The Effect of Medications on Thyroid Function Tests

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1 The Effect of Medications on Thyroid Function Tests Priya Kundra, MD a,b, *, Kenneth D. Burman, MD a,b KEYWORDS Thyroid function Medication Hormone Euthyroid state Abnormal results of thyroid function tests are possible effects of drugs and medications. The pathways of thyroid hormone synthesis, secretion, transport, metabolism, and absorption offer numerous targets for medication interactions (Fig. 1A, B). Normal thyroid secretion depends on thyroid-stimulating hormone (TSH), which is inhibited by thyroid hormones and stimulated by endogenous thyrotropin-releasing hormone (TRH). Circulating iodide is trapped by a specific iodide symporter protein in thyroid cells, after which it is oxidized and incorporated into tyrosine residues of thyroglobulin, which then couple to form thyroxine (T4) and triiodothyronine (T3). T4 and T3 are released from thyroglobulin and then secreted into the circulation. In the periphery, T4 is converted to T3 in the liver and other tissues by the action of 5 0 -T4 monodeiodinases. Type deiodinase predominates in the liver, kidneys, and thyroid; type deiodinase predominates in the brain, pituitary and skin. About 80% of T4 and T3 are metabolized by deiodination and 20% by other pathways that include conjugation with glucuronide and sulfate. T4 and T3 may be conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine; the T4 and T3 formed there may be reabsorbed in the gastrointestinal (GI) tract. In tissues, T3 and T4 are bound to nuclear receptor proteins that interact with regulatory regions of the genes, influencing their expression. In serum, most circulating T4 and T3 bind to proteins including thyroxine-binding globulin (TBG), transthyretin, and albumin. A small percentage (approximately 0.3% of T3 and 0.03% of T4) are unbound and available for binding to tissue T3 receptors. This article focuses on the groups of medications affecting production, regulation, secretion, transport, binding, metabolism, and absorption of T4 and T3. It also focuses on the medications that can clinically influence a Endocrine Section, Washington Hospital Center, 110 Irving Street NW, Washington, DC 20010, USA b Georgetown University Hospital, 3800 Reservoir Road NW, Washington, DC 20007, USA * Corresponding author. Endocrine Section, Washington Hospital Center, 110 Irving Street NW, Washington, DC address: Priya.Kundra@Medstar.net Med Clin N Am 96 (2012) doi: /j.mcna medical.theclinics.com /12/$ see front matter Ó 2012 Elsevier Inc. All rights reserved.

2 284 Kundra & Burman Fig. 1. (A, B) Pathways of thyroid hormone action. TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. (Reprinted from Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995;333:1689, published by The Massachusetts Medical Society; with permission.) thyroid hormone homeostasis and on medications that we think are potentially significant or relevant. It does not include all possible medications that may influence thyroid function tests. Box 1 provides a summary of the drugs involved with altered thyroid function tests discussed in this article. TSH SUPPRESSION Many agents can acutely suppress serum thyrotropin levels to subnormal levels, including dopamine, glucocorticoids, octreotide, and bexarotene. Dopamine infusions at greater than 1 mg/kg/min are known to block TSH release. 1,2 Glucocorticoids, particularly dexamethasone, at as low a dose as 0.5 mg/d and hydrocortisone at 100 mg/d, inhibit TSH secretion. However, clinically higher doses of dexamethasone (ie, >4 mg per day) inhibit extrathyroidal T3 production, leading to lower TSH values. Brabant and colleagues 3 showed that 4 mg of intravenous dexamethasone led to a rapid decrease in TSH concentrations and a decrease in TT3. Also, short-acting octreotide at 100 mg/d inhibits TSH release. 4 However, dopamine, glucocorticoids, and octreotide generally do not lower TSH concentrations to undetectable values (eg, less than 0.01 mu/ml). Bexarotene, a retinoid X receptor ligand, is known to suppress the pituitary TSH-b promoter, leading to central hypothyroidism. Sherman 5 showed that, in patients with T cell lymphoma receiving bexarotene, serum TSH levels decreased in proportion to the dose of bexarotene, with the greatest decrease for doses of more than 300 mg/m 2 with a mean TSH of 0.05 mu/l. Patients developed symptoms of hypothyroidism and thyroid hormone levels returned to normal following

