Bilateral Primary Aldosteronism Research Articles

Bone and mineral metabolism in patients with primary aldosteronism: A systematic review and meta-analysis.

Patients with primary aldosteronism (PA) tend to exhibit a high prevalence of osteoporosis (OP) that may vary by whether PA is unilateral or bilateral, and responsive to PA treatment. To explore relationships between bone metabolism, PA subtypes, and treatment outcomes, we performed a systematic review and meta-analysis. The PubMed, Embase, and Cochrane databases were searched for clinical studies related to PA and bone metabolism markers. Articles that met the criteria were screened and included in the systematic review; the data were extracted after evaluating their quality. R software (ver. 2022-02-16, Intel Mac OS X 11.6.4) was used for the meta-analysis. A total of 28 articles were subjected to systematic review, of which 18 were included in the meta-analysis. We found that PA patients evidenced a lower serum calcium level (mean difference [MD] = -0.06 mmol/L, 95% confidence interval [CI]: -0.10 ~ -0.01), a higher urine calcium level (MD = 1.29 mmol/24h, 95% CI: 0.81 ~ 1.78), and a higher serum parathyroid hormone (PTH) level (MD = 2.16 pmol/L, 95% CI: 1.57 ~ 2.75) than did essential hypertension (EH) subjects. After medical treatment or adrenal surgery, PA patients exhibited a markedly increased serum calcium level (MD = -0.08 mmol/L, 95% CI: -0.11 ~ -0.05), a decreased urine calcium level (MD = 1.72 mmol/24h, 95% CI: 1.00 ~ 2.44), a decreased serum PTH level (MD = 2.67 pmol/L, 95% CI: 1.73 ~ 3.62), and an increased serum 25-hydroxyvitamin D (25-OHD) level (MD = -6.32 nmol/L, 95% CI: -11.94 ~ -0.70). The meta-analysis showed that the ser um PTH level of unilateral PA patients was significantly higher than that of bilateral PA patients (MD = 0.93 pmol/L, 95% CI: 0.36 ~ 1.49) and the serum 25-OHD lower than that of bilateral PA patients (MD = -4.68 nmol/L, 95% CI: -7.58 ~ 1.77). There were, however, no significant differences between PA and EH patients of 25-OHD, or BMD of femoral neck and lumbar spine. BMDs of the femoral neck or lumbar spine did not change significantly after treatment. The meta-analytical results were confirmed via sensitivity and subgroup analyses. Excess aldosterone was associated with decreased serum calcium, elevated urinary calcium, and elevated PTH levels; these effects may be enhanced by low serum 25-OHD levels. The risks of OP and fracture might be elevated in PA patients, especially unilateral PA patients, but could be reduced after medical treatment or adrenal surgery. In view, however, of the lack of BMD changes, such hypothesis needs to be tested in further studies.

Adrenal Ablation Versus Mineralocorticoid Receptor Antagonism for the Treatment of Primary Aldosteronism: A Single-Center Prospective Cohort Study.

Superselective adrenal arterial embolization (SAAE) is an alternative treatment for patients with primary aldosteronism (PA). This single-center prospective cohort study aimed to compare the efficacy of SAAE with mineralocorticoid receptor antagonists (MRA) in treating patients with PA who refused unilateral adrenalectomy. Of the 140 PA patients who were enrolled in the study and completed 12-month follow-up, 74 patients underwent SAAE and 66 received MRA treatment. The clinical and biochemical outcome was compared at 1, 6, and 12 months after the procedure. Baseline clinical and biochemical characteristics of the patients were similar between groups. Office, home, and ambulatory blood pressure reduction at 1 month after discharge was more pronounced in the SAAE group than MRA group (all P < 0.05) while the blood pressure reduction was comparable between the 2 groups at 6 and 12 months. Patients who underwent SAAE took less antihypertensive medications than the MRA group during 12-month follow-up (P < 0.01). Both SAAE and MRA treatment improved renin suppression, aldosterone-to-renin ratio elevation, and hypokalemia at 6 and 12 months, whereas only SAAE but not MRA reduced plasma aldosterone levels. Moreover, SAAE achieved higher rates of complete clinical and biochemical success than MRA (both P < 0.01). Logistic regression found that complete clinical and biochemical success was only directly associated with diagnosis of unilateral PA in contrast to bilateral PA (P < 0.01). The present study provides evidence that SAAE is a reasonable choice of treatment in patients with either unilateral or bilateral PA in terms of clinical and biochemical outcomes. This study was registered at Chictr.org.cn (ChiCTR2100045896).

