Case Presentation: 75 year-old male with nasal NK/T non-Hodgkin lymphoma (stage II B) in second relapse on salvage Pembrolizumab (checkpoint inhibitor) presented with fatigue, skin irritation and arthralgias. Initial blood work showed hyponatremia. Patient had a low plasma osmolality and was euvolemic on exam. Urine sodium was 96MeQ/L. Patient had a low serum cortisol which did not increase as expected with stimulation test. He had a normal TSH, prolactin, FSH and low DHEAS and ACTH levels along with normal urine osmolarity. Pituitary MRI was normal and therefore SIADH and hypophysitis were ruled out. Patient was diagnosed with adrenalitis and started on hydrocortisone with improvement in his sodium levels and symptoms.
Discussion: Programmed cell death protein 1 (PD-1) is expressed on antigen stimulating T-Cells and induce downstream signaling that inhibits T Cell proliferation, cytokine release and cytotoxicity. Many tumor cells express PD-1 ligand (PD-L1) on the cell surface. When PD-1 is bound to PD-L1, all T-Cell effector function is inhibited. Pembrolizumab and other check point inhibitors work as Anti PD-1 and PD-L1 antibodies that can reverse T cell suppression and induce long lasting anti-tumor responses. This can in turn cause inflammation and autoimmune reactions because of an unchecked immune system. Essentially, any organ system can be involved and some of the commonly affected organ systems are the skin (pruritis, rash, and vitiligo) , endocrine glands (hypothyroidism, hyperthyroidism, hypophysitis, and adrenal insufficiency), lungs (pnuemonitis), gasterointestinal (colitis, diarrhea, pancreatitis, and hepatitis), and genitourinary (nephritis and renal failure. In patients presenting with hyponatremia, hypophysitis is more commonly seen than adrenalitis although both have been described. In patients with adrenalitis, there is decrease in aldosterone levels and these patients can therefore present with hyponatremia, low blood pressure, fatigue, nausea, weight loss and skin changes. With hyponatremia, it is very important to follow a systematic approach to properly diagnose and treat the underlying cause. Patients with hyponatremia due to adrenalitis will appear euvolemic, have low plasma osmolality, and urine sodium excretion of greater than 20mEq/L. Once it has been determined that the cause of hyponatremia is not SIADH in these patients, they should promptly be started on hydrocortisone therapy.
Conclusions: This case highlights one of the serious side effects of check point inhibitors. With the growing use of immunotherapy, it is important to be cognizant of serious side effects of these medications. When patients present with hyponatremia it is important to consider immunotherapy related adrenalitis or hypophysitis along with SIADH as part of your differential.