Content

Oral and Local


75 mg/tablet


49–100 mg/tablet

   Calcium ioddle (e.g. Calcidrine syrup)

26 mg/mL

   Echothiophate iodide for ophthalmic solution (e.g., phospholine)

5–41 mg/drop

   Hydriodic acid syrup

13–15 mg/mL

   Lodochlorhydroxyquin (e.g, Entro-Vioform)

104 mg/tablet

   Iodide-containing vitamins


   Iodinated glycerol (e.g., Organidin,blophen)

15 mg/tablet, 25mg/mL

   Idoxuridine ophthalmic solution (e.g., Harplex)

18 mg/drop

   Isopropamide iodide (e.g., Darbid, Combid)

1.8 mg/tablet


0.15 mg/tablet

   Kl (e.g., Quadrinal)

145 mg/tablet, 24 mg/mL

   Lugol's Solution

6.3 mg/drop

   Niacinamide hydroiodide + Kl (e.g., Iodo-Niacin)

115 mg/tablet

   Ponaris nasal emollient

5 mg/0.8 mL


38 mg/drop

Parenteral Preparations

    Sodium iodide, 10%solution

85 mg/mL

Topical Antiseptics

    Iodide tincture

40 mg/mL

   Iodochlorhydroxyquin cream (e.g., Vioform)

    Iodoform gauze (e.g., NuGauze)

4.8 mg/100 mg gauze

   Povidone iodide (e.g., Betadine)

10 mg/mL

Radiology Contrast Agents

    Diatrlzoate meglumine sodium (e.g., Renografin-76)

    Iodized oil

380 mg/mL

   Iopanoic acid (e.g., Telepaque)

333 mg/tablet

   Ipodate (e.g., Oragrafin)

308 mg/cap

   Iothalamate (e.g., Angio-Conray)

480 mg/mL

   Metrizamide (e.g., Amipaque)

483 mg/mL

KI, potassium idide;SSKI, saturated solution of potassium iodide.

aNot U.S. Food and Drug Administration-approved.

bIodide was removed from Organidin and Tuss Organidin in 1995.


In certain susceptible people, the thyroid cannot escape from the transient inhibitory effect of iodide on the organification mechanism. As a result, hypothyroidism may result after prolonged excess iodide administration. The hypothyroidism is usually transient, and thyroid function returns to normal after iodide withdrawal. Although the exact frequency of iodide goiter, hypothyroidism, or both, in subjects with apparently normal underlying thyroid function is not known, they are probably uncommon; in patients with underlying thyroid dysfunction, however, they are common (Table 11F.2). Iodide goiter may occur with or without hypothyroidism. Most patients who develop iodide goiter have received iodides for years. The mechanism by which the inhibitory effect of iodide is sustained in these susceptible people is not clear.


In the case of underlying thyroid disease

   Fetus and neonate, mostly preterm
      Secondary to transplacental passage of iodide and exposure of newbord infants to topical or parenteral iodide-rich substances


      Occasionally reported in infants drinking iodide-rich water (China)and after exposure to excess iodide


      Frequently reported in japanese subjects with and without possible defective organification and autoimmune thyroiditis


      Reported in elderly subjects with and without possible defective organification and autoimmune thyroiditis

   Chronic nonthyroidal illness

      Cystic fibrosis

      Chronic lung disease (Hashimoto's thyoiditis was not excluded)

      Chronic dialysis treatment

      Thalassemia major

      Anorexia nervosa

In the case of underlying thyroid disease

   Hashimoto's thyroiditis

   Euthroid patients previously treated for Graves'diease by 131 thyroidectomy, or antithyroid drugs

   Subclinical hypothroidism, especially in the elderly

   After transient postpartum thyroiditis

   After subacute, painful thyroiditis

   Euthyroid patients with a previous episode of amiodarone-induced destructive thyrotoxicosis

   Euthyroid patients with a epiosode of interferon-α-induced thyroid disorders

Iodide plus other potential goitrogens

   Sulfisoxazole:cystic fibrosis


   Sulfadiazine (?)


Normal Subjects

Iodide-induced goiter occurs in about 10% of the population of Hokkaido, a Japanese island. The inhabitants of this island, particularly the fishermen and their families, consume large quantities of an iodide-rich seaweed called kombu. The quantity of iodide ingested daily may exceed 200 mg. Despite goiter, hypothyroidism is rare. Endemic iodide-induced goiter has also been observed in 64% of children residing in a village in central China (21). These children drank water containing 462 mg iodide per liter. No increased prevalence of lymphocytic thyroiditis was found in these children. Thyroid autoantibodies as well as immunoglobulins that inhibited TSH binding were negative. Thyroid growth-stimulating immunoglobulins were found in 60% of goitrous children but were absent in children without goiter who resided in an area with increased iodide concentrations in the drinking water (22). This finding has yet to be confirmed. In another study, goiter due to iodide-rich drinking water was observed in 10% of the subjects residing in 19 Chinese counties (23). In general, those subjects had normal thyroid function. Other Chinese subjects drinking iodide-rich water had a prevalence of clinical and subclinical hypothyroidism of 2% and 6%, respectively (24). In American workers drinking iodide-rich water serum TSH concentrations were above 4.2 mU/L in 29%. This value decreased to 5% after iodide removal (25). An increased prevalence of hypothyroidism (12), defined by serum TSH concentrations >5 mU/L, was observed in thyroid autoantibody-negative Japanese subjects with an iodide concentration in morning urine samples greater than 75 mM (9.5 mg/L); in subjects with normal iodide excretion, the prevalence of hypothyroidism was only 2% (26). When the iodide intake was restricted, the increased serum TSH concentrations returned to normal in patients with negative antithyroid antibodies, but not in those with antibodies, suggesting that excessive iodide intake should be considered a cause of hypothyroidism in addition to chronic thyroiditis in these areas (27). In an elderly Icelandic population, high urinary iodide excretion rates (median 150 µg/L, range 33 to 703 µg/L) were found to be accompanied by a high prevalence (18) of serum TSH concentrations >4 mU/L. In subjects residing in Jutland with low urinary iodide excretion (median 38 µg/L, range 6 to 770 µg/L), serum TSH levels were low (< 0.4 mU/L) in 10%. The incidence of positive thyroid antibodies was similar in both populations (28). In another study, the cumulative prevalence of overt and subclinical hypothyroidism progressively increased in respect to urinary iodide excretion, being 5%, 12%, and 32%, corresponding to a median urinary excretion of 72, 100, and 513 µg/g creatinine, respectively (29). The prevalence of positive antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-Tg) antibodies was similar in all three groups.

