Bilateral Primary Aldosteronism Research Articles

Circulating miRNAs and Machine Learning for Lateralizing Primary Aldosteronism.

Distinguishing between unilateral and bilateral primary aldosteronism, a major cause of secondary hypertension, is crucial due to different treatment approaches. While adrenal venous sampling is the gold standard, its invasiveness, limited availability, and often difficult interpretation pose challenges. This study explores the utility of circulating microRNAs (miRNAs) and machine learning in distinguishing between unilateral and bilateral forms of primary aldosteronism. MiRNA profiling was conducted on plasma samples from 18 patients with primary aldosteronism taken during adrenal venous sampling on an Illumina MiSeq platform. Bioinformatics and machine learning identified 9 miRNAs for validation by reverse transcription real-time quantitative polymerase chain reaction. Validation was performed on a cohort consisting of 108 patients with known subdifferentiation. A 30-patient subset of the validation cohort involved both adrenal venous sampling and peripheral, the rest only peripheral samples. A neural network model was used for feature selection and comparison between adrenal venous sampling and peripheral samples, while a deep-learning model was used for classification. Our model identified 10 miRNA combinations achieving >85% accuracy in distinguishing unilateral primary aldosteronism and bilateral adrenal hyperplasia on a 30-sample subset, while also confirming the suitability of peripheral samples for analysis. The best model, involving 6 miRNAs, achieved an area under curve of 87.1%. Deep learning resulted in 100% accuracy on the subset and 90.9% sensitivity and 81.8% specificity on all 108 samples, with an area under curve of 86.7%. Machine learning analysis of circulating miRNAs offers a minimally invasive alternative for primary aldosteronism lateralization. Early identification of bilateral adrenal hyperplasia could expedite treatment initiation without the need for further localization, benefiting both patients and health care providers.

5156 Circulating MicroRNA-based Biomarker Combinations for Differentiating Uni- and Bilateral Primary Aldosteronism Using a Machine Learning Approach

Abstract Disclosure: B. Vekony: None. G. Nyiro: None. Z. Herold: None. J. Fekete: None. F. Ceccato: None. S. Gruber: None. L. Kurzinger: None. M. Parasiliti-Caprino: None. B. Szeredas: None. S.K. Nazri: None. V. Fell: None. M. Bassiony: None. E.A. Azizan: None. I. Bancos: None. F. Beuschlein: None. P. Igaz: None. Background: The differentiation of uni- and bilateral forms of primary aldosteronism (PA) is of pivotal clinical relevance. Whereas unilateral PA warrants surgical treatment, bilateral PA is treated by aldosterone antagonists. The most reliable way to differentiate these two entities is adrenal venous sampling (AVS) that is an invasive method with limited availability and requiring great expertise. Aim: To develop a circulating blood-borne microRNA-based approach using machine learning for the differentiation of uni- and bilateral PA. Methods: Circulating microRNA profiling on an Illumina MiSeq platform was performed on total RNA samples isolated from EDTA-anticoagulated blood specimens taken by AVS from 18 pairs of right and left suprarenal veins (10 uni-, 8 bilateral PA). Significantly differentially expressed microRNAs were analyzed by a neural network (90-10% learner-tester cross-validation simulation). From the top 29 significantly differentially expressed microRNAs, 9 were selected for validation by Taqman RT-qPCR on a separate cohort of 30 AVS-confirmed samples (15-15 uni- and bilateral forms) both on plasma samples from adrenal as well as from peripheral veins. The method was finally tested on another independent cohort of peripheral blood samples from 80 patients (40 uni- and 40 bilateral PA). Results: Regarding the 9 microRNAs selected for validation, microRNA abundance was non-significantly lower in peripheral samples compared to AVS samples. By analyzing peripheral plasma samples, ten combinations of 4-8 microRNAs from the pool of 9 microRNAs turned out to have maximal sensitivity and specificity values over 85 %. The best combination included 6 microRNAs with a sensitivity of 86.3 % and a specificity of 87.91 % (AUC = 0.871). The inclusion of further parameters such as imaging, potassium and renin levels did not improve the model’s performance. Conclusion: The analysis of circulating blood-borne microRNAs represents a minimally invasive and potentially reliable way of differentiating uni- and bilateral PA. If bilateral PA is confirmed by the model, no more localization efforts would be necessary thus simplifying the management of PA patients. This would be relevant both from the patient’s and a public health perspective. Presentation: 6/3/2024

