scholarly journals Update on Genetics of Primary Aldosteronism

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 409
Author(s):  
Kiyotaka Itcho ◽  
Kenji Oki ◽  
Haruya Ohno ◽  
Masayasu Yoneda
Keyword(s):  
Genetic Analysis ◽  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Secondary Hypertension ◽  
Voltage Gated ◽  
Intracellular Calcium Signaling ◽  
Recent Developments ◽  
Aldosterone Producing Adenoma ◽  
Idiopathic Hyperaldosteronism ◽  
Ca2 Channels

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5–10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, and CTNNB1 in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca2+ channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.

scholarly journals Is it Possible to Extirpate Cardiovascular Events in Primary Aldosteronism after Surgical Treatment

2010 ◽  
Vol 1 ◽  
pp. JCM.S6316 ◽  
Author(s):  
Tetsuo Nishikawa ◽  
Yoko Matsuzawa ◽  
Jun Saito ◽  
Masao Omura
Keyword(s):  
Surgical Treatment ◽  
Primary Aldosteronism ◽  
Secondary Hypertension ◽  
Adrenal Venous Sampling ◽  
Venous Sampling ◽  
Partial Adrenalectomy ◽  
Aldosterone Producing Adenoma ◽  
Idiopathic Hyperaldosteronism ◽  
Micro Catheter ◽  
Indication For Treatment

It is well known that primary aldosteronism (PA) due to aldosterone-producing adenoma (APA) is a surgically curable secondary hypertension. Thus, the differential diagnosis between unilateral hyperaldosteronemia due to APA and bilateral hyperaldosteronemia due to idiopathic hyperaldosteronism (IHA) is crucial to decide surgical indication for treatment in PA patients. Adrenal venous sampling (AVS) can diagnose the laterality of hypersecretion of aldosterone in those patients, while it is still impossible to differentiate bilateral hypersecretion of bilateral aldosterone-producing adenomas (Blt-APAs) from that of bilateral hyperplasia of IHA. To solve the problem, we try to develop a new method of supper-selective ACTH-stimulated adrenal venous sampling (SS-ACTH-AVS). We performed SS-ACTH-AVS by using a strip-tip type 2.2 Fr micro-catheter (Koshin Medical Inc. Japan). Adrenal effluents were sampled super-selectively at the central veins and at one or two tributaries of adrenal veins in each gland. We would like to emphasize that SS-ACTH-AVS can precisely analyze the situation of hyperfunction of steroidogenesis in each side of adrenals as well as in some tiny lesions inside the adrenal cortex which are not visible in the CT images. Moreover, we can differentiate Blt-APAs from IHA, and postulate the decision of surgical treatment, such as partial adrenalectomy. Thus, we should perform SS-ACTH-AVS especially in the case demonstrating the existence of bilateral adrenal lesions such as unilateral and bilateral tumors, or even no tumor in both sides in the patients with PA.

scholarly journals Masking by hypokalemia—primary aldosteronism with undetectable aldosterone

2020 ◽  
Author(s):  
Rebecca A Boyle ◽  
Jessica E Baker ◽  
Vivek Charu ◽  
William E Rainey ◽  
Vivek Bhalla
Keyword(s):  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Secondary Hypertension ◽  
Extracellular Potassium ◽  
Genetic Studies ◽  
Dynamic Regulation ◽  
Potassium Supplementation ◽  
Potassium Regulation ◽  
Aldosterone Producing Adenoma

Abstract Primary aldosteronism is the most common cause of secondary hypertension; however, the dynamic regulation of aldosterone by potassium is less well studied and current diagnostic recommendations are imprecise. We describe a young man who presented with resistant hypertension and severe hypokalemia. The workup initially revealed undetectable aldosterone despite acute potassium repletion. Chronic potassium supplementation eventually uncovered hyperaldosteronism. In situ genetic studies revealed a gain-of-function KCNJ5 mutation within an aldosterone-producing adenoma that was clinically responsive to changes in extracellular potassium. We highlight a unique presentation of Conn’s syndrome and discuss the implications for the molecular mechanisms of potassium regulation of aldosterone.

scholarly journals Genetic causes of primary aldosteronism

2019 ◽  
Vol 51 (11) ◽  
pp. 1-12 ◽  
Author(s):  
Eric Seidel ◽  
Julia Schewe ◽  
Ute I. Scholl
Keyword(s):  
Calcium Channel ◽  
Primary Aldosteronism ◽  
Secondary Hypertension ◽  
Driver Mutations ◽  
Adrenal Steroid ◽  
Voltage Gated ◽  
Familial Hyperaldosteronism ◽  
A Subunit ◽  
Idiopathic Hyperaldosteronism ◽  
Voltage Gated Calcium Channel

