BACKGROUND:Prior retrospective studies of aldosterone-renin ratio (ARR) measures were confounded by selection bias. METHODS:To define ARR sensitivity independent of case definition, administrative health and diagnostic imaging repositories in Alberta, Canada, were used to construct a 5-component definition for primary aldosteronism (PA) for the most easily recognizable cases. Components included hypertension, hypokalemia, adrenal mass, suppressed renin, and nonsuppressed aldosterone. ARR was omitted from the definition, permitting independent evaluation of the ARR using receiver operating characteristic curve analysis. The definition was validated by adrenal vein sampling and surgical outcomes. RESULTS:Of 931 adrenal vein sampling patients, 19.2% met the 5-component PA case definition; of these, 86.8% had unilateral disease, and of the 76.8% who underwent surgery, 91.2% achieved complete biochemical response. Between 2012 and 2019, 6717 patients with hypertension had ARR measured; 60.9% had computed tomography or magnetic resonance imaging performed for any reason. The prevalence of the 5-component PA cases was 4.8% by direct renin concentration and 6.6% by plasma renin activity. The area under the receiver operating characteristic curve for the ARR was 0.84 (0.81-0.86) and 0.82 (0.78-0.85) when direct renin concentration and plasma renin activity were used. The 90% sensitivity ARR threshold for the 5-component PA case definition was 26 pmol/mIU (direct renin) and 350 pmol/ng per mL/h (renin activity), with specificities of 60% and 56%. At 5% prevalence rates, positive predictive values were 11% and 10%. Commonly recommended ARR screening thresholds of 70 pmol/mIU or 550 pmol/ng per mL/h had sensitivities of 68% and 82%, respectively, for a surgically relevant PA phenotype. CONCLUSIONS:Current ARR thresholds have low-to-moderate sensitivity for cases of PA where adrenal vein sampling and surgery are strong considerations.

Confirmatory testing to verify the diagnosis of primary aldosteronism (PA) in patients who have an abnormal screening result is of uncertain benefit. To perform a blinded assessment of the seated saline suppression test (SSST). Diagnostic test accuracy study. (ClinicalTrials.gov: NCT04422756). The regional Endocrine Hypertension Clinic in Calgary, Alberta, Canada. 156 adults with a positive screening result for PA. The SSST was done by administering 2 L of 0.9% sodium chloride intravenously over 4 hours with the patient seated. Treatment response was considered the reference standard for determining disease status and was based on blood pressure lowering, reduction of antihypertensive drug dose, and normalization of biochemistry. Measures of diagnostic test accuracy, including sensitivity, specificity, positive predictive value, and negative predictive value, were estimated. Post-SSST aldosterone concentrations measured using immunoassay overlapped between treatment responders (median, 329 pmol/L [IQR, 227 to 525 pmol/L]) and nonresponders (median, 255 pmol/L [IQR, 162 to 346 pmol/L]). The SSST could not discriminate between response statuses (area under the curve, 62.1% [95% CI, 45.1% to 79.1%]). The positive and negative likelihood ratios were equivocal for aldosterone cutoffs ranging from 140 to 300 pmol/L. These findings remained consistent after differences in treatment, occurrence of hypokalemia, and laboratory assay used were accounted for. The study population had many patients with high-risk features of PA and few nonresponders. The SSST is associated with a high false-negative rate, and reliance on it may lead to missed opportunities for intervention. The Canadian Institutes of Health Research, Hypertension Canada, and the Heart and Stroke Foundation of Canada.

