Treatment-Refractory Hypothyroidism due to Proteinuria During Combined Immune Checkpoint and Tyrosine Kinase Inhibitor Therapy – A Case Report

Immune checkpoint inhibitors (ICIs) are increasingly used in oncology and commonly cause thyroid dysfunction. Most patients who develop hypothyroidism after ICI-induced thyroiditis respond to standard weight-based levothyroxine replacement. However, causes of treatment-refractory hypothyroidism are less well recognized in this context. We describe an 81-year-old woman with uterine cancer treated with lenvatinib and pembrolizumab who developed ICI-related thyroiditis with subsequent hypothyroidism. Despite progressive levothyroxine dose escalation to nearly twice the expected weight-based dose, thyroid-stimulating hormone (TSH) remained elevated after normalization of free thyroxine (FT4) and triiodothyronine (T3). Evaluation for malabsorption and nonadherence was unrevealing. Further investigation identified significant proteinuria associated with lenvatinib therapy. Given that thyroid hormone circulates primarily bound to plasma proteins, urinary loss of protein-bound thyroid hormone was suspected to contribute to the increased levothyroxine requirement. Following temporary discontinuation and subsequent dose reduction of lenvatinib, proteinuria improved and thyroid function tests (TFTs) normalized, allowing for a reduction in levothyroxine dose. This case highlights that excessive proteinuria can lead to urinary loss of protein-bound thyroid hormone, resulting in apparent levothyroxine resistance. Clinicians should consider renal losses along with gastrointestinal and medication-related causes when thyroid hormone requirements exceed expected dosing. This is particularly relevant in patients receiving combination cancer therapies that increasingly include ICIs.