In primary aldosteronism (PA), two subtypes are distinguished: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). In general, these are treated by adrenalectomy (ADX) and ...mineralocorticoid receptor antagonists (MRA), respectively.
To compare the effects of surgical treatment and medical treatment on quality of life (QoL).
Post hoc comparative effectiveness study within the Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan (SPARTACUS) trial.
Twelve Dutch hospitals and one Polish hospital.
Patients with PA (n = 184).
ADX or MRAs.
At baseline and 6-month and 1-year follow-up, we assessed QoL by two validated questionnaires: RAND 36-Item Health Survey 1.0 (RAND SF-36) and European Quality of Life-5 Dimensions (EQ-5D).
At baseline, seven of eight RAND SF-36 subscales and both summary scores, as well as three of five EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women. The beneficial effects of ADX were larger than for MRAs for seven RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, we detected a difference in favor of ADX in two dimensions and the visual analog scale. Most differences in QoL between both treatments exceeded the minimally clinically important difference. After 1 year, almost all QoL measures had normalized for adrenalectomized patients. For patients on medical treatment, most QoL measures had improved but not all to the level of the general population.
Both treatments improve QoL in PA, underscoring the importance of identifying these patients. QoL improved more after ADX for suspected APA than after initiation of medical treatment for suspected BAH.
Abstract
Context
Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the ...management of PA patients.
Objectives
To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS.
Design and settings
In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes.
Results
AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria.
Conclusion
Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020)
At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were ...reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling cortisol-secreting cells of the adrenal zona fasciculata but are absent in a subset of APAs resembling the aldosterone-secreting cells of the adrenal zona glomerulosa. We performed exome sequencing of ten zona glomerulosa-like APAs and identified nine with somatic mutations in either ATP1A1, encoding the Na(+)/K(+) ATPase α1 subunit, or CACNA1D, encoding Cav1.3. The ATP1A1 mutations all caused inward leak currents under physiological conditions, and the CACNA1D mutations induced a shift of voltage-dependent gating to more negative voltages, suppressed inactivation or increased currents. Many APAs with these mutations were <1 cm in diameter and had been overlooked on conventional adrenal imaging. Recognition of the distinct genotype and phenotype for this subset of APAs could facilitate diagnosis.
Differentiating patients with primary aldosteronism caused by aldosterone-producing adenomas (APAs) from those with bilateral adrenal hyperplasia (BAH), which is essential for choice of therapeutic ...intervention, relies on adrenal venous sampling (AVS)-based measurements of aldosterone and cortisol. We assessed the utility of LC-MS/MS-based steroid profiling to stratify patients with primary aldosteronism.
Fifteen adrenal steroids were measured by LC-MS/MS in peripheral and adrenal venous plasma from AVS studies for 216 patients with primary aldosteronism at 3 tertiary referral centers. Ninety patients were diagnosed with BAH and 126 with APAs on the basis of immunoassay-derived adrenal venous aldosterone lateralization ratios.
Among 119 patients confirmed to have APAs at follow-up, LC-MS/MS-derived lateralization ratios of aldosterone normalized to cortisol, dehydroepiandrosterone, and androstenedione were all higher (P < 0.0001) than immunoassay-derived ratios. The hybrid steroids, 18-oxocortisol and 18-hydroxycortisol, also showed lateralized secretion in 76% and 35% of patients with APAs. Adrenal venous concentrations of glucocorticoids and androgens were bilaterally higher in patients with BAH than in those with APAs. Consequently, peripheral plasma concentrations of 18-oxocortisol were 8.5-fold higher, whereas concentrations of cortisol, corticosterone, and dehydroepiandrosterone were lower in patients with APAs than in those with BAH. Correct classification of 80% of cases of APAs vs BAH was thereby possible by use of a combination of steroids in peripheral plasma.