3 Thyroid Function Tests 285 Box 1 Drugs causing thyroid dysfunction Decrease TSH secretion: Glucocorticoids: inhibit TSH release Dopamine: blocks TSH release Octreotide: inhibits TSH release Bexarotene: suppresses pituitary TSH-b promoter Alter thyroid hormone secretion: Decrease thyroid hormone secretion: iodide, amiodarone, lithium Increase thyroid hormone secretion: iodide, amiodarone Decrease T4 absorption: Cholesystramine, colestipol, sucralfate, ferrous sulfate, aluminum hydroxide, omeprazole Alter T4 and T3 transport in serum: Increase serum TBG: estrogens, heroin, methadone, mitotane, fluorouracil Decrease serum TBG: androgens, anabolic steroids Displacement from protein-binding sites: furosemide, salicylates, meclofenamate, heparin Alter T4 and T3 metabolism: Increase hepatic metabolism: phenobarbital and rifampin Increase hepatic metabolism and displace from binding proteins: phenytoin and carbamazepine Cytokine mediated: Interferon (IFN) a Immune reconstitution: Alemtuzumab Hypothyroidism (tyrosine kinase inhibitors): Sunitinib:? destructive thyroiditis,? blockade of iodine uptake,? inhibition of peroxidase activity Imatinib:? induction of uridine diphosphate-glucuronosylotransferases (UGTs) discontinuation of bexarotene. Smit and colleagues 6 also discovered that, in athyreotic subjects, bexarotene given for 6 weeks decreased free thyroxine (FT4) levels but the ratio of T4 sulfate/ft4 increased by 48%, possibly secondary to induction of T4 sulfation. There seemed to be a greater induction of the enzyme responsible for T4 conjugation with sulfate leading to an increased ratio of sulfated T4/FT4 (T4 sulfate/ft4) because more T4 was present in the sulfated form and less in the free form. EFFECTS OF IODINE Iodine has varied effects on the thyroid gland depending on the dose and duration of iodine exposure and on the underlying thyroid condition. Short-term iodine exposure (usually up to 7 10 days) can inhibit thyroid hormone secretion. This is called the Wolff-Chaikoff effect. However, with continued iodine exposure, there is an escape

4 286 Kundra & Burman from this inhibition and hyperthyroidism can result (termed escape from the Wolff- Chaikoff effect or the Jod-Basedow phenomenon). Several agents can cause iodide-induced hyperthyroidism and many of these can also cause hypothyroidism. Iodide-induced hyperthyroidism generally develops in individuals with multinodular goiter (MNG) or hyperfunctioning thyroid adenoma secondary to the Jod-Basedow phenomenon, in which iodine serves as a substrate for thyroid hormone synthesis. Iodide-induced hypothyroidism generally develops secondary to a failure to escape from the Wolff-Chaikoff effect in chronic autoimmune thyroid disease, or Graves hyperthyroidism. Iodide inhibits thyroidal organification (Wolff-Chaikoff) but usually in up to 48 hours there is a decrease in sodium iodide symporter activity to allow restoration of organification (hence escape from Wolff-Chaikoff). HYPOTHYROIDISM The use of radiocontrast dyes and amiodarone are the most common medicationinduced causes of hypothyroidism. Pharmacologic doses of iodine (up to 180 mg/d) can induce hypothyroidism in euthyroid patients with chronic thyroiditis. 7 In a large male cohort of more than 600 individuals, overt hypothyroidism (TSH >10 mu/l) developed in 5% of patients receiving amiodarone, but subclinical hypothyroidism (TSH mu/l) developed in an additional 25%. 