7454 Angiotensin AT1 Receptor Type 1 (AT1) Autoantibodies In Patients with Primary Aldosteronism

Abstract Disclosure: J.K. Waraich: None. G. Kline: None. M.Y. Choi: None. R.J. Sigal: None. C. Caughlin: None. S.J. Przybojewski: None. A. Leung: None. Background: Primary aldosteronism (PA) is a condition characterized by excessive aldosterone secretion, and accounts for at least 10% - 20% of all cases of hypertension. Determination of PA subtype (i.e., unilateral vs. bilateral aldosterone hypersecretion) is clinically important to inform targeted treatment. We hypothesized that pathogenesis of PA is immune-mediated and autoantibodies to angiotensin receptor type 1 (AT1) may determine PA subtype. Aims: The aim of this study was to examine whether AT1 autoantibodies predict PA subtype. Methods: We conducted a cross-sectional study of patients with PA who were referred for adrenal vein sampling (AVS) for subtyping. AT1 autoantibody titres were measured using an enzyme-linked immunosorbent assay. AT1 antibodies were defined as present when the titre was >17 U/mL, negative if <10 U/mL, and indeterminate if between 10-17 U/mL. AVS was used as a gold standard to determine lateralization and PA . The frequency of positive AT1 autoantibodies was determined according to PA subtype and clinical predictors of lateralization. Baseline patient characteristics were reported as means (and standard deviations) for normally distributed variables, and medians (and interquartile ranges) for non-normally distributed variables. Fisher’s exact test was performed for categorical variables and Kruskal-Wallis test for continuous variables. Results: 54 patients had successful cannulation of both adrenal veins (mean age, 52.7 years; 46.3% male; mean body mass index, 31.2 kg/m2). AT1 antibodies were detected in 14 (25.9%) of the patients, absent in 32 (59.3%), and indeterminate in 8 (14.8%). Among the 25 patients with unilateral PA, 8 (32.0%) had positive AT1 antibodies, 15 (60.0%) negative, and 2 (8.0%) indeterminate. Similarly, among the 29 patients with bilateral PA, 6 (20.7%) had positive AT1 antibodies, 17 (58.6%) negative, and 6 (20.7%) indeterminate. There was no significant association detected between AT1 antibody status and lateralization (p=0.39). There were no associations between AT1 autoantibody status and any of the clinical factors traditionally predictive of PA, including sex (p=0.94), older age (p=0.76), hypokalemia (p=0.91), higher estimated glomerular filtration rate (p=0.46), or magnitude of aldosterone-to-renin ratio elevation (p=0.58). There was also no association between AT1 titres and these factors. Conclusion: AT1 autoantibodies are common in patients with PA; over a quarter of patients who underwent AVS in our study. Although they were not predictive of PA subtype, these results may still suggest that PA is immune-mediated. Future studies comparing AT1 autoantibodies in PA to other controls are underway. Presentation: 6/1/2024

9305 Circulating MicroRNA-based Biomarker Combinations for Differentiating Uni- and Bilateral Primary Aldosteronism Using a Machine Learning Approach

9305 Circulating MicroRNA-based Biomarker Combinations for Differentiating Uni- and Bilateral Primary Aldosteronism Using a Machine Learning Approach

Bilateral superselective adrenal artery embolization for bilateral primary aldosteronism: a novel approach in an efficacy and safety proof-of-principle trial.

