Diagnosis and management of primary bilateral macronodular adrenal hyperplasia

Abstract

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

Frequently asked questions and answers (if any) in patients with adrenal incidentaloma

“…Bilateral adrenal masses, along with cortisol secretion and the documentation of familial cases, suggests a genetic predisposition. Recently, Armadillo repeat containing 5 (ARMC5) mutations have been described in familial cases and in sporadic patients with CS [152,153]. Although ARMC5 mutations reduce the steroid secretory capacity of each cell, the overall cortisol secretion is increased due to massive enlargement of the adrenals [154][155][156].…”

The Potential of Computed Tomography Volumetry for the Surgical Treatment in Bilateral Macronodular Adrenal Hyperplasia: A Case Report

“…However, the procedure also leads to increased surgical mortality compared with unilateral adrenalectomy, and one fifth of patients after bilateral adrenalectomy suffer from Nelson's syndrome or adrenal crisis (Reincke et al 2015;Nagendra et al 2019). In contrast, unilateral adrenalectomy has been reported to lead to remission in more than 90% of BMAH patients with a minimal risk for adrenal insufficiency (Vassiliadi and Tsagarakis 2019). Moreover, recently, a prospective cohort has reported the effectiveness of simultaneous removal of total and partial adrenal glands, so-called adrenal-sparing surgery, with no perioperative complications (Tanno et al 2020).…”

“…However, the utility of CT volumetry remains to be investigated, particularly in BMAH cases harboring pathologically different lesions. Previous reports have shown that BMAH could be concomitant with aldosterone-producing adenomas, pheochromocytomas and also metastasis of non-adrenal origin (Tokumoto et al 2017;Hayakawa et al 2011;Vassiliadi and Tsagarakis 2019). Besides, BMAH is genetically heterogenous and the severity of hypercortisolemia could depend on the genetic causes (Espiard et al 2015;Vassiliadi and Tsagarakis 2019).…”

“…Previous reports have shown that BMAH could be concomitant with aldosterone-producing adenomas, pheochromocytomas and also metastasis of non-adrenal origin (Tokumoto et al 2017;Hayakawa et al 2011;Vassiliadi and Tsagarakis 2019). Besides, BMAH is genetically heterogenous and the severity of hypercortisolemia could depend on the genetic causes (Espiard et al 2015;Vassiliadi and Tsagarakis 2019). Therefore, the concomitant disorders and also the presence of germline mutation may influence the accuracy of the prediction based on CT volumetry.…”

Case Report: Consecutive Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations

“…In contrast, ACTH-independent CS can mainly be attributed to cortisol-producing adrenal adenomas. Adrenocortical carcinomas, uni-/bilateral adrenal hyperplasia, and primary pigmented nodular adrenocortical disease (PPNAD) may account for some of these cases as well ( 3 , 4 ).…”