CONTINUING EDUCATION Uncommon Causes of Thyrotoxicosis* Erik S. Mittra1, Ryan D. Niederkohr1, Cesar Rodriguez1, Tarek El-Maghraby2,3, and I. Ross McDougall1 1Division of Nuclear Medicine and Molecular Imaging Program at Stanford, Department of Radiology, Stanford University Hospital and Clinics, Stanford, California; 2Nuclear Medicine, Cairo University, Cairo, Egypt; and 3Nuclear Medicine, Saad Specialist Hospital, Al Khobar, Saudi Arabia Several of the conditions are self-limiting and do not need Apart from the common causes of thyrotoxicosis, such as prolonged treatment. Graves’ disease and functioning nodular goiters, there are When a patient is thought to be thyrotoxic, a convenient more than 20 less common causes of elevated free thyroid hor- algorithm is to measure free thyroxine (free T ) and mones that produce the symptoms and signs of thyrotoxicosis. 4 thyrotropin (TSH). When the former is higher than normal This review describes these rarer conditions and includes 14 il- lustrative patients. Thyrotropin and free thyroxine should be but the latter is suppressed, thyrotoxicosis is diagnosed. measured and, when the latter is normal, the free triiodothyronine When the former is normal but TSH is low, it is valuable to 123 level should be obtained. Measurement of the uptake of Iis measure free triiodothyronine (free T3); when the latter is recommended for most patients. abnormally high, the diagnosis is T3 toxicosis (2–4). When Key Words: thyrotoxicosis; Graves’ disease; thyroiditis; thyroid both free hormones are normal but TSH is low, the term hormones ‘‘subclinical thyrotoxicosis’’ can be applied (5). Once it has J Nucl Med 2008; 49:265–278 been determined that thyrotoxicosis is present, measure- DOI: 10.2967/jnumed.107.041202 ment of 123I uptake can differentiate among several disor- ders (Table 1). Some have high uptake and, paradoxically, some have low uptake. This distinction is important be- cause most disorders in the latter group are self-limiting Thyrotoxicosis is the syndrome caused by an excess of and do not require treatment with 131I or antithyroid medi- free thyroid hormones. Any or all systems of the body can cations. In contrast, those with high uptake usually do re- be affected. The symptoms and signs depend on the degree quire therapy. It should be recognized that the site of high of elevation of the hormones, the length of time that they uptake might not be in the expected site of the thyroid. have been elevated, the rate at which the hormone levels rose, Conditions associated with elevated uptake of radioiodine and individual variations of patients. For example, a patient are addressed first (6). Several disorders are illustrated by case with ischemic heart disease is more likely to exhibit cardiac reports. The description of each group of thyrotoxic conditions manifestations. The terms ‘‘hyperthyroidism’’ and ‘‘thyro- is followed by a discussion relevant to those specific disorders. toxicosis’’ are often used interchangeably; however, hyper- At the end of the article, there is no repetition of the discus- thyroidism means that the thyroid gland is functioning more sions, but there is a ‘‘Conclusion’’ section. Routine cases of than normal. Therefore, a hyperthyroid patient is thyro- Graves’ disease and toxic nodular goiters are not discussed. toxic, but a thyrotoxic patient need not have an overactive thyroid and is therefore not actually hyperthyroid. Iagaru UNCOMMON CAUSES OF THYROTOXICOSIS WITH and McDougall discussed the treatment of thyrotoxicosis, INCREASED UPTAKE OF RADIOIODINE focusing on common diseases, such as Graves’ disease and Thyrotoxicosis in Newborns toxic nodular disorders (1). In this article, we describe rare Examples. Patient 1 was a newborn baby who was causes of thyrotoxicosis. Nuclear medicine physicians will not irritable and restless. He had sinus tachycardia. Although encounter these often; however, knowledge of the disorders, the mother had been a patient at Stanford University including how to diagnose and manage them, is important. Medical Center, the obstetric care and delivery were pro- vided at a different medical facility. Four days after delivery, Received Feb. 26, 2007; revision accepted Sep. 10, 2007. the physicians noted that the mother had a thyroidectomy For correspondence or reprints contact: I. Ross McDougall, Stanford University Hospital and Clinics, 300 Pasteur Dr., Room H-0101, Stanford, CA scar and determined that she had been treated for Graves’ 94305-5281. hyperthyroidism. She had a distant history of weight loss, E-mail: [email protected] *NOTE: FOR CE CREDIT, YOU CAN ACCESS THIS ACTIVITY THROUGH shaking, palpitations, sweating, and irritation of her eyes. THE SNM WEB SITE (http://www.snm.org/ce_online) THROUGH FEBRUARY Free T4 was