DISCUSSION
We present a case of a dialysis patient who developed central hypothyroidism after using roxadustat. Table 3 is a summary of central hypothyroidism dialysis patients taking roxadustat at our hospital. All cases decreased TSH and fT4 after taking roxadustat. Roxadustat was discontinued in 7 patients, and the dose was reduced in 1 patient, TSH and fT4 recovered. Although central hypothyroidism by roxadustat might be reversible, it takes a longer time to recover thyroid function, if thyroid hormones are severely suppressed for a long period. Therefore, early detection of central hypothyroidism is required. Markedly reduced cholesterol levels would be good markers to speculate hypothyroidism. The decreased cholesterol levels were recovered in all cases after discontinuing or reducing roxadustat in a similar way to recover thyroid function.
The central hypothyroidism in our case was reversible. And the central hypothyroidism would depend on taking roxadustat. Similar cases were reported previously [2,4]. Some drugs, such as retinoid X receptor selective ligands, have been reported to suppress TSH gene promoter activity, thereby causing central hypothyroidism [5]. Therefore, it is speculated that roxadustat caused central hypothyroidism by a similar mechanism. Another possibility is the direct effect on the thyroid hormone receptor. Roxadustat has a similar chemical structure to T3. It would have a stronger affinity for the thyroid hormone receptor TRβ than T3 [6]. Thereby, it acts as an agonist on the thyroid hormone receptor TRβ present in the hypothalamus and pituitary gland, suppressing TSH secretion. Additionally, it has been reported that roxadustat may partially cross the blood-brain barrier in mice [7]. Therefore, it is possible that orally administered roxadustat crosses the blood-brain barrier, and binds to thyroid hormone receptor TRβ. These are possible mechanisms of central hypothyroidism after using roxadustat.
In our case, cholesterol levels were markedly reduced in the condition of central hypothyroidism. Thyroid hormones have important effects on cell development, growth, and metabolism, and are expressed and act in almost all tissues [8,9]. Thyroid hormone binds to thyroid hormone receptors in the nucleus and lowers cholesterol levels through TRβ. TRβ stimulation increases LDL receptor expression in the liver, resulting in plasma clearance of LDL cholesterol [10]. As described previously, it is speculated that roxadustat binds to TRβ [6], increases the expression of LDL receptors, and lowers cholesterol. Therefore, it is speculated that reduced cholesterol levels are an agonistic effect of roxadustat on the TRβ1 receptor in the liver. All of the seven cases, including the present case, showed significant cholesterol reduction during treatment with roxadustat, which improved after discontinuation or reduction of the drug. Hypocholesterolemia is presumed to be a TRβ-mediated effect similar to the TSH secretion effect of roxadustat in the brain, so the detection of hypocholesterolemia is an important marker for finding central hypothyroidism.
We experienced a dialysis case with hormonal dynamics similar to central hypothyroidism caused by roxadustat. A decrease in cholesterol was observed during the administration of roxadustat, and the patient developed symptoms after discontinuing roxadustat. The TRH stress test after discontinuing the drug showed a normal response, and this condition was judged to be a reversible change. It was speculated that roxadustat acts suppressively as an agonist in the hypothalamus and pituitary gland, and as an agonist in target organs.