Over-the-Counter Drug-Induced Thyroid Disorders
Iodine is essential for proper thyroid gland function. Kelp, seaweed, and multivitamins with added iodine are some of the over-the-counter (OTC) supplements that contain relatively high amounts of iodine. These supplements, marketed under various trade names with the claim of improving thyroid health, are readily available in the United States for self-treatment of various ailments.
People without underlying thyroid disease usually remain euthyroid, despite the ingestion of large amounts of iodine. [1–4] Other individuals, upon exposure to iodine, may develop thyroid dysfunction and autoimmunity. There is some evidence that iodine ingestion, especially if taken in an acute fashion, may be responsible for the development of thyroiditis and thyroid antibodies. [3–5] In this paper, we report four patients who developed thyroid dysfunction after ingesting OTC drugs containing large concentrations of iodine.
All patients described in this report were selected from the Endocrinology Clinic at the Walter Reed National Military Medical Center (WRNMMC), Bethesda, Maryland. Certain endocrinologists at this facility perform detailed thyroid laboratory studies, including serum and urine iodine levels, in selected patients. All laboratory tests were performed either at Quest Diagnostics (Quest Diagnostics, Chantilly, VA) or the WRNMMC Clinical Laboratories. Serum iodine and urine iodine levels were measured by inductively coupled plasma/mass spectrometry (ICP/MS) (assay performed by Quest Diagnostics). Power Doppler ultrasound examinations were performed using a 5 to 12 MHz linear probe (iU22; Philips Healthcare, Andover, MA). Doppler vascularity was described as increased or decreased blood flow.
A 35-year-old Caucasian female presented to the endocrine clinic in April 2009 with a history of hyperactivity, insomnia, heat intolerance, and a weight loss of 35 pounds over 3 months. Physical examination revealed a heart rate of 98 beats per minute (bpm), blood pressure (BP) of 108/58 mm Hg, mild bilateral proptosis, a diffusely enlarged thyroid gland weighing approximately 50 grams and of a firm consistency, and a fine tremor of outstretched fingers. Laboratory values showed that the complete blood count, liver associated enzymes, calcium, phosphorus, and alkaline phosphatase were normal. Serum thyroid stimulating hormone (TSH) was <0.001 μIU/mL (reference, 0.23 to 4.2 μIU/mL), free thyroxine (T4) = 5.21 ng/dL (reference, 0.89 to 1.76 ng/dL), triiodothyronine (T3) = 667 ng/dL (reference, 60 to 181 ng/dL), thyroid stimulating immunoglobulin (TSI) = 187% (reference, <125%), thyroid binding inhibitory immunoglobulin (TBII) = 52% (reference, <16%), and serum iodine level = 82 μg/L (normal, 52 to 109 μg/L). Thyroid ultrasound revealed a mildly enlarged gland with heterogeneous texture and markedly increased vascularity involving both lobes and the isthmus. The 24-hour 131I-uptake was 80.8% (normal, 8 to 30%), and a technetium scan (99m TcO 4−) showed homogeneous trapping, confirming the diagnosis of Graves’ disease. After a lengthy discussion with the patient, she preferred prolonged treatment with methimazole (MMI). The patient gained 20 pounds and had significant improvement in her hyperthyroid symptoms.
In February 2010, while still taking methimazole (2.5 mg per day), the patient reported to the endocrine clinic complaining of 40-pound weight loss, insomnia, marked heat intolerance, and anxiety. Her heart rate was 120 bpm, her BP was 108/80 mm Hg, she had fine tremors of the hands, and she again had mild exophthalmos. Examination of the thyroid gland showed a 60-g diffusely enlarged goiter that was firm in consistency. A bruit was also heard over the thyroid gland. Thyroid function studies showed a TSH level <0.001 mIU/mL, free T4 = 6.87 ng/dL, and total T3 = 938 ng/dL. The TSI was 210% and TBII was 74%. Thyroid ultrasound revealed an increased goiter size with markedly increased vascularity. Upon further questioning, the patient admitted that she had been taking OTC Tri-iodine TM (EuroPharma, Green Bay, WI), which contains 12.5 mg of elemental iodine, and that she had been taking 3 capsules daily for several days each month since December 2009 in order to improve her thyroid status. Both the patient’s urine and serum iodine levels were markedly elevated, with values of 1,962 μg/24 hours (normal, <500 μg/24 hours) and 385 μg/L, respectively (Fig. 1). The dose of methimazole was increased to 60 mg per day. The patient was advised to stop taking Tri-iodine TM and start a low-iodine diet. Even after 2 months of high-dose methimazole treatment, the patient remained thyrotoxic for the next 4 months. Only after 8 more months did her TSH level reach 0.48 μIU/mL, and she preferred to remain on methimazole. In October 2010, her TSH finally normalized.