Superselective adrenal artery embolization (SAAE) offers a novel approach for treating primary aldosteronism (PA). In this study, we aimed to assess the efficacy and safety of SAAE for the treatment of PA based on the lateralization results obtained from adrenal vein sampling (AVS).In this prospective study, we enrolled 40 patients with PA who underwent SAAE. The patients were categorized into two groups, unilateral PA and bilateral PA, based on AVS results. Clinical parameters and biochemical markers were assessed at 3 and 12 months postoperatively. The primary outcomes were changes in blood pressure and defined daily dose (DDD) of antihypertensive medications compared to baseline. Thirty-eight patients achieved technical success, with favorable clinical and biochemical efficacy rates. At three months postoperatively, the clinical efficacy rates were 79.2% and 78.6% for the UPA and BPA groups, respectively. At 12 months, the rates were 83.3% and 71.4%, respectively. Both groups exhibited a significant decrease in average blood pressure at 3 and 12 months compared with baseline (P < 0.001), and there was also a notable reduction in DDD (P < 0.05). At three months, the biochemical efficacy rates were 61.9% and 58.3% in the UPA and BPA groups, respectively. Due to loss to follow-up, biochemical indicators were not assessed at 12 months postoperatively. No severe adverse reactions occurred during or after SAAE. Patients with both UPA and BPA can benefit from SAAE. The superiority of bilateral adrenal artery embolization in the treatment of BPA over unilateral adrenal artery embolization requires further investigation.

Typing diagnostic value of 68Ga-pentixafor PET/CT for patients with primary aldosteronism and unilateral nodules.

Our goal was to compare the lateralization of 68Ga-pentixafor PET/CT with adrenal vein sampling (AVS) in primary aldosteronism (PA) patients with unilateral lesions. We retrospectively enrolled 61 patients with PA and all patients showed unilateral nodular lesions on CT and underwent 68Ga-Pentixafor PET/CT. The general clinical data, imaging and AVS results were collected. The diagnostic efficiency of 68Ga-Pentixafor PET/CT imaging in PA patients was calculated by visual and semi-quantitative analysis to compare the consistency with AVS, and the correlation between CXCR4 express and 68Ga-Pentixafor uptake was performed. The study included 42 unilateral PA (UPA) and 19 bilateral PA (BPA). The area under curve (AUC) of 68Ga-Pentixafor PET/CT to diagnosis UPA with 10 min maximum standardized uptake value (SUVmax) > 8.17 was 0.82 ([0.70-0.90], P < 0.001), and the sensitivity and specificity were 0.64 and 0.90, respectively. The maximal AUC of 68Ga-pentixafor PET/CT for the diagnosis UPA in patients with nodules with a diameter ≥1 cm was 0.87 ([0.73-0.95],P both <0.001,[10 min SUVmax=8.17 and 10 min mean standardized uptake value (SUVmean)=5.57]), and the sensitivity and specificity were 0.73 and 0.93, respectively. Unilateral adrenalectomy and significant CXCR4 expression were present in 32 UPA, including 27 aldosterone-producing adenoma and 5 idiopathic adrenal hyperplasia. Additionally, 68Ga-pentixafor uptake in adrenal lesions was significantly correlated with CXCR4 expression, and statistical differences in 68Ga-pentixafor uptake among IRS subgroups. 68Ga-Pentixafor PET/CT can be helpful for subtyping diagnosis of PA patients with unilateral adrenal nodular, showing significant potential in non-invasive PA classification.

Suppressed Renin Status Is a Risk Factor for Cardiocerebrovascular Events in Bilateral Primary Aldosteronism Treated With Mineralocorticoid Receptor Antagonists

