Aldosterone-producing adenoma and other surgically correctable forms of primary aldosteronism

Amar, Laurence; Plouin, Pierre‐François; Steichen, Olivier

doi:10.1186/1750-1172-5-9

Cited by 68 publications

(44 citation statements)

References 83 publications

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“…8 In recent years, major advances in the knowledge of the genetic basis of APA development have been made. The activation of the calcium signaling pathway is central for the regulation of aldosterone production, in particular by increasing the expression of CYP11B2, encoding aldosterone synthase.…”

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Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

et al. 2014

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A rterial hypertension is a major cardiovascular risk factor that affects 10% to 40% of the adult population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of ≈10% in referred patients and 4% in primary care but as high as 20% in patients with resistant hypertension. [1][2][3][4][5] PA is caused by the excessive production of aldosterone from the adrenal cortex, resulting in hypertension associated with high plasma aldosterone levels, low plasma renin activity, and varying degrees of hypokalemia and metabolic alkalosis. Long-term consequences include an increased risk of myocardial infarction, stroke, and atrial fibrillation. 6,7 Abstract-Primary aldosteronism is the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been described in aldosterone-producing adenomas (APAs). Our aim was to investigate the prevalence of somatic mutations in these genes in unselected patients with APA (n=474), collected through the European Network for the Study of Adrenal Tumors. Correlations with clinical and biochemical parameters were first analyzed in a subset of 199 patients from a single center and then replicated in 2 additional centers. Somatic heterozygous KCNJ5 mutations were present in 38% (180/474) of APAs, whereas ATP1A1 mutations were found in 5.3% (25/474) and ATP2B3 mutations in 1.7% (8/474) of APAs. Previously reported somatic CACNA1D mutations as well as 10 novel CACNA1D mutations were identified in 44 of 474 (9.3%) APAs. There was no difference in the cellular composition of APAs or in CYP11B2, CYP11B1, KCNJ5, CACNA1D, or ATP1A1 gene expression in APAs across genotypes. Patients with KCNJ5 mutations were more frequently female, diagnosed younger, and with higher minimal plasma potassium concentrations compared with CACNA1D mutation carriers or noncarriers. CACNA1D mutations were associated with smaller adenomas. These associations were largely dependent on the population structure of the different centers. In conclusion, recurrent somatic mutations were identified in 54% of APAs. Young women with APAs are more likely to be KCNJ5 mutation carriers; identification of specific characteristics or surrogate biomarkers of mutation status may lead to 12 Mutations in KCNJ5 and ATP1A1 affect adrenal ZG cell membrane potential and intracellular ionic homeostasis, with chronic depolarization leading to opening of voltage-dependent calcium channels and activation of calcium signaling and aldosterone production. 10,12,13 Finally, somatic mutations in the CACNA1D encoding the Ca v 1.3 channel (calcium channel, voltage dependent, L type, α-1d subunit) have been identified in APA. The altered residues are located in particular segments bordering the channel pore.14,15 These changes result in channel activation and opening at lower voltages, leading, l...

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Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

et al. 2014

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“…Indeed, the screening and confirmatory procedures varied among centers, with different criteria used for selecting the patients for adrenalectomy. 10,13,[25][26][27] These differences cover the clinical and diagnostic spectrum of PA and, thus, provide a reliable estimate of the true prevalence of KCNJ5 mutations in APA. The frequency of KCNJ5 mutations was found to be higher in patients selected on more conservative criteria (Table 3); together with the younger age and higher aldosterone levels at diagnosis, this suggests that KCNJ5 mutations may be associated with a more florid phenotype.…”

