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.