scholarly journals SOMATIC MUTATIONS IN ADRENALS FROM PATIENTS WITH PRIMARY ALDOSTERONISM NOT CURED AFTER ADRENALECTOMY SUGGEST COMMON PATHOGENIC MECHANISMS BETWEEN UNILATERAL AND BILATERAL DISEASE

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e9
Author(s):  
Inès Hacini ◽  
Kelly De Sousa ◽  
Sheerazed Boulkroun ◽  
Tchao Meatchi ◽  
Laurence Amar ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Pathogenic Mechanisms ◽  
Bilateral Disease

Abstract 277: Mutations in the KCNJ5 Gene Imply a Higher Lateralization Index at Adrenal Vein Sampling for Primary Aldosteronism

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Teresa M Seccia ◽  
Franco Mantero ◽  
Claudio Letizia ◽  
Maniselvan Kuppusamy ◽  
Marlena Barisa ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Contralateral Side ◽  
Adrenal Vein ◽  
K Channel ◽  
Coding Region ◽  
Aldosterone Secretion ◽  
Adrenal Vein Sampling ◽  
Lateralization Index

Background. The mutations that affect the selectivity filter of the KCNJ5 K+ channel can play a role in triggering and/or maintaining aldosterone oversecretion in primary aldosteronism (PA). We therefore hypothesized that these somatic mutations can be associated with an increased aldosterone secretion from the APA, thus translating in raised plasma aldosterone concentrations (PAC) in the ipsilateral adrenal vein. Aim. To investigate if the lateralization index (LI) at adrenal vein sampling (AVS) is higher in the patients with an APA carrying the mutation (KCNJ5mut), as compared to those without the mutation (KCNJ5wt). Methods. Ninety-two consecutive PA patients who underwent AVS and received diagnosis of APA based on the four corners criteria were recruited. Unequivocal information on the presence or absence of the KCNJ5 mutations was available for each patient. The selectivity index (SI) was calculated as ratio between the right or left adrenal vein PCC (PCCside) and the infrarenal IVC PCC and a cutoff of 2.00 was used. The lateralization index (LI) was calculated in the bilaterally selective AVS as the ratio of PAC/PCC at the APA side to PAC/PCC at the contralateral side. We sequenced the KCNJ5 coding region spanning aminoacids 122 to 199, which include the selectivity filer. Results. The overall prevalence rate of KCNJ5 somatic mutations was 34%; G151R, L168R and T158A mutations were found in 19, 10 and 1 APA respectively. The G151E mutation was not found. The KCNJ5mut and KCNJ5wt groups were similar for gender, age, sK+ levels, while PAC and ARR were higher, and PRA lower (all p<0.05) in the KCNJ5 mut group. In the latter group the LI was higher than in the KCNJ5wt group (29.3± 6.7 vs 16.7±3.9, p< 0.02). This was due to a PAC/PCC ratio which was higher in the adrenal vein ipsilateral to the APA side and lower contralaterally in the KCNJ5mut group. Conclusions. These results provide direct in vivo evidence for a higher aldosterone secretion from APA carrying the KCNJ5 mutations, which translates into higher values of the LI, compared to the tumors without such mutations. Hence, the presence of these KCNJ5 mutations can affect the accuracy of the AVS-based diagnosis of the subtype of PA.

scholarly journals PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas

2016 ◽  
Vol 101 (8) ◽  
pp. 3010-3017 ◽  
Author(s):  
Yara Rhayem ◽  
Luis G. Perez-Rivas ◽  
Anna Dietz ◽  
Kerstin Bathon ◽  
Christian Gebhard ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Functional Characterization ◽  
Cushing's Syndrome ◽  
Antihypertensive Medications ◽  
Unilateral Adrenalectomy ◽  
Vitro Analysis

Context: Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol. Objective: The objective of the study was to investigate PRKACA somatic variants identified in APA cases. Design: Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues. Setting and Patients: APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution. Results: PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels. Conclusions: We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.

