Cushing´s syndrome due to bilateral adrenal cortical disease: Bilateral macronodular adrenal cortical disease and bilateral micronodular adrenal cortical disease

Abstract

Cushing´s syndrome (CS) secondary to bilateral adrenal cortical disease may be caused by bilateral macronodular adrenal cortical disease (BMACD) or by bilateral micronodular adrenal cortical disease (miBACD). The size of adrenal nodules is a key factor for the differentiation between these two entities (>1cm, BMACD and <1cm; miBACD). BMACD can be associated with overt CS, but more commonly it presents with autonomous cortisol secretion (ACS). Surgical treatment of BMACD presenting with CS or with ACS and associated cardiometabolic comorbidities should be the resection of the largest adrenal gland, since it leads to hypercortisolism remission in up to 95% of the cases. Medical treatment focused on the blockade of aberrant receptors may lead to hypercortisolism control, although cortisol response is frequently transient. miBACD is mainly divided in primary pigmented nodular adrenocortical disease (PPNAD) and isolated micronodular adrenocortical disease (i-MAD). miBACD can present at an early age, representing one of the main causes of CS at a young age. The high-dose dexamethasone suppression test can be useful in identifying a paradoxical increase in 24h-urinary free cortisol, that is a quite specific in PPNAD. Bilateral adrenalectomy is generally the treatment of choice in patients with overt CS in miBACD, but unilateral adrenalectomy could be considered in cases with asymmetric disease and mild hypercortisolism. This article will discuss the clinical presentation, genetic background, hormonal and imaging features and treatment of the main causes of primary bilateral adrenal hyperplasia associated with hypercortisolism.

Clinical Characteristics and Long-Term Outcomes of Adrenal Tumors in Children and Adolescents

“…I-MAD is composed of multiple small adrenocortical nodules ( < 1 cm), which produce cortisol [5]. Genetic defects in PRKACA are one of the main causes [37]. In the human adrenal glands, PRKACA encodes the catalytic protein kinase A isoform, and activating mutations of PRKACA increase the activities of protein kinase A and its downstream target, cAMP response element-binding protein (CREB) [37].…”

“…Genetic defects in PRKACA are one of the main causes [37]. In the human adrenal glands, PRKACA encodes the catalytic protein kinase A isoform, and activating mutations of PRKACA increase the activities of protein kinase A and its downstream target, cAMP response element-binding protein (CREB) [37]. Recently, germline mutations in PDE11A [38] and PDE8B [39] have been described in a few patients with i-MAD.…”

Subtyping of Cushing’s Syndrome: A Step Ahead

“…A Unilateral adrenal adenoma is the main cause of ACTH-independent CS; it can be associated with alterations of cAMP-dependent or β-catenin pathways [69]. PBMAH is rare and characterized by multiple bilateral adrenal nodules > 10 mm in diameter, usually sporadic or sometimes familial [70,71]. Steroidogenesis is dysregulated in PBMAH: the aberrant expression of ectopic and/or eutopic G-protein coupled receptors combined with autocrine non-CRHdependent ACTH secretion (gastric inhibitory polypeptide, β-adrenergic ligands, 5-hydroxytryptamine, luteinizing hormone , and antidiuretic hormone) [72] enables cortisol secretion.…”

Steroid profiling using liquid chromatography mass spectrometry during adrenal vein sampling in patients with primary bilateral macronodular adrenocortical hyperplasia

“…Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a benign neoplastic disorder characterized by multiple nodules ≥ 10mm in diameter on both adrenals. The clinical presentation is variable, ranging from asymptomatic to overt symptoms of Cushing's Syndrome (CS), and less commonly mineralocorticoid and/or androgens excess (1)(2)(3). This high heterogeneity and lack of specific symptoms renders PBMAH difficult to identify, and criteria for medical treatment or adrenalectomy still remain to be established.…”