Circulating Plasma Concentrations of ACE2 in Primary Aldosteronism and Cardiovascular Outcomes.

ContextThe plasma concentrations of angiotensin-converting enzyme 2 ([pACE2) has been independently associated with cardiovascular diseases.ObjectiveHigher [pACE2] concentrations could be found in patients with primary aldosteronism (PA) and might lead to increased cardiovascular events.MethodsUsing an inception observational cohort, we examined [pACE2] among 168 incident patients with PA. The expression of ACE2, serine protease 2 (TMPRSS2), and metalloprotease 17 (ADAM17) were assessed in peripheral blood mononuclear cells (PBMCs).ResultsIncident PA and EH patients had similarly elevated [pACE2] (47.04 ± 22.06 vs. 46.73 ± 21.06 ng/ml, p= 0.937). Age was negatively (β, -2.15, p= 0.033) and higher serum potassium level (β, 2.29, p= 0.024) was positively correlated with higher [pACE2] in PA patients. Clinical complete hypertension-remission after adrenalectomy (PASO criteria) was achieved in 36 (50%) of the 72 surgically-treated uPA patients. At follow-up, the [pACE2] decreased in surgically-treated patients who had (p< 0.001) or had no (p= 0.006) hypertension-remission, but the [pACE2] attenuation was not significant in uPA (p= 0.085) and biPA (p= 0.409) administered with minerocorticoid receptor antagonist (MRA). Persistently elevated [pACE2] (> 23ng/ml) after targeted treatments was related to all-cause mortality and cardiovascular events among PA patients (HR, 8.8, p = 0.04); with a mean followed up of 3.29 years. TMPRSS2 mRNA expression was higher in uPA (p= 0.018) and EH (p= 0.038) patients than that in normotensive controls; it was also decreased after adrenalectomy (p< 0.001).ConclusionsPA and EH patients had elevated [pACE2] and higher expression of TMPRSS2 mRNA compared to those of normotensive population. Persistently elevated [pACE2] (> 23ng/ml) after targeted treatments was associated the risk of mortality and incident cardiovascular events.

Bilateral primary aldosteronism prediction by Integer scoring system

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Development and validation of model for sparing adrenal venous sampling in diagnosing unilateral primary aldosteronism.

Current guidelines recommend adrenal venous sampling (AVS) to identify unilateral primary aldosteronism (UPA) before offering adrenalectomy. However, AVS is costly and technically challenging, limiting its use to expert centres. To establish a model to predict UPA, and therefore, bypass the need for AVS prior to surgery. The model was developed in a Chinese cohort and validated in an Australian cohort. Previously published prediction models of UPA were also tested. primary aldosteronism patients with a definite subtyping diagnosis based on AVS and/or surgery. Diagnostic value of the model. In the development cohort (268 UPA and 88 bilateral primary aldosteronism), combinations of different levels of low serum potassium (≤3.0 or 3.5 mmol/l), high PAC (≥15-30 ng/dl), low PRC (≤2.5-10 μIU/ml) and presence of unilateral nodule on adrenal CT (>8-15 mm in diameter) showed specificity of 1.00 and sensitivity of 0.16-0.52. The model of serum potassium 3.5 mmol/l or less, PAC at least 20 ng/dl, PRC 5 μIU/ml or less plus a unilateral nodule at least 10 mm had the highest sensitivity of 0.52 (0.45-0.58) and specificity of 1.00 (0.96-1.00). In the validation cohort (84 UPA and 117 bilateral primary aldosteronism), the sensitivity and specificity of the model were 0.13 (0.07-0.22) and 1.00 (0.97-1.00), respectively. Ten previous models were tested, and only one had a specificity of 1.00 in our cohorts but with a very low sensitivity [0.07 (0.04-0.10) and 0.01 (0.00-0.06) in our development and validation cohorts, respectively]. A combination of high PAC, low PRC, low serum potassium and unilateral adrenal nodule could accurately determine primary aldosteronism subtype in 13-52% of patients with UPA and obviate the need for AVS before surgery.

Adrenal Venous Sampling Could Be Omitted before Surgery in Patients with Conn's Adenoma Confirmed by Computed Tomography and Higher Normal Aldosterone Concentration after Saline Infusion Test.