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.

scholarly journals Precise Mapping of Intra-Adrenal Aldosterone Activities Provides a Novel Surgical Strategy for Primary Aldosteronism

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 976-984 ◽  
Author(s):  
Takumi Kitamoto ◽  
Kanako Kiriyama Kitamoto ◽  
Masao Omura ◽  
Tomoko Takiguchi ◽  
Yuya Tsurutani ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Primary Aldosteronism ◽  
Clinical Success ◽  
Surgical Strategy ◽  
Computed Tomography Imaging ◽  
Partial Adrenalectomy ◽  
Tomography Imaging ◽  
Bilateral Disease ◽  
Precise Mapping ◽  
Aldosterone Producing Adenoma

Segmental selective adrenal venous sampling (sAVS) elucidates an intraadrenal aldosterone activity map (IAMap), which allows us to design a novel surgical treatment strategy for patients with primary aldosteronism. We evaluated the usefulness of sAVS by analyzing 278 patients with whom we had prospectively used IAMap using the criteria of sAVS for surgical indication between 2009 and 2015. We evaluated its diagnostic accuracy using pathological and postsurgical biochemical and clinical outcomes. One hundred twenty and 158 patients were diagnosed with unilateral and bilateral disease, respectively, through sAVS. The concordance of lateralization diagnosis with computed tomography imaging was 66.6%. Among the unilateral patients, we performed partial adrenalectomy in 68 patients whose IAMap showed focal aldosterone hypersecretion from computed tomography-detectable tumor in the affected adrenal gland. All of them achieved complete biochemical success 1 year after surgery. Furthermore, 25 of 158 bilateral disease patients underwent surgical resection because they were preoperatively diagnosed as bilateral aldosterone-producing adenomas by IAMap. These cases showed complete or partial biochemical success (28.0% and 72.0%, respectively); 36.0% showed complete clinical success. Pathological studies demonstrated that all 145 resected specimens possessed aldosterone-producing adenoma or multiple nodules (132 and 13 cases, respectively), and none showed diffuse hyperplasia. IAMap accurately diagnosed both bilateral and unilateral aldosterone-producing adenomas and diffuse hyperplasia before surgery. sAVS allows a novel surgical strategy for selected PA patients with favorable outcomes.

scholarly journals Minireview: Potassium Channels and Aldosterone Dysregulation: Is Primary Aldosteronism a Potassium Channelopathy?

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Celso E. Gomez-Sanchez ◽  
Kenji Oki
Keyword(s):  
Potassium Channel ◽  
Calcium Channel ◽  
G Protein ◽  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Membrane Depolarization ◽  
Zona Glomerulosa ◽  
Aldosterone Secretion ◽  
K Channels ◽  
Inward Rectifying Potassium Channel

Primary aldosteronism is the most common form of secondary hypertension and has significant cardiovascular consequences. Aldosterone-producing adenomas (APAs) are responsible for half the cases of primary aldosteronism, and about half have mutations of the G protein-activated inward rectifying potassium channel Kir3.4. Under basal conditions, the adrenal zona glomerulosa cells are hyperpolarized with negative resting potentials determined by membrane permeability to K+ mediated through various K+ channels, including the leak K+ channels TASK-1, TASK-3, and Twik-Related Potassium Channel 1, and G protein inward rectifying potassium channel Kir3.4. Angiotensin II decreases the activity of the leak K+ channels and Kir3.4 channel and decreases the expression of the Kir3.4 channel, resulting in membrane depolarization, increased intracellular calcium, calcium-calmodulin pathway activation, and increased expression of cytochrome P450 aldosterone synthase (CYP11B2), the last enzyme for aldosterone production. Somatic mutations of the selectivity filter of the Kir3.4 channel in APA results in loss of selectivity for K+ and entry of sodium, resulting in membrane depolarization, calcium mobilization, increased CYP11B2 expression, and hyperaldosteronism. Germ cell mutations cause familial hyperaldosteronism type 3, which is associated with adrenal zona glomerulosa hyperplasia, rather than adenoma. Less commonly, somatic mutations of the sodium-potassium ATPase, calcium ATPase, or the calcium channel calcium channel voltage-dependent L type alpha 1D have been found in some APAs. The regulation of aldosterone secretion is exerted to a significant degree by activation of membrane K+ and calcium channels or pumps, so it is not surprising that the known causes of disorders of aldosterone secretion in APA have been channelopathies, which activate mechanisms that increase aldosterone synthesis.