Abstract Primary aldosteronism is characterized by at least partially autonomous production of the adrenal steroid hormone aldosterone and is the most common cause of secondary hypertension. The most frequent subforms are idiopathic hyperaldosteronism and aldosterone-producing adenoma. Rare causes include unilateral hyperplasia, adrenocortical carcinoma and Mendelian forms (familial hyperaldosteronism). Studies conducted in the last eight years have identified somatic driver mutations in a substantial portion of aldosterone-producing adenomas, including the genes KCNJ5 (encoding inwardly rectifying potassium channel GIRK4), CACNA1D (encoding a subunit of L-type voltage-gated calcium channel CaV1.3), ATP1A1 (encoding a subunit of Na+/K+-ATPase), ATP2B3 (encoding a Ca2+-ATPase), and CTNNB1 (encoding ß-catenin). In addition, aldosterone-producing cells were recently reported to form small clusters (aldosterone-producing cell clusters) beneath the adrenal capsule. Such clusters accumulate with age and appear to be more frequent in individuals with idiopathic hyperaldosteronism. The fact that they are associated with somatic mutations implicated in aldosterone-producing adenomas also suggests a precursor function for adenomas. Rare germline variants of CYP11B2 (encoding aldosterone synthase), CLCN2 (encoding voltage-gated chloride channel ClC-2), KCNJ5, CACNA1H (encoding a subunit of T-type voltage-gated calcium channel CaV3.2), and CACNA1D have been reported in different subtypes of familial hyperaldosteronism. Collectively, these studies suggest that primary aldosteronism is largely due to genetic mutations in single genes, with potential implications for diagnosis and therapy.

Abstract 12591: Impact of Aldosterone Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Takeshi Matsumoto ◽  
Yukihito Higashi ◽  
Nozomu Oda ◽  
Akimichi Iwamoto ◽  
Yumiko Iwamoto ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Primary Aldosteronism ◽  
Vascular Function ◽  
Cardiovascular Events ◽  
Plasma Renin ◽  
Secondary Hypertension ◽  
Plasma Aldosterone Concentration ◽  
Significant Difference ◽  
Aldosterone Producing Adenoma ◽  
Rock Activity

Background: Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs) activity. Primary aldosteronism (PA) is a most common cause of secondary hypertension. Recent studies have shown that risk of cardiovascular events is higher in patients with PA than in patients with essential hypertension (EH). However, there is little information on the relationship between subtype of PA and the grade of atherosclerosis. The purpose of this study was to evaluate the vascular function and ROCK activity in patients with PA. Methods: Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone producing adenoma (APA) group (50.7±14.3 years, 9 males), 23 patients with idiopathic hyperaldosteronism (IHA) group (55.8±9.9 years, 12 males), and 33 age-, gender-, and blood pressure-matched EH group (54.9 ± 10.7 years, 18 males). Results: FMD was significantly lower in the APA group than in the IHA group and EH group (3.2±2.0% vs. 4.6±2.3% and 4.4±2.2%, P<0.05, respectively), whereas there was no significant difference in FMD between the IHA group and EH group. There was no significant difference in the response of nitroglycerine in three groups. ROCK activity was significantly higher in the APA group than in the IHA group and EH group (1.29±0.57 vs. 1.00±0.46 and 0.81±0.36, P<0.05 and P<0.001, respectively), whereas there was no significant difference in ROCK activity between the IHA group and EH group. FMD correlated with age (r=-0.31, P<0.01), brachial arterial diameter (r=-0.44, P<0.01), plasma aldosterone concentration (PAC) (r=-0.35, P<0.01) and plasma renin activity ratio (ARR) (r=-0.34, P<0.01). ROCK activity correlated with age (r=-0.24, P=0.04), PAC (r=0.33, P<0.01) and ARR (r=0.46, P<0.01). Conclusions: APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EH. These findings suggest that APA may have a higher risk of future cardiovascular events.

