IODIDE INDUCED THYROTOXICOSIS (IIT)

The earliest report on thyrotoxicosis induced by administration of iodine is probably that of JF Coindet in the Ann Chim Phys (Paris) (16;252,1821), cited by Orgiazzi and Mornex (81). In 1859 Röser, cited elsewhere (82), noted that treating goiter with iodine could result in hyperthyroidism. He used the term "goiter cachexia" for this condition. Later the term Jod-Basedow was applied, although it should be realized that, in most instances, iodide induced hyperthyroidism does not involve patients with incipient Basedow-Graves' disease. Multinodular goiter may be rendered thyrotoxic by the administration of stable iodine. In their review on iodide-induced thyrotoxicosis Fradkin and Wolff (83) speculate that a decreased sensitivity to the Wolff-Chaikoff effect under conditions of moderate iodide excess would lead to iodide induced thyrotoxicosis (IIT). The Wolff-Chaikoff effect involves blockade of iodide organification and hormone synthesis by high intrathyroidal iodide. To date, there is no biochemical or pathological basis for the hypothetical difference in iodide sensitivity or autoregulation of thyroidal iodide metabolism in IIT. It may even be that the mechanism is heterogeneous in different patients with pre-existing thyroid disorders. IIT may be subdivided into different groups: 1. patients from endemic goiter areas; 2. patients with previous non-endemic goiter; 3. patients with previous or with actual Graves' disease and 4. patients without apparent previous thyroid disease (83). Sources of iodide in patients with IIT are listed in Table 13-6.

One of the best known reports on IIT is that by Connoly et al. 84 They found a steep rise in the incidence of thyrotoxicosis in the late months of 1966 in Tasmania (Australia), which was an area of iodine deficiency with a high prevalence of goiter. It appeared that this increase was due to addition of potassium iodide to bread in early 1966. The increased incidence occurred predominantly in subjects older than 40 years, in whom a rise in incidence from 50 to a maximum of 130 cases per 100,000 was seen in '67 to '68. By 1974 the incidence decreased to about the pre-epidemic level. It was also evident that most thyrotoxic patients had nodular goiter and few patients had Graves' disease. Later it was recognized that there was a pre-epidemic increase in incidence of thyrotoxicosis caused by the use of iodofor disinfectants on dairy farms (85).

Figure 13-10

In Figure 13-10 the age specific incidence of thyrotoxicosis in this area between 1960 and 1974 is depicted. It can be seen that despite the continued increase in the iodide supply the prevalence of IIT decreased after its peak around 1967 - 1968. It was argued that this increase in thyrotoxicosis starting from 1964 in this area of relative iodine deficiency with a high prevalence of goiter was due to autonomy in the nodular goiters. For a review of IIT induced by iodine prophylaxis in Tasmania and other countries (see 85a). IIT has also been reported after use of iodinated drugs, X-ray contrast agents, iodochloroxyquinoline, iodine-containing contrast agents, disinfectants, and drugs (86,87,87a). Rarely a thyrotoxic storm is precipitated. Other common sources of iodine causing IIT are iodine containing drugs, vitamin pills, expectorants and kelp. Subjects with longstanding goiter are especially susceptible to IIT. A pre-existing thyroid disorder has been present in at least 20% of patients. Spontaneous reversal to euthyroidism may occur after a mean period of 6 months in 50% of patients. Return to euthyroidism may be preceded by subclinical hypothyroidism (88) Use of non-ionic contrast media do not prevent development of IIT (89)

There is evidence from human and animal studies that chronic excess iodine intake may modulate thyroid autoimmunity and lead to thyrotoxicosis in genetically susceptible individuals. However because studies report IIT in subjects without (apparent) pre-existing thyroid disorder, it is still doubtful if iodide on its own merit induces thyroid autoimmunity (90) A necrotic effect of iodide excess has been demonstrated in vivo in various animal species and also in human thyroid follicles in vitro (91)