ObjectiveMineralocorticoid receptor antagonists are the recommended medical therapy for bilateral primary aldosteronism (BPA). Patients with BPA have higher risk of cardiocerebrovascular disease (CCVD) than those with essential hypertension. There is no consensus on the criteria to assess the effectiveness of medical therapy for BPA. This study aimed to investigate the incidence of and risk factors for CCVD after medical therapy of BPA. MethodsWe conducted a retrospective cohort study including 240 patients with BPA treated with mineralocorticoid receptor antagonists. The posttreatment plasma renin activity (PRA) was defined as unsuppressed (PRA, ≥1 ng/mL/h); otherwise, it was defined as suppressed. We analyzed the association of posttreatment PRA status with CCVD outcomes. ResultsOf patients with BPA, 7.1% (17/240) developed CCVD at a median follow-up of 5.0 (range, 2.96-7.66) years. Moreover, 57.1% of patients had a PRA of ≥1 ng/mL/h after treatment. Patients with a PRA of <1 ng/mL/h had a higher incidence of CCVD (12.6% vs 2.9%, P < .05) and were at higher risk than those with a PRA of ≥1 ng/mL/h (hazard ratio, 4.50 [95% CI, 1.47-13.83; P < .05]; adjusted hazard ratio, 3.98 [95% CI, 1.22-13.02; P < .05]). ConclusionPatients with BPA who receive pharmacologic treatment have a high incidence of CCVD. PRA may be an indicator that mineralocorticoids are being adequately antagonized.

Abstract P305: Resolution of Resistant Hypertension with Unilateral Adrenalectomy in Bilateral Primary Aldosteronism: A Case Report from Jordan

Introduction: Primary aldosteronism (PA) is a common cause of resistant hypertension. The standard of care for bilateral hyperaldosteronism is medical management, while surgery is often preferred for unilateral cases. Case Presentation: We report the case of a 53-year-old female with an 18-year history of hypertension. She presented with uncontrolled blood pressure despite adherence to seven antihypertensive medications. Blood tests, including creatinine, urea, and electrolytes, were within normal limits, as was the renal ultrasound. Serum aldosterone was 136.3 pg/mL, and plasma renin activity was 0.23 ng/mL/hr, with a ratio of 593. Her antihypertensive medications were changed to hydralazine, moxonidine, and verapamil. A Seated Saline Suppression Test performed a month later, with 2 liters of saline infused over 4 hours, showed that serum aldosterone levels failed to suppress, confirming the diagnosis of PA. Three-Phase adrenal CT revealed a well-defined adenoma in the left adrenal gland measuring 4.5 x 3.4 cm, and a small adenoma in the right adrenal gland measuring 1.2 x 1 cm. Adrenal Vein Sampling indicated excess aldosterone secretion from both adrenal glands, confirming bilaterality.Therefore, high-dose spironolactone was added to her antihypertensive regimen; however, her BP remained elevated after 2 months of therapy. The option of surgically removing the adrenal gland with the larger adenoma in hopes of reducing the total burden of aldosterone was discussed with the patient as the only remaining option of improving her BP control. The patient agreed and a laparoscopic left adrenalectomy was performed. Histopathological examination ruled out malignancy. Immediate preoperative BP was 151/90 mmHg. The surgery was uneventful. All antihypertensive medications were withheld postoperatively. On the third postoperative day her BP was consistently below 130 mmHg systolic and below 85 mmHg diastolic. Her BP remained well controlled with gradual resumption of bisoprolol 5 mg/day and spironolactone 50 mg/day Conclusion: Despite the bilaterality of primary aldosteronism in this case, the patient's hypertension did not respond to medical treatment, necessitating surgical intervention. The unilateral adrenalectomy of the larger adenoma proved sufficient to significantly improve her persistently elevated blood pressure. This case underscores the potential efficacy of targeted surgical treatment in managing resistant hypertension associated with bilateral adrenal disease.

Usefulness of the Upright Posture Test in the Diagnosis of Primary Aldosteronism.

