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.

Keywords: Cushing´s syndrome; adrenalectomy; bilateral macronodular adrenal cortical disease; bilateral micronodular adrenal cortical disease; primary pigmented nodular adrenocortical disease.

Figure 1

Pathophysiology of bilateral macronodular adrenal cortical disease and bilateral micronodular adrenal cortical disease In normal adrenocortical cells, the MC2R receptor is activated by ACTH, leading to the activation of the G subunits of the latter activates the adenylate cyclase, which converts the ATP in cAMP. The phosphodiesterases (PDE) inactivates cAMP in AMP. cAMP is binding by the regulatory (R) subunits of the PKA, leading to the release of the catalytic (C) subunits. The catalytic subunits phosphorylate their targets, including the cAMP Response Element-Binding protein (CREB), which activates genes involved in steroidogenesis. ARMC5 blocks the cell cycle in G1 phase and induces apoptosis. (A) In BMACD, the PKA pathway is activated by a ACTH locally produced by clusters of corticotropin adrenal cells, b mutations in the gene coding for MC2R, c mutations in gene GNAS, d mutations in phosphodiesterase genes, e duplication of the catalytic subunit C, and f ARMC5 mutations, which lead to the activation of the cell cycle and the loss of apoptosis. (B) In PPNAD and iMAD, the PKA pathway is activated by (a2) mutations in the regulatory subunit R of PKA and (b2) mutations in phosphodiesterases genes, and (c2) duplication of the catalytic subunit.

Figure 2

Radiological appearance of BMACD in the unenhanced CT and MRI. Unenhanced CT shows bilateral adrenal hyperplasia secondary to the existence of several well-defined, confluent nodular lesions (A1), with negative density values in the non-contrast CT, compatible with lipid-rich adenomas (A2). In MRI, axial (B1) and coronal (B2) sections, there are a right nodular conglomerate of 46x19x29 mm, and in the left adrenal gland 2 nodules of 34x17 mm and 26x21 mm, compatible with adenomas.

Figure 3

Protocol for the study of aberrant receptors in patients with adrenal Cushing´s syndrome. The study of aberrant receptors may be carried out in four consecutive or not-consecutive days. A change of < 25% of the cortisol level is considered as no response; a change between 25-49% as a partial response and a change ≥50% as a complete positive response to the test. Mixed standard food test consists in the administration of a mixed standard meal (450 calories, 46% of carbohydrates, 32% of lipids and 22% of proteins) and the measured of serum cortisol after 60 minutes of the ingestion and then every hour until complete 180 minutes. In the wandering test, the patient must walk for 2 hours, and then serum cortisol is measured every 30 minutes until complete 240 minutes.