Discussion
Hypothyroidism is a very common chronic condition, with primary hypothyroidism (failure of the thyroid gland) accounting for more than 99 % of cases (1). By contrast, central hypothyroidism (caused by insufficient TSH stimulation of the thyroid gland) accounts for a small proportion of cases and is often accompanied by deficiency in other pituitary axes (hypopituitarism), such as cortisol, growth hormone and sex hormone deficiency. Hypopituitarism is a rare condition that is usually caused by pituitary adenoma or tumours/cysts in or near the pituitary gland, or as a result of surgery, radiotherapy, infiltrative disease or modern immunotherapy (2).
Isolated central hypothyroidism is extremely rare and generally congenital (3). It can be challenging to diagnose because TSH will usually be low or 'inappropriately' normal, and therefore the diagnosis is dependent on free T4 and free T3. A key differential diagnosis is non-thyroidal illness syndrome, a condition in which acute illness also leads to a decrease in free thyroid hormones along with low TSH.
Anaemia is a common complication in patients with chronic kidney disease, with a prevalence ranging from 15 % with any stage of CKD to over 50 % in patients with stage 5 (4). Renal anaemia is associated with increased mortality (5), and thus it is treated with iron supplementation and erythropoiesis-stimulating agents, with a target haemoglobin above 10.0 g/dL (6).
An oral alternative to erythropoiesis-stimulating agents has recently become available, roxadustat (7), which is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PH). In Norway, it was used in approximately 281 patients with renal anaemia in 2023 (8). Through the reversible inhibition of HIF-PH, the stimulating effects of roxadustat include increased plasma levels of endogenous erythropoietin, reduction in hepcidin, an increased number of transporter proteins and increased iron uptake. Overall, this results in improved iron bioavailability, increased haemoglobin and increased red cell mass (7).
Several case reports have been published with a similar clinical course to that of our patient (9, 10), and a recent retrospective study (11) found significantly lower thyroid parameters (TSH, free T4 and free T3) in patients treated with roxadustat compared with erythropoietin. The likely cause is roxadustat's structural similarity to triiodothyronine (T3), which results in reduced secretion of TSH via a feedback mechanism (the receptor THRβ) in the pituitary gland. This in turn leads to reduced stimulation of the thyroid gland and a net reduction in the release of thyroid hormones (T4 and T3) into the blood stream (12).
Patient's perspective
I found I was getting more tired and forgetful, and I had difficulty concentrating. I also developed dry skin and mucous membranes, decreased appetite, constipation, and muscle and joint pain. One month after stopping roxadustat, I noticed an improvement in my symptoms.
We consider it highly likely that our patient had transient isolated central hypothyroidism secondary to treatment with roxadustat. Hypothyroidism can cause significant symptoms, and therefore it is imperative to monitor the thyroid function of patients receiving roxadustat treatment. The analysis of free T3 and free T4 in addition to TSH is essential, since the condition may not necessarily be detected with TSH alone. The case has been notified as an adverse drug reaction to the Norwegian Medicines Agency.