Treatment with povidone-iodide for 3 to 133 months resulted in subclinical hypothyroidism in 3 of 27 patients with neurologic diseases and negative antithyroid antibodies (30). These findings suggest that iodide-induced hypothyroidism might appear even in subjects with no underlying thyroid disease, and it is not strictly correlated with the presence of thyroid autoimmunity.

Histologic examination of the thyroid of patients with iodide-induced hypothyroidism revealed the presence of lymphocytic infiltration in only half the specimens examined. In the other specimens, hyperplastic changes in the follicles with papillary folding, cuboidal or columnar change of cells with clear and vesicular cytoplasm, and markedly reduced colloid in the distended follicles were seen. These changes were reversible after iodide withdrawal (31). In contrast to these findings, the administration of a single dose of 50 to 70 mg of potassium iodide (KI) to children for iodide prophylaxis following the Chernobyl reactor accident was not accompanied by an increment in serum TSH concentrations (32). Usually, serum T4 and T3 concentrations are low or low-normal and serum TSH is increased in patients with iodide-induced hypothyroidism. The thyroid radioactive iodide uptake would be expected to be very low in these patients; however, about 30% have a normal or high thyroid radioactive iodide uptake (33). Similar findings have been observed in European but not US patients who developed iodide-induced hypothyroidism after amiodarone administration (34,35).

Perinatal Period

Iodide readily crosses the placenta and is concentrated by the fetal thyroid. Large quantities of iodide administered to pregnant women resulted in goiter in the newborn, probably because the fetal thyroid is inordinately sensitive to the inhibitory effect of iodide on hormone synthesis (36). By ultrasonography and cordocentesis, goiter and hypothyroidism have been diagnosed in a fetus whose asthmatic mother consumed 2 to 3 spoonfuls per day of a syrup containing 130 mg/15 mL of iodide (37). Severe goitrous hypothyroidism was recently reported in a newborn infant with a history of iodide exposure in utero derived from an expectorant used by the mother (38). Whether the inhibitory effect was exerted on the organification mechanism or on the release of thyroid hormones, or both, is not clear. Studies in rats strongly suggest that the inhibitory effects are exerted in utero as well as in the late neonatal period, which corresponds to the last few weeks of human fetal life (39). Iodides are actively transported by breast tissue and secreted into the milk, and the administration of iodides to nursing mothers could result in iodide-induced hypothyroidism and goiter in their infants.

The thyroid of the fetus and newborn can be exposed to iodide from various routes. Vaginal douching with iodide-containing solutions in nonpregnant women results in a small increase in the serum TSH concentration (40). In contrast, in nonpregnant women vaginal disinfection with povidone-iodide vaginal pessaries and obstetric cream does not affect serum iodide concentrations and thyroid function (41,42). Transient hypothyroidism of the newborn, as indicated by an elevation of the serum TSH, has been reported to follow the application of vaginal solutions of povidone-iodide and in a few cases after povidone-iodide cream application (43) during the last trimester and during labor (36,43), or topical application of povidone-iodide to the skin of the newborns. The latter appears to be more common in premature, low-birthweight infants (44). Serum TSH concentrations above 20 mU/L occurred in 25% of the cases, promptly normalizing after the iodide-containing antiseptic was discontinued (45). The injection of small amounts of an iodinated contrast dye through nonradiopaque silastic catheters in premature infants induced hypothyroidism in some and thyrotoxicosis in others (44,46).

The administration of a single dose of 15 mg of KI to newborn infants for iodide prophylaxis after the Chernobyl nuclear reactor accident resulted in a transient increase of serum TSH concentrations in 0.4% of the 3,214 treated infants (32). In the same population, the exposure in utero to iodide due to maternal iodide prophylaxis did not result in an increase in congenital hypothyroidism (32).

Iodide contamination is the major cause of transient neonatal hypothyroidism (47), responsible for 3% of recalls at screening for congenital hypothyroidism (48). Because these reports emanate primarily from continental Europe, where mild iodide deficiency is present, it is possible that iodide deficiency might predispose the fetal and neonatal thyroid to the inhibitory effect of iodide. According to this hypothesis the supplementation of 150 µg iodide /day to pregnant women in Denmark, a mild to moderate iodide deficiency area, resulted in a significant increase of the percentage of cord serum TSH values above 10 mU/L, 41% in neonates whose mothers were supplemented with iodide and 31% in the control group (49). Brown et al reported that transient hypothyroidism is not a common sequela of routine skin cleansing with iodide in premature newborn infants in the United States, an iodide sufficient area (50). Furthermore, Momotani and colleagues (51) reported that only 2 of 35 newborns whose mothers had been treated with 6 to 40 mg iodide daily from 11 to 37 weeks of gestation for Graves' disease had elevated cord serum TSH concentrations. It is possible that the lack of fetal iodide-induced hypothyroidism in these newborns was due to the concomitant presence of autoimmune thyroid hyperfunction and the high ambient iodide intake in Japan.

Drugs containing iodide also may induce hypothyroidism in the fetus. Bartalena et al. (52) reviewed 64 cases of pregnant women treated with amiodarone. Hypothyroidism was detected in 17% of the progeny. All neonates had transient hypothyroidism.


