IODINE SUPPRESSION OF THE GRAVES’ THYROID
Iodide affects the metabolism of the diffusely hyperplastic thyrotoxic gland in a way radically different from its action on the normal gland. Years ago, Plummer demonstrated that Graves' disease can be temporarily or permanently controlled by the administration of iodide 125. The amount needed is 6 mg/day or more. Administration of large doses of iodide to laboratory animals causes a temporary inhibition of iodide organification, the Wolff-Chaikoff block. High intrathyroidal iodide concentration is the crucial factor inducing this response 126. The same phenomenon occurs in humans, and thyrotoxic patients are especially sensitive to this effect. The thyroid uptake of 131I is acutely depressed in thyrotoxic patients by administration of 2 mg potassium iodide, whereas more than 5 mg is needed to depress uptake in normal subjects. Concentrations of serum iodide above 5 µg/dl block binding in the thyrotoxic gland 104-107.
The biochemical mechanism of the Wolff-Chaikoff block is not clear. Iodide does not prevent TSH or TSAb binding to the TSH membrane receptor, but does inhibit both TSH-stimulated adenyl cyclase production of cAMP, and cAMP actions. Since iodide inhibition of cAMP production and action is blocked by methimazole, it is hypothesized that an oxidized iodide intermediate is involved. Alternatively, the block of iodination may be caused by depression of H2O2 generation. Whether the inhibition of iodide transport and binding relate to the recognized changes in cAMP formation is not known (see also Chapter 5).
In animals the block of iodide binding is transient; during continuous iodide administration, binding recommences. This escape also occurs in most normal humans. Few individuals who take large doses of iodine continuously ever develop myxedema. Adaptation to excess iodine in animals involves a reduction of iodide transport into the thyroid, a lowering of intrathyroidal iodide content, and escape from the Wolff-Chaikoff block. This adaptation occurs independently of TSH action. Possibly because the Graves' gland is hyperactive under continued stimulation by TSAb, it may remain blocked by administered iodide, and hormone production may remain suppressed. (Actually in about 1/3 of patients the gland is only partially blocked, and in another third escape occurs after a few weeks.) A similar sensitivity to inhibition by iodide occurs in Hashimoto's thyroiditis, hyperfunctional adenomas, and possibly the normal gland when stimulated by exogenous TSH 127. Myxedema can often be induced by administration of iodide to patients who have had a partial thyroidectomy for Graves' disease 128,129. Thus, there is an inherent susceptibility of these glands to the action of iodine. Sensitivity of the gland in Graves' disease to iodide is also demonstrated with the iodide-perchlorate test 128. In this test, it is seen that the dose of iodide required to block organification in Graves' disease is much smaller than that in the normal subject. The inhibition of binding by iodide is revealed by administration of perchlorate, which discharges the accumulated 131I present in the gland as free iodide.
Coincident with the block in uptake, iodide also causes a marked reduction in the release of previously formed hormone from the thyrotoxic gland. This phenomenon has been repeatedly observed and helps to explain the beneficial therapeutic effect of iodide in Graves' disease, as originally recognized by Plummer. Iodide administration blocks release of hormone from the gland but does not completely prevent hormone synthesis, for under these circumstances the gland gradually accumulates an increased store of organic iodine. Ochi et al 130 have shown that chronic administration of iodide in Graves' disease blocks the stimulating effect on hormone release of both TSH and TSAb. It is this block of release, rather than a block of hormone synthesis, that is responsible for the dramatic rapid beneficial therapeutic effects of iodide administration 131. The block of hormone release that occurs in the thyroid of Graves' disease can be observed, although not uniformly, in the normal gland and in the normal gland made hyperactive by repeated administration of exogenous TSH. Iodide also inhibits the release of hormone from autonomous hyperfunctioning adenomas, presumably in the absence of endogenous TSH. This observation also indicates that iodide block is by a direct action on the thyroid gland.
Thus, the Graves' gland appears to be unusually sensitive to small amounts of iodide, as manifested by (1) a block of iodide uptake and binding and (2) a block of hormone release. Perhaps these are two parts of the same fundamental process. Sensitivity to iodide may be related to the TSAb dependent, hyperactive, iodide-concentrating mechanism of the Graves' gland.
A further abnormality in intrathyroid iodine metabolism is that the toxic gland continuously spills into the circulation large amounts of nonthyroxine iodide, in addition to hormone 132. The iodide may be a product of the deiodination of iodotyrosines released from TG during its hydrolysis.
The incidence of Graves' disease in Olmstead County, MN was found to be 30 cases per 100,000 annually 133. A thorough examination of an English town by Tunbridge and associates found an incidence of 100 - 200 cases per 100,000 per year, significantly higher than the previous estimates 134. In this report, it was also found that 2.7% of women and .23% of men had either current Graves' disease or a history of Graves' disease. This survey also noted that goiter was present in 15% of women, antithyroid antibodies in 10.3% of women, and that hypothyroidism was about two-thirds as common as Graves' disease. A recent update in this area showed a continuing incidence of 80 cases/100,000 women/year 135. Data attest to a lifelong incidence of autoimmune thyroid disease of > 6%, comprised roughly equally by Graves' disease, Hashimoto's thyroiditis and idiopathic hypothyroidism.
The distribution of Graves' disease around the globe, so far as data is available, appears to be relatively equal, affecting all countries and races.
Graves' disease is most typically a disease of adult women in
the age group between 30 and 60, and has an incidence roughly eight times greater in women
than in men 134-135. Aside from the
infrequent occurrence of postnatal thyrotoxicosis due to maternal antibodies, the
incidence of spontaneous Graves' disease in children before the age of ten is most
unusual, but the incidence climbs with each decade until about age 60 134-135. The greater incidence in women is
typical of most thyroid diseases including multinodular goiter and differentiated thyroid
carcinoma, and the mechanism for this association is unknown. One possibility is that
female reproductive activity somehow stresses the thyroid. Another possibility is that the
promoter for certain genes such as Class II HLA molecules may have estrogen receptor
response elements and thus be activated more easily in women. The well known familial
distribution of Graves' disease recognized by all clinicians caring for patients is
thought to be explained by inheritance of specific genes, as detailed previously.