BACKGROUND:Lateralization by adrenal vein sampling (AVS) is the gold standard for diagnosis of unilateral primary aldosteronism. Aldosterone production from the contralateral gland suggests bilateral disease; however, little is known regarding outcomes from patients with grossly elevated (but asymmetrical) contralateral aldosterone production after unilateral adrenalectomy. METHODS:A retrospective chart review was performed of cases from the Calgary AVS database with (1) successful AVS (selectivity index ≥3 bilaterally after cosyntropin stimulation); (2) lateralization by AVS (lateralization index ≥3), stimulated or unstimulated; (3) absence of contralateral suppression (contralateral suppression index ≥2 on the nondominant side) stimulated or unstimulated; and (4) underwent unilateral adrenalectomy guided by AVS lateralization. Postsurgical outcomes were classified per PASO criteria. RESULTS:A total of 29 cases met inclusion criteria and underwent unilateral adrenalectomy with postsurgical outcomes available. Of patients with biochemical follow-up data, 20 of 27 had a complete biochemical response and 3 of 27 a partial response (median follow-up time of 10.3 weeks, interquartile range, 4.0-18.3). Four of 29 patients had a complete clinical response, while 18 of 29 patients had a partial clinical response (median follow-up time of 27.3 weeks, interquartile range, 10.7-35.6), such that 75% of patients had either complete or partial clinical response to unilateral adrenalectomy. CONCLUSIONS:In patients with bilateral (elevated contralateral suppression index) but asymmetrical primary aldosteronism, unilateral adrenalectomy can achieve positive biochemical and clinical outcomes in the short to mid-term. Elevated contralateral suppression index should not necessarily preclude recommendation of unilateral adrenalectomy in patients with lateralized primary aldosteronism, though longer-term studies are needed to clarify the rates of disease recurrence and benefits of a debulking procedure.

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

Abstract Patients with primary aldosteronism (PA) have increased morbidity and mortality compared to those with essential hypertension. Accurate detection of lateralized PA is important so that affected patients can receive potentially curative adrenalectomy. However, around 40% of patients with lateralized PA have “normal” adrenal glands on computed tomography (CT). Additional independent review of imaging has been shown to improve diagnostic accuracy in many areas of imaging. Therefore, the authors sought to establish if multi‐reader re‐assessment of previously reported normal CT scans would result in increased detection of surgically remediable disease. The authors found that re‐assessment of CT imaging by one, two, or three additional radiologists (or a combination thereof) slightly increased the detection of lateralized disease, but these differences were not statistically significant (p > .05). Readers had low inter‐observer agreement (kappa = 0.17). If detection of a discrete nodule on CT was made a prerequisite for adrenal vein sampling (AVS), a second read by another reviewer would still result in an excess of missed cases (84.2%, 36.8%, and 65.8%, respectively, for each of the three independent reviewers). Therefore, a “normal” CT does not preclude the possibility of lateralized PA. Adrenal vein sampling should still be strongly considered wherever available and whenever surgery is considered for treatment of PA, irrespective of CT findings.

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

Adrenal vein sampling (AVS) is a recommended if not required final diagnostic step in the investigation of primary aldosteronism, the most common cause of remediable secondary hypertension. Successful adrenal vein sampling is operator-dependent. Having performed over 600 such procedures at our centre over 20 years, our single-operator experience is described in detail for the purpose of training future radiologists as well as for use by those who are planning to start an AVS programme of their own. This updated review considers new developments in primary aldosteronism disease understanding that are relevant for AVS performance and protocols, along with technical enhancements that may be used for special cases. Detailed understanding of variant anatomy and tips for successful cannulation are keys to success, along with an endocrinology and clinical chemistry partnership for continuous quality control. A successful AVS programme offers patients a hope for cure of resistant hypertension.

