3.2.4 Disorders of iodine excess

Iodine is an essential substrate for the biosynthesis of thyroid hormone because both thyroxine (T₄) and triiodothyronine (T₃) contain iodine. An adequate supply of dietary iodine is therefore necessary for the maintenance of normal thyroid function. Dietary iodine intake is increasing in many regions, especially in developed countries, mainly due to iodization of salt or bread, and it is well known that various drugs and foods contain large quantities of iodine (1), e.g. seaweeds, such as konbu (Laminaria japonica), contain 0.3% of iodine dry weight. Furthermore, large doses of iodine are used for prophylaxis against exposure to ¹³¹I. Excess iodine, as well as iodine deficiency, can induce thyroid dysfunction. The response of the thyroid gland to excess iodine and disorders due to excess iodine are the main subject of this chapter.

The thyroid gland has intrinsic mechanisms responsive to variations in the quantity of iodine available and often to the resulting changes in thyroidal organic iodine content. Autoregulation was originally defined as a regulation of thyroidal iodine metabolism independent of thyroid-stimulating hormone (TSH) or other external stimulations, and the major autoregulating factor was considered to be excess iodide (2).

In the animal thyroid, acute inhibition of thyroidal organification of iodine by excess iodide, escape from the acute inhibitory effects, and changes of thyroid radio-iodine uptake in hypophysectomized animals in response to variations in dietary iodine intake are representative examples of autoregulation. The acute inhibitory effect of excess iodide is temporary and escape occurs despite continuous administration of iodide.

Despite the numerous reports on the effects of excess iodide on the thyroid gland, little is known about the exact mechanism of autoregulation. A fundamental phenomenon of the acute inhibitory effect is an inhibition of organification of intrathyroidal iodide in response to a marked elevation of plasma iodide (3). Thyroid peroxidase-catalysed iodination requires thyroid peroxidase, an acceptor (protein or free tyrosine), iodide, and hydrogen peroxide. Preincubation of dog thyroid slices with excess iodide greatly inhibits iodide organification and hydrogen peroxide generation stimulated by TSH and carbamylcholine. When iodide supply is sufficient, hydrogen peroxide generation is the limiting step for iodide organification, and it is suggested that the inhibitory effect of iodide on hydrogen peroxide generation is associated with the acute inhibitory effect (4, 5). On the other hand, the effect of excess iodide on an acceptor (thyroglobulin or free tyrosine), which is also associated with organification of intrathyroidal iodide, has not been clarified.

Iodinate phospholipids and iodinated derivatives of arachidonic acid or iodolactone inhibit organification of iodide in both calf thyroid slices and homogenates (6). It is possible that iodinated arachidonic acid plays an important role in the acute inhibitory effect of excess iodide.

In animal experiments designed to test the duration of inhibition by excess iodide on organic binding of iodide in the thyroid, it was shown that this effect is transient despite the continued maintenance of a high level of plasma total iodine (7). Originally, this was the definition of ‘escape from acute inhibitory effects’. However, the term ‘escape’ is now widely used, as described later.

The amounts of iodide taken up by the thyroid and incorporated in iodoamino acids and iodothyronines differ greatly according to dietary iodide intake, but the amounts of T₄ and T₃ released from the thyroid are remarkably constant in humans. Although, this is called ‘adaptation to excess iodide’, this adaptation is another concept of escape observed in experimental animals, since the acute inhibitory effect (Wolff–Chaikoff effect) is not observed in humans (see below).

Clinically, the term escape is also widely used. In patients with Graves’ diseases, treatment with inorganic iodide decreases their serum T₄ and T₃ concentrations quickly, but subsequently, many patients escape from its inhibitory effects. Details of the mechanism of this escape are described in the following section.