scholarly journals Somatic Mutations in the KCNJ5 Gene Raise the Lateralization Index: Implications for the Diagnosis of Primary Aldosteronism by Adrenal Vein Sampling

2012 ◽  
Vol 97 (12) ◽  
pp. E2307-E2313 ◽  
Author(s):  
Teresa M. Seccia ◽  
Franco Mantero ◽  
Claudio Letizia ◽  
Maniselvan Kuppusamy ◽  
Brasilina Caroccia ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations ◽  
Adrenal Vein ◽  
Adrenal Vein Sampling ◽  
Lateralization Index

scholarly journals OR34-04 Efficiency of Adrenal Venous Sampling in the Treatment Choice of Primary Aldosteronism (AVSTAT Study)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Mitsuhide Naruse ◽  
Felix Beuschlein ◽  
Mirko Parasiliti Caprino ◽  
Jaap Deinum ◽  
William Drake ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Clinical Decision ◽  
Pressure Control ◽  
Primary Objective ◽  
Adrenal Venous Sampling ◽  
Venous Sampling ◽  
Bilateral Disease ◽  
Good Blood Pressure Control ◽  
Number Of Patients ◽  
Unilateral Disease

Abstract BACKGROUND: Adrenal venous sampling (AVS) is strongly recommended for a subtype diagnosis of primary aldosteronism (PA) if adrenalectomy (ADX) is desired by the patient. Given various issues related to AVS such as technical demand, invasive nature, expensive cost and radiation exposure, AVS is expected to lead efficiently to the subtype diagnosis and ADX. Aim: Primary objective was to assess the performance of AVS to determine treatment of PA by investigating the ratio of unilateral disease and rate of ADX following AVS in patients with unilateral disease. Methods: Sixteen major referral centers in ENS@T (n=10) and Japan (n=6) participated in the study. Study period was from 2006 to 2018. Data on total number of PA patients, AVS (total number and number of successful procedures), number of patients with unilateral diseases, and number of patients that underwent ADX were collected by a questionnaire-based survey. In addition, reasons for not proceeding to ADX in patients with a unilateral diagnosis were investigated. The diagnosis of PA was based on the positive case detection and at least one positive result in confirmatory testing. Results: Total number of confirmed PA patients and conducted AVS showed a dramatic increase during the past decade (PA: 1061 pts/ 2006–2011 to 3718 pts/ 2012–2018; AVS: 720/ 2006–2011 to 2448/ 2012–2018). Success rate of AVS was improved from 79.0% (2006–2011) to 92.5% (2012–2018). Both rate of unilateral PA and ADX of successful procedures decreased from 42.7% (2006–2011) to 37.3% (2012–2018) and from 40.8% (2006–2011) to 34.9% (2012–2018), respectively. Of the patients with successful AVS, bilateral disease was diagnosed in 63.5% (1812/2854 pts). Of the unilateral PA patients, 11.9% (125/ 1054 pts) were not subjected to ADX. The rate of the patients not subjected to ADX was significantly higher in Japan than in ENS@T centers both in patients with successful AVS (75.8% vs. 53.4%) and with unilateral disease (19.9% vs. 8.6%). Clinical decision against ADX in unilateral disease was made by the physicians in 33.3%, the patients in 33.3%, and both in 33.3%. Medical factors for Dr.’s decision against ADX in unilateral disease included good blood pressure control, normokalemia, comorbidities (e.g. DM, CKD), non-lateralized CT findings (e.g. no tumor, contralateral tumor), and discordant results among different criteria of AVS. Conclusions: High prevalence of bilateral disease and change of treatment policy after implementation affected the efficiency of AVS as an essential diagnostic procedure prior to ADX. Development of non-invasive procedures to exclude bilateral PA and more strict indication of AVS are warranted.

scholarly journals Adrenal Nodularity and Somatic Mutations in Primary Aldosteronism: One Node Is the Culprit?