BACKGROUND Targeted treatment of primary aldosteronism (PA) is informed by adrenal vein sampling (AVS), which remains limited to specialized centers. Clinical prediction models have been developed to help select patients who would most likely benefit from AVS. Our aim was to assess the performance of these models for PA subtyping. METHODS This external validation study evaluated consecutive patients referred for PA who underwent AVS at a tertiary care referral center in Alberta, Canada during 2006-2018. In alignment with the original study designs and intended uses of the clinical prediction models, the primary outcome was the presence of lateralization on AVS. Model discrimination was evaluated using the C-statistic. Model calibration was assessed by comparing the observed vs. predicted probability of lateralization in the external validation cohort. RESULTS The validation cohort included 342 PA patients who underwent AVS (mean age, 52.1 years [SD, 11.5]; 201 [58.8%] male; 186 [54.4%] with lateralization). Six published models were assessed. All models demonstrated low-to-moderate discrimination in the validation set (C-statistics; range, 0.60-0.72), representing a marked decrease compared with the derivation sets (range, 0.80-0.87). Comparison of observed and predicted probabilities of unilateral PA revealed significant miscalibration. Calibration-in-the-large for every model was >0 (range, 0.35-1.67), signifying systematic underprediction of lateralizing disease. Calibration slopes were consistently <1 (range, 0.35-0.87), indicating poor performance at the extremes of risk. CONCLUSIONS Overall, clinical prediction models did not accurately predict AVS lateralization in this large cohort. These models cannot be reliably used to inform the decision to pursue AVS for most patients.

Background Patients with primary aldosteronism (PA) without apparent adrenal nodularity have not been well characterised in the literature. The aim of this study was to assess for unilateral aldosterone hypersecretion among patients with primary aldosteronism with normal-appearing adrenals using adrenal vein sampling (AVS). Methods In this cross-sectional study performed at a Canadian tertiary care centre, we reviewed all consecutive PA patients lacking a definitive adrenal nodule who were referred for AVS in the work-up of PA between January 2006 and May 2018. AVS indications included an elevated aldosterone-to-renin ratio and high-probability features of PA. Results In total, 174 patients were included (mean age, 52.0 years; 62.6% male), and 70 (40.2%) had unilateral aldosterone hypersecretion. There was a positive linear association between higher age categories (by decade) and lateralisation (P = 0.03). For every decade of age, there was a 30% higher odds of lateralisation (odds ratio, 1.03 per year; 95% confidence interval, 1.00-1.05). The frequency of lateralisation was higher in males compared with females (47.7% vs 27.7%), with a 2-fold greater odds of unilateral disease (odds ratio, 2.38; 95% confidence interval, 1.23-4.61). Traditional biomarkers of lateralisation among patients with adrenal nodules (eg, serum potassium and aldosterone-to-renin ratio levels) were not predictive of lateralisation in this population. Conclusions Many patients with PA who lack definitive adrenal nodules have lateralising disease. Efforts to optimise referrals for AVS may be prioritised by focusing on patients most likely to have unilateral disease, especially males and older adults.

Adrenal vein sampling (AVS) and computed tomography (CT) often show confusingly discordant lateralisation results in primary aldosteronism (PA). We tested a biochemical algorithm using AVS data to detect cortisol cosecretion as a potential explanation for discordant cases.

Background Adrenal vein sampling (AVS) failure is mainly due to right adrenal vein unavailability. Multinomial regression modelling (MRM) and left adrenal vein-to-peripheral vein ratio (LAV/PV) were proposed to predict the lateralization index without the right AVS. Objective To assess external validity of MRM and LAV/PV to predict lateralization index when right adrenal vein sampling is missing. Design Diagnostic retrospective study. Patients Development and validation cohorts included AVS of 174 and 122 patients, respectively, from 2 different centres. Measurements Development and validation cohort data were used, respectively, for calibration and for validation of MRM and LAV/PV to predict the lateralization index without the right adrenal vein sampling. Sensitivity and specificity of MRM and LAV/PV were compared between both centres at different pre-established specificity thresholds based on receiver operating characteristic curves generated from the development cohort data. Results At a specificity threshold of 95% set in the development cohort, specificity values exceeded 90% (range, 90.6%-98.8%) for all verified MRM and LAV/PV models in the validation cohort. Corresponding sensitivities for MRM and LAV/PV, respectively, range from 54.1% to 83.7% and 32.8% to 88.4% for the development cohort compared to 33.3%-87.5% and 2.8%-79.2% for the validation cohort. Overall, diagnostic accuracy of both methods was higher to detect right (82.8%-93.5%) than left (70.2%-80.6%) lateralization index status in both centres. Conclusions Minimal changes in specificity from development to validation cohorts validate the use of MRM and LAV/PV to predict the lateralization index when the right AVS is missing. Both methods had better accuracy for right than left lateralization detection.