8 Hashimoto thyroiditis is the most common risk factor for the development of amiodarone-induced hypothyroidism (AIT). AIT typically occurs between 6 and 12 months of treatment with amiodarone. If amiodarone cannot be discontinued, levothyroxine (L-T4) therapy can be initiated. Amiodarone administration to euthyroid subjects results in a decrease in serum T3 levels and an increase in serum T4, free T4, reverse T4, and TSH levels. These results are related to a decrease in intracellular T4 transport, inhibition of type deiodinase and pituitary type deiodinase, as well as antagonizing T3 binding to its nuclear receptor in the pituitary. 9 The dose of L-T4 needed to normalize TSH may be higher in patients treated with amiodarone as a result of the decreased intrapituitary T3 production caused by inhibition of pituitary type deiodinase. Basaria and Cooper 10 outlined surveillance and management of AIT (Fig. 2). HYPERTHYROIDISM Radiocontrast agents, which contain as much as 140 to 180 mg/ml of iodine, may cause hyperthyroidism within several weeks after exposure. Generally, pharmacologic doses of iodine (180 mg/d) can cause hyperthyroidism in patients with nontoxic nodular goiter, solitary autonomous goiter, or underlying Graves disease. 7 The frequency, timing, and duration of hyperthyroidism caused by various radiocontrast dyes may vary, in part depending on the underlying condition, but these issues have not been well studied. Amiodarone can cause hyperthyroidism by 2 mechanisms: iodine-induced hyperthyroidism or induction of thyroiditis. In the United States, 3% to 5% of patients treated with amiodarone become hyperthyroid, usually between 4 months and 3 years after the initiation of the drug. 8 There are 2 types of amiodaroneinduced hyperthyroidism. Type 1 typically occurs in individuals with nontoxic MNG or Graves disease and type 2 is a drug-induced destructive thyroiditis. Many patients have an overlap syndrome between type 1 and type 2 disease. Basaria and Cooper 10 compared AIT type 1 and 2 (Table 1). Traditionally, large doses of antithyroid drugs have been used to treat type 1 AIT, including methimazole 40 to 80 mg per day or propylthiouracil (PTU) 400 to 800 mg per day. For patients with type 2, prednisone is considered to be the treatment of choice. With daily prednisone at doses of 40 to 60 mg, there is rapid improvement

5 Thyroid Function Tests 287 Check TSH, FT4, T3 and Anti-TPO antibody before starting amiodarone If TSH normal, repeat every 3-6 months If TSH >4.5, FT4 elevated and duration is < 3 months, observe If TSH >4.5, FT4 normal or high and > 6 months subclinical hypothyroidism If TSH >4.5, FT4 low overt hypothyroidism If symptomatic or pregnant: LT4 treatment If asymptomatic, repeat TSH in 3 months LT4 therapy Fig. 2. Surveillance and management of amiodarone-induced hypothyroidism. TPO, thyroid peroxidase. (Reprinted from Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118:709, published by Elsevier; with permission.) in thyroid function in most patients. Basaria and Cooper 10 also comment on surveillance and management of amiodarone-induced hyperthyroidism (Fig. 3). Our experience is that many patients may have an overlap between these 2 types of hyperthyroidism. Treatment approaches should be individualized and the patients monitored closely. Table 1 AIT type 1 and 2 Factor AIT Type 1 AIT Type 2 Preexisting thyroid disease Yes (multinodular goiter or No latent Graves) Physical examination Goiter, nodule(s) Normal to slightly firm. Occasionally tender. Duration of amiodarone 1 2 y >2 y Thyroid function tests High FT4, T3 normal or high High FT4, T3 normal or high Thyroid autoantibodies Absent (unless Graves) Absent Radioiodine uptake Low Very low Thyroid ultrasound Multinodular goiter or Graves Heterogeneous Color flow Doppler Increased flow Normal or decreased flow Therapy Stop amiodarone, if possible; Prednisone high-dose antithyroid drugs Subsequent hypothyroidism No Often Reprinted from Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118:711, published by Elsevier; with permission.

