Background: Immune checkpoint inhibitors including nivolumab, an anti-programmed cell death protein 1 antibody, are\nrecently developed cancer immunotherapy agents. Immune checkpoint inhibitors are known to cause autoimmune-related\nside effects including endocrine dysfunctions. However, there are few reports on late-onset isolated adrenocorticotropic\nhormone (ACTH) deficiency caused by nivolumab.\nCase presentation: The patient was a 72-year-old female. When she was 64 years old, she was diagnosed with malignant\nmelanoma of the left thigh accompanied by left inguinal lymph node metastases, and she received several courses of\nchemotherapy for malignant melanoma followed by the resection of these lesions. At 71 years of age, multiple metastases\nwere found and treatment with nivolumab 2 mg/kg every 3 weeks was initiated. Six months later, replacement with\nlevothyroxine was started because of hypothyroidism following mild transient thyrotoxicosis. Eleven months after the\nbeginning of nivolumab, the treatment was discontinued because of tumor expansion. Four months after the\ndiscontinuation of nivolumab, general malaise and appetite loss worsened, and 2 months later, hyponatremia\n(Na; 120-127 mEq/L) and hypoglycemia (fasting plasma glucose; 62 mg/dL) appeared. Her ACTH and cortisol\nlevels were extremely low (ACTH; 9.6 pg/mL, cortisol; undetectable). Challenge tests for anterior pituitary\nhormones showed that responses of ACTH and cortisol secretion to corticotropin-releasing hormone were\ndisappeared, although responses of other anterior pituitary hormones were preserved. Thus, she was diagnosed with\nisolated ACTH deficiency. Her symptoms were improved after treatment with hydrocortisone.\nConclusions: The present report showed a case of late-onset isolated ACTH deficiency accompanied by hyponatremia,\nwhich was diagnosed 6 months after the discontinuation of nivolumab. The effects of nivolumab last for a long time\nand the side effects of nivolumab can also appear several months after discontinuation of the drug. Repeated\nmonitoring of serum sodium levels may be a beneficial strategy to find the unexpected development of adrenal\ninsufficiency even after discontinuation of nivolumab.
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