CONTEXT:Many patients with unilateral primary aldosteronism (PA) have normal adrenal imaging, but little is known about their outcome following adrenalectomy.OBJECTIVE:To evaluate biochemical and clinical outcomes after adrenalectomy in patients with unilateral PA and normal-appearing adrenal imaging.DESIGN:Retrospective cohort study of patients seen between January 2006 and May 2018.SETTING:A Canadian tertiary care PA referral center.PATIENTS:Consecutive individuals with PA, normal cross-sectional adrenal imaging, and lateralizing adrenal vein sampling (AVS) who underwent adrenalectomy during the study period.PRIMARY OUTCOME:Biochemical response to adrenalectomy graded according to the Primary Aldosteronism Surgical Outcome criteria.RESULTS:A total of 40 patients were included. Biochemical outcomes were available for 33 people (mean age, 54.7 years; 91% male; median follow-up, 2.7 months), with 28 (85%) showing a complete or partial response and 5 (15%) with no response. Clinical outcomes were available for 36 people (mean age, 54.6 years; 86% male; median follow-up, 9.8 months), with 31 (86%) demonstrating a complete or partial response and 5 (14%) with no response.CONCLUSIONS:The prognosis after adrenalectomy is highly favorable for patients with unilateral PA and normal-appearing adrenal imaging. Patients with lateralizing disease should be considered for surgery despite apparently normal adrenal imaging.

Context: The reproducibility of adrenal vein sampling (AVS) is unknown.Objective: This work aimed to determine reproducibility of biochemical results and diagnostic lateralization in patients undergoing repeat AVS.Methods: A retrospective chart review was conducted of single-center, single-operator AVS procedures at a tertiary care center. Included were patients with confirmed primary aldosteronism (PA) undergoing repeat AVS because of concerns about technical success or discordant diagnostic results. Simultaneous AVS was performed by an experienced operator using a consistent protocol of precosyntropin and postcosyntropin infusion. Among successfully catheterized adrenal veins (selectivity index >= 2), the correlation of the adrenal(aldosterone/cortisol) (A/C) ratio was measured between the first and second AVS. The secondary outcome measure was diagnostic agreement on repeat AVS lateralization (lateralization index >= 3).Results: There were 46 sets of AVS from 23 patients at a median of 3 months apart. There was moderate correlation in A/C ratios in the adrenal veins and inferior vena cava (Spearman r = 0.49-0.59, P < .05) pre cosyntropin. Post cosyntropin, the correlation was better (Spearman r = 0.67-0.76, P < .05). In technically successful AVS, there was moderate correlation between the repeated lateralization indices (Spearman r = 0.53, P < .05). In 15 patients in whom repeat AVS was performed because of apparent lateralization discordance with computed tomography imaging, the final diagnosis was the same in the second AVS procedure. Initial failed AVS was successful 75% of the time on repeat attempt.Conclusion: Repeat AVS was feasible and usually successful when an initial attempt failed. There was modest correlation between individual repeat adrenal A/C ratios and lateralization indices when AVS was performed twice. The final lateralization diagnosis was identical in all cases. This demonstrates that AVS is a reliable and reproducible localizing test in PA.