LC-MS/MS-based steroid profiling during AVS achieves higher aldosterone lateralization ratios in patients with APAs than immunoassay. LC-MS/MS also enables multiple measures for discriminating unilateral from bilateral aldosterone excess, with potential use of peripheral plasma for subtype classification.
Abstract
The mineralocorticoid receptor (MR) is a member of the nuclear receptor steroid-binding family. The classical MR ligand aldosterone controls electrolyte and fluid homeostasis after binding ...in renal epithelial cells. However, more recent evidence suggests that activation of extrarenal MRs by aldosterone negatively impacts cardiovascular health independent of its effects on blood pressure: high levels of aldosterone associate with an increased cardiovascular event rate, where MR antagonists exert beneficial effects on cardiovascular mortality. The most important cause for cardiovascular events is atherosclerosis that is currently considered a low-grade inflammatory disorder of the arterial wall. In this inflammatory process, the innate immune system plays a deciding role, with the monocyte-derived macrophage being the most abundant cell in the atherosclerotic plaque. Intriguingly, both monocytes and macrophages express the MR, and a growing body of evidence shows that these cells are skewed into a pro-inflammatory and pro-atherosclerotic phenotype via MR stimulation. In this review, we detail the current perspective on the role of the monocyte and macrophage MR in atherosclerosis development and provide a comprehensive framework of the effects of MR activation of the innate immune system that might drive the pro-atherosclerotic outcome.
Context:
In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically ...challenging, difficult to interpret, and commonly held to be risky.
Objective:
The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers.
Design and Settings:
The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide.
Participants:
Eligible centers were identified from those that had published on PA and/or AVS in the last decade.
Main Outcome Measure:
The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS.
Results:
Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19–100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007).
Conclusions:
Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.
•LC–MS/MS based quantification of 15 steroids in peripheral and adrenal venous samples.•Sensitivity sufficient for reliable aldosterone measurements in peripheral plasma.•Utility for clinical work-up ...of primary aldosteronism due to included hybrid steroids.•AV/pV step-ups for most other steroids higher than for cortisol.•Cosyntropin stimulation during AVS changes relative adrenal secretion of steroid.
Steroid profiling for diagnosis of endocrine disorders featuring disordered production of steroid hormones is now possible from advances in liquid chromatography with tandem mass spectrometry (LC–MS/MS). Adrenal venous (AV) measurements of aldosterone and cortisol are a standard practice in the clinical work-up of primary aldosteronism, but do not yet take advantage of steroid profiling.
A novel LC–MS/MS based method was developed for simultaneous measurement of 15 adrenal steroids: aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, pregnenolone, cortisone, cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, 21-deoxycortisol, 18-oxocortisol and 18-hydroxycortisol. These were compared in peripheral venous (pV) and AV plasma from 70 patients undergoing AV sampling with and without cosyntropin stimulation. Aldosterone and cortisol levels measured by LC–MS/MS were compared with those measured by immunoassay.
Reproducibility of measurements with coefficients of variation ≤10% as well as analytical sensitivity sufficient to measure low pV levels particularly of aldosterone demonstrate the utility of the assay for profiling adrenal steroids in primary aldosteronism. Method comparisons indicated assay and concentration dependent differences of cortisol and aldosterone concentrations measured by immunoassay and LC–MS/MS. Median AV/pV ratios of 11-deoxycortisol (53.0), 17-hydroxyprogesterone (33.4), pregnenolone (62.4), androstenedione (40.6) and dehydroepiandrosterone (33.3) were 2.9- to, 5.4-fold larger than those for cortisol (11.6), with additionally generally larger increases than for cortisol with than without cosyntropin stimulation.
Our LC–MS/MS assay, in addition to improvements over existing immunoassay measurements of aldosterone and cortisol, offers profiling of 13 other adrenal steroids, providing a potentially useful method for the clinical work-up of patients with primary aldosteronism. In particular, the larger AV/pV ratios of several steroids compared to cortisol suggest more sensitive alternatives to the latter for assessing positioning of AV sampling catheters.
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