To assess the usefulness of the upright posture stimulation test (UPT) in the confirmation of primary aldosteronism (PA) in patients in whom saline tests (ST) were inconclusive. One hundred eighty-seven adult patients with possible PA were retrospectively included and compared to 25 control subjects. Blood samples were obtained after a 1-hour supine posture and during 2 hours of ambulation. An increase in plasma aldosterone concentration (PAC) ≥ 50% with a suppressed renin (≤10.1 ng/L; ≤1 ng/mL/hour) and a cortisol increase ≤50% were considered abnormal. PA patients had higher basal PAC and lower basal direct renin concentration (DRC) (P < .0001) and a higher maximal PAC (P = .0025) and lower maximal DRC (DRCmax) (P < .0001) during UPT compared to controls. PA was confirmed in 145 patients (77.5%), based on either oral/IV ST or UPT. DRCmax ≤12 ng/L during UPT was a predictor of PA (receiver operating characteristic curve sensitivity 93.8%, specificity 88%), and 95.6% of PA patients increased PAC ≥50% on UPT (median 222.2%), while renin remained suppressed. All 41 PA patients with false-negative IV ST (PAC < 162 pmol/L) and 88.9% with borderline response (162-240 pmol/L) had a DRCmax ≤12, while, respectively, 97.6% and 100% increased aldosterone by ≥50%. Similar responses to UPT were found in lateralized (28/63) and bilateral PA source (35/63). PA diagnosis increased from 23.6% to 88.8% using UPT results instead of IV ST and were confirmed at pathology and clinical outcome after adrenalectomy (n = 22). UPT can be useful to confirm PA, particularly in patients with suspected false-negative ST.

Rationality and implication of catheter-based adrenal ablation for bilateral primary aldosteronism.

Mineralocorticoid receptor antagonists (MRAs) for bilateral primary aldosteronism (PA) are the mainstay option recommended by guidelines, but poor compliance occurs due to numerous side effects. We aimed to examine whether catheter-based adrenal ablation could be an alternative treatment for bilateral PA.644 PA patients were included from a total of 6054 hypertensive patients. Adrenal CT scan and adrenal venous sampling (AVS) were both performed for PA subtype classification. Clinical and biochemical outcomes were assessed at 6 months after treatment according to the Primary Aldosteronism Surgical Outcome (PASO) criteria.93 patients with PA were recruited to be treated by adrenal ablation, including 25 bilateral PA and 68 unilateral PA according to AVS results. Office SBP and DBP significantly decreased from baseline levels, serum potassium levels increased and ARR significantly decreased (p < 0.01) in both the bilateral and unilateral groups. In the bilateral group, complete, partial and absent clinical success was achieved in 6 (24.0%), 11 (44.0%) and 8(32.0%) patients, respectively. In the unilateral group, complete, partial and absent clinical success was achieved in 12 (17.6%), 37 (54.4%), and 19 (27.9%) patients, respectively. The numbers of patients achieving complete, partial, and absent biochemical success were 15 (60.0%), 6 (24.0%), and 4 (16.0%), respectively, in the bilateral group versus 37 (54.4%), 9 (13.2%), and 22 (32.3%), respectively, in the unilateral group. In conclusion, we provide evidence for the beneficial outcomes of unilateral adrenal ablation for patients with bilateral PA. Our findings provide insight into an alternative option for patients with bilateral excess aldosterone.

Clinical characteristics of primary aldosteronism screened from Chinese patients with hypertension: The China primary aldosteronism prospective study.

We investigated the clinical characteristics of primary aldosteronism (PA) screened from patients with hypertension in China. The participants were hypertensive patients who were suspected of PA and registered in the China Primary Aldosteronism Prospective Study. Plasma aldosterone-to-renin ratio (ARR) was used as the screening test. In patients screened positive for PA, that is, an ARR exceeding the thresholds and plasma aldosterone concentration (PAC)>100 pg/mL, a confirmatory test was performed for diagnosis. Patients with PA underwent a CT scan and adrenal venous sampling for subtyping. Of the 1497 screened patients, 754 (50.4%) had an ARR exceeding the diagnostic threshold and 637 (84.5% of those eligible) were registered. These registered hypertensive patients with suspected PA had a mean (standard deviation) age of 52.6±12.1 years, and included 442 (58.6%) women. In multiple stepwise logistic regression, the significant odds ratios for the presence of diagnosed (n=490) versus suspected and non-diagnosed PA (n=147) were 4.54 (95% CI: 2.78-7.39) for a history of hypokalemia, 0.79 (95% CI: 0.64-0.98) for a 0.9mmol/l higher serum total cholesterol, and 2.25 (95% CI: 1.63-3.10) for a doubling of PAC in the supine or standing/sitting position. In multiple stepwise logistic regression, the significant odds ratios for the presence of unilateral (n=135) versus bilateral PA (n=53) were 3.04 (95% CI: 1.90-4.87) for a 0.4mmol/l lower minimum serum potassium concentration and 1.86 (95% CI: 1.20-2.86) for a 0.3mmol/l higher serum high-density lipoprotein cholesterol. PA might be a biochemical continuum in the adrenal hypersecretion of aldosterone as well as hypokalemia.