A 29-year-old female presented with symptoms of nervousness, irritability, heat intolerance, and unexpected weight loss of 15 pounds over 6 months. The patient had no neck pain, eye symptoms, or any systemic symptoms such as fever or chills. She was not taking any prescription drugs. Physical examination revealed that her HR was 102 bpm and her BP was 108/65 mm Hg. She had fine tremor of the outstretched fingers, and a normal eye examination. The thyroid gland was not palpable; no thyroid bruit was heard. Examinations of the heart, lungs, and abdomen were normal. Deep tendon reflexes were brisk. A clinical diagnosis of thyrotoxicosis was made. Laboratory tests revealed TSH = 0.001 μIU/mL, free T4 = 4.3 ng/dL, T3 = 321 ng/dL, thyroid peroxidase antibody (TPO Ab) = 18 IU/mL, thyroglobulin antibody (Tg Ab) = 8 IU/mL, TSI = 63%, and TBII <6%. The 131I-uptake was less than 1%, and a technetium thyroid scan could not visualize the thyroid gland. Additional laboratory tests showed a serum iodine level = 290 μg/L, 24-hour urine iodine = 821 μg (normal, <500 μg), erythrocyte sedimentation rate = 14 mm/h, interleukin-6 = 1.12 pg/mL (normal, 0.31 to 5.0 pg/mL), C-reactive protein = 0.12 mg/dL (normal, 0 to 0.744 mg/dL), and serum thyroglobulin <0.2 ng/mL (normal, 2 to 35 ng/mL). A diagnosis of iatrogenic thyrotoxicosis was considered. The patient at this time mentioned that she had been taking Thyromine TM (Pacific Natural, Burbank, CA) (containing L-tyrosine, thyroid powder from a bovine source, adrenal powder from a bovine source, and other ingredients, such as gugulipid, nori, ginger extract, and piper longum). The patient reported taking 2 capsules three times a day for the previous 9 months. She was advised to discontinue taking Thyromine TMand was also placed on atenolol (25 mg daily) and a low iodine diet. Two months later, her symptoms completely resolved. Physical examination revealed a HR of 54 bpm, BP of 104/70 mm Hg, no hand tremors, no ophthalmopathy, and a barely palpable thyroid gland. Deep tendon reflexes were normal. Laboratory tests revealed TSH = 0.92 μIU/mL, free T4 = 1.45 ng/dL, total T3 = 139 ng/dL, serum iodine = 57 μg/L, and 24-hour urine iodine = 280 μg. The atenolol was discontinued and the patient remained clinically and biochemically euthyroid.
A 58-year-old female presented to the endocrine clinic with tiredness, dry skin, and 10-pound weight gain. She did not have any other symptoms of hypothyroidism. The physical examination results were: HR = 68 bpm, BP = 110/66 mm Hg, thyroid slightly enlarged with a rubbery consistency, weighing approximately 30 g, and no palpable thyroid nodule. Thyroid function tests revealed TSH = 3.9 μIU/mL, free T4 = 1.11 ng/dL, TPO Ab = 1,910 IU/mL (normal, <35 IU/mL), Tg Ab = 386 IU/mL (normal, <20 IU/mL), and serum iodine = 68 μg/L (Fig. 2). Ultrasound of the thyroid gland revealed a diffusely enlarged gland with a heterogeneous texture, consistent with Hashimoto’s thyroiditis. The patient was treated with 50 μg of levothyroxine 5 days per week. Four months later, she noticed no changes in symptoms, and physical examination at that time was normal, including a thyroid gland weight of 20 g. The serum TSH was 1.1 μIU/mL, free T4 = 1.62 ng/dL, TPO Ab = 1,158 IU/mL, and Tg Ab = 194 IU/mL. Two months later, the patient presented with cold-intolerance, dry skin, constipation, and a weight gain of 10 pounds. A physical examination showed a HR of 67 bpm and BP of 128/70 mm Hg. The thyroid gland was diffusely enlarged, rubbery in consistency, and weighed approximately 60 g. The patient admitted taking Iodoral TM (Optimox Corporation, Torrance, CA), which contains 12.5 mg of elemental iodine. The patient reported taking the product twice a day for 2 months prior to this visit. Thyroid function tests showed serum TSH = 168 μIU/mL, free T4 = 0.32 ng/dL, TPO Ab = 4,670 IU/mL, and Tg Ab = 786 IU/mL. The serum iodine level was 428 μg/L, and the 24-hour urine iodine was 3,281 μg (Fig. 2). Thyroid ultrasound revealed a diffusely enlarged gland with marked heterogeneity. The right thyroid lobe measured 3.2 cm × 2.9 cm × 6.7 cm; the isthmus was 0.8 cm. The left thyroid lobe measured 2.8 cm × 2.6 cm × 5.9 cm, with decreased vascularity throughout the gland. The patient was placed on 137 μg of levothyroxine along with a low-iodine diet. Three months later, her hypothyroid symptoms completely resolved. On physical examination her HR was 70 bpm, her BP was 114/72 mm Hg, there was no evidence of Graves’ ophthalmopathy, and her thyroid gland weighed 20 g and had a rubbery consistency. Thyroid function tests results were: TSH = 1.7 μIU/mL, free T4 = 1.20 ng/dL, TPO Ab = 790 IU/mL, Tg Ab = 41 IU/mL, serum iodine = 88 μg/L, and 24-hour urine iodine = 328 μg. Nine months later, the patient remained clinically and biochemically euthyroid on a reduced dose of 75 μg of levothyroxine daily.