Amiodarone induced thyroid disease

Amiodarone is a powerful anti-arrhytmic drug . Because of its high iodine content (37.2%), it has been the cause of IIT in many patients from all parts of the world. Its basic molecular structure has some similarities to that of iodothyronines, and amiodarone may also interfere with thyroid hormone transport into cells and with pathways of intracellular thyroid hormone metabolism. In particular it interferes with 5' monodeiodination of thyroid hormones leading to a decrease of both intra- and extracellularly T3 derived from T4, thus inducing tissue hypothyroidism. Estimation of serum total or free T4 in patients using amiodarone is not specific because these parameters may be elevated in both hyperthyroid, euthyroid and hypothyroid patients receiving amiodarone. The last 2 conditions are explained by a decrease in T4 metabolic clearance by amiodarone inhibition of T4 transport into tissues and of subsequent T4 deiodination. This results in high T4 plasma values. If however the serum TSH is suppressed (and serum T3 is elevated as well), the patient is probably thyrotoxic. A normal and elevated TSH points to euthyroidism and hypothyroidism respectively. An exceptional case of myxedema coma leading to death, despite intervention with thyroxine and triiodothyronine, occurred in a patient after long-term amiodarone therapy (92). In this patient T4 administration did not increase serum T3, evidently because of inhibition of peripheral T3 production from T4. The fact that there was also no positive reaction of this patient to administration of T3 was possibly explained by interference of nuclear T3 binding by desethylamiodarone (DEA), the major metabolite of amiodarone. (92ab) In a study of 467 patients chronically treated with amiodarone, hypothyroidism developed in 28 patients (6%). Hypothyroidism occurs predominantly in patients with preexisting thyroid autoimmune disease and in areas of normal iodine intake (versus iodine induced hyperthyroidism, see below, in areas of iodine deficiency) (92a,92ac)

Amiodarone has also been the cause of hyperthyroidism in many patients(83). It is used in many cardiac patients, particularly in France. Reported incidences of IIT due to amiodarone vary between 0.003% and 11.5%. In the largest series of patients, amiodarone-induced IIT occurred in 30 out of 1448 patients(83).

There are two forms of amiodarone- induced thyrotoxicosis (92ad). Type 1 is due to iodine-induced increase of thyroid hormone synthesis, whereas type 2 involves iodine- or amiodarone-induced cytotoxic damage of the thyroid gland, resulting in leakage of iodothyronines into the circulation. The picture of type 2 on electron microscopy shows two characteristics of damage, i.e.multilamellar lysosomal inclusions and intramitochondrial glycogen inclusions, and a morphological picture of thyrocyte hyperfunction (92b). No inflammatory changes are present. Differential diagnosis between the two types may be difficult on clinical grounds. Thyroid radioactive uptake is usually low to normal in type 1,but low to suppressed in type 2. Serum interleukine 6 levels are normal to slightly elevated in type 1 and markedly elevated in type 2. Color flow sonography differentiates between the two conditions. Type 1 shows normal vascularity or increased vascularity with patchy distribution, while type 2 shows absent vascularity. (92ac)

Amiodarone- associated IIT is a serious problem in many instances, because of the co-existing heart disease of these patients and treatment may often be difficult. Administration of a combination of methimazole and potassium perchlorate has been reported to be effective in type 1 (95,96). Perchlorate was used in a dosage of 1 g per day for up to 40 days in combination with 40 mg methimazole. After discontinuation of perchlorate, methimazole was continued if the patient continued to use amiodarone. Patients became euthyroid after 2 - 5 weeks despite continued use of amiodarone. As potassium perchlorate is a drug that potentially causes aplastic anemia, its use should be limited to those patients who cannot be controlled by methimazole alone. However, in cases of amiodarone induced thyrotoxicosis type 1, amiodarone should, if possible, be discontinued. In a few patients this is not possible, and in a subgroup of these patients temporary use of perchlorate may be necessary. During its use careful hematological examinations should be regularly performed. Induction of thyroid dysfunction by amiodarone seems especially to occur inpatients with congenital heart disease. Of 92 such patients, 19 became hyperthyroid and 14 hypothyroid (92aa).

Treatment of type 2 thyrotoxicosis consists of administration of prednisone, starting with a dose of e.g. (40) mg/day. Normalization of thyroid hormone levels is achieved in about one week (94). Patients with previous type 2 thyrotoxicosis are at risk to develop hypothyroidism, when given excessive iodine. Amiodarone-induced hyperthyroidism has also been successfully treated by administration of the oral cholecystographic agent sodium ipodate (oragrafin), along with a thionamide. A small series of five patients all became euthyroid in 15-21 weeks without adverse effects. The treatment is presumably effective because of the very potent inhibition of iodothyronine 5' monodeiodinase caused by the oral cholecystographic agents (92ae).

X-ray contrast agents also cause IIT. They contain between 30 - 50% of iodine and many grams are used for roentgenologic visualization of organs. Those patients who have multinodular goiter, or live in countries where iodine intake is low, for instance in parts of Germany and Italy (98), are especially at risk. Clinicians should be aware that IIT often develops several weeks after administration of X-ray contrast agents. Follow-up of such patients after X-ray procedures is therefore advisable and in some cases prophylactic administration of methimazole may be necessary. Considering the wide use of X-ray contrast agents, the probability of inducing IIT by these substances must be low. However, the incidence of IIT may be inversely related to the iodine intake of the area, which is relatively high in the United States, but low in many other countries of the world.