6 288 Kundra & Burman Check TSH, Free T4, T3 and Anti-TPO antibody before starting amiodarone Repeat 3-6 months if TSH normal If TSH <.1 mu/l and FT4 and T3 are normal or minimally increased; repeat in 2-4 weeks TSH <.1 mu/l; FT4 elevated, T3 elevated or 50% higher than baseline ultrasound and doppler study of the thyroid stop amiodarone if possible If studies suggest Type I AIT, start high dose antithyroid drugs If studies suggest Type 2 AIT, start prednisone Fig. 3. Surveillance and management of amiodarone-induced hyperthyroidism. (Reprinted from Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005;118:712, published by Elsevier; with permission.) LITHIUM Lithium can cause goiter, hypothyroidism, chronic autoimmune thyroiditis, and possibly hyperthyroidism. The mechanism by which lithium inhibits thyroid hormone secretion is not well understood. In vitro, lithium decreases colloid droplet formation within thyroid follicular cells, a reflection of decreased pinocytosis of colloid from the follicular lumen. 11 The efficiency of proteolytic digestion of thyroglobulin within phagolysosomes also may be impaired. The inhibition of thyroid hormone results in an increase in pituitary TSH and an enlarged thyroid gland. The prevalence of goiter may be as high as 50% and usually occurs within the first 2 years of treatment. 12 Hypothyroidism has been reported in 5% to 20% of patients treated with lithium, usually occurs within the first 2 years of therapy, and tends to be subclinical in nature. Lithium treatment usually need not be discontinued if levothyroxine replacement is initiated. It is likely that many patients who develop hypothyroidism during lithium treatment have underlying chronic autoimmune thyroiditis. In addition, lithium may induce autoimmune thyroid disease. Furthermore, Burman and colleagues 13 evaluated 7 patients who were euthyroid after treatment of Graves disease and showed that lithium administration in these patients resulted in lowering of T3, T4, and reverse T3 concentrations likely related to an inhibitory effect on thyroid hormone synthesis and release. IFN There are 3 different types of thyroid dysfunction associated with IFN a treatment: (1) autoimmune (often subclinical) hypothyroidism, (2) destructive thyroiditis, and (3) Graves-like hyperthyroidism. Hypothyroidism is more common than hyperthyroidism. Immune modulation may be a cause because IFN a is associated with development of

7 Thyroid Function Tests 289 antithyroid peroxidase antibodies in approximately 20% of patients. These abnormalities can occur as early as 4 weeks and as late as 23 months after initiation. In patients treated with IFN a, hypothyroidism occurs in 2.4% to 19%, with most patients having thyroid peroxidase (TPO) antibodies (87%). 14 Hypothyroidism can be transient, subsiding after discontinuation of IFN a. Koh and colleagues 15 showed that as many as 56% of patients had permanent hypothyroidism. In hypothyroidism, levothyroxine therapy is indicated without the need to withdraw IFN therapy. Destructive thyroiditis usually occurs in the first few weeks of IFN treatment in close temporal relationship with the appearance of thyroid autoantibodies, especially thyroglobulin antibodies. In addition, ribavarin along with IFN for the treatment of hepatitis C does not modify the thyroid autoantibody pattern, but is associated with a higher risk of hypothyroidism. 16 Thyrotoxicosis is frequently mild and transient without overt clinical manifestations and may be diagnosed only by obtaining frequent thyroid function tests. The duration of destructive thyroiditis is variable, ranging from a few weeks to a few months. IFN treatment may also cause hyperthyroidism, which may occur after a transient phase of destructive thyroiditis or following a period of hypothyroidism. Hyperthyroidism related to IFN is associated with thyroid-stimulating immunoglobulin (TSI) antibodies and increased uptake on technetium scintigraphy, but not with features of ophthalmopathy. TSH measurements should be performed every 8 to 12 weeks during IFN a treatment. When destructive thyroiditis is present, treatment with b-blockade is often useful to control the signs and symptoms of thyrotoxicosis. When IFN causes hyperthyroidism, antithyroid agents such as methimazole or propylthiouracil may be administered if clinically indicated in the setting of thyrotoxicosis. ALEMTUZUMAB Thyroid autoimmunity resulting from immune reconstitution from lymphocytopenia has been reported in the literature in patients receiving alemtuzumab, a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes. In 216 patients with multiple sclerosis treated with alemtuzumab, 32 developed hyperthyroidism and 15 developed hypothyroidism. 