Application value of adrenal venous sampling in the surgical treatment of primary aldosteronism.

The diagnosis of primary aldosteronism (PA) is critical for determining treatment strategies. The aim of the present study was to investigate the clinical value of preoperative adrenal venous sampling (AVS) for determining the benefit of PA surgery. Patients diagnosed with PA at Liaocheng People's Hospital (Liaocheng, China) between January 2015 and December 2020 were selected and divided into two groups: Group A underwent adrenal computed tomography (CT) only, whereas Group B underwent adrenal CT and successful AVS. Subsequently, the improvement rate of adrenal CT and adrenal CT + AVS in the treatment of PA was compared. A total of 164 patients were included, with an average age of 46.69±13.64 years. There were 62 patients in Group A and 102 in Group B. Among the patients diagnosed with unilateral lesions on adrenal CT scan, 82.61% of patients in group A and 87.72% in group B showed improvement; however, the difference was not significant (χ2=0.534, P=0.465). Among the patients diagnosed with bilateral lesions on adrenal CT images, 62.50% of patients in Group A and 91.11% of patients in Group B showed improvement (P=0.019). In conclusion, unilateral adrenal lesions detected by CT did not benefit significantly from surgical decision-making after AVS. AVS should be advised for all patients with bilateral adrenal PA who are willing to undergo adrenal surgery, which is conducive to correct lateral segmentation and improve treatment choices.

Targeted Treatment Reverses Increased Left Cardiac Work in Unilateral vs. Bilateral Primary Aldosteronism.

The incidence of cardiovascular complications may be higher in unilateral than bilateral primary aldosteronism (PA). We compared noninvasive hemodynamics after targeted therapy of bilateral vs. unilateral PA. Adrenal vein sampling was performed, and hemodynamics recorded using radial artery pulse wave analysis and whole-body impedance cardiography (n = 114). In 40 patients (adrenalectomy n = 20, spironolactone-based treatment n = 20), hemodynamic recordings were performed after 33 months of PA treatment. In initial cross-sectional analysis, 51 patients had bilateral and 63 unilateral PA. The mean ages were 50.6 and 54.3 years (P = 0.081), and body mass indexes 30.3 and 30.6 kg/m2 (P = 0.724), respectively. Aortic blood pressure (BP) and cardiac output did not differ between the groups, but left cardiac work was ~10% higher in unilateral PA (P = 0.022). In the follow-up study, initial and final BPs in the aorta were not significantly different, while initial cardiac output (+13%, P = 0.015) and left cardiac work (+17%, P = 0.009) were higher in unilateral than bilateral PA. After median treatment of 33 months, the differences in cardiac load were abolished, and extracellular water volume was reduced by 1.3 and 1.4 l in bilateral vs. unilateral PA, respectively (P = 0.814). These results suggest that unilateral PA burdens the heart more than bilateral PA, providing a possible explanation for the higher incidence of cardiac complications in unilateral disease. A similar reduction in aldosterone-induced volume excess was obtained with targeted surgical and medical treatment of PA.

Machine learning-based differentiation of uni- and bilateral primary aldosteronism using circulating microRNA combinations

Machine learning-based differentiation of uni- and bilateral primary aldosteronism using circulating microRNA combinations

Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism.

Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism.

Clinical prediction model for primary aldosteronism subtyping and special focus on adrenal volumetric assessment.