scholarly journals Disordered CYP11B2 Expression in Primary Aldosteronism

2017 ◽  
Vol 49 (12) ◽  
pp. 957-962 ◽  
Author(s):  
Celso Gomez-Sanchez ◽  
Maniselvan Kuppusamy ◽  
Martin Reincke ◽  
Tracy Williams
Keyword(s):  
Primary Aldosteronism ◽  
Secondary Hypertension ◽  
Zona Glomerulosa ◽  
Common Type ◽  
Older Individuals ◽  
Cell Clusters ◽  
Cellular Expression ◽  
Normal Individuals ◽  
Aldosterone Producing Adenoma

AbstractPrimary aldosteronism is the most common type of secondary hypertension affecting 6–10% of patients with primary hypertension. PA is mainly caused by unilateral hyperaldosteronism due to an aldosterone-producing adenoma, unilateral hyperplasia with or without micronodules or bilateral zona glomerulosa hyperplasias with or without macro or micronodules. The development of antibodies against the terminal enzyme of aldosterone biosynthesis (CYP11B2) has permitted the further characterization of normal adrenals and resected adrenals from patients with primary aldosteronism. Normal adrenals exhibit two different patterns of cellular expression of CYP11B2: young individuals display a relatively uniform expression of the enzyme throughout the zona glomerulosa while the adrenals of older individuals have dispersed CYP11B2-expressing cells but have more groups of cells called aldosterone-producing cell clusters (APCC). APAs exhibit different patterns of CYP11B2 staining that vary from uniform to homogeneous. There are also a proportion of cells within the APA that co-express different enzymes that are not normally co-expressed in normal individuals. Approximately 30% of patients with unilateral hyperaldosteronism do not have an APA, but either have an increased number of CYP11B2 expressing micronodules or hyperplasia of the zona glomerulosa. In summary, the studies reported in this review are shedding new light on the pathophysiology of primary aldosteronism. The wide variation in histopathological features of the adenomas and concurrent presence of APCCs raises the possibility that most cases of unilateral production of aldosterone actually might represent bilateral asymmetric hyperplasia with nodules frequently due to the development of somatic aldosterone-driving mutations.

The relation among aldosterone, galectin-3, and myocardial fibrosis: a prospective clinical pilot follow-up study

2016 ◽  
Vol 64 (6) ◽  
pp. 1109-1113 ◽  
Author(s):  
Che-Wei Liao ◽  
Yen-Tin Lin ◽  
Xue-Ming Wu ◽  
Yi-Yao Chang ◽  
Chi-Sheng Hung ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Primary Aldosteronism ◽  
Plasma Renin ◽  
Secondary Hypertension ◽  
Left Ventricular ◽  
Galectin 3 ◽  
Registration Number ◽  
Cyclic Variations ◽  
Pressure Concentration ◽  
Aldosterone Producing Adenoma

Primary aldosteronism has been associated with myocardial fibrosis, and is the most common cause of secondary hypertension. We previously showed that aldosterone can induce the secretion of galectin-3. The aim of this study was to investigate the association between myocardial fibrosis and plasma galectin-3 level in patients with primary aldosteronism. We prospectively analyzed 11 patients with aldosterone-producing adenoma (APA) who received adrenalectomy from December 2006 to October 2008, and 17 patients with essential hypertension as controls. Levels of plasma galectin-3 were determined in both groups, and both groups underwent echocardiography with cyclic variations of integrated backscatter (CVIBS) to characterize tissue initially and 1 year after surgery in the APA group. Diastolic blood pressure, concentration of plasma aldosterone and aldosterone-renin ratio were significantly higher, and serum potassium level and plasma renin activity significantly lower in the APA group compared to the controls. In addition, left ventricular mass index was significantly higher and CVIBS significantly lower in the APA group (7.3±2.0 vs 9.2±1.7 dB, p=0.015). Furthermore, the concentration of plasma galectin-3 was significantly higher in the APA group (2.1±0.9 vs 1.1±0.6 ng/mL, p=0.005) compared to the controls. CVIBS was correlated to plasma galectin-3 level. In the APA group, CVIBS increased significantly (7.3±2.0 to 9.2±2.4 dB, p=0.032) and plasma galectin-3 decreased (2.1±0.9 to 1.2±0.6, p=0.049) 1 year postadrenalectomy. The patients with APA had increased myocardial fibrosis, and this was associated with a higher plasma galectin-3 level. Both increased myocardial fibrosis and plasma galectin-3 level recovered at least partially after adrenalectomy.Trial registration number200611031R; Results.

scholarly journals GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

2018 ◽  
Vol 178 (3) ◽  
pp. R101-R111 ◽  
Author(s):  
Silvia Monticone ◽  
Fabrizio Buffolo ◽  
Martina Tetti ◽  
Franco Veglio ◽  
Barbara Pasini ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Ion Homeostasis ◽  
Germline Mutations ◽  
Genetic Horizon ◽  
Electrolyte Homeostasis ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma ◽  
Mineralocorticoid Hormone ◽  
Generation Sequencing

Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years, the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis is yet to be uncovered.