Purpose: Adrenal venous sampling (AVS) performed to distinguish unilateral and bilateral primary aldosteronism (PA) is invasive and poorly standardized. This study aimed to identify non-invasive characteristics that can select the patients with unilateral PA who could bypass AVS before surgery. Methods: A single-center study collected a total of 450 patients with PA. Development and validation cohorts included 242 and 208 patients. The AVS was successful in 150 and 138 patients from the cohorts, and the unilateral PA was found in 96 and 94 patients, respectively. Clinical factors independently associated with lateralized AVS in multivariable logistic regression were used to construct a unilateral PA prediction score (SCORE). Results: The proposed SCORE was calculated as a sum of the prevalence of adrenal nodule on computed tomography (2 points) and plasma/serum aldosterone concentration ≥ 165 ng/L after the saline infusion test (SIT) (1 point). Importantly, the SCORE = 3 points identified 48% of unilateral PA patients with a specificity of 100% in the development cohort. The zero rate of false-positive classifications was preserved with the same cut-off value in the validation cohort. Conclusions: AVS could be omitted before surgery in patients with typical Conn´s adenoma provided the aldosterone concentration ≥ 165 ng/L after the SIT.

Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome.

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in aldosterone-producing adenomas (aldosteronomas). All variants in these genes lead to the activation of calcium signaling, the major trigger for aldosterone production. Genetic causes of familial hyperaldosteronism have been expanded through the report of germline pathogenic variants in KCNJ5, CACNA1H and CLCN2 genes. Moreover, PDE2A and PDE3B variants were associated with bilateral PA and increased the spectrum of genetic etiologies of PA. Of great importance, the genetic investigation of adrenal lesions guided by the CYP11B2 staining strongly changed the landscape of somatic genetic findings of PA. Furthermore, CYP11B2 staining allowed the better characterization of the aldosterone-producing adrenal lesions in unilateral PA. Aldosterone production may occur from multiple sources, such as solitary aldosteronoma or aldosterone-producing nodule (classical histopathology) or clusters of autonomous aldosterone-producing cells without apparent neoplasia denominated aldosterone-producing micronodules (non-classical histopathology). Interestingly, KCNJ5 mutational status and classical histopathology of unilateral PA (aldosteronoma) have emerged as relevant predictors of clinical and biochemical outcome, respectively. In this review, we summarize the most recent advances in the pathogenesis of PA and discuss their impact on clinical outcome.

Pathophysiology of bilateral hyperaldosteronism.

Renin-independent aldosterone production from one or both affected adrenal(s), a condition known as primary aldosteronism (PA), is a common cause of secondary hypertension. In this review, we aimed to summarize recent findings regarding pathophysiology of bilateral forms of PA, including sporadic bilateral hyperaldosteronism (BHA) and rare familial hyperaldosteronism. The presence of subcapsular aldosterone synthase (CYP11B2)-expressing aldosterone-producing micronodules, also called aldosterone-producing cell clusters, appears to be a common histologic feature of adrenals with sporadic BHA. Aldosterone-producing micronodules frequently harbor aldosterone-driver somatic mutations. Other potential factors leading to sporadic BHA include rare disease-predisposing germline variants, circulating angiotensin II type 1 receptor autoantibodies, and paracrine activation of aldosterone production by adrenal mast cells. The application of whole exome sequencing has also identified new genes that cause inherited familial forms of PA. Research over the past 10 years has significantly improved our understanding of the molecular pathogenesis of bilateral PA. Based on the improved understanding of BHA, future studies should have the ability to develop more personalized treatment options and advanced diagnostic tools for patients with PA.

Machine learning approach to predict subtypes of primary aldosteronism is helpful to estimate indication of adrenal vein sampling.

