Introduction: Pembrolizumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are immune checkpoint inhibitors (ICIs) that enhance immune-mediated tumor clearance. However, they may trigger immune-related adverse events (irAEs), including hypophysitis—a rare but potentially life-threatening pituitary inflammation, most strongly linked to CTLA-4 blockade and increased with combination therapy. Description: A 71-year-old man with metastatic melanoma was treated with dual immune checkpoint inhibitors: pembrolizumab (PD-1) and ipilimumab (CTLA-4). After 14 weeks, he developed worsening fatigue and weakness, followed by six days of escalating symptoms including nausea, vomiting, and a new headache. On arrival, he was lethargic and hypotensive (BP 82/55 supine, 70/40 standing). He denied visual changes. Labs showed hyponatremia (Na 121 mEq/L), acute kidney injury (creatinine 3.1 mg/dL), and normal WBC count (6,500/μL). Hormonal evaluation revealed central adrenal insufficiency (low cortisol), central hypothyroidism (low TSH and T4), and hypogonadotropic hypogonadism (low LH and FSH), consistent with suspected immune checkpoint inhibitor–induced hypophysitis. Discussion: Immune checkpoint inhibitors (ICIs), especially CTLA-4 blockade with ipilimumab, are associated with endocrine immune-related adverse events (irAEs), notably hypophysitis. The incidence is 10–15% with ipilimumab, < 1% with PD-1 inhibitors, and higher with combination therapy. CTLA-4 expression on pituitary cells may trigger direct T-cell–mediated inflammation. Hypophysitis often presents with fatigue, nausea, hypotension, and hyponatremia. Central adrenal insufficiency is the most critical and potentially life-threatening feature, requiring urgent ICU recognition. Central hypothyroidism and hypogonadism also occur. Diagnosis relies on hormonal assays; MRI may show pituitary enlargement but is sometimes normal. Glucocorticoid replacement is first-line, typically with stress-dose hydrocortisone. Thyroid hormone should be started only after steroid therapy to avoid adrenal crisis. Most patients require lifelong hormone replacement. As ICIs become more common, intensivists must stay vigilant for endocrine irAEs. Prompt recognition and hormone replacement are essential to prevent ICU-level morbidity.
Khan et al. (Sun,) studied this question.