It's Not Always SIAD: Immunotherapy-Triggered Endocrinopathies Enter the Field of Cancer-Related Hyponatremia

While the syndrome of inadequate antidiuresis (SIAD) is still the most common cause of hyponatremia in cancer patients, the rise in endocrine immune-related adverse events (irAEs) owing to immune checkpoint inhibitors (ICI) considerably shaped the differential diagnosis of electrolyte disorders in cancer patients. We report here 3 cases of different endocrine irAEs, first manifesting with new-onset hyponatremia under ICI therapy for malignant melanoma: one with primary adrenal insufficiency, one with hypophysitis, and one with autoimmune type 1 diabetes. Early diagnosis of endocrine toxicities can save lives but may be challenging and essentially delayed by subtle or nonspecific clinical presentation and a lack of readily available endocrinological laboratory evaluation in the primary care setting. This exemplary case series demonstrates the broad spectrum of endocrinopathies that physicians should be aware of under ICI therapy and emphasizes new-onset hyponatremia as a possibly early, simple, and low-cost biomarker of irAEs, which may be considered as a red flag in patients receiving checkpoint blockade. As ICI-induced endocrinopathies are still under-represented in clinical practice guidelines, we here propose an updated algorithm for diagnosis of cancer-related hyponatremia, highlighting the important diagnostic steps to be considered before making the diagnosis of SIAD.