Over-the-Counter-Drug-Induced Thyroid Disorders
Over-the-Counter-Drug-Induced Thyroid Disorders
Patients with nodular goiter living in areas of iodine deficiency have a high frequency of hyperthyroidism after the introduction of iodine. It is assumed that thyrotoxicosis occurs because of underlying autonomy in the thyroid gland, and with increased dietary iodine supply, the autonomous areas synthesize more thyroid hormones independently of normal regulatory mechanisms (the Jod-Basedow phenomenon). However, iodine-induced thyrotoxicosis may also occur in patients without underlying thyroid disease.
In the patient with Graves' disease (case 1), there was an acute exacerbation of thyrotoxic symptoms that correlated with the biochemical findings, even though her Graves' disease was controlled with thionamide therapy. Interestingly, this patient had a normal initial serum iodine level. The subsequent iodine overload was confirmed by elevated serum and urine iodine levels. The increased serum TSI and TBII levels suggest that this acute exacerbation was possibly mediated by an underlying autoimmune mechanism. Following treatment, which included a low-iodine diet, her clinical symptoms resolved and her biochemical tests were normal, supporting a possible cause-effect relationship. The fact that this patient required a relatively high dose of methimazole therapy for a prolonged period is also consistent with iodine-induced exacerbation of Graves' disease. In populations in North America and other iodine-replete areas, iodine-induced thyrotoxicosis may occasionally develop after therapy with high doses of iodine (e.g., amiodarone therapy, exogenous administration of iodinated radiocontrast agents, or consumption of kelp-containing dietary supplements). It has been suggested that these patients have subclinical hyperthyroidism before iodine repletion, and thus it is not surprising to find that OTC iodine supplements may aggravate thyrotoxicosis in patients with Graves' disease or multinodular goiter. Acute iodine administration improves thyroid function in patients with hyperthyroidism; however, escape from the Wolf-Chaikoff effect takes place over several days. Since thyroid functions were not measured soon after the iodine ingestion in our patient, the expected improvement of thyroid functions (Wolf-Chaikoff effect) was not detected and the hyperthyroid state probably reflects the escape phenomenon in this patient. The patient in case 1, who had pre-existing Graves' disease, was taking 10 to 20 mg of iodine per day, which is about 67 to 133 times the recommended daily allowance of 150 μg, with an upper limit of 1,100 μg in normal healthy adults. The second patient reported here (case 2), developed drug-induced thyrotoxicosis after taking an OTC thyroid extract containing Thyromine. The laboratory findings, including elevated serum T3 levels and radiological images, support a diagnosis of thyroid extract-induced thyrotoxicosis. The normalization of thyroid function after discontinuation of the drug supports an exogenous OTC drug as the cause for the clinical and biochemical findings encountered in this patient.
Generally, patients at risk for iodine-induced hypothyroidism include those with chronic autoimmue thyroiditis, postpartum or subacute granulomatous thyroiditis, Graves' hyperthyroidism previously treated with subtotal thyroidectomy or 131I therapy, and after hemithyroidectomy for thyroid nodules, patients with cystic fibrosis and thallassemia major in conjunction with repeated blood transfusions, and rarely patients with a normal thyroid gland. In the 2 patients with Hashimoto's thyroiditis (cases 3 and 4), the overt hypothyroidism was presumably precipitated by ingestion of excess iodine. It is possible that worsening hypothyroidism was the natural progression of the Hashimoto's thyroiditis, but the temporal relationship of hypothyroidism and elevated iodine levels in the serum and urine support the conclusion that the acute hypothyroid state was indeed induced by exogenous iodine administration. Finally, the improvement in the hypothyroid state as reflected by a reduction in levothyroxine dose is also consistent with iodine-induced hypothyroidism.
Very few previous studies have documented serial changes in urine and serum iodine levels in patients taking excess iodine. The time course for improvement in serum and urine iodine levels as seen in this report varied from 2 to 3 months.
