High-Dose Thyroid Hormone Replacement in Bexarotene-Induced Central Hypothyroidism

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Background: Central hypothyroidism is a rare disorder characterized by a defect in thyroid hormone production by an otherwise normal thyroid gland due to decreased stimulation by TSH. Medications are an uncommon cause. Case Presentation: A 72-year-old man was referred for evaluation of a low TSH. He had a long history of hypothyroidism, euthyroid on levothyroxine, and was diagnosed with cutaneous T cell lymphoma (CTCL). Due to disease progression on dapsone, PUVA and TAR baths, he was started on bexarotene. Soon after, he developed recurrent symptoms of hypothyroidism including fatigue, cold intolerance, dry skin, and myalgias. Workup revealed a TSH of <0.01 ulU/mL (0.27-4.20) with a free T4 of 0.6 ng/dl (0.9-1.7). After evaluation, his levothyroxine dose was increased. Repeat labs 3 months later showed a TSH of <:0.01 with a free T4 0.8 ng/dl and T3 43 ng/dl (80-200). Over several months, levothyroxine titration to a supraphysiologic dose of 800 mcg daily was required, despite optimal administration, to normalize FT4. Given persistent hypothyroid symptoms and a low T3 level, liothyronine 5 mcg BID was added and resulted in clinical and biochemical euthyroidism. Clinical Lessons: Unlike in primary thyroid disorders, the TSH assay is unreliable in central hypothyroidism since values can be low, normal, or even mildly elevated; regardless, TSH has subnormal bioactivity. Ineffectual TSH leads to a low T4, which is a required for diagnosis. Bexarotene, a derivative of Vitamin A, is a retinoid X receptor (RXR) selective ligand approved for the treatment of CTCL. The exact mechanism of bexarotene-induced thyroid dysfunction is not clear, although it involves both central and peripheral effects. Bexarotene inhibits TSH gene expression by decreasing the activity of the thyrotropin β subunit gene promoter in a dose-dependent and thyroxine-independent manner; TSH levels drop as early as 4-8 hours after exposure. Bexarotene also directly lowers T4 and T3 levels, even in athyreotic patients, by negatively impacting deiodinase activity and hepatic conjugation. Stopping bexarotene is often not possible given its effectiveness in CTCL. Therefore, thyroid hormone should be initiated with the goal of achieving a normal FT4, although as the current case demonstrates, massively supraphysiologic doses and/or the addition of liothyronine may be necessary to achieve clinical euthyroidism.