Urinary excretion of 19-noraldosterone, 18, 19-dihydroxycorticosterone and 18-hydroxy-19-norcorticosterone in patients with aldosterone-producing adenoma or idiopathic hyperaldosteronism

1992 ◽  
Vol 126 (6) ◽  
pp. 484-488 ◽  
Author(s):  
Y Takeda ◽  
I Miyamori ◽  
K Iki ◽  
R Takeda ◽  
P Vecsei
Keyword(s):  
Urinary Excretion ◽  
Primary Aldosteronism ◽  
Aldosterone Producing Adenoma ◽  
Idiopathic Hyperaldosteronism

Urinary excretion of 19-noraldosterone. 18, 19-dihydroxycorticosterone (18, 19(OH)2-B), 18-hydroxy-19-norcorticosterone (18-OH-19-nor-B), 18-hydroxycorticosterone (18-OH-B), 18-hydroxycortisol (18-OH-F) and aldosterone were measured in 25 patients with primary aldosteronism, 16 with an aldosterone-producing adenoma and 9 with idiopathic hyperaldosteronism. In patients with idiopathic hyperaldosteronism, urinary 19-noraldosterone (207±51 pmol/day), 18, 19(OH)2-B (21±4.2 nmol/day) and 18-OH-19-nor-B (879±21 3 pmol/day) levels were lower but not significantly different from 19-noraldosterone (263±56 pmol/day), 18, 19(OH)2-B (40±8.7 nmol/day) and 18-OH-19-nor-B (1322±267 pmol/day) seen in patients with aldosterone-producing adenoma. Urinary aldosterone did not differ significantly between patients with idiopathic hyperaldosteronism and those with aldosterone-producing adenoma. Both urinary 18-OH-B and 18-OH-F excretion were significantly higher in aldosterone-producing adenoma (39±5.2 nmol/day, 1660±318 nmol/day, respectively) compared with patients with idiopathic hyperaldosteronism (19±3.3 nmol/day, 541±93 nmol/day. respectively) (p<0.05). Though urinary 18-OH-F and 18-OH-B concentrations were useful markers, the mineralocorticoid steroids which we can only now measure, 19-noraldosterone, 18, 19(OH)2-B and 18-OH-19-nor-B, could not be used to distinguish the two subsets of primary aldosteronism.

scholarly journals Adrenal venous sampling for primary aldosteronism: laboratory medicine best practice

2017 ◽  
Vol 70 (11) ◽  
pp. 911-916 ◽  
Author(s):  
Gregory Kline ◽  
Daniel T Holmes
Keyword(s):  
Primary Aldosteronism ◽  
Best Practice ◽  
Laboratory Medicine ◽  
Secondary Hypertension ◽  
Adrenal Venous Sampling ◽  
Venous Sampling ◽  
Aldosterone Antagonists ◽  
Bilateral Disease ◽  
Patient Preparation ◽  
Aldosterone Producing Adenoma

Primary aldosteronism (PA) is the most common form of secondary hypertension and is critical to identify because when caused by an aldosterone-producing adenoma (APA) or another unilateral form, it is potentially curable, and even when caused by bilateral disease, antihypertensives more specific to PA treatment can be employed (ie, aldosterone antagonists). Identification of unilateral forms is not generally accomplished with imaging because APAs may be small and elude detection, and coincidental identification of a non-functioning incidentaloma contralateral to an APA may lead to removal of an incorrect gland. For this reason, the method of choice for identifying unilateral forms of PA is selective adrenal venous sampling (AVS) followed by aldosterone and cortisol analysis on collected samples. This procedure is technically difficult from a radiological standpoint and, from the laboratory perspective, is fraught with opportunities for preanalytical, analytical and postanalytical error. We review the process of AVS collection, analysis and reporting. Suggestions are made for patient preparation, specimen labelling practices and nomenclature, analytical dilution protocols, which numerical results to report, and the necessary subsequent calculations. We also identify and explain frequent sources of confusion in the aldosterone and cortisol results and provide an example of tabular reporting to facilitate interpretation and communication between laboratorian, radiologist and clinician.

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