The administration of 40 to 65 mg iodide per day to euthyroid children residing in Greece resulted in serum TSH concentrations above 4.2 mU/L in 75% A similar finding was observed in euthyroid children who had transient neonatal hypothyroidism. In contrast, adult subjects did not have any increment in serum TSH concentrations (53). This finding suggests that in children, the autoregulatory mechanisms is immature and therefore the thyroid is susceptible to the inhibitory effects of excess iodide on hormone synthesis.

Chronic Nonthyroidal Illness

Patients with chronic nonthyroidal illness usually are not susceptible to the inhibitory effect of iodide despite the multiplicity of thyroid dysfunction. However, certain diseases may predispose the patient to iodide-induced thyroid dysfunction (54).

Iodide-induced hypothyroidism has been reported in patients with a variety of chronic lung diseases, including asthma, treated for a prolonged period with iodide-containing expectorants. However, underlying Hashimoto's thyroiditis predisposing these patients to the inhibitory effect of iodide was not ruled out (8,9).

Children with cystic fibrosis, especially those treated with sulfisoxazole, are particularly susceptible to iodide-induced hypothyroidism (55). No apparent thyroid dysfunction was found in these patients, although accumulation of lipofuscin has been observed in the thyroids of patients with cystic fibrosis. The significance of the latter finding is unclear because lipofuscin is found in the thyroid of mice fed large quantities of iodides.

In children and adults with thalassemia major and requiring chronic blood transfusions, iodide administration (60 mg/day) resulted in subclinical hypothyroidism (TSH >5 mU/L) in 60%. TSH returned to basal levels 2 to 3 weeks after iodide withdrawal. It appears that hemosiderosis renders the thyroid of these patients susceptible to the inhibitory effects of iodide (56).

Patients with chronic renal failure frequently have thyroid dysfunction, including thyroid enlargement and abnormal thyroid function tests. Some of these abnormalities are due to chronic disease, although iodides have been suspected as a potential pathogen because they are used as antiseptics in these patients. In one study, however, no relationship was found between thyroid abnormalities due to iodide and application of iodide-containing antiseptics (57). In another study, iodide-induced hypothyroidism was diagnosed in 3% of patients on chronic dialysis treatment (58). In these patients the thyroid was enlarged, thyroid radioactive uptake was normal or elevated, the iodide-perchlorate discharge test was positive, and no lymphocytic infiltration was present at cytologic examination. After restriction of iodide intake in 83% of patients with renal dysfunction and increased serum TSH concentrations, the thyroid function tests were normalized (59).

The use of mucolytic expectorants containing iodinated glycerol is particularly frequent in elderly subjects, although this problem may abate in the United States because iodide has been removed from the products. The occurrence of mild hypothyroidism after iodinated glycerol administration was observed in an elderly patient with a previous episode of severe hypothyroidism induced by KI administration, as well as in subjects without known thyroid disorders (60). In these subjects, the abnormalities of thyroid function resolved spontaneously after therapy was withdrawn.

Iodide-induced hypothyroidism has been reported in patients with anorexia nervosa (61,62). In one patient, excessive iodide intake resulting from kombu ingestion induced severe hypothyroidism despite negative antithyroid antibodies (62). After withdrawal of kombu, thyroid function returned to normal. Kombu is used in Japan as a low-calorie food, and one package contains approximately 13 mg of iodide.

In Japanese hypothyroid patients with negative thyroid antibodies, restriction of iodide intake resulted in a decrement of urinary iodide excretion from a median value of 834 µg I/g creatinine to 123 µg I/g creatinine a week later and a parallel decrement of serum TSH concentrations from 123 to 4 mU/L. Furthermore, during long-term follow-up these patients remained euthyroid, except for one subject, who resumed excessive iodide intake (63).


Chronic Lymphocytic Thyroiditis

Patients with chronic lymphocytic (Hashimoto') thyroiditis often develop hypothyroidism due to thyroid destruction by the autoimmune process and the presence of TSH-blocking antibodies. In about 60% of patients, an abnormal iodide-perchlorate discharge test suggests a defect in the intrathyroidal organic binding of iodide. Administration of pharmacologic quantities of iodide (180 mg/day) resulted in hypothyroidism in more than 60% of the patients in one study. The iodide-perchlorate discharge test was positive in patients who developed iodide-hypothyroidism and negative in those who did not (8,9). The failure of the thyroid to escape from the inhibitory effect of iodide is probably due to a persistent Wolff-Chaikoff effect and not to inhibition of the release of T4 and T3 from the thyroid. Direct measurement of intrathyroidal thyroid hormone content, however, has not been performed. In Bio-Breeding/Worcester (BB/Wor) rats, which are genetically susceptible to chronic lymphocytic thyroiditis, pharmacologic quantities of iodide surprisingly do not consistently induce hypothyroidism, and no demonstrable abnormality in intrathyroidal organification of iodide was found (64). In BB/Wor sublines with the most extensive lymphocytic thyroiditis, however, iodide administration does induce hypothyroidism (65). Contradictory results have been obtained when patients with Hashimoto's thyroiditis were exposed to a moderately increased iodide intake. The administration of 1.5 mg iodide daily for 3 months in patients with Hashimoto's thyroiditis did not induce hypothyroidism (66). A few Japanese patients with primary hypothyroidism due to lymphocytic thyroiditis and a high iodide intake became euthyroid when the iodide intake was restricted (67). This phenomenon has been confirmed in other studies (63,68). However, a large number of these patients had a relapse of hypothyroidism even in the presence of normal serum nonhormonal iodide concentrations (63).

Small quantities of iodide given chronically to four patients with Hashimoto's disease who resided in an area of sufficient iodide intake did not induce any changes in thyroid function (11). Of 40 patients, 8 with high TPO antibody levels residing in an area of mild iodide deficiencydeveloped subclinical or overt hypothyroidism following the ingestion of only 250 µg KI/day for 4 months (69). These patients had serum TSH concentrations >3 mU/L before iodide supplementation. During iodide supplementation, the TPO antibody titer did not change. In another study conducted in patients with autoimmune thyroiditis also residing in an area of low iodide intake, small quantities of iodide caused a transient increase in serum T4 and T3 concentrations (70). Small quantities (150 µg/day) of iodide given to moderately iodide-deficient TPO-positive pregnant women did not induce or worsen post partum thyroid disease (71).