Primary aldosteronism (PA) is a common disease. Especially in unilateral PA (UPA), the risk of cardiovascular disease is high and proper localization is important. Adrenal vein sampling (AVS) is commonly used to localize PA, but its availability is limited. Therefore, it is important to predict the unilateral or bilateral PA and to choose the appropriate cases for AVS or watchful observation. The purpose of this study is to develop a model using machine learning to predict bilateral or unilateral PA to extract cases for AVS or watchful observation. We retrospectively analyzed 154 patients diagnosed with PA and who underwent AVS at our hospital between January 2010 and June 2021. Based on machine learning, we determined predictors of PA subtypes diagnosis from the results of blood and loading tests. The accuracy of the machine learning was 88% and the top predictors of the UPA were plasma aldosterone concentration after the saline infusion test, aldosterone to renin ratio after the captopril challenge test, serum potassium and aldosterone-to-renin ratio. By using these factors, the accuracy, sensitivity, specificity and the area under the curve (AUC) were 91%, 70%, 99% and 0.91, respectively. Furthermore, we examined the surgical outcomes of UPA and found that the group diagnosed as unilateral by the predictors showed improvement in clinical findings, while the group diagnosed as bilateral by the predictors showed no improvement. Our predictive model based on machine learning can support to choose the performance of adrenal vein sampling or watchful observation.

Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Aldosterone and Primary Aldosteronism: Star Performers in Hypertension Research

Aldosterone and Primary Aldosteronism: Star Performers in Hypertension Research

PD07-04 ROLE OF UNILATERAL ADRENALECTOMY IN BILATERAL PRIMARY ALDOSTERONISM

You have accessJournal of UrologyAdrenal (PD07)1 Sep 2021PD07-04 ROLE OF UNILATERAL ADRENALECTOMY IN BILATERAL PRIMARY ALDOSTERONISM Yu-Cheng Lu, Kuo-How Huang, Vin-Cent Wu, Kwan-Dun Wu, and Fang-Yu Cha Yu-Cheng LuYu-Cheng Lu More articles by this author , Kuo-How HuangKuo-How Huang More articles by this author , Vin-Cent WuVin-Cent Wu More articles by this author , Kwan-Dun WuKwan-Dun Wu More articles by this author , and Fang-Yu ChaFang-Yu Cha More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001975.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Mineralcorticoid receptor antagonist was the first-line treatment in bilateral adrenal hyperplasia (BAH) with primary aldosteronism (PA). Some patients were refractory to medical treatment and required second line therapy, such as unilateral adrenalectomy (UA). In this study, we investigated blood pressure and biochemical responses and identified predictive factors in patients with PA after UA. METHODS: From January, 2010 to November, 2018, 102 patients with complete adrenal vein sampling (AVS) as well NP-59 test and confirmatory diagnoses of PA were enrolled. All these patients received UA and followed up for 12 months subsequently. We collected and analyzed all possible correlated parameters that might interfere the clinical and biochemical outcomes. RESULTS: A total of 102 patients were stratified into two groups by AVS and NP-59 results: 20 (19.6%) patients had BAH in Group A and 82 (80.4%) patients had unilateral lesion in Group B. Patients in Group B had better blood pressure control after UA (p<0.001). Both groups had significant improvement in serum aldosterone-renin ratio (ARR), potassium level and reduction of anti-hypertensive drugs. (Group A: p=0.013, p=0.003 and p=0.020 respectively; Group B: p<0.001, p<0.001 and p<0.001 respectively). Patients in Group A had worse clinical outcome with 40% failure rate (p=0.020) but there was no difference in biochemical outcome (p=0.065). Multivariate logistic regression analysis indicated that preoperative ARR (OR: 0.999, p=0.031) could predict biochemical success at 12-month after UA but there were no predictors found for clinical success. CONCLUSIONS: Patients with bilateral PA generally had worse clinical outcome after UA. However, significantly reduced ARR, serum potassium and usage of anti-hypertensive drugs were noted after UA. This study indicated that UA could be beneficial in some patients with bilateral PA and should not be excluded as a treatment option. Source of Funding: No © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e106-e106 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yu-Cheng Lu More articles by this author Kuo-How Huang More articles by this author Vin-Cent Wu More articles by this author Kwan-Dun Wu More articles by this author Fang-Yu Cha More articles by this author Expand All Advertisement Loading ...

Limited diagnostic utility of partially successful adrenal vein sampling for primary aldosteronism subtyping.

