Bexarotene: A Rare Cause of Misleading Thyroid Function Tests

Bexarotene is a very rare cause of central hypothyroidism (CH) and its effects have been reported to be dose-dependent; however, the available data in the literature on dose-dependent effects are variable. The standard practice of monitoring thyroid function using thyroid-stimulating hormone (TSH) to adjust levothyroxine (LT4) dose does not apply to bexarotene since it causes CH. In CH, TSH is not reliable. Hence free tetraiodothyronine (fT4) level is used to monitor and adjust the LT4 dose. We report a case of an 81-year-old Caucasian male with cutaneous T-cell lymphoma (CTCL) who was treated with bexarotene. His pre-treatment TSH was normal at 1.6 µIU/mL (reference range: 0.46-4.68 µIU/mL). Post-bexarotene, the total tetraiodothyronine (T4) level was within the reference range, but a downward trend was noted. Eventually, total triiodothyronine (T3) dropped to a low level of 0.61 ng/mL (reference range: 0.97-1.69 ng/mL), and LT4 was initiated. Bexarotene dose was increased, but LT4 was not increased by the primary physician who relied on TSH level, which was low, and hence the existing LT4 dose was maintained. The patient had persistent symptoms of hypothyroidism and, eventually, a diagnosis of CH was made. The symptoms of hypothyroidism improved after normalizing fT4, with an increase in the LT4 dose. This case represents an example of missed CH due to bexarotene, which led to suboptimal LT4 replacement impacting the quality of life for the patient.


Introduction
The standard practice in the management of primary hypothyroidism involves monitoring of thyroidstimulating hormone (TSH) to guide dose adjustments for levothyroxine (LT4). However, an exception to this is central hypothyroidism (CH), which is caused mostly by pituitary tumor/surgery and drugs. In this situation, TSH is unreliable and hence free tetraiodothyronine (fT 4 ) is used for monitoring and adjusting the LT4 dose. The goal set for fT 4 is just above the 50th percentile of the normal reference range (0.8-2.19 ng/dL) to achieve a good quality of life. Recognizing the drugs that can cause CH and changing the practice of hypothyroidism management accordingly are important to prevent therapeutic mishaps. Bexarotene is a synthetic retinoid, which selectively activates the retinoid X receptor [1]. Bexarotene is a rare but wellrecognized cause of CH, and it has been reported to cause dose-dependent suppression of TSH [2]. In the last decade, several new drugs have been reported to cause CH, and providing continuing medical education to primary care physicians is very important. In this case report, we discuss the challenges of diagnosing and managing bexarotene-induced CH in the primary care setting.

Case Presentation
An 81-year-old Caucasian male presented to the endocrinology office for the management of hypothyroidism in February 2020. The patient had initially presented in 2014 with a rash on the left palm and wrist (Figure 1), and right thigh. He had undergone a biopsy and had been diagnosed with cutaneous Tcell lymphoma (CTCL) (mycosis fungoides). He had been started on bexarotene 150 mg (two tablets of 75 mg each) daily in August 2015, and the dose had been temporarily increased to 300 mg (two tablets of 75 mg each) daily during disease exacerbation. Bexarotene had been tapered down to 150 mg per day whenever the flares had resolved. His baseline TSH had been 1.6 µIU/mL (reference range: 0.46-4.68 µIU/mL). He had follow-up labs ordered for total tetraiodothyronine or total T 4 by the oncologist, which had been normal until March 2016 but showed a downward trend. In April 2016, total triiodothyronine or total T 3 had been low at 0.61 ng/mL (reference range: 0.97-1.69 ng/mL), and LT4 50 µg daily had been initiated by the oncologist (Table 1). Subsequently, the patient had been followed up by the primary care physician for the management of hypothyroidism.

FIGURE 1: Initial rash of mycoses fungoides on the left palm and wrist
Lab reviews had revealed that the T 4 or fT 4 decreased when the dose of bexarotene was increased (all available labs are summarized in Table 1). Conversely, the T 4 or fT 4 levels increased when bexarotene was decreased or stopped. The patient had been maintained on LT4 50 µg daily until March 2017 when both bexarotene and LT4 had been held during the hospitalization for sepsis due to pneumonia. This discontinuation had normalized the fT 4 levels to 1.13 ng/dL in March, and to 1.3 ng/dL in April 2017.
Although bexarotene had been restarted after three weeks in April 2017, LT4 had not been restarted until May 2017. By May 2017, fT 4 had dropped to 0.5 ng/dL and LT4 75 mcg was restarted. The patient had persistently low T 4 , fT 4 , and T 3 values, but LT4 had not been increased beyond 75 µg daily, because of concerns related to suppressed TSH. The patient was initially seen by the endocrinologist in February 2020 because of a persistent abnormal thyroid function test. He was not using biotin and had not received iodinated contrast previously. Pertinent review of symptoms included decreased exercise tolerance, muscle aches and pain in the extremities, decreased appetite, cold intolerance, and easy bruising. On physical examination, the thyroid was normal in size, with no palpable nodules and no bruit on auscultation.

Discussion
Bexarotene is a synthetic retinoid, which selectively activates the retinoid X receptor and is used to treat CTCL. It has a peak plasma concentration two hours after ingestion and a half-life of seven hours [1]. Bexarotene selectively inhibits TSH secretion and can therefore lead to CH [2]. In vitro studies have shown that ligands for the retinoid X receptor suppressed the activity of thyrotropin β-subunit gene promoter [3,4]. The decrease in TSH concentrations was reported to be greater in patients who had received higher doses of bexarotene [2]. In phase II and phase III clinical trials in the United States,  reported that 30-40% of patients exhibited hypothyroidism at a bexarotene dose of 300 mg/m 2 /day, and approximately 50% of patients exhibited this outcome at doses of more than 300 mg/m 2 /day (i.e., 500 or 650 mg/m 2 /day) [5,6].
According to the United Kingdom consensus statement on safe clinical prescribing of bexarotene, TSH suppression of bexarotene is dose-dependent (Scarisbrick et al., 2013) [7]. Thus, preventive supplementation with LT4 may be appropriate when using bexarotene. It was recommended that LT4 be initiated from day one. LT4 can be started at a low dose of 25-50 µg daily and subsequently titrated to keep the fT 4 in the upper third of the reference range [7]. In our patient, the suppression of TSH was observed when increasing the LT4 dose, which was misleading to primary care providers. Earlier detection of the etiology of the patient's CH may have resulted in more appropriate dose adjustments leading to improved symptoms and better quality of life.
It is important to recognize that changes in bexarotene dose may influence the LT4 dose. LT4 dose requirement may increase with an increase in bexarotene dose. Likewise, the LT4 dose requirement may decrease with a decrease in bexarotene dose or with its discontinuation. Therefore, frequent monitoring of thyroid lab panels and knowledge about changes in bexarotene dose are important. Familiarity and early recognition of bexarotene-induced CH with both TSH and fT 4 testing can lead to early diagnosis and management of the condition, thereby improving treatment outcomes for the patient.

Conclusions
Bexarotene causes CH and the effect seems to be dose-dependent. Preventive supplementation with LT4 may be appropriate when using bexarotene. Recognizing the drugs that can cause CH and changing the practice of hypothyroidism management to include a complete thyroid lab panel accordingly are critical to prevent therapeutic mishaps.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Vishnu Sundaresh has received payment from a patient education research grant from Radius Health Inc; however, it is not related to this manuscript and presents no conflict of interest with the presented case report. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.