2014 ◽  
Vol 99 (7) ◽  
pp. E1341-E1351 ◽  
Author(s):  
T. Dekkers ◽  
M. ter Meer ◽  
J. W. M. Lenders ◽  
A. R. M. Hermus ◽  
L. Schultze Kool ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Somatic Mutations

scholarly journals SAT-556 Use of ACTH-Stimulated Lateralization Indices Underestimates Surgically Curable Primary Aldosteronism

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nicholas Yozamp ◽  
Barry Sacks ◽  
Jonathan Underhill ◽  
Tali Fudim ◽  
Anand Vaidya
Keyword(s):  
Primary Aldosteronism ◽  
Vena Cava ◽  
Adrenal Vein ◽  
Imaging Data ◽  
Acth Stimulation ◽  
Cross Sectional ◽  
Bilateral Disease ◽  
Discordance Rate ◽  
Repeated Sampling ◽  
Separate Cohort

Abstract Introduction: Adrenal venous sampling (AVS) is recommended to assess laterality in primary aldosteronism to determine whether a patient has unilateral, or surgically curable, disease. Institutional practices differ in whether ACTH stimulation is used or not and if so, whether values are obtained after a single injection of ACTH or during an ACTH infusion. Studies have demonstrated appreciable discordance between lateralization based on unstimulated versus stimulated AVS. Objective: To assess the influence of ACTH-stimulation on lateralization indices. Methods: We performed a retrospective cross-sectional analysis of 140 patients who underwent AVS between 2012–2019. We then validated these findings in a separate cohort of 233 patients who underwent AVS between 2008–2016. AVS was performed using simultaneous, unstimulated, and triplicate sampling from the inferior vena cava (IVC) and bilateral adrenal veins, followed by repeated sampling in duplicate or triplicate from each site following a bolus of 250 ug of ACTH (cosyntropin). The lateralization index (LI) was defined as the quotient of the aldosterone-to-cortisol ratios from each adrenal vein, and the categorical definition of lateralization was defined as a LI ≥ 2 (unstimulated) and LI ≥ 4 post-ACTH. Results: The median unstimulated LI was 8.7 compared to 8.9 post-ACTH. Seventy-one of 140 patients (51%) had a decrease in LI following the ACTH bolus. Overall lateralization discordance was 21.4%, with the majority of this discordance (90%) attributed to situations where there was an unstimulated LI ≥ 2 that became a post-ACTH LI &lt; 4, thereby transforming a unilateral interpretation into one of bilateral disease. Comparing the group that had an increase in LI after ACTH to the group that had a decrease in LI, the latter had significantly higher rates of lateralization pre-ACTH (89% vs 74%, p=0.02) and significantly lower rates of lateralization post-ACTH (50% vs 78%, p=0.001). All of these general findings were validated in the separate cohort of 233 patients. The discordance rate between pre-ACTH lateralization and available imaging data was 32%; the same discordance rate was found when comparing post-ACTH lateralization to imaging. Conclusions: The administration of ACTH during AVS causes an increase in LI in half of patients and a decrease in LI in the other half. Using conventional cut-offs, pre-ACTH and post-ACTH lateralization indices disagree on laterality more than 20% of the time and almost always involve pre-ACTH unilateral disease that is classified as bilateral disease post-ACTH. These findings underscore that while ACTH stimulation may be useful for confirming adrenal vein selectivity, the decrease in post-ACTH LI may result in misclassification of surgically curable primary aldosteronism in a substantial proportion of patients.

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