Fulminant ACTH decrease following diabetic ketoacidosis induced by immune checkpoint inhibitor combination therapy with nivolumab and ipilimumab: A case report

Abstract

Rationale: The increasing use of immune checkpoint inhibitors (ICIs) for treating malignant tumors result in the concomitant rise of immune-related adverse events (irAEs). This case report may provide useful insight to understanding the etiology of ICI-induced hypophysitis, a severe irAE leading to potentially fatal secondary adrenal insufficiency. Patient concerns: An 81-year-old Japanese man was hospitalized for diabetic ketoacidosis following 4 courses of ICI combination therapy with nivolumab and ipilimumab for metastatic renal cell carcinoma. Diagnosis: Insulin secretion was depleted, leading to diagnosis of fulminant type 1 diabetes. Adrenocorticotropic hormone (ACTH) and cortisol levels were very high (60.8 pmol/L and 1575 nmol/L, respectively) upon admission. ACTH and cortisol returned to normal ranges on the 2nd day. On the 8th day, an ACTH loading test showed intact cortisol response (peak value 519 nmol/L). However, on the 14th day, there was a sharp decrease in ACTH and cortisol levels (10.5 pmol/L and 47 nmol/L, respectively) accompanied by fatigue and a drop in blood pressure to 97/63 mm Hg. As secondary adrenal insufficiency was suspected, hydrocortisone replacement was initiated. An ACTH loading test on the 17th day revealed low cortisol peak (peak value 232 nmol/L), indicating sudden disruption of adrenal function. Magnetic resonance imaging showed no abnormal findings and there was no other pituitary hormone deficiency. These findings, along with the patient clinical course, suggest that secondary adrenal insufficiency was caused by acute ACTH producing cell destruction as an irAE associated with ICI therapy. Interventions: The patient hyperglycemia and ketoacidosis were treated using extracellular fluid and insulin therapy. After development of adrenal insufficiency, hydrocortisone 20 mg was started, and the patient symptoms improved. Outcomes: He was continued on insulin therapy, hydrocortisone, and reinitiated nivolumab. Lessons: This case provides a detailed course of the fulminant onset of ACTH deficiency during ICI administration, emphasizing the importance of close monitoring.

Adrenal Insufficiency and Thyrotoxicosis Following Combined Immune Checkpoint Inhibitor Use: A Case Report and Literature Review

“…Although there have been several reports of multiple endocrine irAEs caused by ICI combination therapy, only four cases of AI and thyrotoxicosis due to nivolumab and ipilimumab therapy have been reported (Table 4) [21][22][23][24]. Previous reports indicate that the duration before the onset of hypophysitis and thyrotoxicosis caused by a combination of anti-PD-1 and anti-CTLA-4 antibodies differs, averaging 10.3 weeks and two weeks after the first administration, respectively [4][5][6].…”