Graves' Disease

Before the discovery of antithyroid drugs, the sole medical treatment of Graves' thyrotoxicosis was the chronic administration of large quantities of iodide. Most patients were reasonably well controlled on this regimen, but thyrotoxicosis recurred in some patients, and a few patients developed reversible hypothyroidism. When patients with Graves' disease treated with iodide-131 (131I) were given iodide (250 mg/day) 1 to 2 weeks after 131I therapy, 60% developed transient hypothyroidism. Euthyroid patients treated years earlier either with 131I or thyroidectomy also developed hypothyroidism during the administration of pharmacologic quantities of iodide. The hypothyroidism was transient, and thyroid function returned to normal after iodide withdrawal. All patients who developed hypothyroidism had a positive iodide-perchlorate discharge test (8,9).

In euthyroid subjects previously treated with antithyroid drugs for Graves' disease, the chronic administration of 10 drops of a saturated solution of potassium iodide (SSKI) induced an increase in basal or TRH-stimulated serum TSH concentrations irrespective of iodide-perchlorate discharge test results (72). Basal and TRH-stimulated serum TSH concentrations returned to normal 60 days after SSKI withdrawal.

Postpartum Thyroiditis

Women euthyroid after a previous episode of postpartum thyroid dysfunction are prone to iodide-induced hypothyroidism. In 9 of 11 women, the administration of 300 mg iodide daily for 3 months induced hypothyroidism and, in some, goiter. As observed in patients with other thyroid diseases prone to develop iodide-induced hypothyroidism, a positive iodide-perchlorate discharge test was common (73). Two months after the iodide was withdrawn, thyroid function returned to normal (73). Consonant with those observations are findings suggesting that small doses of iodide administered to patients expected to develop postpartum thyroiditis may intensify rather than ameliorate the disease (74).

Post-subacute Thyroiditis

The chronic administration of large quantities of iodide (300 mg/day) to euthyroid patients long after an episode of painful subacute thyroiditis resulted in a significant increase in the serum TSH concentration in 10 of 18 subjects. Most of these patients had only a slight increase in serum TSH concentration, but two had values >50 mU/L and developed a goiter. A positive iodide-perchlorate discharge test was highly predictive of the occurrence of iodide-induced hypothyroidism (75). Persistent autoimmunity was found up to 39 months after the onset of subacute thyroiditis (76). The serum of these patients was negative for anti-Tg and antimicrosomal antibodies. The nature of the thyroid antigens reacting with serum antibodies in these patients has not been clearly defined, but the antigens were contained in the 2,000-g supernatant of crude thyroid extract. These findings may explain the subtle thyroid defects frequently observed in these patients and their sensitivity to iodide excess.

Post-hemithyroidectomy for Benign Nodules

Patients undergoing hemithyroidectomy for benign thyroid nodules are also susceptible to hypothyroidism when pharmacologic quantities of iodide are administered for a prolonged period (77). No underlying defect in thyroid hormone synthesis could be detected. Similar effects were observed in hemithyroidectomized BB/Wor rats prone to develop lymphocytic thyroiditis (78). This suggests that the hyperfunctioning thyroid remnant is unable to adapt to iodide excess.

After Thyroid Dysfunction Induced by Interferon-α

Treatment of patients with chronic active hepatitis with recombinant interferon-α (rIFN-α) is frequently complicated by the occurrence of autoimmune thyroiditis, thyrotoxicosis, or hypothyroidism (79,80) and a positive iodide-perchlorate discharge test (80). Pharmacologic quantities of iodide administered to euthyroid patients who had previously developed thyroid dysfunction during rIFN-α treatment resulted in subclinical thyroid dysfunction in some of the patients, independent of the presence of positive thyroid antibodies (81).


Several drugs exert mild inhibitory effects on the intrathyroidal organification of iodide, although not when administered alone. When these drugs are administered with excess iodide, however, or when dietary iodide intake is greatly elevated, hypothyroidism or goiter may ensue.

Lithium is frequently used in the treatment of manic-depressive psychosis. It has multiple effects on thyroid function, including inhibition of thyroid hormone release and inhibition of organification of iodide, as judged by a positive iodide-perchlorate discharge test, and may induce goiter or hypothyroidism, especially in patients with Hashimoto's thyroiditis. Iodide-induced hypothyroidism has been reported in a patient receiving lithium.

The sulfonamides sulfadiazine and sulfisoxazole are mild inhibitors of thyroid hormone synthesis. Sulfisoxazole enhanced the inhibitory effects of iodide on hormone synthesis in patients with cystic fibrosis, resulting in goiter in many patients and mild hypothyroidism in others (55). The sulfonylurea hypoglycemic drugs, although potential goitrogens, had no significant inhibitory effect on iodide metabolism in patients, even when these drugs were administered with iodide-containing substances. Surprisingly, rIFN-α, which frequently induces different thyroid disorders, when administered with excess iodide does not potentiate the effect of iodide on thyroid function (82).

Iodide-Induced Thyrotoxicosis

Iodide-induced thyrotoxicosis is not a single etiologic entity. Since the initial description by Coindet in 1821 (83) and the subsequent definition by Breuer and Kocher in 1904, iodide-induced thyrotoxicosis has been reported in patients with a variety of underlying thyroid diseases. As shown in Table 11F.3 iodide-induced thyrotoxicosis may occur in patients with iodide-deficiency goiter, in euthyroid patients with Graves' disease after antithyroid drug therapy, in patients with multinodular goiters who reside in areas of iodide repletion or deficiency, and in people with no evidence of underlying thyroid disease (8,9,84,85). The pathogenesis and epidemiology of iodide-induced thyrotoxicosis have been thoroughly reviewed elsewhere (86,87).