Failure of adrenal vein sampling (AVS) due to difficult cannulation of the right adrenal vein (AV) frequently precludes subtyping of patients with primary aldosteronism (PA) before adrenalectomy. According to a recent study, lateralized PA could be accurately predicted from partial AVS data based on the gradient of the aldosterone-to-cortisol ratios (ACR) between left AV and inferior vena cava (IVC) (LAV/IVC index). We aimed to validate the diagnostic utility of this index for PA subtyping in our cohort. A retrospective cross-sectional study included all patients who underwent bilaterally successful AVS at our centre and were diagnosed with either bilateral PA according to AVS or with lateralized PA after successful adrenalectomy from November 2004 to the end of 2019. Final diagnoses were compared to originally suggested LAV/IVC index cut-offs of ≥ 5.5 for ipsilateral disease and of ≤ 0.5 for contralateral disease, respectively. The inclusion criteria were met in 168 patients: 46 women and 122 men, aged 54 years on average (range 32-72 years); 67 with lateralized and 101 with bilateral PA. LAV/IVC index using cut-offs of ≥ 5.5 or ≤ 0.5 anticipated ipsilateral (left lateralized) PA with a sensitivity of 32% and specificity of 97%, while a sensitivity of 47% and specificity of 95%, were found for contralateral (right lateralized) PA in our cohort. The overall inappropriate adrenalectomy rate was 29.7% (p = 0.314 for comparison between sides). When ascertaining ipsilateral disease (LAV/IVC index ≥ 5.5), 4 out of 16 patients (25%) would have been incorrectly sent to left adrenalectomy. Inappropriate right adrenalectomy would have occurred in 7 out of 21 patients (33.3%) when predicting contralateral disease (LAV/IVC index of ≤ 0.5). Thus, 11 patients with bilateral PA (6.5% of the entire cohort) would have been misclassified as lateralized PA and referred to surgery. Failed lateralization would have occurred in 61.2% of patients overall (53.3% for overlooked contralateral disease, 67.6% for missed ipsilateral disease; p = 0.723 for comparison between sides). Based on our cohort, we conclude that application of the suggested LAV/IVC index cut-offs did not predict lateralized PA with the high accuracy previously reported.

The Value of Different Single or Combined Indexes of the Captopril Challenge Test in the Diagnosis of Primary Aldosteronism.

ObjectiveThe result interpretation of the captopril challenge test (CCT) for the diagnosis of primary aldosteronism (PA) is not standardized. Superiorities of different indexes in the CCT have not been fully investigated. We aimed to comprehensively evaluate the value and influence factors of different CCT-associated indexes in the diagnosis of PA.MethodsWe enrolled 312, 85, 179 and 97 patients in the groups of PA, essential hypertension (EH), unilateral PA (UPA) and bilateral PA (BPA), respectively. For each single index investigated, we computed diagnostic estimates including the area under the receiver operating characteristic curve (AUC). We performed pre-specified subgroup analyses to explore influence factors. We assessed the diagnostic value of combined indexes in binary logistic regression models.ResultsPost-CCT aldosterone to renin ratio (ARR) (AUC = 0.8771) and plasma aldosterone concentration (PAC) (AUC = 0.8769) showed high value in distinguishing PA from EH, and their combination (AUC = 0.937) was even superior to either alone. The diagnostic efficacy was moderately high for post-CCT aldosterone to angiotensin II ratio (AA2R) (AUC = 0.834) or plasma renin activity (PRA) (AUC = 0.795) but low for the suppression percentage of PAC (AUC = 0.679). Post-CCT PAC had a significantly higher AUC in the UPA than BPA subgroup (AUC = 0.914 vs 0.827, P<0.05).ConclusionWe can take post-CCT ARR and PAC altogether into account to distinguish PA from EH, while caution should be taken to interpret CCT results with the suppression percentage of PAC. Post-CCT PAC may perform better to identify the unilateral than bilateral form of PA.

Concomitant Pheochromocytoma and Primary Aldosteronism: A Case Series and Literature Review.

ContextThe detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood.ObjectiveTo investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an approach to its diagnosis and management.MethodsWe conducted a retrospective case series of adult patients with concomitant PHEO and PA at Mayo Clinic from 2000-2020 and an additional review of cases before 2000 and from the medical literature. Clinical, biochemical, radiologic, and histologic parameters were measured.ResultsFifteen patients (53% men, median age 53 years) were diagnosed with concomitant PHEO and PA. The majority presented with hypertension (13, 87%) and hypokalemia (13, 87%), and 6 (40%) presented with symptoms suggestive of catecholamine excess. All patients who underwent preoperative workup for catecholamine excess (14, 93%) were found to have biochemical levels above the upper limits of normal. Adrenal vein sampling (AVS) was performed in 9 patients (60%), where 5 (56%) were diagnosed with bilateral PA, and 4 (44%) with unilateral PA. Patients underwent either unilateral (12, 80%) or bilateral (3, 20%) adrenalectomy. Biochemical improvement or resolution of catecholamine excess was confirmed in all cases with documented measurements. Recurrence of PHEO was not observed. Six patients (40%) displayed persistent PA postoperatively.ConclusionConcomitant PHEO and PA is a rare but likely underreported condition. Hypertension with or without hypokalemia should prompt evaluation for PA, while any indeterminate adrenal mass should be assessed for PHEO. Coexisting disease warrants consideration of AVS to determine the laterality of PA to ensure appropriate management.