Abstract Background: Adrenal venous sampling (AVS) is performed to distinguish between unilateral or bilateral source of aldosterone in primary aldosteronism (PA). Unilateral aldosteronomas should lead to suppression of renin and contralateral (CL) aldosterone secretion, assessed by the CL suppression ratio. We recently found that CL aldosterone suppression was relatively rare using the ratio of basal aldosterone concentration of the opposite adrenal vein/periphery (AOPP/AP) in contrast to the traditional cortisol-corrected aldosterone ratio ((A/C)OPP(A/C)P). Pathology studies showed frequent zona glomerulosa (ZG) hyperplasia adjacent to a dominant aldosteronoma, which could also indicate probable ZG hyperplasia in the CL adrenal. The ratio of basal CL suppression could be a usefull parameter to predict cure following unilateral adrenalectomy (UA), but controversy remains in the literature. Objectives: 1. To evaluate the prevalence of basal CL suppression using the AOPP/AP ratio as compared to the (A/C)OPP/(A/C)P ratio at previously established cut-offs. 2. To determine the best cut-off to predict clinical and biochemical surgical cure in two Canadian referral centers. 3. To compare the accuracy of the AOPP/AP ratio to the basal lateralization ratio (LR) and the post-ACTH LR in predicting the surgical outcome. Methods: 330 patients with PA and successful bilateral simultaneous basal and post-ACTH stimulated AVS (selectivity index >2 basally and >5 post-ACTH) were included; 124 patients found to be lateralized underwent UA. The follow-up data were evaluated for clinical and biochemical cure at 3 and 12 months using the PASO criteria. Results: Using AOPP/AP and (A/C)OPP/(A/C)P at the cut-off of 1, the prevalence of CL suppression is 6% and 45%, respectively. The median CL suppression ratio is 2.3 (1.3-5.1) in lateralized cases of PA using AOPP/AP. Using ROC curves, the AOPP/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)OPP/(A/C)P is associated with biochemical cure only. The cut-offs for AOPP/AP offering the best sensitivity and specificity for clinical and biochemical cures at 12 months are 2.15 (Se 63% and Sp 71%) and 6.15 (Se 84% and Sp 77%), respectively. Basal LR and post-ACTH LR are associated with clinical cure but only the post-ACTH LR is associated with biochemical cure. Conclusions: Basal CL suppression defined by the AOPP/AP ratio is rare and incomplete compared to the traditional (A/C)OPP/(A/C)P ratio in lateralized cases of PA. This may reflect the frequent micronodular hyperplasia adjacent to dominant aldosteronomas and possibly in the CL adrenal. Basal CL aldosterone suppression may predict clinical postoperative outcome, but with modest accuracy.

CONTEXT:Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes.OBJECTIVES:To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure.METHODS:In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria.RESULTS:Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure.CONCLUSIONS:In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.

BACKGROUND:Subtyping of primary aldosteronism (PA) using imaging and adrenal vein sampling (AVS) may yield discordant results, causing confusion in management. Interpretation criteria for AVS lateralization may affect discordance rates.METHODS:We identified consecutive patients with PA who underwent AVS at a quaternary care center between January 2006 and May 2018. Patient demographics, laboratory results, diagnostic imaging, and AVS results were retrieved. Adrenal cross-sectional imaging was compared with AVS findings. The presence of lateralization was defined using varying thresholds for the lateralization index (LI) from >2:1 to >5:1. Discordance was defined by a unilateral lesion on imaging with contralateral or nonlateralization on AVS.RESULTS:A total of 342 patients were included; 68.7% had hypokalemia. With cross-sectional imaging, 191 (55.6%) patients had unilateral lesions, 47 (13.7%) had bilateral lesions, and 104 (30.4%) had normal imaging. Overall discordance rates were high, ranging from 22% to 28% for LI thresholds of >2:1 and >5:1, respectively. Discordance between imaging and AVS was positively correlated with LI threshold stringency (P < 0.001). Patients with normal or bilateral lesions on imaging frequently lateralized on AVS. Lateralization, when present, was approximately equal between left and right sides, irrespective of the LI threshold.CONCLUSIONS:Discrepancies between imaging and AVS were common, even among patients with nonspecific imaging. Discordance was greatest with the strictest AVS interpretation criteria. Even under the most lenient thresholds, apparent discordance between imaging and AVS exceeded 20% and may limit the ability to make surgical decisions. Reliance on imaging alone for detecting lateralization may be misleading.