A 38-year-old female presented with fatigue, but had no neck pain or other symptoms of hypothyroidism. On physical examination, her HR was 76 bpm, her BP was 128/84 mm Hg, there was no ophthalmopathy, the thyroid weighed 25 g and had a normal consistency, and there were no palpable thyroid nodules. The serum TSH was 3.1 μIU/mL, free T4 = 0.99 ng/dL, TPO Ab = 890 IU/mL, Tg Ab = 174 IU/mL, and serum iodine = 79 μg/L (Fig. 2). Thyroid ultrasound revealed normal gland size (right lobe, 1.7 cm × 1.4 cm × 2.8 cm; isthmus, 0.34 cm; left lobe, 1.87 cm × 1.76 cm × 3.2 cm). Both lobes demonstrated mild and diffuse heterogeneity with decreased vascularity. A diagnosis of Hashimoto’s thyroiditis was made. Although the patient was counseled regarding a low-dose levothyroxine therapy, she did not want to take any synthetic medications. Six months later, she presented with worsening fatigue, a weight gain of 12 pounds, dry skin, and excessive somnolence. On physical examination, her HR was 64 bpm, her BP was 138/88 mm Hg, and there was no ophthalmopathy. The thyroid gland was diffusely enlarged, with a rubbery consistency, and was estimated to weigh 80 g. Thyroid function tests showed TSH = 94 μIU/mL, free T4 = 0.63 ng/dL, and total T3 = 63 ng/dL, TPO Ab = 1,112 IU/mL, and Tg Ab = 213 IU/mL (Fig. 2). Thyroid ultrasound confirmed a diffuse goiter (right lobe, 3.23 cm × 2.76 cm × 6.92 cm; isthmus, 0.84 cm; left lobe, 2.96 cm × 3.56 cm × 7.32 cm). Both lobes and the isthmus showed marked heterogeneity with pseudonodules and decreased vascularity. At this time, the patient admitted that she was taking OTC Iodoral TM, which contains 12.5 mg of elemental iodine. She took 1 tablet three times daily for 3 months prior to this visit. The patient’s serum iodine level was 728 μg/L and her 24-hour urine iodine level was 3,181 μg. The patient was advised to begin a low-iodine diet and was started on levothyroxine at 125 μg daily. Three months later, her serum iodine was 101 μg/L, 24-hour urine iodine was 380 μg, TSH was 3.1 μIU/L, and free T4 was 1.14 ng/dL. Over the next several months, she became euthyroid and her goiter resolved to a normal size gland. Nine months later, she remained euthyroid on a daily dosage of 50 μg of levothyroxine.
Patients with nodular goiter living in areas of iodine deficiency have a high frequency of hyperthyroidism after the introduction of iodine. [1–4] 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). [1–4] However, iodine-induced thyrotoxicosis may also occur in patients without underlying thyroid disease. [1–8]
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. [1–10] 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).[8,11–12] 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 TM. 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, [1,4,8–11,14–20] and rarely patients with a normal thyroid gland. [4,8–11,21] 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. [6,7] 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. [4,22–28] 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.
In conclusion, OTC preparations containing large concentrations of iodine, sold under various trade names, can lead to significant thyroid dysfunction in susceptible individuals. There is no valid reason for taking high-dose OTC iodine supplements, which have been demonstrated to cause harm and have no known benefit.
Savoie J, Massin J, Thomopoulos P, Leger F. Iodine-induced thyrotoxicosis in apparently normal thyroid glands. J Clin Endocrinol Metab. 1975;41:685–691.