Iodide supplementation for endemic, iodide-deficiency goiter

Iodide administration to patients with euthyroid Graves'disease, espacially those in remission after antithyroid dgru therapy

Nontoxic nodular goiter

Autonomously functioning adenoma

Nontoxic diffuse goiter

Iodide administation to patients with no underlying thyroid disease, especially in areas of mild-to-moderate iodide deficiency

Iodide-Induced Thyrotoxicosis in Endemic Iodide-Deficient Areas

Widespread iodination of salt or administration of iodized oil has almost eliminated endemic goiter in many countries. The incidence of iodide-induced thyrotoxicosis in areas previously considered iodide deficient varied from 0% in Austria to 7% in Sweden after iodination programs. The incidence of iodide-induced thyrotoxicosis in one endemic goiter area has been estimated to be up to 2% (88). The natural course of the disease was mild, and it resolved spontaneously. Recently, in Denmark, a population with moderate iodide deficiency, the prevalence of thyrotoxicosis increased after iodide supplementation, which increased iodide intake, 50 µg/day (89).

Most patients (85) who develop thyrotoxicosis have multinodular goiters, and they are elderly. Eight patients with iodide-induced thyrotoxicosis, diagnosed in Lucerne, Switzerland had a mean age of 61 years (90). Iodide-induced thyrotoxicosis occurs in 1.2% of all thyrotoxic patients with a mean age of 65 years (91). The risk of developing thyrotoxicosis is particularly high in these patients. Most are euthyroid before iodide administration, but they may have a nonsuppressible radioactive iodide uptake and low or undetectable serum TSH values. Approximately 20% of patients with multinodular goiters in Greece have either abnormal suppression of the radioactive iodide uptake or an undetectable serum TSH (A Vagenakis, unpublished observations). These patients are at risk to develop iodide-induced thyrotoxicosis. Similar results have been reported from central Europe (92). Single oral doses of 200, 400, and 800 mg iodide administered to goitrous adult subjects residing in Sudan induced four cases of thyrotoxicosis.

However, in the three groups of subjects, serum TSH concentrations < 0.1 mU/L were present in 6% to 17% 12 months after iodide administration (93). Similar data have been reported 2 years after iodized salt distribution in Zaire. Among 190 adult subjects with nodular goiter, 14 (7) developed severe thyrotoxicosis and 2 required antithyroid drug treatment (94). Thyroid-stimulating antibodies were absent in all patients. Surprisingly, these alterations lasted longer than 1 year (95). In Zimbabwe, following the iodination of salt at a level of 30 to 90 parts per million, a threefold increase of iodide-induced thyrotoxicosis was observed (96). Furthermore, there were more deaths in that population, mainly from cardiac complications. In contrast, Azizi et al (97) observed a prevalence of iodide-induced thyrotoxicosis of only 0.6% during an observation period of 4 years following the injection of 1 mL iodized oil containing 480 mg iodide.

It appears, therefore, that thyroid autonomy and thyrotoxicosis become evident when iodide repletion permits the autonomous tissue to synthesize and release excess quantities of thyroid hormone. The importance of thyroid autonomy for the development of iodide-induced thyrotoxicosis is strengthened by a report of iodide-induced thyrotoxicosis in a woman with a multinodular goiter treated with suppressive doses of T4 and simultaneously exposed to high quantities of iodide (98). Attempts have been made to associate these events with thyroid autoimmunity, but the results are conflicting. Long-acting thyroid stimulator (LATS) or LATS protector was found in some patients but not in others (88). In another study, no change in the incidence of thyroid autoantibodies was found after oral iodized oil administration (99).

These observations suggest that the increased incidence of thyrotoxicosis in endemic areas after iodide exposure is due to an increased supply of iodide to patients with underlying macro- or micronodular disease with autonomous thyroid nodules or with underlying latent Graves'disease. This is consonant with studies from Belgium and Greece (100,101), in which the administration of small quantities of iodide (0.5 mg/day) to patients with autonomous nodules induced frank thyrotoxicosis. In Austria in 1990, salt iodination was doubled, from 10 to 20 mg KI/kg because urinary iodide excretion ranged from only 42 to 72 µg I/g creatinine (102). This increase was accompanied by an increase in the incidence of overt thyrotoxicosis from 30.5 to 41.7 cases per 100,000 in 1992 and a more marked increment of overt Graves' thyrotoxicosis from 10.4 to 20.9 cases per 100,000 in 1993.

It is interesting to note that among 147 patients reported in the literature who developed sporadic thyrotoxicosis without preexisting thyroid abnormality, 137 cases occurred in areas with urinary iodide excretion of 40 to 80 µg/day or iodide intake of < 50 µg/day (84). It is evident, therefore, that the remarkably greater incidence of iodide-induced thyrotoxicosis in continental western Europe than in the United Kingdom, United States, and Japan is at least partially due to the iodide deficiency that occurs in Europe in contrast to the latter three countries, where iodide intake is sufficient.

It should be noted that notwithstanding the seriousness of iodide-induced thyrotoxicosis in the elderly in these areas, most observers agree that the risk should not undermine the benefits that iodide sufficiency in children and women, and should not prevent the proper correction of iodide deficiency in a community.

Iodide-Induced Thyrotoxicosis in Iodide-Sufficient Areas

In nonendemic euthyroid goiter areas, the incidence of iodide-induced thyrotoxicosis is low. The prevalence of goiter in the United States is about 3%, and it is surprising that only a few cases have been reported since the initial report from Boston (103), where four of eight patients with goiter developed severe iodide-induced thyrotoxicosis after administration of 180 mg iodide daily for several weeks. Although suppression scans or TRH stimulation tests were not performed, it is likely that the susceptible patients had nonsuppressible thyroid function. Many apparently euthyroid patients with a multi-nodular goiter who reside in iodide-replete areas may have abnormal suppression test results. Iodide-induced thyrotoxicosis also has been reported in other patients residing in the United States (84,104).

