Thyroid dysfunction from antineoplastic agents

Abstract

Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.

Figure 1

Normal thyroid hormone physiology. Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus into the hypophyseal portal vein, which carries it to the anterior pituitary. The anterior pituitary releases thyroid-stimulating hormone (TSH) in response to TRH. TSH acts on the thyroid to stimulate all steps involved in thyroid hormone biosynthesis and secretion. Thyroxine (T4) is secreted together with triiodothyronine (T3) from the thyroid. Some is bound to thyroxine-binding globulin (TBG), transthyretin, and albumin, whereas the remainder is free and exerts physiological effects. In hypothyroid patients, thyroid hormone is ingested as levothyroxine. Exogenous or endogenous T4 is monodeiodinated to the active form of the hormone, T3, by types 1 or 2 deiodinase present in peripheral tissues. Both T4 and T3 exert negative feedback on TRH secretion from the hypothalamus and on TSH secretion from the pituitary.

Figure 2

Interpretation of common tests of thyroid function. There are other possible rare causes of elevated free thyroxine (T4) with normal or elevated thyroid-stimulating hormone (TSH). These include thyroid hormone resistance; treatment with amiodarone or high-dose propranolol (which reduces conversion of T4 to triiodothyronine [T3]); amphetamine-induced hyperthyroxinemia; or some patients on antipsychotic medications. TSH provides the single best assessment of thyroid status. If it is abnormal, or if a pituitary etiology of thyroid dysfunction is suspected, the measurement of a free T4 is the next step. Note that an estimation of free thyroxine should be done, rather than simply a total T4. This can be done by a direct measurement of free T4 or the total T4 combined with an indirect determination of the fraction of free thyroid hormone (usually a determination of T3 resin uptake, or thyroid hormone–binding ratio). A radioactive iodine uptake (RAIU) is helpful to determine the etiology of thyrotoxicosis, with a value above 25% being consistent with hyperthyroidism (usually Graves disease), vs a destructive thyroiditis in which the uptake is very low. A thyroid scan is usually not necessary for making this distinction.

Figure 3

Thyroid hormone metabolism. Thyroid hormone is inactivated primarily by type 3 deiodinase (D3), which removes one iodine from the 3 or 5 position of triiodothyronine (T3) or thyroxine (T4), forming compounds that will not bind to the thyroid hormone receptor. About 20% of T4 is conjugated to sulfate or glucuronide and cleared by biliary excretion. D1, D2 = Type 1 and type 2 deiodinase, respectively; rT3 = Reverse triiodothyronine; T2 = 3, 3′ diiodothyronine.

Figure 4

Intracellular action of thyroid hormone. Thyroid hormone acts mainly via nuclear receptors. Thyroxine (T4) and triiodothyronine (T3) enter the cells, and T4 can be converted to its active form, T3, by intracellular type 2 deiodinases. T3 will bind to the thyroid hormone receptor (TR), which associates with the retinoid X receptor (RXR). The complex binds to the thyroid response element (TRE), which interacts with DNA and increases or decreases mRNA transcription. This leads to altered protein expression, which leads to most of the physiological effects of thyroid hormone. In addition, this will reduce thyroid-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) production.