As mentioned above, the term escape has wide-ranging concepts. In this section, the mechanism of escape from the acute inhibitory effect, which has been identified through in vivo experiments in rats, is mainly described. It is suggested that decreased iodide transport is an important mechanism in escape from the acute inhibitory effect of excess iodide. Braverman and Ingbar reported that adaptation to the acute Wolff–Chaikoff effects is caused by a decrease in iodide transport into the thyroid, which reduces the intrathyroidal iodide to concentrations that were insufficient to sustain the decreased organification of iodide (8). After cloning of the sodium-coupled iodide cotransporter or sodium-iodide symporter (NIS) (9), the role of this protein was re-examined, and it was suggested that a decrease of NIS protein resulting in a decrease in thyroidal iodine transport plays an important role in the escape phenomenon (10). In addition, other factors, such as iodinated arachidonic acid, are suggested to decrease iodide transport. However, high concentrations of iodide can enter into thyroid cells independently from active iodine transport. It is still unclear whether active transport can act as a ‘main controller’ of escape when thyroid is exposed to a huge amount of iodide.

Although several factors that are associated with acute blocking effects during organification of intrathyroidal iodide have been identified, the effects of these factors in the escape from the acute inhibitory effects phenomenon is still unknown. As described in the following section, factors other than iodide transport have been identified in adaptation in normal individuals and escape in patients with Graves’ disease.

When the iodide dose reaches over 1 mg/day in humans, thyroidal uptake of tracer doses of radio-iodine decreases, and the administration of perchlorate or thiocyanate results in discharge of radio-iodine from the thyroid, indicating a proportional decrease in organification of thyroidal iodide. There is no evidence, however, that overall organification is actually decreased by excess iodide; that is, there is no evidence for an acute Wolff–Chaikoff effect in humans. If a large dose is given, thyroid radio-iodine uptake is so low that the absolute iodine uptake cannot be calculated. Therefore, it is not possible to prove either the Wolff–Chaikoff effect or the escape from it in humans.

Acute administration of small or moderate doses of iodide does not change the percentage of thyroid uptake of concomitantly administered radio-iodine, leading to a linear increase in absolute iodine uptake. With progressively larger doses of iodide, thyroidal radio-iodine uptake decreases, but absolute iodine uptake calculated from thyroid radio-iodine and serum and urinary iodide concentrations increases (2). On the other hand, chronic iodide administration decreases thyroidal radio-iodine uptake, but absolute iodine uptake increases as the intake of iodide increases. Serum levels of T₃ and T₄, and degradation of thyroid hormone are not affected (2). A recent study demonstrated that the administration of a large quantity of iodine (80 mg) for 2 weeks was accompanied by an increase of intrathyroidal total iodine, while intrathyroidal T₃ and T₄ contents and serum T₄ and T₃ remained unchanged (11).

The thyroid usually utilizes iodide from two routes to produce thyroid hormone (Fig. 3.2.4.1): transport iodide, which comes from serum iodide (external iodide), and iodide derived from the deiodination of iodotyrosine freed from thyroglobulin (internal iodide) (2). However, absolute iodine uptake or thyroidal organic iodine formation, which is calculated from the incorporation of serum radioactive iodide into thyroidal organic iodine, represents only organification of external iodide. If internal iodide is completely reutilized, organification of internal iodide should be from 2–4 times greater than that of external iodide, because the amount of iodotyrosine iodine freed from thyroglobulin is from 2 to 4 times greater than that transported from the blood, and release of iodotyrosine iodine should be roughly equal to the organification of external iodide in a steady state. If organification of internal iodide could be decreased when that of external iodide is increased, then the organification of external iodide could be increased from 2–4 times without changing total thyroidal iodination and hormone production. It should be noted that utilization of internal iodide is at the maximum in iodide-deficient individuals.

Acute administration of iodide decreases serum T₃ and T₄ levels and ameliorates thyrotoxicosis in patients with Graves’ disease. However, the acute effect is due to inhibition of hormone release, and there is little evidence that the Wolff–Chaikoff effect occurs in Graves’ patients. In patients, absolute iodine uptake increases several-fold during iodide treatment. Thyroidal organic iodine formation in Graves’ disease is increased by iodide treatment despite a significant decrease in T₃ and T₄ secretion. In addition, thyroidal organic iodine formation did not change after escape from inhibition of hormone release when serum T₃ and T₄ levels increased to their pretreatment levels (12). The dissociation between thyroidal organic iodine formation and T₃ and T₄ release in Graves’ patients is another unexplained feature of autoregulation.

