Unmasking Refractory Hypothyroidism: Persistent Iron-Levothyroxine Interaction Despite Appropriate Dose Separation

Refractory hypothyroidism despite high-dose levothyroxine therapy is most commonly attributed to poor adherence or gastrointestinal malabsorption; however, drug-drug interactions remain an important and frequently under-recognised cause. Oral iron is known to impair levothyroxine absorption through chelation, and current clinical guidance recommends dose separation to mitigate this effect. We report the case of a 44-year-old woman with severe biochemical hypothyroidism, with thyroid-stimulating hormone (TSH) >100 mU/L (reference range: 0.27-4.2 mU/L), free thyroxine (FT4) 2.4 pmol/L (reference range: 11-22 pmol/L), and free triiodothyronine (FT3) 1.4 pmol/L (reference range: 3.5-6.5 pmol/L), despite reported adherence to escalating doses of levothyroxine up to 250 µg daily over nine months. She was concurrently taking oral ferrous sulphate 200 mg once nightly for iron deficiency anaemia, while levothyroxine was taken first thing in the morning, ensuring a separation interval of at least four hours in accordance with standard recommendations. A supervised levothyroxine absorption test performed according to the Manchester University NHS Foundation Trust Levothyroxine Absorption Test Protocol demonstrated adequate gastrointestinal absorption of levothyroxine, effectively excluding true malabsorption. Following discontinuation of oral iron and administration of intravenous iron, there was rapid biochemical improvement, with normalisation of TSH to 0.42 mU/L within six weeks. This case highlights that a clinically significant iron-levothyroxine interaction may persist despite appropriate dose separation. Clinicians should maintain a high index of suspicion for pharmacological interference in patients with refractory hypothyroidism.