A case of ACTH-independent macronodular adrenal hyperplasia associated with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant neoplasia syndrome characterized by the occurrence of tumors in the parathyroid glands, pancreas, and anterior pituitary. Approximately 30-40% of MEN1 patients also have adrenal lesions, such as hyperplasia, benign adenoma, and adrenocortical carcinoma. Most of the cases are hormonally silent. We describe the case of a 60-year-old man with bilateral macronodular adrenal lesions, in addition to parathyroid tumors, multiple insulinomas, and non-functioning pituitary microadenoma. Endocrinological tests revealed subclinical hypercortisolism; midnight cortisol level rose slightly (8.0 μg/dL), although basal plasma ACTH and cortisol levels were within the normal range (19.5 pg/mL and 12.0 μg/dL, respectively). One and 8 mg dexamethasone suppression tests showed cortisol levels of 2.3 and 9.8 μg/dL, respectively. (131)I-adosterol scintigraphy under dexamethasone suppression revealed bilateral adrenal uptake with right-sided predominance. The histological features of the removed right adrenal gland were consistent with ACTH-independent macronodular adrenal hyperplasia (AIMAH): immunoreactivity of 17α-hydroxylase was predominantly observed in the small compact cells, while that of 3β-hydroxysteroid dehydrogenase was exclusively expressed in the large clear cells. The glucose-dependent insulinotropic polypeptide (GIP) receptor was expressed at high levels in compact cells, suggesting that GIP is responsible for the development of AIMAH. Unilateral small adrenal lesions were detected in the patient's 2 children, who also presented with MEN1 symptoms. Genetic abnormalities in the MEN1, p27, and p18 genes were not found, however, the present case may provide a clue to the understanding of the etiology of MEN1 and AIMAH.