Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas

Abstract

P rimary aldosteronism (PA) is the leading cause of secondary hypertension with a prevalence of 4.3% in the general hypertensive population and 9.5% of patients referred to hypertension units. 1 The diagnosis of PA is fundamental because these patients are at an increased risk of cardiovascular and cerebrovascular complications and metabolic syndrome compared with patients with primary hypertension and similar cardiovascular risk profiles. [2][3][4][5] The underlying cause of PA in the majority of patients is either bilateral adrenal hyperplasia (BAH, also called idiopathic hyperaldosteronism) or unilateral aldosterone-producing adenoma (APA). These subtypes must be differentiated to permit a targeted therapeutic strategy: surgical removal of APA or pharmacological treatment of BAH with mineralocorticoid receptor antagonists. Adrenal venous sampling (AVS) is the gold standard to localize the source of aldosterone excess and to discriminate between unilateral and bilateral forms of the disease. However, AVS is a technically demanding and invasive procedure requiring a dedicated radiologist. The reliable differentiation of APA and BAH by an alternative technique could potentially circumvent the requirement of AVS in patients with BAH that account for around two thirds of all cases of PA. 6 Subsequently, for the APA subtype, both clinician and patient would be highly motivated to perform/undergo AVS to confirm unilateral PA and define the side of aldosterone excess before adrenalectomy.Somatic mutations have been identified in APA in 4 genes (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) to date that all lead to an increase in constitutive aldosterone production. 7 In a large European study, the combined prevalence of APA mutations in these 4 genes was found to be 54% with 38% Abstract-Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography-tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. 9 Intriguingly, mutations in ATP1A1, ATP2B3, and CACNA1D that stimulate aldosterone production have been identified recently in aldosterone-producing cell clusters of normal adrenal glands from kidney donors; in contrast, mutations in KCNJ5 were not detected. 10In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma samples ...

Mass Spectrometry–Based Adrenal and Peripheral Venous Steroid Profiling for Subtyping Primary Aldosteronism

“…Although we could not establish similar utility in the present study, we could confirm 8.5-fold higher peripheral venous plasma concentrations of 18-oxocortisol in patients with APAs than BAH, a finding also consistent with earlier studies (25,26,37 ). We have also established elsewhere that increases in plasma 18-oxocortisol among patients with APAs are particularly prominent and largely confined to tumors with somatic KCNJ5 (potassium channel, inwardly rectifying subfamily J, member 5) mutations (39 ). In earlier work, Gordon et al established that increases of 18-oxocortisol are largely confined to patients with angiotensin-unresponsive APAs (38 ).…”

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma

“…[16][17][18][19][20] An interesting novel approach consists of the measurement of a selected steroid profile by mass spectrometry. 21,22 Nevertheless, additional diagnostic steps will be needed to localize potential APA.…”

Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance

“…These results indicate that the peripheral level of 18oxoF, which is significantly affected by APA secretion, can be a clinically useful biomarker not only to differentiate APA from BHA but also to avoid unnecessary surgery for non-functioning adrenocortical nodules concurrent with hyperplasia or microadenoma . However, Williams et al (2016) demonstrated that the 18oxoF concentration in APA cases with KCNJ5 mutations was 18-and 16-fold higher in lateralized adrenal veins and peripheral vein plasma, respectively, compared with that in APA cases with other mutations (ATP1A1, ATP2B3, and CACNA1D). The cause of the upregulation of 18oxoF synthesis in APA cases remains unclear.…”