Mineralocorticoid Receptor Antagonist Effect on Aldosterone to Renin Ratio in Patients With Primary Aldosteronism.

Although current international guidelines recommend to avoid mineralocortcoid receptor antagonists in patients undergoing screening test for primary aldosteronism, a recent report suggested that mineralocorticoid receptor antagonist treatment can be continued without significant influence on screening results. We aimed to evaluate the effect of mineralocorticoid receptor antagonists on the aldosterone to renin ratio in patients with primary aldosteronism. We prospectively enrolled 121 patients with confirmed primary aldosteronism who started mineralocorticoid receptor antagonist (canrenone) treatment. Eighteen patients (11 with unilateral and 7 with bilateral primary aldosteronism) constituted the short-term study cohort and underwent aldosterone, renin, and potassium measurement after 2 and 8 weeks of canrenone therapy. The long-term cohort comprised 102 patients (16 with unilateral and 67 with bilateral primary aldosteronism, and 19 with undetermined subtype) who underwent hormonal and biochemical re-assessment after 2 to 12 months of canrenone therapy. Renin and potassium levels showed a significant increase, and the aldosterone to renin ratio displayed a significant reduction compared with baseline after both a short- and long-term treatment. These effects were progressively more evident with higher doses of canrenone and after longer periods of treatment. We demonstrated that canrenone exerted a deep impact on the diagnostic accuracy of the screening test for primary aldosteronism: the rate of false negative tests was raised to 16.7%, 38.9%, 54.5%, and 72.5% after 2 weeks, 8 weeks, 2 to 6 months, and 7 to 12 months of mineralocorticoid receptor antagonist treatment, respectively. Mineralocorticoid receptor antagonists should be avoided in patients with hypertension before measurement of renin and aldosterone for screening of primary aldosteronism.

Machine learning based models for prediction of subtype diagnosis of primary aldosteronism using blood test

Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1%). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.

The Impact of ACTH on Peripheral Steroids Differs between Unilateral and Bilateral Primary Aldosteronism

Background: ACTH is thought to contribute to aldosterone excess in primary aldosteronism (PA), possibly via aberrant melanocortin type 2 receptor (MC2R) expression in aldosterone producing adenomas (APAs). Dynamic manipulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as a non-invasive tool for distinguishing unilateral PA (UPA) from bilateral PA (BPA), but existing data are minimal. Objective: To characterize the steroid responses to intrinsic ACTH variations and extrinsic HPA manipulation in UPA and BPA. Methods: We conducted comprehensive dynamic testing in PA patients, who were subtyped based on adrenal vein sampling. Peripheral plasma samples were collected from each patient at 6 time-points: morning; midnight; after 1 mg dexamethasone suppression (DST); and after cosyntropin stimulation (at 15’, 30’, and 60’). We quantified 15 steroids by mass spectrometry in each sample. Next generation sequencing was used to detect aldosterone-driver somatic mutations in APAs from 39 cases with available tissue. The Mann-Whitney test, Wilcoxon signed rank test, and repeated measures two-way ANOVA were employed, as appropriate. Penalized logistic regression was used to select steroids that best distinguished UPA from BPA. Receiver operating characteristic (ROC) curves were then plotted using the predicted score from the logistic regression model with the selected steroids, and area under the curves (AUC) were computed. Results: We included 80 PA patients, median age 51 (range, 26–76), 50% men, 40 with each subtype, both groups with similar age and sex distribution. Morning and midnight concentrations of 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), aldosterone, and 18-hydroxycorticosterone (18OHB) were higher in patients with UPA vs. BPA (p<0.001 for all). In response to cosyntropin stimulation, the UPA group had larger increments of aldosterone, 18oxoF, 11-deoxycorticosterone, corticosterone, and 11-deoxycortisol than the BPA group (p<0.05 for all). Following DST, aldosterone,18OHF, and 18oxoF were higher in UPA than in BPA patients (p<0.01 for all). Overall, cortisol and cortisone serum concentrations were similar between the two subtypes. Of the UPA cases, 27 (69%) had KCNJ5 mutations. Relative to UPA patients with other mutations, the KCNJ5 group had higher 18oxoF and 18OHF at baseline; higher 18oxoF and corticosterone after both dynamic tests; and lower aldosterone after DST. The highest AUC for PA subtyping was achieved using cosyntropin stimulated steroids (0.957), while baseline data reached an AUC of 0.909. Conclusions: Steroid responses to dynamic HPA testing differs between UPA and BPA: 18oxoF and 18OHF are less suppressible, while several steroids are disproportionally amplified by ACTH in patients with UPA vs. BPA. Such non-invasive tests could circumvent the need for adrenal vein sampling in a subset of PA patients.