Autoregulation was originally defined as regulation of thyroidal iodine metabolism that was independent of TSH. However, the development of sensitive assays of serum TSH and free T₄ concentration made it possible to determine significant changes in serum levels of these hormones even within the normal range (13). Serum free T₄ decreased and serum TSH increased significantly, mostly within the normal range, and the size of the thyroid gland increased in normal subjects given 27 mg iodine daily for 4 weeks (Fig. 3.2.4.2) (14). After iodide withdrawal, all values returned to baseline levels.

Serum TSH responses to thyrotropin-releasing hormone (TRH) are increased in normal subjects given moderate to large doses of iodides, indicating an antithyroid effect. In addition, administered iodide (as little as 0.75–1.5 mg daily) to normal subjects results in unsustained increases in serum TSH levels and TSH responses to TRH (Table 3.2.4.1) (13). These findings indicate that even moderate doses of iodide have antithyroid actions. Thus, several phenomena of autoregulation may, in fact, be dependent on TSH, and the definition of autoregulation may have to be reconsidered, because serum TSH levels are significantly increased by excess iodide at least in normal humans.

Disorders of iodine excess differ depending on the type and amount of iodide administered, the duration of exposure to iodide, and the background of individuals, i.e. whether they are in iodine-deficient or iodine-sufficient areas, or whether they are apparently euthyroid or have underlying thyroid diseases.

Excess intake of iodine, e.g. an iodine-rich diet (seaweed) or drinking water, in the long-term causes iodide-induced endemic goitre. It was detected in about 10% of the population of some areas on the coast of Hokkaido, Japan, so-called coast goitre. The inhabitants consume iodine-rich seaweed, konbu, and the mean urinary excretion of iodine in the endemic goitre areas was 23 mg/day. Despite the goitre, all patients were clinically euthyroid (15). About 90% of the inhabitants in these areas were free from clinical thyroid abnormalities.

In the prospective study among Japanese men (n = 10), oral administration of iodine tablets (27 mg daily total iodine dose) for 4 weeks caused an average 16% increase in thyroid volume. Serum TSH levels were significantly increased, but the values remained within the normal range, except for two men, and were accompanied by a small decline in serum free T₄ concentration within the normal range (14).

Smaller doses of iodide than those in the preceding report can increase the thyroid volume. Endemic iodide-induced goitre by the intake of iodine-rich (462 μg/l) drinking water was detected by echogram in 65% (n = 120) of children living in a village in central China. All children were clinically euthyroid except for two cases of overt hypothyroidism (16). Another study in China demonstrated that more than adequate (median urinary iodine excretion, 243 mg/L) or excessive iodine intake (median, 651 mg/L) was associated with elevated TSH but not with goitre (17). In an international sample of 6- to 12-year-old children from five continents with iodine intakes ranging from adequate to excessive, urinary concentrations of more than 500 μg/l are associated with increasing thyroid volume (18).

Overall, chronic loads of excess iodine for a period of time induce increasing thyroid volume but few individuals develop hypothyroidism. Although the mechanism remains unclear, failure to escape from the antithyroid effect may account for, or contribute to, iodide-induced hypothyroidism. Iodide-induced goitre and hypothyroidism disappear spontaneously within 2–6 weeks after iodide withdrawal (15). The thyroid radioactive iodine uptake rate in iodide-induced goitre varies with iodine intake. Histological examination of thyroid glands was performed in iodide-induced hypothyroid patients living in Kanazawa and Kurobe cities located on the west coast of Honshu Island in Japan. Hyperplastic changes in the follicle were observed and the change was reversible after iodine restriction. Lymphocytic infiltration was present in about one-half of them (19).