Iodide-induced thyrotoxicosis was identified in 13 of 60 hospitalized thyrotoxic elderly subjects in Australia (105,106) and Germany (107) who had undergone nonionic contrast radiography. These subjects did not have TPO antibodies, and a thyroid scan revealed the presence of a multinodular goiter. In a prospective study in elderly subjects, frank thyrotoxicosis was uncommon following the administration of nonionic contrast agents, whereas subclinical thyrotoxicosis was observed (108). To reduce the incidence of iodide-induced thyrotoxicosis, the prophylactic use of methimazole or perchlorate given the day before and for 2 weeks after radiographic contrast agent administration to patients with thyroid autonomy has been suggested (109,110). However, the risk of iodide-induced thyrotoxicosis after coronary angiography was too low to recommend prophylactic therapy in unselected patients (111). Iodide-induced thyrotoxicosis also has been described in travelers (travelers' thyrotoxicosis) following the ingestion of iodinated preparations for water purification (112,113). In all three cases, TPO antibodies were present at the time of the diagnosis of thyrotoxicosis. In a U.S. prospective study in eight normal subjects, the ingestion of four iodide purification tablets dissolved in water daily for 3 months markedly increased urine and serum iodide concentrations, and increased thyroid volume secondary to a small increase in TSH due to small decreases in serum T4 and T3 values (114).

The large difference in the rate of occurrence of iodide-induced thyrotoxicosis between iodide-deficient and iodide-replete areas is difficult to explain. It is possible that people with increased iodide intake are “resistant” to iodide- induced thyrotoxicosis because the sensitivity of the autoregulatory mechanism has changed, rendering the thyroid better able to handle the excessive quantities of iodide.

A characteristic of iodide-induced thyrotoxicosis in patients with multinodular goiter is its transient, although at times protracted, course. The thyrotoxicosis maneuver worsen after iodide withdrawal due to the abrupt release of preformed T4 and T3 from the thyroid. Serum T4 is invariably increased, and serum T3 is usually but not always elevated. Serum TSH is undetectable, and there is no response to TRH. Radioactive iodide uptake is usually low, but occasionally may be normal or increased. Due to the large store of preformed hormone in the thyroid, therapy is more difficult (see later section on amiodarone-induced thyroid disease).

Latent Graves' Disease

Antithyroid drug therapy for Graves' disease reduces thyroidal iodide content, and the thyroid is iodide depleted. Overt thyrotoxicosis can develop only if sufficient iodide is available. It has been reported that a small increase in dietary iodide from either iodide ingestion or thyroid hormone administration increases the frequency of recurrence of thyrotoxicosis after antithyroid drug therapy. The difference in remission rates between the United States and Europe and the preference of American thyroidologists to treat Graves' thyrotoxicosis with radioactive iodide instead of antithyroid drugs is attributed, at least in part, to the higher recurrence rate of Graves' disease in the United States due to adequate iodide intake (115). Administration of large quantities of iodide to patients with latent Graves' disease may result in thyrotoxicosis.

Consonant with this view are recent observations in Graves' disease patients treated with antithyroid drugs. In one study (116), simultaneous administration of methimazole and ipodate reduced the effectiveness of the antithyroid drug. In another study, iodide administration to patients rendered euthyroid after antithyroid drug therapy was accompanied by frank thyrotoxicosis in some and by an absent serum TSH response to TRH in others (72). Excess iodide administered to thyrotoxic patients with Graves' disease significantly increased TSH receptor antibody levels, suggesting that this phenomenon was responsible for iodide-induced thyrotoxicosis in these patients (117).

Unusual episodes of iodide-induced thyrotoxicosis have been observed in a few patients suffering from severe burns treated with povidone iodide (118) and in a patient who had metastatic thyroid carcinoma (119). In a patient with a TSH-producing pituitary tumor with mild thyrotoxicosis, accidental exposure to iodide resulted in severe thyrotoxicosis, which improved after iodide withdrawal (A Vagenakis, unpublished observation).

Amiodarone-Induced Thyroid Disease

Amiodarone, a benzofuranic derivative containing 75 mg iodide per 200-mg tablet, is widely used for the long-term treatment of cardiac arrhythmia. About 9 mg iodide is released daily during the metabolism of the drug (300-mg dose), which has a prolonged half-life of at least 100 days. Beyond its effects on the heart, amiodarone is a potent inhibitor of type I deiodinase, TSH secretion, and it is frequently associated with iodide-induced thyroid dysfunction. Amiodarone-induced thyrotoxicosis occurs in about 10% of patients residing in iodide-deficient areas (84,120,121). In the United States, amiodarone-induced hypothyroidism is more common, occurring in up to 20% of patients, whereas thyrotoxicosis is far less common. These differences are attributed to a higher ambient iodide intake in the United States (120,122).

The etiology of amiodarone-induced hypothyroidism can be partially explained by the excess iodide released during the metabolism of the drug. Measurements of intrathyroid iodide content by fluorescence imaging revealed increased iodide content in patients who developed hypothyroidism (70). Evidence for the essential role of iodide in the pathogenesis of amiodarone-associated hypothyroidism stems from the observation that administration of potassium perchlorate, which prevents thyroid iodide uptake and increases the release of inorganic iodide from the thyroid, restored euthyroidism in some patients. Perchlorate also can protect against inhibition of thyroid function and the resulting hypothyroidism caused by excess iodide, presumably by reducing the formation of an iodinated inhibitor (123,124). One study showed that hypothyroidism returned on withdrawal of potassium perchlorate (124). Iodide-induced hypothyroidism is also related to the presence of thyroid autoimmunity. Circulating antithyroid antibodies are common in patients who develop hypothyroidism during amiodarone treatment (120,122). Hypothyroidism is easy to diagnose because serum TSH is invariably high. T4 treatment is indicated and does not require interruption of amiodarone therapy. However, in a single patient with amiodarone-induced hypothyroidism, continuation of amiodarone treatment induced destructive thyrotoxicosis (125).