Concomitant Pheochromocytoma and Primary Aldosteronism: A Case Series and Literature Review

Objective: The detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood. Our objectives were to investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an approach to its diagnosis and management. Design: Retrospective case series from 2000–2020 at a single institution tertiary center; additional review of previously known cases before 2000 and from the medical literature. Patients and Measurements: Adult patients with concomitant PHEO and PA. Clinical, biochemical, radiologic, and histologic parameters were reviewed. Results: Fifteen patients (53% men, median age 53 years) were diagnosed with concomitant PHEO and PA. The majority presented with hypertension (13, 87%) and hypokalemia (13, 87%), but only 6 (40%) presented with symptoms suggestive of catecholamine excess. All patients with preoperative work-up for catecholamine excess (14, 93%) were found to have elevated plasma or urinary metanephrines/catecholamines above the upper limit of normal. Adrenal vein sampling (AVS) was performed in 9 (60%) patients, where 5 (56%) were diagnosed with bilateral PA, and 4 (44%) with unilateral PA. All patients underwent either unilateral (12, 80%) or bilateral (3, 20%) adrenalectomy to treat their PHEO and/or PA. Postoperative catecholamines and/or catecholamine breakdown products normalized or improved in 13 (87%) patients and were not measured in 2. Recurrence of PHEO was not observed. Six (40%) displayed persistent PA postoperatively, where 4 required long-term mineralocorticoid blockade. Conclusions: Concomitant PHEO and PA is a rare but likely under-reported condition. Hypertension with or without hypokalemia should prompt evaluation for PA, while any indeterminate adrenal mass should be worked up for PHEO. Coexisting disease warrants consideration of AVS to determine the laterality of PA to ensure appropriate management.

Tolerability and Efficacy of Long-Term Medical Therapy in Primary Aldosteronism

Introduction: Patients with primary aldosteronism (PA) have increased cardiovascular risk and studies have found that medical therapy fails to ameliorate this. This may be due to side effects and limited efficacy of medications at tolerable doses. Methods: We conducted a retrospective study on 201 patients with PA treated with medical therapy (spironolactone, eplerenone or amiloride) for PA from 2000–2020 at two tertiary centres. Patients were assessed for efficacy to achieve clinical and biochemical control, and for side effects. Results: 53.7% of patients achieved blood pressure <140/90mmHg, 44.6% achieved serum potassium ≥4.3mmol/L, and 63.2% achieved renin levels >1ng/ml/hr. Concordance between biochemical control as assessed by potassium and renin levels was 49%. 45.3% of patients experienced side effects, with 8.5% switching to another medication, 18.9% decreasing dose, and 10.0% stopping medications altogether. Risk factors for side effects were spironolactone use, dose ≥50mg, duration of treatment ≥1 year, male gender and unilateral PA. Patients with unilateral PA, compared to bilateral PA, used higher median doses of spironolactone, 75mg vs 50mg, P<0.001, but more had persistent hypokalemia, 20.5% versus 6.4%, P=0.007. 44 patients with unilateral PA underwent surgery after initial medical therapy, which further improved systolic and diastolic BP, from 142 to 134mmHg, P<0.001, and from 85 to 79mmHg, P<0.001, respectively. Conclusion: Dose-dependent side effects limit the efficacy of medical therapy in PA. Future prospective studies should assess the best monitoring strategy for biochemical control during long-term medical therapy. In patients with unilateral PA, surgery remains a better option compared to life-long medications.