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Hypothyroidism Due to Ethionamide
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     To the Editor: Ethionamide (Trecator-SC, Wyeth-Ayerst) is an antimycobacterial drug used as a second-line agent in the treatment of multidrug-resistant tuberculosis. It is structurally similar to methimazole, has been shown to inhibit thyroid hormone synthesis, and was last reported to cause hypothyroidism in 1984.1 Before that report, only three other cases of hypothyroidism related to ethionamide were documented.1 We now report the case of a 57-year-old Indian-American woman with Takayasu's arteritis, coronary artery disease, and multidrug-resistant tuberculosis in whom hypothyroidism developed while she was receiving 250 mg of ethionamide twice daily for three months. She had previously been euthyroid (thyrotropin level, 2.1 μU per milliliter; normal range, 0.35 to 5.5), but after treatment (Figure 1) her thyrotropin level increased to 19.4 μU per milliliter.

    Figure 1. Thyroid Function in the Patient over Time.

    Ethionamide was discontinued for other reasons, and her serum thyrotropin level decreased to 5.4 μU per milliliter. Ethionamide was restarted six months later because of suspected recurrent multidrug-resistant tuberculosis. Within four months of restarting ethionamide, the patient had symptoms of severe hypothyroidism. An echocardiogram revealed a reduced ejection fraction (45 percent, a decrease from 60 percent six months earlier) and a new 1.5-cm pericardial effusion. Clinical evaluation revealed a small goiter, a thyrotropin level of 136 μU per milliliter, a thyroxine level of 1.6 μg per deciliter (normal range, 4.5 to 10.9), and an elevated thyroglobulin level (232 ng per milliliter; normal range, 4 to 40). A test for thyroid peroxidase antibodies was negative. The patient was treated with 88 μg of levothyroxine daily, which was reduced to 50 μg per day after ethionamide was discontinued once the course of therapy was completed. Four weeks later, the thyrotropin level was 1.2 μU per milliliter. The patient reported feeling well, and a repeated echocardiogram showed a normal ejection fraction and a marked decrease in the size of the pericardial effusion.

    Although ethionamide-induced hypothyroidism is noted as a possible adverse effect in the package insert,2 as well as in summary statements about treatment of multidrug-resistant tuberculosis,3 it appears that this complication is not widely known among practicing physicians. Ethionamide is not generally included in references that list medications that may cause hypothyroidism.4 Hypothyroidism due to ethionamide is, at least in part, reversible after withdrawal of the drug. There is emerging evidence from a World Health Organization global project that although tuberculosis strains that are sensitive to standard antimycobacterial drugs remain the most prevalent, there are epidemics and several "hot spots" of multidrug-resistant tuberculosis around the world, for which second-line agents, such as ethionamide, are commonly used.3,5 Thus, physicians treating patients who have multidrug-resistant tuberculosis should be aware of this potential complication of ethionamide therapy. Thyroid function should be carefully monitored in all patients treated with ethionamide, and ethionamide should be included in any list of drugs that may cause hypothyroidism.

    Marie E. McDonnell, M.D.

    Lewis E. Braverman, M.D.

    John Bernardo, M.D.

    Boston Medical Center

    Boston, MA 02118

    marie.mcdonnell@bmc.org

    References

    Drucker D, Eggo MC, Salit IE, Burrow GN. Ethionamide-induced goitrous hypothyroidism. Ann Intern Med 1984;100:837-839.

    Trecator-SC. Madison, N.J.: Wyeth, October 2003 (package insert).

    Treatment of tuberculosis. MMWR Morb Mortal Wkly Rep 2003;52:26-26.

    Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison's principles of internal medicine. 16th ed. New York: McGraw-Hill, 2005:Table 320-4.

    Nachega JB, Chaisson RE. Tuberculosis drug resistance: a global threat. Clin Infect Dis 2003;36:Suppl 1:S24-S30.