The precise mechanisms of iodine-induced thyroid disorders are not clear. Thyroid nodules may synthesize excessive thyroid hormones when presented with enough iodine due to a constitutive somatic mutation of the TSH receptor in the nodules. It is possible that a similar mechanism may operate in Graves' disease with TSI-mediated hormone synthesis. The exact mechanism of iodine-induced hyperthyroidism—the so called Jod-Basedow phenomenon—in patients without an underlying thyroid disease is not known. It may be concluded that defective autoregulation of thyroid hormone biosynthesis and/or interference with MMI action may contribute to the development of iodine-induced hyperthyroidism in susceptible individuals. Excessive iodine intake may affect the thyroid's response to MMI therapy in patients with Graves' disease in several ways. A high concentration of intrathyroidal iodine may affect the action of MMI, and it has been demonstrated that MMI inhibition of thyroid peroxidase is competitive with iodine. Additionally, Engler et al suggested that it may be helpful to restrict iodine intake in hyperthyroid patients treated with thionamides. Martino et al suggested that amiodarone-induced thyrotoxicosis is due to excessive thyroid hormone synthesis induced by iodine load, and Fragu et al reported a marked increase in the intrathyroidal iodine content in patients with amiodarone-induced thyrotoxicosis, irrespective of the presence of an intrinsic thyroid abnormality. Finally, Azizi demonstrated that patients living in iodine-deficient areas require lower dosages of MMI.
Failure to escape from the Wolf-Chaikoff effect may explain the iodine-induced hypothyroid state in patients with Hashimoto's thyroiditis. Autoimmune thyroiditis has been induced by the excessive iodine administration in strains of rats and chickens that are genetically predetermined to develop this disease. Experimental data also suggest a direct toxic effect of excess iodine on iodide-deficient thyroid glands. Although the precise mechanism is unclear, these two mechanisms may be involved in the worsening of hypothyroidism in a patient with pre-existing Hashimoto's thyroiditis.
Many over-the-counter supplements marketed for thyroid health in the U.S. reportedly contain high levels of unlabeled T4 and T3, as well as iodine. In addition, development of congenital hypothyroidism in 3 infants born to women in the U.S. who were taking OTC high-dose iodine supplements was recently reported.
Discussion
Patients with nodular goiter living in areas of iodine deficiency have a high frequency of hyperthyroidism after the introduction of iodine. It is assumed that thyrotoxicosis occurs because of underlying autonomy in the thyroid gland, and with increased dietary iodine supply, the autonomous areas synthesize more thyroid hormones independently of normal regulatory mechanisms (the Jod-Basedow phenomenon). However, iodine-induced thyrotoxicosis may also occur in patients without underlying thyroid disease.
In the patient with Graves' disease (case 1), there was an acute exacerbation of thyrotoxic symptoms that correlated with the biochemical findings, even though her Graves' disease was controlled with thionamide therapy. Interestingly, this patient had a normal initial serum iodine level. The subsequent iodine overload was confirmed by elevated serum and urine iodine levels. The increased serum TSI and TBII levels suggest that this acute exacerbation was possibly mediated by an underlying autoimmune mechanism. Following treatment, which included a low-iodine diet, her clinical symptoms resolved and her biochemical tests were normal, supporting a possible cause-effect relationship. The fact that this patient required a relatively high dose of methimazole therapy for a prolonged period is also consistent with iodine-induced exacerbation of Graves' disease. In populations in North America and other iodine-replete areas, iodine-induced thyrotoxicosis may occasionally develop after therapy with high doses of iodine (e.g., amiodarone therapy, exogenous administration of iodinated radiocontrast agents, or consumption of kelp-containing dietary supplements). It has been suggested that these patients have subclinical hyperthyroidism before iodine repletion, and thus it is not surprising to find that OTC iodine supplements may aggravate thyrotoxicosis in patients with Graves' disease or multinodular goiter. Acute iodine administration improves thyroid function in patients with hyperthyroidism; however, escape from the Wolf-Chaikoff effect takes place over several days. Since thyroid functions were not measured soon after the iodine ingestion in our patient, the expected improvement of thyroid functions (Wolf-Chaikoff effect) was not detected and the hyperthyroid state probably reflects the escape phenomenon in this patient. The patient in case 1, who had pre-existing Graves' disease, was taking 10 to 20 mg of iodine per day, which is about 67 to 133 times the recommended daily allowance of 150 μg, with an upper limit of 1,100 μg in normal healthy adults. The second patient reported here (case 2), developed drug-induced thyrotoxicosis after taking an OTC thyroid extract containing Thyromine. The laboratory findings, including elevated serum T3 levels and radiological images, support a diagnosis of thyroid extract-induced thyrotoxicosis. The normalization of thyroid function after discontinuation of the drug supports an exogenous OTC drug as the cause for the clinical and biochemical findings encountered in this patient.
