**3. Adrenal Insu**ffi**ciency**

Adrenal insufficiency caused by ICI treatment includes primary and secondary adrenal insufficiency caused by hypopituitarism. Most cases are considered to have secondary adrenal insufficiency, and primary adrenal insufficiency is thought to be less frequent, with a reported incidence of 1.4% (95% confidence interval (CI): 0.9–2.2) for ipilimumab, 2.0% (95% CI: 0.9–4.3) for nivolumab, and 5.2% (95% CI: 2.9–9.2) to 7.6% (95% CI: 1.2–36.8) for nivolumab or pembrolizumab combined with ipilimumab [12]. The time of onset is estimated as one to several months after the start of treatment [22,30]. The symptoms of adrenal insufficiency are nonspecific and include fatigue, anorexia, abdominal pain, nausea, weight loss, hypotension, and hypoglycemia. The appearance of hyponatremia, eosinophilia, and neutropenia suggests the development of adrenal insufficiency. A low morning serum cortisol level despite an elevated plasma ACTH level suggests primary adrenal insufficiency, whereas a low plasma ACTH level suggests secondary adrenal insufficiency. Serum cortisol levels of ≥18 μg/dL are considered to indicate the absence of adrenal dysfunction, while adrenal dysfunction is represented by serum cortisol levels of <4 μg/dL. When the serum cortisol level is ≥4 μg/dL and <18 μg/dL, a rapid ACTH tolerance test or an insulin-hypoglycemia test can confirm the diagnosis [31]. Bilateral adrenal enlargement on abdominal computed tomography (CT) and fluorodeoxyglucose (FDG) uptake in the bilateral adrenal glands on positron emission tomography (PET) have been reported; however, similar findings may be observed in cases of adrenal metastasis, which warrant careful judgment [32]. With regard to the pathogenesis of primary adrenal insufficiency caused by ICI treatment, adrenal autoantibodies have been detected in one case of pembrolizumab-induced adrenal insufficiency, although several points remain to be clarified [31].