In iodine-sufficient individuals without pre-existing thyroid diseases, occasional loads of excess iodide by iodine-rich foods or radiology contrast agents may induce subtle changes in thyroid function, including transient subclinical hypothyroidism, but iodide-induced hypothyroidism is exceedingly rare and the majority of individuals remain euthyroid. The average dietary iodine intake has been reported to be 1–3 mg in Japan (2) and iodine intake from seaweeds, especially Konbu, averaged 1.2 mg/day (20), but the amount of dietary iodine intake changes day by day from 0.1 to 30 mg even in the same person. The differences in the prevalence of thyroid abnormalities are not significant between Japan and other countries (Nagasaki and Whickham studies) (21, 22).

The thyroid gland in Graves’ disease is sensitive to iodide. Thyroid radioactive iodine uptake rate decreases with much smaller quantities of iodide in hyperthyroid patients than in euthyroid individuals. Thyroid function of hyperthyroid patients treated with iodide improves quickly. The inhibition of thyroid hormone secretion is usually evident sooner than that caused by antithyroid drugs. Subsequently, many patients escape from its inhibitory effects. Seventy per cent of patients treated by using 10 mg potassium iodine escape within a year (12, 13).

Individuals with underlying Hashimoto’s thyroiditis (23) or those with a previous history of postpartum thyroiditis are susceptible to the development of hypothyroidism upon exposure to iodine excess. Hypothyroidism is usually reversible after withdrawal of iodide (23). Individuals after an episode of subacute thyroiditis or patients who have undergone partial thyroidectomy are also prone to iodide-induced hypothyroidism.

Iodide-induced thyrotoxicosis has been observed when iodine is given as a prophylactic measure to prevent endemic goitre and hypothyroidism in iodine-deficient areas. The incidence of iodide-induced thyrotoxicosis in areas previously considered to be iodine deficient varied from 0% in Austria to 7% in Sweden after iodination programmes (24). Most patients with iodide-induced thyrotoxicosis have multinodular goitre. It appears that masked thyroid autonomy becomes evident by iodine repletion. The natural course of thyrotoxicosis is mild and restores spontaneously.

The frequency of iodide-induced thyrotoxicosis in individuals with an apparently normal thyroid living in iodine-sufficient areas is low. Iodide-induced thyrotoxicosis after coronary angiography with a contrast agent occurred only 0.25% of euthyroid not at-risk patients within 12 weeks (25).

Iodide-induced thyrotoxicosis sometimes occurs in patients with pre-existing euthyroid multinodular goitre. It was identified in 13 of 60 hospitalized thyrotoxic elderly patients with multinodular goitre in Australia and Germany who had undergone nonionic contrast radiography (26).

Patients previously treated for Graves’ hyperthyroidism are also susceptible to iodide-induced thyrotoxicosis. Antithyroid drug therapy for Graves’ disease reduces thyroidal iodide content. A small increase in dietary iodide increases thyroidal iodide content and, subsequently, leads the recurrence of thyrotoxicosis. Simultaneous administration of methimazole and ipodate may reduce the effectiveness of the antithyroid drug (27). The biochemical pattern is frequently that of T₄ toxicosis, and the thyroid radioactive iodine uptake is often undetectable. The thyrotoxic state is frequently, but not always, self-limiting (28).

Amiodarone, a benzofuran-derived iodine-rich drug for the treatment of arrhythmia (a daily dose of 200 mg generates 6 mg iodine/day), induces thyrotoxicosis. The frequency of amiodarone-induced thyrotoxicosis is relatively high (9.6%) in iodine-deficient areas, but it is low (2%) in iodine-sufficient areas (29). Amiodarone-induced thyrotoxicosis is due to excess iodine (type 1) or to amiodarone-related destructive thyroiditis (type 2), although mixed forms often occur. In type 1, the administration of thionamides is used for the treatment, while steroids are the most useful therapeutic option in type 2 (30).

It has been agreed that we should not hesitate to use iodine prophylaxis in iodine-deficient areas despite the possibility of iodide-induced thyrotoxicosis. The risk of iodide-induced thyrotoxicosis does not undermine the benefits of iodide supplements to prevent endemic goitre and hypothyroidism which are serious public health problems in iodine-deficient areas. Education to ensure the proper correction of iodide deficiency is needed.