Our aim was to develop a prediction model based on a simple score with clinical, laboratory, and imaging findings for the subtype diagnosis of primary aldosteronism (PA). The contribution of adrenal volumetric assessment to PA subtyping was also investigated. Thirty-five patients with adequate cannulation in adrenal venous sampling (AVS) were included. Laboratory data, the saline infusion test (SIT), and the AVS results of patients with PA were retrospectively evaluated. Volumetric assessment was performed using magnetic resonance imaging (MRI) and the ratio of adrenal volumes was calculated after adjusting for gender- and side-specific mean reference values of both adrenal glands. The AVS was consistent with unilateral PA in 49% and bilateral in 51% of the patients. Hypertension as a reason for work-up, the highest aldosterone/lowest potassium value higher than 12, the percentage of plasma aldosterone concentration (PAC) reduction after SIT by equal or less than 43.5%, the use of oral potassium replacement, unilateral disease at pre-AVS imaging, and a ratio of adjusted adrenal volumes equal to or below 1.7 were indicative of unilateral disease in univariate logistic regression analysis concerning the distinction of PA subtyping (p < 0.05). Multivariate logistic regression analysis also revealed that adrenal volumetric assessment has an impact on PA subtyping (p < 0.05). In the prediction model, when each of the six parameters that were significant in the univariate logistic regression analysis was assigned one point, < 4 predicted bilateral PA, whereas ≥ 4 predicted unilateral PA (AUC:0.92, p < 0.001). This prediction model before AVS may serve as a convenient and practical approach, while an adjusted adrenal volumetric assessment can make a positive contribution to PA subtyping.

Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling for the subtyping of primary aldosteronism: a prospective study.

Adrenal venous sampling (AVS) is key for primary aldosteronism subtype identification. However, the value of adrenocorticotropic hormone (ACTH) stimulation in AVS is still controversial. In this prospective study, we investigated the role of continuous ACTH infusion on the performance and interpretation of bilateral simultaneous AVS using a standard protocol in 59 primary aldosteronism patients. We analyzed the selectivity index and lateralization index in AVS pre and post-ACTH and estimated the prognosis of patients who underwent adrenalectomy with different cutoff points of lateralization index post-ACTH. The confirmed success rate of bilateral adrenal vein catheterization increased from 84% pre-ACTH to 95% post-ACTH. Fifty percent of the patients had a decline in lateralization index post-ACTH, 30% of patients showed unilateral primary aldosteronism pre-ACTH but bilateral primary aldosteronism post-ACTH according to lateralization index at least 2 pre-ACTH and lateralization index at least 4 post-ACTH. The outcomes of the patients with primary aldosteronism after adrenalectomy indicated that all patients achieved clinical and biochemical success regardless of lateralization index at least 4 or less than 4 post-ACTH. Receiver operating characteristic curves showed that lateralization index cutoff 2.58 post-ACTH stimulation yielded the best threshold in lateralization with a sensitivity of 73.1% and a specificity of 92.9%. ACTH stimulation increased the AVS success rates in patients with primary aldosteronism, reduced lateralization index in some cases and decreased the proportion of identified unilateral primary aldosteronism, resulting in some patients losing the opportunity for disease cure. Compared with lateralization index at least 4, a lower cutoff point of lateralization index at least 2.58 after ACTH stimulation has better accuracy of lateralization diagnosis.

What We Know about and What Is New in Primary Aldosteronism.

Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension. Notably, hypokalaemia is present in only 28% of patients with PA and is not a primary indicator. The association of PA with an escalated cardiovascular risk profile, independent of blood pressure levels, is notable. Patients with PA exhibit a heightened incidence of cardiovascular events compared to counterparts with essential hypertension, matched for age, sex, and blood pressure levels. Despite its prevalence, PA remains frequently undiagnosed, underscoring the imperative for enhanced screening protocols. The diagnostic process for PA entails a tripartite assessment: the aldosterone/renin ratio (ARR) as the initial screening tool, followed by confirmatory and subtyping tests. A positive ARR necessitates confirmatory testing to rule out false positives. Subtyping, achieved through computed tomography and adrenal vein sampling, aims to distinguish between unilateral and bilateral PA forms, guiding targeted therapeutic strategies. New radionuclide imaging may facilitate and accelerate such subtyping and localisation. For unilateral adrenal adenoma or hyperplasia, surgical intervention is optimal, whereas bilateral idiopathic hyperplasia warrants treatment with mineralocorticoid antagonists (MRAs). This review amalgamates established and emerging insights into the management of primary aldosteronism.

