Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Nishimoto, Katsutaro; Tomlins, Scott A.; Kuick, Rork; Cani, Andi K.; Giordano, Thomas J.; Hovelson, Daniel H.; Liu, Chia Jen; Sanjanwala, Aalok R.; Edwards, Michael A.; Gómez-Sánchez, Celso E.; Nanba, Kazutaka; Rainey, William E.

doi:10.1073/pnas.1505529112

Cited by 262 publications

(270 citation statements)

References 47 publications

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“…Mechanisms responsible for such aldosterone gradient in the adrenal vein in non-PA patients remain to be elucidated. Whether aldosterone-producing cell clusters with CYP11B2 expression 26,27 has a pathological significance in the higher side of adrenal in these 8 patients requires further investigation. The aldosterone gradient in the gray zone (LI=2-4) should be carefully interpreted in the subtype diagnosis of PA to avoid inappropriate adrenalectomy.…”

Section: Discussionmentioning

confidence: 99%

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

et al. 2016

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Adrenal venous sampling is considered to be the most reliable diagnostic procedure to lateralize aldosterone excess in primary aldosteronism (PA). However, normative criteria have not been established partially because of a lack of data in non-PA hypertensive patients. The aim of the study was to investigate aldosterone concentration and its gradient in the adrenal vein of non-PA hypertensive patients. We retrospectively studied the results of cosyntropin-stimulated adrenal venous sampling in 40 hypertensive patients who showed positive screening testing but negative results in 2 confirmatory tests/captopril challenge test and saline infusion test. Plasma aldosterone concentration, aldosterone/cortisol ratio, its higher/lower ratio (lateralization index) in the adrenal vein with cosyntropin stimulation were measured. Median plasma aldosterone concentration in the adrenal vein was 25 819 pg/mL (range, 5154–69 920) in the higher side and 12 953 (range, 1866–36 190) pg/mL in the lower side ( P <0.001). There was a significant gradient in aldosterone/cortisol ratio between the higher and the lower sides (27.2 [5.4–66.0] versus 17.3 [4.0–59.0] pg/mL per μg/dL; P <0.001) with lateralization index ranging from 1.01 to 3.87. The aldosterone lateralization gradient was between 1 to 2 in 32 patients and 2 to 4 in 8 patients. None of the patients showed lateralization index ≥4. The present study demonstrated that plasma aldosterone concentration in the adrenal veins showed significant variation and lateralization gradient even in non-PA hypertensive patients. Adrenal venous sampling aldosterone lateralization gradients between 2 and 4 should be interpreted with caution in patients with PA because these gradients can be found even in patients with negative confirmatory testing for PA.

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Section: Discussionmentioning

confidence: 99%

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

et al. 2016

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“…Among blacks in the Jackson Heart Study,6 aldosterone was positively associated with insulin resistance, while higher levels of aldosterone across the spectrum were associated with a dose‐dependent higher risk of the development of type 2 diabetes mellitus over 8 years. Recent observations demonstrate that aldosterone can be produced autonomously from aldosterone producing cell clusters within morphologically normal adrenal glands with a large spectrum and high prevalence of subclinical aldosteronism 7, 8, 9. Thus, we examined the association of aldosterone and PRA with glucose metabolism and incident diabetes mellitus across the spectrum of aldosterone levels in a multiethnic cohort to determine if there are racial/ethnic differences.…”

Section: Introductionmentioning

confidence: 99%

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

Joseph

Tcheugui

Effoe

et al. 2018

JAHA

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BackgroundMechanistic studies suggest that aldosterone impairs glucose metabolism. We investigated the cross‐sectional associations of aldosterone and plasma renin activity with fasting plasma glucose, insulin resistance (IR), β‐cell function, and longitudinal association with incident diabetes mellitus among adults in MESA (the multiethnic study of atherosclerosis) prospective cohort study.Methods and ResultsHomeostatic model assessment of IR (HOMA2‐IR) and HOMA2‐β were used to estimate IR and β‐cell function, respectively. Incident diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL or anti‐diabetic medication use at follow‐up. Linear regression was used to examine cross‐sectional associations of aldosterone with fasting plasma glucose, HOMA2‐IR and HOMA2‐β; Cox regression was used to estimate hazard ratios (HR) for incident diabetes mellitus with multivariable adjustment. There were 116 cases of incident diabetes mellitus over 10.5 years among 1570 adults (44% non‐Hispanic white, 13% Chinese American, 19% Black, 24% Hispanic American, mean age 64±10 years, 51% female). A 100% increase in log‐aldosterone was associated with a 2.6 mg/dL higher fasting plasma glucose, 15% higher HOMA2‐IR and 6% higher HOMA2‐β (P<0.01). A 1‐SD increase in log‐aldosterone was associated with a 44% higher risk of incident diabetes mellitus (P<0.01) with the greatest increase of 142% (P<0.01) observed in Chinese Americans (P for interaction=0.09 versus other ethnicities). Similar cross‐sectional findings for log‐plasma renin activity existed, but log‐plasma renin activity was not associated with incident diabetes mellitus after full adjustment.ConclusionsAldosterone is associated with glucose homeostasis and diabetes mellitus risk with graded associations among Chinese Americans and blacks, suggesting that pleiotropic effects of aldosterone may represent a modifiable mechanism in diabetes mellitus pathogenesis with potential racial/ethnic variation.

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“…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. 10 In 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 in PA patients with confirmed lateralization of aldosterone production. Our aim was to identify distinct steroid fingerprints associated with APA genotype that could potentially have a wider clinical application for the selection of unilateral patients with PA to undergo AVS.…”

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Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas

et al. 2016

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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 ...

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Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands

Cited by 262 publications

References 47 publications

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

Adrenal Venous Sampling in Patients With Positive Screening but Negative Confirmatory Testing for Primary Aldosteronism

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

Genotype-Specific Steroid Profiles Associated With Aldosterone-Producing Adenomas

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