Case Presentation: A 73-year-old woman with past medical history of metastatic endometrial adenocarcinoma previously treated with Pembrolizumab (stopped 4 months prior) presented with six weeks of persistent fatigue, myalgias, nausea, and vomiting. On presentation, she was noted to be hypotensive with labs notable for hyponatremia and hypomagnesemia. She appeared lethargic with dry mucous membranes and poor skin turgor. There was no evidence of skin hyperpigmentation, with muscle strength and sensation grossly preserved. Gynecologic oncology was consulted, as the initial leading differential diagnosis was failure to thrive secondary to worsening metastatic disease in setting of treatment holiday. Imaging revealed an overall stable disease burden. She was initiated on supportive care with subsequent hyponatremia workup demonstrating an elevated urine osmolality and elevated urine sodium, despite IV fluid resuscitation. Morning cortisol level was nearly undetectable with associated low ACTH. TSH was normal, suggesting against multiple endocrinopathies. Endocrinology was consulted and she was initiated on hydrocortisone therapy. A cosyntropin stimulation test was foregone to allow for prompt treatment and prevent progression to adrenal crisis. Within hours, she had marked improvement in her symptoms. In the setting of her prior immunotherapy treatment, she was diagnosed with Pembrolizumab-associated secondary adrenal insufficiency with isolated ACTH deficiency
Discussion: It is critical to consider organic causes of failure to thrive rather than anchoring on a diagnosis. In patients with known metastatic disease, it can be misleading to assume symptoms are due to worsening disease burden. Identifying the clinical features of adrenal insufficiency can be challenging in hospitalized patients due to the spectrum of non-specific symptoms. Early detection of adrenal insufficiency is critical and often relies on physicians having a high index of clinical suspicion to prevent escalation to adrenal crisis. In recent years, the use of immune checkpoint inhibitors has become a mainstay of cancer treatment. Immune and inflammatory-related adverse events are an increasingly reported disease entity. Endocrine-related adverse events are often irreversible with unknown mechanisms of toxicity. General internists must be aware of both immunotherapy use history and the spectrum of associated adverse events to ensure prompt diagnosis. Pembrolizumab, an anti-programmed death-1 (PD1) therapy, is rarely associated with the adverse effect of adrenal insufficiency. Even less commonly reported is secondary adrenal insufficiency with isolated ACTH deficiency, as was identified in the case above. While uncommon, this diagnosis should be considered in patients presenting with symptoms suggestive of adrenal dysfunction with prior history of anti-PD1 treatment. Treatment comprises life-long corticosteroids with an overall good prognosis.
Conclusions: Pembrolizumab is associated with the rare adverse effect of adrenal insufficiency, with incidence largely confined to a handful of case reports. Even less commonly described, is secondary adrenal insufficiency with isolated ACTH deficiency. Symptomatology can lead to hospitalization and is often managed by general practitioners in the absence of an oncologist. While uncommon, this diagnosis should be considered in patients presenting with symptoms suggestive of adrenal dysfunction with prior history of anti-PD1 treatment.