Generally, patients at risk for iodine-induced hypothyroidism include those with chronic autoimmue thyroiditis, postpartum or subacute granulomatous thyroiditis, Graves' hyperthyroidism previously treated with subtotal thyroidectomy or 131I therapy, and after hemithyroidectomy for thyroid nodules, patients with cystic fibrosis and thallassemia major in conjunction with repeated blood transfusions, and rarely patients with a normal thyroid gland. In the 2 patients with Hashimoto's thyroiditis (cases 3 and 4), the overt hypothyroidism was presumably precipitated by ingestion of excess iodine. It is possible that worsening hypothyroidism was the natural progression of the Hashimoto's thyroiditis, but the temporal relationship of hypothyroidism and elevated iodine levels in the serum and urine support the conclusion that the acute hypothyroid state was indeed induced by exogenous iodine administration. Finally, the improvement in the hypothyroid state as reflected by a reduction in levothyroxine dose is also consistent with iodine-induced hypothyroidism.
Very few previous studies have documented serial changes in urine and serum iodine levels in patients taking excess iodine. The time course for improvement in serum and urine iodine levels as seen in this report varied from 2 to 3 months.
The precise mechanisms of iodine-induced thyroid disorders are not clear. Thyroid nodules may synthesize excessive thyroid hormones when presented with enough iodine due to a constitutive somatic mutation of the TSH receptor in the nodules. It is possible that a similar mechanism may operate in Graves' disease with TSI-mediated hormone synthesis. The exact mechanism of iodine-induced hyperthyroidism—the so called Jod-Basedow phenomenon—in patients without an underlying thyroid disease is not known. It may be concluded that defective autoregulation of thyroid hormone biosynthesis and/or interference with MMI action may contribute to the development of iodine-induced hyperthyroidism in susceptible individuals. Excessive iodine intake may affect the thyroid's response to MMI therapy in patients with Graves' disease in several ways. A high concentration of intrathyroidal iodine may affect the action of MMI, and it has been demonstrated that MMI inhibition of thyroid peroxidase is competitive with iodine. Additionally, Engler et al suggested that it may be helpful to restrict iodine intake in hyperthyroid patients treated with thionamides. Martino et al suggested that amiodarone-induced thyrotoxicosis is due to excessive thyroid hormone synthesis induced by iodine load, and Fragu et al reported a marked increase in the intrathyroidal iodine content in patients with amiodarone-induced thyrotoxicosis, irrespective of the presence of an intrinsic thyroid abnormality. Finally, Azizi demonstrated that patients living in iodine-deficient areas require lower dosages of MMI.
Failure to escape from the Wolf-Chaikoff effect may explain the iodine-induced hypothyroid state in patients with Hashimoto's thyroiditis. Autoimmune thyroiditis has been induced by the excessive iodine administration in strains of rats and chickens that are genetically predetermined to develop this disease. Experimental data also suggest a direct toxic effect of excess iodine on iodide-deficient thyroid glands. Although the precise mechanism is unclear, these two mechanisms may be involved in the worsening of hypothyroidism in a patient with pre-existing Hashimoto's thyroiditis.
Many over-the-counter supplements marketed for thyroid health in the U.S. reportedly contain high levels of unlabeled T4 and T3, as well as iodine. In addition, development of congenital hypothyroidism in 3 infants born to women in the U.S. who were taking OTC high-dose iodine supplements was recently reported.