Multifocal, Asymmetric Bilateral Primary Aldosteronism Cannot be Excluded by Strong Adrenal Vein Sampling Lateralization: An International Retrospective Cohort Study.

Primary aldosteronism (PA) has been broadly dichotomized into unilateral and bilateral forms. Adrenal vein sampling (AVS) lateralization indices (LI) ≥2 to 4 are the standard-of-care to recommend unilateral adrenalectomy for presumed unilateral PA. We aimed to assess the rates and characteristics of residual PA after AVS-guided adrenalectomy. We conducted an international, retrospective, cohort study of patients with PA from 7 referral centers who underwent unilateral adrenalectomy based on LI≥4 on baseline and/or cosyntropin-stimulated AVS. Aldosterone synthase (CYP11B2) immunohistochemistry and next generation sequencing were performed on available formalin-fixed paraffin-embedded adrenal tissue. The cohort included 283 patients who underwent AVS-guided adrenalectomy, followed for a median of 326 days postoperatively. Lack of PA cure was observed in 16% of consecutive patients, and in 22 patients with lateralized PA on both baseline and cosyntropin-stimulated AVS. Among patients with residual PA postoperatively, 73% had multiple CYP11B2 positive areas within the resected adrenal tissue (versus 23% in those cured), wherein CACNA1D mutations were most prevalent (63% versus 33% in those cured). In adjusted regression models, independent predictors of postoperative residual PA included Black versus White race (odds ratio, 5.10 [95% CI, 1.45-17.86]), AVS lateralization only at baseline (odds ratio, 8.93 [95% CI 3.00-26.32] versus both at baseline and after cosyntropin stimulation), and CT-AVS disagreement (odds ratio, 2.75 [95% CI, 1.20-6.31]). Multifocal, asymmetrical bilateral PA is relatively common, and it cannot be excluded by robust AVS lateralization. Long-term postoperative monitoring should be routinely pursued, to identify residual PA and afford timely initiation of targeted medical therapy.

Urine steroid metabolomics as a diagnostic tool in primary aldosteronism

Primary aldosteronism (PA) causes 5–10% of hypertension cases, but only a minority of patients are currently diagnosed and treated because of a complex, stepwise, and partly invasive workup. We tested the performance of urine steroid metabolomics, the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the identification and subtyping of PA. Mass spectrometry-based multi-steroid profiling was used to quantify the excretion of 34 steroid metabolites in 24-hour urine samples from 158 adults with PA (88 with unilateral PA [UPA] due to aldosterone-producing adenomas [APAs]; 70 with bilateral PA [BPA]) and 65 sex- and age-matched healthy controls. All APAs were resected and underwent targeted gene sequencing to detect somatic mutations associated with UPA. Patients with PA had increased urinary metabolite excretion of mineralocorticoids, glucocorticoids, and glucocorticoid precursors. Urine steroid metabolomics identified patients with PA with high accuracy, both when applied to all 34 or only the three most discriminative steroid metabolites (average areas under the receiver-operating characteristics curve [AUCs-ROC] 0.95–0.97). Whilst machine learning was suboptimal in differentiating UPA from BPA (average AUCs-ROC 0.65–0.73), it readily identified APA cases harbouring somatic KCNJ5 mutations (average AUCs-ROC 0.79–85). These patients showed a distinctly increased urine excretion of the hybrid steroid 18-hydroxycortisol and its metabolite 18-oxo-tetrahydrocortisol, the latter identified by machine learning as by far the most discriminative steroid. In conclusion, urine steroid metabolomics is a non-invasive candidate test for the accurate identification of PA cases and KCNJ5-mutated APAs.