Marked lowering of high-density lipoprotein cholesterol levels due to high dose bexarotene therapy

Bexarotene is a retinoid X receptor agonist, which is currently used for the treatment of cutaneous T-cell lymphoma (CTCL). It is known to induce central hypothyroidism as well as dyslipidemia including elevation of triglycerides (TG) and low-density lipoprotein cholesterol along with slight lowering of high-density lipoprotein cholesterol (HDL-C). Marked lowering of HDL-C has never been previously reported in bexarotene-treated patients and whether it is related to hypothyroidism remains unclear.

A 49-year-old African female with a history of CTCL on treatment with bexarotene of 300 mg/d, presented with serum total cholesterol level of 249 mg/dL (6.4 mmol/L), TG level of 92 mg/dL (1.03 mmol/L), HDL-C level of 78 mg/dL (2.02 mmol/L), thyroid stimulating hormone (TSH) of 0.68 μIU/mL, and free thyroxine level of 0.5 ng/dL. Six months later, on increasing the bexarotene dose to 600 mg daily, serum TG increased to 310 mg/dL (3.5 mmol/L) and HDL-C dropped to 3 to 5 mg/dL (0.077-0.13 mmol/L), whereas the TSH was undetectable (0.01 μIU/mL). Despite adequate levothyroxine replacement to 225 μg daily resulting in free thyroxine levels up to 1.5 ng/dL, HDL-C remained extremely low of 4 to 9 mg/dL (0.103-0.233 mmol/L). Bexarotene was discontinued due to poor response of CTCL, 3 months after which her HDL-C levels returned to baseline of 80 to 90 mg/dL (2.07-2.33 mmol/L).

High dose bexarotene can markedly lower HDL-C levels, which normalize on discontinuation of the drug. Lowering of HDL-C with bexarotene may be due to an increase in cholesterol ester transfer protein activity and appears to be independent of central hypothyroidism.