Amiodarone-induced thyrotoxicosis results from two different mechanisms. The iodide released during the metabolism of the drug is responsible for the thyrotoxicosis in many cases. Predisposing factors include micro- and macronodular goiter, which are common in older patients who most often require amiodarone. Thyroid autoimmunity also has been incriminated as a predisposing factor, and antithyroid antibodies have been found in some patients (126) but not in others (127). In one study, the prevalence of serum thyroid-stimulating antibodies and TSH-binding inhibiting antibodies was similar to that in patients with spontaneous thyrotoxicosis (127). Amiodarone may also induce destructive thyroiditis, resulting in thyrotoxicosis, as suggested by clinical, histologic, and in vitro studies (128,129,130). The ultrastructural changes in the rat thyroid gland induced by amiodarone differ from those induced by excess iodide, and include disruption of subcellular organelles with a marked dilation of the endoplasmic reticulum (131). The clinical and laboratory characteristics of amiodarone-induced thyrotoxicosis are presented in Table 11F.4.


 Iodide-induced thyrotoxicosis (type I)

Destructive thyrotoxicosis (type II)

Underlying thyroid abnormality



Thyroidal RAIU

Low, rarely normal or elevated Slightly elevated


Serum IL-6 concentrations

Slightly elevated

Occasionaly markedly elevagted

Cytologic findings


Abundant colloid, hystiocytes

Pathogenic mechanism

Excessive thyroid hormome synthesis

Excessive thyroid hormone release (destructive thyroiditis)cells

Reponse to thionamides



Response to perchlorate



Response to glucocorticoids



Subsequent hypothyroidism



Effect to excess idide following the thyrotoxic phase

Likly iodide-induced hypothyroidism

Possible recurrence of thyrotoxicosis

Color-flow Doppler sonography

Normal or increased blood flow

Decreased blood flow

?, not known; IL, interleukin; RAIU, radioiodide uptake.

From Bartalena L, Grasso L, Bragioni S, et al. Serum interleukin-6 in amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab 1994;78:423, modified with permission.

The evaluation of thyroid function is difficult in patients receiving amiodarone therapy. Serum T4 may be elevated, serum T3 decreased, and serum TSH slightly high in a euthyroid subject receiving the drug. Thyrotoxicosis is best confirmed by an elevation of serum T3 and free T3 concentrations as well as by an increase in sex hormone–binding globulin (132). The distinction between iodide-induced thyrotoxicosis (type I) and destructive thyrotoxicosis (type II) may be achieved by measurement of serum interleukin-6, which is elevated in some but not all cases of the destructive form (133), and by fine-needle biopsy, which yields cytologic findings consistent with thyroiditis (129). Color-flow Doppler sonography may show hypervascularity in type I amiodarone-induced thyrotoxicosis and hypovascularity in type II (134). The thyroid radioiodide uptake is always low in the destructive form and is most often low in the iodide-induced form, although may occasionally be normal or even elevated in Europe but not in the United States.

Distinction between the two forms is important for determining therapy. Amiodarone should almost always be discontinued. Large doses of antithyroid drugs are recommended for iodide-induced thyrotoxicosis. If this treatment fails, potassium perchlorate (250 mg three times daily) should be added (135,136). The latter drug blocks thyroid iodide uptake, thereby decreasing the intrathyroidal iodide content. If the thyroid radioiodide uptake is elevated, 131I therapy is an alternative.

In patients with destructive thyrotoxicosis, administration of large doses of glucocorticoids is rapidly effective (129,137). Also, iopanoic acid has been successfully employed in the treatment of type II amiodarone-induced thyrotoxicosis (138,139). In a prospective and randomized study (139), both iopanoic acid and a glucocorticoid ameliorated the thyrotoxicosis. However, patients treated with the latter reached the euthyroid state more rapidly than those treated with iopanoic acid (139); normal serum T3 concentrations were achieved after an average of 8 days. Relapses are frequent as the glucocorticoid dose is tapered (140). When the distinction between type I and type II amiodarone-induced thyrotoxicosis is not possible or when the two forms coexist in the same patient, a stepwise treatment approach is advisable, beginning with an antithyroid drug and potassium perchlorate. If after 1 month the patient is still thyrotoxic, potassium perchlorate can be discontinued and prednisone can be added, tapering the latter when the serum free T4 concentrations are normalized. Lastly, the antithyroid drug can be reduced and discontinued when the urinary iodide excretion is < 200 µg daily (141).

Surgery has been successfully used for the treatment of amiodarone-induced thyrotoxicosis (142,143) in patients with type I (144) and rarely type II (145). Patients with type I amiodarone-induced thyrotoxicosis can be treated with iopanoic acid prior to thyroidectomy (144).

After recovering from amiodarone-induced destructive thyrotoxicosis, patients may develop permanent hypothyroidism (125,129) as a result of fibrosis of the gland (146). The iodide-perchlorate discharge test result was positive in 60% of euthyroid patients who had recovered from amiodarone-induced destructive thyrotoxicosis (147). Chronic administration of 300 mg iodide daily to these patients induced a marked increase in basal and TRH-stimulated serum TSH concentrations, which returned to normal after iodide withdrawal.

In view of the high incidence of thyroid dysfunction, amiodarone should be administered with caution to patients with preexisting goiter or a history of thyroid disease. Adult patients with β-thalassemia have been shown to be particularly prone to develop both thyrotoxicosis and hypothyroidism during amiodarone therapy (148). Before beginning amiodarone treatment, a careful examination is required; serum TSH and TPO antibodies values must be obtained. During amiodarone treatment, measurement of serum TSH is required approximately every 6 months in order to detect the development of mild thyroid disorders.