17 These events occurred with the presence of thyroid autoantibodies in 96% of affected patients and occurred up to 30 months after the last dose. Similarly, 4 patients with type 1 diabetes developed hyperthyroidism after immune suppressive therapy had been stopped 2 to 21 months earlier for a failing islet cell graft. 18 These 4 patients had a pretransplant positivity for TPO autoantibodies. It is hypothesized that drug-induced lymphopenia in patients with previously existing occult autoimmune thyroiditis predisposes to a reactivation of autoimmune mechanisms when T-lymphocytes are repopulated and thus to an aberrant immune reconstitution. TBG Medications may increase or decrease serum TBG concentrations, thereby causing changes in serum total, but not free, T4 and free T3 (FT3) concentrations. The most common cause of an increase in serum TBG concentration is the administration of estrogen (eg, birth control pills). Estrogens produce increased sialylation of TBG, which decreases its rate of clearance and raises its serum concentration. The increase in TBG in serum is dose dependent. In a study by Mandel and colleagues 19 of women with hypothyroidism who were receiving T4 and became pregnant, an increase of 45% in the dose was needed to maintain normal serum TSH concentrations because of estradiol-induced increases in TBG and 30% to 40% increase in plasma volume. 20

8 290 Kundra & Burman In addition, in women with hypothyroidism treated with thyroxine, estrogen therapy may increase the need for thyroxine. 21 Serum TBG concentrations are increased in about 50% of patients who use heroin or are treated with methadone. 22 There was a significant increase in the mean concentration of TT3, TT4, and TBG in the serum of 145 clinically euthyroid patients on maintenance methadone for approximately 6 weeks at doses of 15 to 45 mg/d compared with euthyroid controls not on methadone. 23 In contrast, free T4 and TSH levels were not different in the 2 groups. The increase in serum TBG, which can lead to increased TT4 and TT3 levels, may result from liver disease rather than from specific effects of these drugs. Mitotane and fluorouracil are also associated with increases in serum concentrations of total T4 and T3 and likely increase the serum concentration of TBG. Patients taking androgens or anabolic steroids have decreased serum TBG. 24 At therapeutic concentrations, several drugs inhibit binding of T4 and T3 to TBG. Large doses of furosemide (>80 mg) result in a transient increase in serum-free T4 concentrations and a decrease in serum total T4 concentrations. 21 Several nonsteroidal antiinflammatory drugs have similar effects. 25 Salicylates (in doses of >2.0 g per day) and salsalate (in doses of g per day) also inhibit the binding of T4 and T3 to TBG; salicylates inhibit binding to transthyretin as well. 26 Initially, the inhibition of binding to TBG results in transiently increased circulating thyroid hormone levels that cause transfer of T4 and T3 into intracellular sites, resulting in temporary TSH suppression and leading to a reduced thyroid hormone secretion. In particular, a study of 25 healthy adults receiving salsalate and aspirin at 1 g 4 times a day for 1 week showed an approximately 30% to 50% decrease in TT4, TT3, and TSH compared with timeadjusted baseline levels, but TSH remained within normal levels. 26 These thyroid function abnormalities are drug and dose dependent and can last several days after a large dose of salsalate. Serum-free T4 increases transiently after administration of heparin. 27 This increase is caused by in vitro inhibition of protein binding of T4 by free fatty acids generated as a result of the ability of heparin to activate lipoprotein lipase. 