C. Benjamin So

Background: Uncontrolled hypertension is prevalent in sub‐Saharan Africa and a major contributor to premature morbidity. The reasons may not be identical to those reported in studies of Black patients in Western countries. Recent African immigration to western Canada permits the study of hypertension mechanisms in African Black patients. Methods: Retrospective study of 15 years' experience (2010–2025) with hypertensive first‐generation African immigrants to a resistant hypertension clinic in Alberta, Canada. Results: With uniform screening for primary aldosteronism (PA), PA was found in 93% of all African patients (n=114) versus 46.8% in non‐African referred patients (n=792; P 277 pmol/L, so diagnosis was not due solely to low renin. Only 17% had adrenal abnormalities on imaging. In those with adrenal vein sampling, there were no cases where unilateral adrenal disease was seen both before and after cosyntropin without adrenal nodules; contralateral suppression was present in just 14%. Cortisol cosecretion was present in many of those with visible adrenal nodules and in the few with adrenalectomy, none achieved both a complete clinical and biochemical response. Conclusions: Among first‐generation African immigrants with hypertension, 93% fit a clear diagnosis of PA, a prevalence figure far in excess of any other population ever reported. Most of the PA phenotype was bilateral aldosterone excess; surgical cases and complete responders to adrenalectomy were rare. This, the largest detailed study of PA in African patients with hypertension, if confirmed, has important implications for hypertension assessment and treatment for African Black patients.

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.

BACKGROUND: Confirmatory testing to identify lateralizing primary aldosteronism (PA) is of uncertain benefit. METHODS: Blinded clinical trial where patients with high-risk features for PA underwent the seated saline suppression test (SSST). All patients received adrenal vein sampling, where lateralization was defined by an aldosterone/cortisol ratio ≥3:1 comparing the dominant versus the nondominant sides. The primary outcome was the overall diagnostic accuracy of the SSST in identifying lateralizing PA using postinfusion aldosterone concentrations of ≥140 pmol/L (5.0 ng/dL) and ≥280 pmol/L (10.1 ng/dL) with immunoassay, and ≥162 pmol/L (5.8 ng/dL) with liquid chromatography/tandem mass spectrometry. RESULTS: A total of 160 patients completed the trial. Lateralizing PA was diagnosed in 98 patients (61.3%). The overall diagnostic accuracy of the SSST using an aldosterone cutoff of ≥140 pmol/L (5.0 ng/dL) and ≥280 pmol/L (10.1 ng/dL) was 64.4% (95% CI, 56.4–71.8) and 67.5% (95% CI, 59.7–74.7), respectively. A positive result was equivocal at the lower cutoff of ≥140 pmol/L (5.0 ng/dL; positive likelihood ratio, 1.1 [95% CI, 1.0–1.3]) and minimally informative at the higher cutoff of ≥280 pmol/L (10.1 ng/dL; positive likelihood ratio, 1.9 [95% CI, 1.3–2.7]). Negative results modestly ruled against lateralization using cutoffs of ≥140 pmol/L (5.0 ng/dL) and ≥280 pmol/L (10.1 ng/dL; negative likelihood ratio, 0.3 [95% CI, 0.1–0.9]; and 0.5 [95% CI, 0.3–0.7], respectively). The SSST properties were similar with liquid chromatography/tandem mass spectrometry. CONCLUSIONS: Aldosterone suppression testing is unreliable for anticipating adrenal vein sampling outcomes. The SSST may misinform diagnostic-treatment decisions. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04422756.

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.

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.

Objective: Adrenal vein sampling (AVS) is considered the gold-standard for identifying unilateral primary aldosteronism (PA), but is sensitive to any asymmetry in cortisol production. Subclinical autonomous cortisol production likely contributes to discordance between cross-sectional imaging and AVS. Design and Methods: Retrospective chart review was performed of patients in Calgary, Alberta who (1) had a diagnosis of PA with clear adrenal mass, (2) had discordant AVS and cross-sectional imaging, and (3) underwent dexamethasone-suppressed NP59-iodocholesterol adrenal scintigraphy (n = 25). Postoperative biochemical and clinical outcomes were evaluated. Surgical pathology was analyzed with immunohistochemical staining for CYP11B1 and CYP11B2. Results: NP59 scanning demonstrated autonomous steroidogenesis from the same side as the computed tomography (CT)-identified lesion, despite discordant AVS results, in 19/25 cases. Out of the 16 patients who underwent adrenalectomy (guided by NP59), 11 cases had a final diagnosis of cortisol-producing adenoma with bilateral PA, while the final diagnosis in the remaining 5 cases was cortisol-producing adenoma with unilateral PA (defined by a complete biochemical response). All cases preoperatively had low/suppressed adrenocorticotropin hormone that rose postadrenalectomy, in keeping with the resolution of cortisol autonomy. Adrenal vein sampling incorrectly diagnosed the subtype of PA or falsely localized the side of aldosterone excess in 10/16 cases. Conclusions: Discordant CT and AVS results in patients with PA and obvious adrenal mass are often explained by subclinical asymmetric cortisol excess. Clinicians should be aware of the limitations of AVS in the presence of subtle autonomous cortisol secretion and must be able to counsel patients regarding the possible outcomes from surgery when discordant lateralization is present.

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. 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. 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. 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.

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.

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. 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. 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). 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–pituitary–adrenal 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.

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 centre 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 non-lateralization on AVS. Results A total of 342 patients were included and 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 LI thresholds. 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 still exceeded 20% and may limit the ability to make surgical decisions. Reliance on imaging alone for detecting lateralization may be misleading.