Iodide as a Pathogen

Animal studies suggest that iodide administration has an important role in the development of autoimmune thyroid disease. Spontaneous lymphocytic infiltration of the thyroid has been observed in hamsters, beagles, nonobese diabetic mice, Buffalo rats, BB/Wor rats, and obese-strain chickens (149,150,151,152). Spontaneous lymphocytic thyroiditis occurs in about 30% of 90-day-old rats who also develop spontaneous insulin-dependent diabetes mellitus (BB/Wor rats) (64,150). The administration of iodide in their drinking water (0.05% sodium iodide) from 30 to 90 days strikingly increased the prevalence of lymphocytic thyroiditis to approximately 75% or more (64). Excess iodide administration to strains of rats that do not develop spontaneous thyroiditis does not induce histologic changes in the thyroid.

The mechanism by which iodide excess increases the occurrence of autoimmune thyroiditis may be due to the enhanced immunogenicity of iodide-rich Tg, as demonstrated in obese-strain chickens (153). Conversely, immunization of the BB/Wor rat with iodide-poor Tg did not induce thyroiditis (154). However, in obese-strain chickens, iodide excess induced thyroid infiltration only in predisposed animals (155), and the greatest effect was observed when iodide was given to the embryos (156). Furthermore, an essential requirement for the development of iodide-induced thyroiditis is the uptake and metabolism of iodide within the gland (156). Other mechanisms for the development of iodide-induced thyroiditis, such as cellular damage due to elevated oxygen-free radicals, direct cytotoxic effects of iodide or autoregulation of major histocompatibility class I, and increased expression of intrathyroidal TNF-α have been proposed (155,157,158,159). In contrast to the present view that excess iodide increases the occurrence of autoimmune thyroiditis, iodide deficiency in Wistar rats led to goiter formation with signs of lymphocytic infiltration (160).

The relationship of iodide intake to the occurrence of Hashimoto's thyroiditis in humans is controversial. Some studies (161,162) have strongly suggested that increased iodide intake is associated with an increased incidence of Hashimoto's thyroiditis, especially when iodide is introduced into endemic goiter regions. In a randomized, double-blind, placebo-controlled study conducted in patients with endemic goiter, administration of 0.5 mg/day of KI for 6 months induced high serum anti-Tg antibody and antimicrosomal antibody levels in 19%. Fine-needle aspiration biopsy confirmed the presence of lymphocytic infiltration of the thyroid gland (163). These signs of thyroid autoimmunity disappeared after iodide withdrawal. The presence of lymphocytes in thyroid fine-needle aspiration specimens increased from 6% to 14% after the elimination of iodide deficiency in Greece (164). Also, the injection of 1 mL iodized oil intramuscularly in patients with nontoxic goiter living in Greece was accompanied by an increase in thyroid lymphocytic infiltration from 25% to 68% (165), and iodide prophylaxis has been followed by a threefold increase in the prevalence of autoimmune thyroiditis in schoolchildren (166). Similar results were reported by Markou et al in a study of iodide prophylaxis in Azerbaijan. The incidence of thyroid antibodies increased from 1% to 9% in 12 months in schoolchildren given 380 mg iodized oil orally (167). In elderly women residing in an area of adequate iodide intake, the prevalence of antimicrosomal antibodies was far higher than in those living in an area of mild iodide deficiency (149). In contrast, other studies did not find a relationship between iodide intake and the prevalence of thyroid autoimmunity (15,88). A lower prevalence of anti-TPO antibodies in children and adolescents following 5 years of iodide prophylaxis has been also reported (168). Possible explanations for these discrepant findings on the effect of iodide supplementation on thyroid autoimmunity are suggested by studies from Morocco and Sri Lanka (169,170,171). In these studies, following iodide prophylaxis the prevalence of thyroid antibodies increased, but decreased later to baseline or lower values. In a recent study iodide intake did not affect the pattern of epitope recognition by polyclonal TPO antibodies in elderly subjects (172).

The mechanism by which iodide interacts with the immune system is unknown. In the presence of iodide, the production of immunoglobulin G from human peripheral blood lymphocytes was increased after stimulation with pokeweed mitogen. These studies suggest that factors other than iodide, such as human leukocyte antigen type or unknown environmental influences, contribute to the development of Hashimoto's thyroiditis. Evidence is emerging concerning the role of iodide in modulating the effects of growth factors in the thyroid. Transforming growth factor-β, a well-known inhibitor of cell growth, is substantially decreased in multinodular goiters, and iodide induced its production (173). Lastly, pharmacologic concentrations of iodide partially inhibit the in vitro growth of FRTL-5 thyroid cells, but not of thyroid follicular cells obtained from autonomously growing feline multinodular goiters, suggesting that the inhibitory action of iodide on thyroid cell growth is a constitutive trait of each thyrocyte (174).

Raising dietary iodide intake has clinical implications. As mentioned earlier, iodide-induced thyrotoxicosis is likely to become more common, particularly in iodide-deficient areas. In Great Britain, iodide intake has tripled during the past 30 years, and the incidence of thyrotoxicosis due to toxic multinodular goiter correlates closely with the previous prevalence of endemic goiter (175). A seasonal increase in thyrotoxicosis was observed in Great Britain, perhaps related to increased iodide intake from milk (176). In contrast, in New Zealand no relationship has been observed between the iodide content in milk, mean 24-hour urinary iodide excretion, and the seasonal incidence of thyrotoxicosis (177).

Another possible consequence of iodide supplementation is that Graves' disease may become more difficult to control with antithyroid drugs. The presence of iodide deficiency is associated with a higher remission rate after treatment with antithyroid drugs. The response to thionamide drugs is rapid in Graves' disease patients who reside in iodide-deficient areas, and the dose required to control the disease is smaller (178) (see Chapter 45).

The increase in dietary iodide also has resulted in a decrease in the thyroid radioactive iodide uptake and a corresponding increase in the dose of radioactive iodide required to control thyrotoxicosis. In Cardiff, Wales, the required dose in 1967 was 7.2 mCi (267 MBq), which increased to 12.6 mCi (465 MBq) in 1982. The results of surgery are also influenced by the ambient iodide intake. The incidence of recurrent thyrotoxicosis after thyroid surgery for Graves' disease in an area of high iodide intake was five times higher and that of hypothyroidism five times lower than in areas where the iodide intake was low (175).


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