28 MEDICATIONS THAT INTERFERE WITH T4 AND T3 METABOLISM T4 and T3 are metabolized enzymatically mainly by deiodination but also by glucuronidation and sulfation. Phenobarbital and rifampin increase T4 and T3 metabolism by stimulating hepatic microsomal drug-metabolizing enzyme activity. 29,30 Patients with hypothyroidism who are treated with phenobarbital cannot augment thyroid hormone production and secretion, thereby exacerbating their hypothyroidism. Phenytoin and carbamazepine augment the rate of thyroid hormone metabolism and displace thyroid hormone from the serum binding proteins, principally TBG. 31 In 9 euthyroid patients treated with phenytoin at therapeutic levels, mean serum T4 decreased to 60% of that of the control group and mean T3 decreased to 78% of that of the control group. 31 In 10 euthyroid patients treated with carbamazepine at therapeutic levels, mean serum T4 decreased to 74% of that of the control group and mean T3 decreased to 83% of that of the control group. Serum FT4 concentrations remained unchanged by ultrafiltration and TSH levels remained within normal range in patients treated with phenytoin and carbamazepine. Hypothyroid patients treated with T4 may need a higher LT4 dose when treated with any of these agents. MEDICATIONS THAT INTERFERE WITH GI ABSORPTION OF EXOGENOUS LEVOTHYROXINE Multiple medications have been reported to impair the absorption of exogenous thyroxine and decrease its efficacy. Normally, about 80% of a usual dose of

9 Thyroid Function Tests 291 levothyroxine (eg, mg per day) is absorbed, mostly in the jejunum and the upper part of the ileum. 32 The bile acid binding resins, cholestyramine and colestipol, bind thyroid hormones and decrease their absorption. A decrease in serum T4 concentrations and an increase in serum TSH concentrations occurred when cholestyramine was administered to patients with hypothyroidism treated with T4. 33 Calcium carbonate reduces the absorption of exogenous T4. In a prospective cohort of 20 hypothyroid patients taking 1200 mg of elemental calcium (as calcium carbonate) for 3 months, the mean serum-free and total T4 concentrations decreased significantly during coadministration of calcium carbonate, by 8% and 7% respectively. 34 The mean serum TSH concentration increased by 69%, with 20% of patients having serum TSH concentrations greater than the normal range. These changes resolved after calcium carbonate was discontinued. Sucralfate, ferrous sulfate, and aluminum hydroxide also bind T4 in the gut, but their effect is smaller and also less consistent than those described earlier Normal gastric acid secretion seems to be necessary for normal thyroid hormone absorption. Centanni and colleagues 38 showed that, in 10 patients treated with omeprazole for multinodular goiter, a 37% increase in the dose of levothyroxine was required after 6 months to obtain similar TSH levels to those of patients treated without omeprazole. Italian coffee (espresso) has also been shown to interfere with T4 intestinal absorption. Benvenga and colleagues 39 reported 8 patients in whom coffee given with L-T4 compared with water lowered the average and peak incremental increases in serum T4. These changes are unrelated to change in intragastric ph and result from an interaction that makes L-T4 less available for absorption. It is unknown whether these effects are applicable more widely with varying types of coffee, and to what extent these findings apply clinically. SUNITINIB Sunitinib is an inhibitor of vascular endothelial growth factors (VEGF) tyrosine kinase and platelet-derived growth factor receptors used to treat renal cell cancer (RCC) and GI stromal tumors (GIST). 40 The potential mechanisms by which sunitinib might induce thyroid dysfunction include destructive thyroiditis, blockade of iodine uptake, and inhibition of peroxidase activity. Desai and colleagues 41 investigated 42 euthyroid patients receiving 50 mg of sunitinib for 2 to 4 weeks with 2 weeks of no therapy for 4 to 6 cycles. Hypothyroidism was developed by 15/42 patients after an average of 50 weeks. All patients normalized TSH values after receiving thyroxine. Two sonographic findings in hypothyroid patients showed atrophy of the thyroid gland, suggesting destructive thyroiditis as a cause. Rini and colleagues 42 investigated 66 patients with RCC treated with sunitinib (50 mg daily for first 28 days of a 