Background: Constituitively high and nonsuppressible aldosterone levels are considered to be the hallmark of primary aldosteronism. We observed a high proportion of primary aldosteronism patients with surprisingly low aldosterone levels in peripheral veins during adrenal vein sampling (AVS) and sought to further characterize the phenomenon. Methods: Database analysis of patients with primary aldosteronism at the University of Calgary who underwent AVS under intravenous sedation. Aldosterone levels following sedation were compared with aldosterone measured at diagnosis in the free-living state. A validation analysis was performed on a similar database from the University of British Columbia. Results: Seventy-two percent of 127 patients had AVS aldosterone levels more than 30% lower than their outpatient aldosterone measure (468 vs. 278 pmol/l, P< 0.001). Thirty-nine percent of patients had aldosterone levels less than 200 pmol/l and 13% had levels less than 140 pmol/l during AVS. Repeat analysis on the UBC cohort produced similar results with 88% having an aldosterone more than 30% lower than the outpatient measure (median aldosterone 568 vs. 201 pmol/l, P< 0.001). Conclusion: A majority of primary aldosteronism patients have markedly lower aldosterone levels during sedated AVS compared with those found during outpatient diagnosis. In the absence of confounding medications, hypokalemia, circadian timing, postural variation and with low correlation to measures of hypothalamic-pituitaryadrenal activity, this suggests that many primary aldosteronism patients may, at times, have aldosterone levels that are surprisingly low-normal. This finding challenges the concept that a persistently high and nonsuppressible aldosterone level is a sine qua non of primary aldosteronism.

In patients with primary aldosteronism (PA), adrenal venous sampling (AVS) is recommended to differentiate between unilateral (UNI) or bilateral (BIL) adrenal disease. A recent study suggested that lateralization could be predicted, based on the ratio of aldosterone/cortisol levels (A/C) between the left adrenal vein (LAV) and inferior vena cava (IVC), with a 100% positive predictive value (PPV). This study aimed to validate those findings utilizing a larger, multi-institutional cohort.

OBJECTIVES:Adrenal vein sampling (AVS) is intended to confirm unilateral forms of primary aldosteronism, which are amenable to surgical cure. Excessively strict AVS criteria to define lateralization may result in many patients incorrectly categorized as bilateral primary aldosteronism and opportunity for surgical cure missed. METHODS:Retrospective review of an AVS-primary aldosteronism database in which surgical cases are verified by standardized outcomes. Having used 'less strict' AVS criteria for lateralization, we examined the distribution of AVS lateralization indices in our confirmed unilateral primary aldosteronism cases both with and without cosyntropin stimulation. The proportion of proven unilateral cases that would have been missed with stricter AVS interpretation criteria was calculated. Particular focus was given to the proportion of missed cases according to use of international guidelines. False-positive lateralization with 'less strict' interpretation was also calculated. RESULTS:Of 80 surgical primary aldosteronism cases, 10-23% would have been missed with AVS lateralization indices of 3 : 1 to 5 : 1, with or without cosyntropin. If strict selectivity indices (for confirmation of catheterization) were combined with strict lateralization indices, up to 70% of unilateral primary aldosteronism cases could have been missed. Use of Endocrine Society AVS guidelines would have missed 21-43% of proven unilateral cases. 'Less strict' AVS interpretation yielded one case (1.2%) of false lateralization. CONCLUSION:Excessively strict AVS interpretation criteria will result in a high rate of missed unilateral primary aldosteronism with subsequent loss of opportunity for intervention. Use of more lenient lateralization criteria will improve the detection rate of unilateral primary aldosteronism with very low false-positive rate.

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