high, TSH was suppressed, and she had been 2009. No potential conflict of interest relevant to this article was reported. treated with propylthiouracil. She developed severe thyroid COPYRIGHT ª 2008 by the Society of Nuclear Medicine, Inc. orbitopathy, which was treated with high doses of prednisone UNCOMMON CAUSES OF THYROTOXICOSIS • Mittra et al. 265 TABLE 1 The baby was treated with antithyroid medications but Unusual Causes of Thyrotoxicosis remained thyrotoxic for 3 y and had a thyroidectomy at that age. He continued to be thyrotoxic, with elevated free T Increased uptake of Decreased uptake of 4 radioiodine radioiodine and suppressed TSH, and was treated with methimazole. As a result of persistent fetal and neonatal thyrotoxicosis, the Neonatal thyrotoxicosis Thyroiditis patient had premature closure of skull sutures and deafness. Neonatal Graves’ disease Subacute thyroiditis Activated TSH receptor Abscess: acute thyroiditis At 12 y of age, a decision was made to treat the patient with TSI in milk Silent thyroiditis radioiodine. Methimazole was stopped for 5 d, and imaging Excess TSH Recurrent silent thyroiditis of the neck and trunk with 123I demonstrated uptake only in Pituitary tumor Familial silent thyroiditis the thyroid bed. He was treated with 460 MBq (12.5 mCi) Resistance to thyroid Postpartum thyroiditis of 131I and is now taking replacement L-thyroxine. This hormone Excess TSH-like material Recurrent postpartum patient has constitutively activated TSH receptors. thyroiditis Discussion. Thyrotoxicosis in neonates is very uncommon Hydatidiform mole Radiation thyroiditis (7). When a baby is exposed to high levels of free thyroid Choriocarcinoma Internal radiation hormones in utero, it is at increased risk of being born pre- Increased uptake in External radiation maturely or small, and fetal mortality is increased. Premature abnormal site Metastatic thyroid cancer Traumatic thyroiditis closure of cranial sutures and reduced intelligence are noted, Struma ovarii Carcinomatous and cardiac failure can occur. The most likely cause of hyper- pseudothyroiditis thyroidism in a newborn is neonatal Graves’ disease attribut- Lingual thyroid Exogenous thyroid able to passive transplacental transfer of thyroid-stimulating Other ectopic sites Thyrotoxicosis factitia antibodies from mother to baby, as was the case in patient 1. In Thyrotoxicosis factitia veterinarius this siuation, the maternal level of TSI, an IgG antibody, is high Thyrotoxicosis and remains elevated during the pregnancy (8–10). In contrast, medicamentosa in most pregnant patients with Graves’ disease, the levels of Thyrotoxicosis insistiates TSI decrease as the pregnancy progresses. Maternal antibodies, Hamburger thyrotoxicosis both good and bad, are passively transferred to the fetus. The Medication for weight loss Wilson’s syndrome mother can be euthyroid and, if so, usually has been treated for Excess iodine (jod basedow) Graves’ hyperthyroidism (11). Guidelines indicate that mea- Radiographic contrast surement of TSH receptor antibodies should be obtained in a Amiodarone types I and II patient who has had surgery or 131I for Graves’ hyperthyroid- Iodine supplementation ism or who is taking antithyroid medications during pregnancy Miscellaneous Lithium (12). Management of the baby in utero is beyond the scope of Interferon this article, but when the diagnosis is suggested, careful Interleukin monitoring of the fetal size and heart rate and the size of the Denileukin diftitox fetal thyroid by ultrasound is important (13). Leuprolide acetate Although the second patient was hyperthyroid from Marrow transplant (transfer of TSI) birth, he does not have neonatal Graves’ disease. His mother did not have Graves’ disease, there was no evidence of thyroid autoimmunity or abnormal thyroid function, and his disease persisted despite antithyroid medications and and external beam radiation. She also had pretibial dermo- thyroidectomy. The cause is a mutation, usually substitution pathy. The patient elected to have a thyroidectomy so that of one base in the DNA responsible for the production of the she could conceive as early as possible because she was 35 y TSH receptor or the related G protein complex. This muta- old. The baby was then diagnosed with neonatal Graves’ tion results in activation of the TSH receptor without the disease, which was confirmed by thyroid function tests. presence of TSH or TSH-like stimulators, such as thyroid- Propylthiouracil and propranolol were administered for 4 stimulating antibodies. The patient now takes L-thyroxine after wk. The baby then required no therapy for thyrotoxicosis. In 131I therapy. Thyrotoxicosis in the case of an activated TSH retrospect, in utero the baby had been noted to have per- receptor or G protein