42-day cycle). One or more thyroid function abnormalities of hypothyroidism were found in 56/66 at a median cycle of 2 with a range of 1 to 14. Rini and colleagues 42 suggested that sunitinib prevented binding of VEGF to normal thyroid cells and/or impaired thyroid blood flow resulting in thyroiditis. Grossmann and colleagues 43 studied 12/ 25 patients who developed thyroid dysfunction after receiving sunitinib 50 mg/ d for 28 days for each 6-week cycle for metastatic renal cell carcinoma. Of these, 2 had a transiently reduced TSH with normal FT4 and FT3, 4 developed hypothyroidism without evidence of preceding hyperthyroidism, and 6 developed hyperthyroidism. Ultimately, 8 developed permanent hypothyroidism. It was postulated that, in the 6 patients who had thyrotoxicosis, thyroiditis was likely because of (1) rapid improvement in thyroid function tests with progression to hypothyroidism, (2) high thyroglobulin levels, (3) high FT4/FT3 ratio, and (4) decreased uptake on thyroid scan. Mannavola and colleagues 44 investigated 24 patients with GIST given 4 weeks

10 292 Kundra & Burman of daily treatment with sunitinib at a dose of 50 mg orally and 2 weeks of withdrawal. After 1 to 6 cycles, 46% developed hypothyroidism. Thyroid sonographic abnormalities or variations in serum thyroglobulin and antithyroid antibodies were not found. 123 I was reduced, suggesting blockade of iodine uptake as a potential mechanism of hypothyroidism. Salem and colleagues 45 showed that FRTL-5 cells treated with 10 mm of sunitinib did not affect iodide efflux, but did increase influx at 24 hours in a dose-dependent manner. Wong and colleagues 46 discovered that 21/40 patients receiving sunitinib 50 mg daily for 4 weeks in a 6-week cycle (up to 48 months) developed hypothyroidism. Sunitinib inhibited peroxidase activity in the iodination and guaiacol assay. The antiperoxidase activity of sunitinib was 25% to 30% of that of PTU. In addition, Alexandrescu and colleagues 47 reported a case of sunitinibassociated lymphocytic thyroiditis without circulating antithyroid antibodies. There is a wide spectrum of thyroid alterations associated with sunitinib therapy, likely modulated by various molecular mediators. No prospective studies have evaluated the early treatment of subclinical hypothyroidism in patients treated with tyrosine kinase inhibitors. Systematic assessment of thyroid function at baseline and at the beginning of each treatment cycle is recommended. Treatment with levothyroxine should be based on clinical context and laboratory evaluation and may be considered, particularly if the TSH exceeds 10 miu/l. 48 There are many other multikinase inhibitors being used clinically, but, in general, their likelihood of causing thyroid perturbations has not been adequately studied. IMATINIB Imatinib belongs to the 2-phenylaminopyridine class and targets BCR-ABL, plateletderived growth factor receptor, and c-kit receptor tyrosine kinases. De Groot and colleagues 49 treated 11 patients (10 with medullary thyroid cancer and 1 with GIST) on levothyroxine and imatinib ( mg) for an average of 6 months. TSH levels increased to 384% (228%) of upper limits, whereas FT4 and FT3 decreased respectively to 59% (17%) and 63% (4%). De Groot and colleagues 49 suggested induction of UGTs involved in conjugation and T4/T3 clearance as a cause of hypothyroidism. In athyreotic patients, thyroidal compensation does not occur and the dose of levothyroxine sodium should be increased in a timely manner. SUMMARY In summary, drug-induced thyroid disorders are common in clinical practice. It is important to recognize the various drugs contributing to thyroid dysfunction for a timely intervention to help achieve a euthyroid state. Box 1 provides a summary of the drugs involved with altered thyroid function tests. REFERENCES 1. Brabant K, Prank C, Hoang-Vu RD, et al. Hypothalamic regulation of pulsatile thyrotropin secretion. J Clin Endocrinol Metab 1991;72(1): Agner T, Hagen C, Anderson A, et al. Increased dopaminergic activity inhibits basal and metoclopramide-stimulated prolactin and thyrotropin secretion. J Clin Endocrinol Metab 1986;62(4): Brabant G, Brabant U, Ranft K, et al. Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration. J Clin Endocrinol Metab 1987;65(1):83 8.

