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A patient suffering from Graves' disease is given thiocyanate by his physician. Thiocyanate helps in the treatment of Graves' disease by:
Inhibiting thyroid peroxidase
Inhibiting thyroid deiodinase
Inhibiting beta-adrenergic receptors
Inhibiting iodide follicular uptake
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Thiocyanate and perchlorate both act to inhibit the Na-I symporter located on the basolateral membrane of thyroid epithelial cells. By decreasing iodide uptake, these drugs act to decrease the amount of thyroid hormone synthesized.
Following the uptake of iodide, iodide and thyroglobulin are secreted into the follicular lumen. In the lumen, thyroid peroxidase-mediated reactions lead to the formation of thyroid hormones attached to thyroglobulin. Following TSH stimulation, this complex is brought back into the cell, thyroid hormones are cleaved from thyroglobulin, and the hormones are secreted into circulation.
Reid et al. review the diagnosis and treatment of hyperthyroidism. They describe Graves' disease as the most common cause leading to hyperthyroidism, and other causes include thyroiditis, toxic adenomas, and some drugs. Using a thyroid-stimulating hormone level test and/or radionucleotide uptake test help pinpoint the cause.
Erdogan investigates the role of thiocyanate in thyroid dysregulation. Thioacyanate, a metabolite of cyanide (detoxification), inhibits the transport of iodide.
Illustration A depicts thyroid hormone synthesis. Note the Na-I sympoter on the basolateral surface; it is there where thiocyanate acts and inhibits the symporter.
Answer 1: PTU is a drug that inhibits thyroid peroxidase.
Answer 2: Thiocyanate does not act on 5'-iodinase.
Answer 3: Thiocyanate does not act on thyroid deiodinase. The function of thyroid deiodinase is the release of T4/T3 from thyroglobulin.
Answer 4: Propanolol is a drug that inhibits beta-adrenergic receptors.
Biofactors. 2003;19(3-4):107-11. PMID: 14757960 (Link to Abstract)
Reid JR, Wheeler SF.
Am Fam Physician. 2005 Aug 15;72(4):623-30. PMID: 16127951 (Link to Abstract)
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A 25-year-old Hispanic male presents with heat intolerance and recent weight loss. Serum analysis shows increased levels of T4 and T3, as well as the presence of thyroglobulin-stimulating immunoglobulins. The patient is found to be tachycardic and has marked edema and waxy discoloration in his legs. Which of the following would be consistent with this patient's disease?
Increased TSH release
Multinucleate giant cells present in the thyroid
The presence of thyroglobulin-stimulating immunoglobulins in the serum indicates that the patient has Graves disease. Important hallmarks of Graves disease are hyperthyroidism, exophthalmos, and pretibial myxedema.
Graves disease is an autoimmune disease whereby self-antigens from the thyroid activate the immune system. This leads to the formation of antibodies that stimulate the TSH receptor on thyroid cells (hyperthyroidism). Generated immune cells may also infiltrate and attack extraocular muscles and tissue leading to exophthalmos. Furthermore, pretibial myxedema (a type of edema in the legs with a "waxy" appearance) may result from immune cell infiltration in the shin region.
Reid et al. review the diagnosis and treatment of hyperthyroidism: "The most common cause of hyperthyroidism is Graves disease. Other common causes include thyroiditis, toxic multinodular goiter, toxic adenomas, and side effects of certain medications. The diagnostic workup begins with a thyroid-stimulating hormone level test. When test results are uncertain, measuring radionuclide uptake helps distinguish among possible causes."
Heufelder analyzes the current understanding of exophthalmos, stating that "circulating T cells in patients with GD, directed against certain antigens on thyroid follicular cells, recognize antigenic epitopes that are shared by tissues contained in the orbital space". More specifically, "preadipocytes and fibroblasts, most likely act as target and effector cells of the orbital immune process, respectively."
Answer 1: Hyperthyroidism is consistent with sympathetic overactivity, not underactivity.
Answer 2: Anti-thyroglobulin (as well as anti-thyroid) immunoglobulins are more consistent with Hashimoto thyroiditis (hypothyroidism).
Answer 4: Due to the high levels of thyroid hormones, TSH levels are expected to be low.
Answer 5: Multinucleate giant cells are consistent with subacute thyroiditis.
Rev Endocr Metab Disord. 2000 Jan;1(1-2):87-95. PMID: 11704996 (Link to Abstract)
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A 25-year old Caucasian female presents with symptoms of Graves' disease. Her doctor prescribes medications and sends the patient home. After two months of therapy, the patient returns upset that her exophthalmos has not gone away. Which of the following drugs should the physician have prescribed to treat the exophthalmos?
No treatment as this will resolve naturally
Though beta-blockers such as propanolol/metropolol and PTU are beneficial in preventing thyrotoxicosis, they do not treat exophthalmos. Corticosteroids can be used to help alleviate exophthalmos.
Exophthalmos occurs due to lymphocytic infiltration in the retro-orbital region and not due to beta-adrenergic over-stimulation. It is believed that cells in the retro-orbital region express TSH receptors leading to T-cell infiltration and an autoimmune response. Corticosteroids may be used in the treatment of exophthalmos in order to control the underlying inflammation.
Reid et al. review the diagnosis and treatment of hyperthyroidism reporting that the most common cause of hyperthyroidism is Graves' disease. Other common causes of hyperthyroidism include thyroiditis, toxic multinodular goiter, toxic adenomas, and medication side effects. The diagnostic workup begins with measuring the thyroid-stimulating hormone (TSH) level.
Maheshwari et al. explain that exophthalmos in Graves' disease results from a complex interplay of orbital fibroblast, cytokines, immune cells, autoantibodies, environmental and genetic factors. Of note, exophthalmos does not improve with thyroid-suppressing drugs and mainly requires glucocorticoids for treatment.
Illustration A shows a patient with exophthalmos. Note the forward protrusion of the globe from the orbit.
Answers 1 and 2: Beta-blockers are effective in reducing thyrotoxicosis, however they do not help in reducing exophthalmos
Answer 3: PTU helps reduce the amount of thyroid hormone produced, however does not help to reduce exophthalmos
Answer 5: This will not resolve spontaneously and requires treatment
Maheshwari R, Weis E.
Indian J Ophthalmol. 2012 Mar-Apr;60(2):87-93. PMID: 22446901 (Link to Abstract)
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