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Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism

et al. 2012

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Abstract-Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, nϭ380) and peripheral (APA, nϭ344; bilateral adrenal hyperplasia, nϭ174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; PϽ10 Ϫ3) and in younger patients (42.1Ϯ1.0 versus 47.6Ϯ0.7 years; PϽ10 Ϫ3 ) and were associated with higher preoperative aldosterone levels (455Ϯ26 versus 376Ϯ17 ng/L; Pϭ0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. H ypertension is a major cardiovascular risk factor that affects between 10% and 40% of the population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows for the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence between 6% and 12% of hypertensives and as high as 20% in patients with resistant hypertension. 1-5 PA occurs as the result of a dysregulation of the mechanisms controlling adrenal aldosterone production, ultimately leading to hypertension with low plasma renin and elevated aldosterone sometimes associated with hypokalemia. Among subtypes of PA, aldosteroneproducing adenoma (APA) and bilateral adrenal hyperplasia (BAH; also known as idiopathic hyperaldosteronism) together account for Ϸ95% of cases. [1][2][3] Aldosterone production from the adrenal zona glomerulosa is tightly controlled to maintain electrolyte and fluid homeostasis by the kidney. Thus, the two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Glomerulosa cell membrane depolarization leads to openi...

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“…1,2 Localizing the source of excessive aldosterone secretion is critical to select the appropriate therapy. Unilateral PA can be treated by laparoscopic adrenalectomy, which normalizes serum potassium concentrations in almost all cases and cures or improves hypertension in >80% of patients.…”

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Influence of Diagnostic Criteria on the Interpretation of Adrenal Vein Sampling

et al. 2015

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P atients with primary aldosteronism (PA) have either bilateral (idiopathic hyperplasia) or unilateral (aldosterone-producing adenoma or unilateral hyperplasia) adrenal disease. 1,2 Localizing the source of excessive aldosterone secretion is critical to select the appropriate therapy. Unilateral PA can be treated by laparoscopic adrenalectomy, which normalizes serum potassium concentrations in almost all cases and cures or improves hypertension in >80% of patients.3,4 By contrast, medical management with mineralocorticoid receptor antagonists is recommended as the first-line treatment in bilateral PA. 5Adrenal vein sampling (AVS) is currently considered the gold standard to differentiate unilateral from bilateral aldosterone hypersecretion and is recommended in almost all patients with PA who are eligible for surgical management. 5,6 The accuracy of catheter placement in the adrenal veins can be verified from the cortisol concentration in the adrenal veins divided by that in the inferior vena cava or a peripheral vein (selectivity index [SI]). If the SI reaches the predefined cut-off, the lateralization index (LI) is then used to classify PA into unilateral or bilateral disease. The LI is defined as the highest aldosterone/ cortisol concentration ratio (dominant adrenal vein) divided by the lowest aldosterone/cortisol concentration ratio (nondominant adrenal vein). Some investigators also propose the use of the contralateral suppression index, defined by the aldosterone/ cortisol concentration ratio of the nondominant adrenal vein divided by the peripheral aldosterone/cortisol concentration ratio.7 However, the protocol of AVS (simultaneous or sequential bilateral AVS, use of cosyntropin or not, and the protocol of cosyntropin infusion) and the SI and LI cut-offs used to interpret the results are not currently standardized. 7-9We have interpreted a large number of AVS procedures with criteria used in 4 reference centers or proposed by a recent consensus statement. 6,[10][11][12] The first objective of this study was to examine to which extent the interpretation of AVS may differ according to the criteria used for its interpretation. The second goal was to assess the reproducibility of this interpretation when multiple blood samples were drawn from the same adrenal vein. Methods PatientsThis retrospective study included all patients who underwent AVS in our hypertension referral center between January 2001 and July Abstract-Guidelines promote the use of adrenal vein sampling (AVS) to document lateralized aldosterone hypersecretion in primary aldosteronism. However, there are large discrepancies between institutions in the criteria used to interpret its results. This study evaluates the consequences of these differences on the classification and management of patients. The results of all 537 AVS procedures performed between January 2001 and July 2010 in our institution were interpreted with 4 diagnostic criteria used in experienced institutions where AVS is performed without cosyntropin (Brisbane, Padua, Paris, an...

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Aldosterone-producing adenoma and other surgically correctable forms of primary aldosteronism

Cited by 68 publications

References 83 publications

Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

Genetic Spectrum and Clinical Correlates of Somatic Mutations in Aldosterone-Producing Adenoma

Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism

Influence of Diagnostic Criteria on the Interpretation of Adrenal Vein Sampling

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