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12 294 Kundra & Burman 26. Samuels MH, Pillote K, Asher D, et al. Variable effects of nonsteroidal antiinflammatory agents on thyroid test results. J Clin Endocrinol Metab 2003; 88(12): Jain R, Uy HL. Increase in serum free thyrosine levels related to intravenous heparin treatment. Ann Intern Med 1996;124(1 Pt 1): Jaume JC, Mendel CM, Frost PH, et al. Extremely low doses of heparin release lipase activity into the plasma and can thereby cause artifactual elevations in the serum-free thyroxine concentration as measured by equilibrium dialysis. Thyroid 1996;6: Oppenheimer JH, Bernstein G, Surks MI. Increased thyroxine turnover and thyroidal function after stimulation of hepatocellular binding of thyroxine by phenobarbital. J Clin Invest 1968;47: Isley WL. Effect of rifampin therapy on thyroid function tests in a hypothyroid patient on replacement L-thyroxine. Ann Intern Med 1987;107: Surks MI, DeFesi CR. Normal serum free thyroid hormone concentrations in patients treated with phenytoin or carbamezipine. JAMA 1996;275: Hays MT. Thyroid hormone and the gut. Endocr Res 1988;14(2-3): Harmon SM, Siefert CF. Levothyroxine-cholestyramine interaction reemphasized. Ann Intern Med 1991;115: Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA 2000;283: Sherman SI, Tielens ET, Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. Am J Med 1994;96(6): Campbell NR, Hasinoff BB, Stalts H, et al. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med 1992;117(12): Sperber AD, Liel Y. Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Arch Intern Med 1992;152(1): Centanni M, Gargano L, Canettieri G, et al. Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N Engl J Med 2006;354: Benvenga S, Bartolone L, Pappalardo MA, et al. Altered intestinal absorption of L-thyroxine caused by coffee. Thyroid 2008;18(3): Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007;25(7): Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal tumors. Ann Intern Med 2006;145: Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99: Grossmann M, Premaratne E, Desai J, et al. Thyrotoxicosis during sunitinib treatment for renal cell carcinoma. Clin Endocrinol 2008;69(4): Mannavola D, Coco P, Vannachi G, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 2007;92(9): Salem AK, Fenton MS, Marion KM, et al. Effect of sunitinib on growth and function of FRTL-5 thyroid cells. Thyroid 2008;18(6): Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 2007;17(4): Alexandrescu DT, Popoveniuc G, Farzanmehr H, et al. Sunitinib-associated lymphocytic thyroiditis without circulating antithyroid antibodies. Thyroid 2008; 18(7):

13 Thyroid Function Tests Torino F, Corsello S, Longo R, et al. Is hypothyroidism a clinically relevant toxicity of tyrosine kinase inhibitors? Thyroid 2009;19(5): De Groot JW, Zonnenberg BA, Plukker JT, et al. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 2005;78:433 8.