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Renin‐secreting tumours are rare causes of secondary hypertension and hypokalaemia. They are usually surgically curable, hence proper diagnostic work‐up and tumour localisation is essential. In this paper, we present three Swedish patients recently diagnosed with renin secreting tumours, two with reninomas and one with an extrarenal renin‐producing tumour, to illustrate diagnostic challenges. We also discuss the biochemical work‐up, the pros and cons of different imaging techniques (computer tomography [CT], magnetic resonance imaging and [18F]fluorodeoxyglucose‐positron emission tomography‐CT), as well as how renal vein sampling (RVC) may contribute to localisation of the tumour. [ABSTRACT FROM AUTHOR]

This document summarizes a study on the clinical outcomes of surgical management for primary aldosteronism (PA) when adrenal vein sampling (AVS) results are inconclusive. AVS is the preferred method for subtyping PA, but it can be challenging to successfully cannulate both adrenal veins. The study found that patients who had successful AVS and underwent unilateral adrenalectomy achieved clinical and biochemical remission. Patients with inconclusive AVS results were managed either surgically or with medical therapy, and the majority of those who underwent surgery achieved biochemical remission. The study suggests that inconclusive AVS results, along with imaging findings, can help guide surgical decision-making, but further research is needed to validate these findings. It also emphasizes that patients who are not candidates for surgery should not undergo AVS. [Extracted from the article]

Objectives: In patients with primary aldosteronism (PA), multiple adrenocortical nodules may be present on the surgical side. The aim of this study was to clarify the pathological diagnosis and the node‐by‐node diagnostic capability of segmental adrenal venous sampling (sAVS). Design: Retrospective study. Patients: A total of 162 patients who underwent adrenalectomy following sAVS were studied. Measurements: Multiple nodules on the surgical side were extracted while referring to contrast‐enhanced computed tomography images. We also performed a detailed histopathological analysis of the resected specimens from patients undergoing sAVS, which included immunohistochemistry for CYP11B2. Results: In 11 (6.8%) patients, two to three nodules were detected on the surgical side. All patients were diagnosed by sAVS with at least one aldosterone‐producing adenoma (APA) for localized aldosterone elevation in tributaries. Seven patients showed a lateralization index value of ≥4 after ACTH stimulation. Histopathologically and clinically, two patients had two or three CYP11B2‐positive APAs, and the other nine patients both APAs and non‐APAs. The positive predictive value of the most suspected APA, that is, the drainer that showed the highest aldosterone level by sAVS, was 11/11 (100%, 95% confidence interval [CI]: 71.5%–100%), while that for the second and third suspected APA was 3/7 (42.9%, 95% CI: 9.9%–81.6%), and they were significantly different (p =.01). Further, the positive predictive value of non‐APA was 4/4 (100%, 95% CI: 39.8%–100%). Conclusions: The sAVS could correctly diagnose the aldosterone production in multiple ipsilateral adrenal nodules. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the impact of indices of adrenal venous sampling (AVS) on postsurgical outcomes in patients with primary aldosteronism (PA). Design and Patients: This retrospective study determined biochemical and clinical outcomes based on ACTH‐stimulated AVS parameters (lateralisation index [LI], contralateral ratio [CLR], and ipsilateral ratio [ILR]) in 251 patients with PA at 3 months after surgery. Results: Modified complete biochemical success was achieved in 8 of 12 (66.7%) patients with LI = 3–4, 39 of 47 (83.0%) with LI = 4–10, and 155 of 169 (91.7%) with LI ≥ 10 (p =.004 for trend). Modified complete biochemical success was achieved in 29 of 38 (76.3%) patients with CLR ≥ 1 and ILR ≤ 2, 73 of 86 (84.9%) with CLR = 0.25–1 and ILR > 2, and 100 of 104 (96.2%) with CLR < 0.25 and ILR > 2 (p =.001 for trend). After adjusting for confounders, modified complete biochemical success was associated with an LI ≥ 10 (odds ratio [OR] = 6.32; 95% confidence interval [CI] = 1.33–29.93) using LI = 3–4 as a reference and combined CLR < 0.25 and ILR > 2 (OR = 11.49; 95% confidence interval [CI] = 2.49–53.01) using combined CLR ≥ 1 and ILR ≤ 2 as a reference. Using combined CLR ≥ 1 and ILR ≤ 2 as a reference, complete clinical success was associated with combined CLR < 0.25 and ILR > 2 (OR = 3.10; 95% CI = 1.03–9.28) and combined CLR = 0.25–1 and ILR > 2 (OR = 4.92; 95% CI = 1.64–14.76). Conclusion: LI ≥ 10 may be appropriate for achieving biochemical success. With ILR > 2, CLR < 0.25, and CLR < 1 may be appropriate for achieving biochemical and clinical success, respectively. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus (T2DM) and hypertension commonly coexist; however, underlying primary aldosteronism (PA) can lead to worsening of hypertension, glycemia and cardiovascular risk. We aim to screen patients with T2DM and hypertension for PA by conducting a prospective monocentric study from Western India, which included adults with T2DM and hypertension from the outpatient diabetes clinic. Design: Prospective study. Patients and Measurements: Patients with an aldosterone renin ratio of ≥1.6 ng/dl/µIU/ml with plasma aldosterone concentration (PAC) ≥ 10 ng/dl were considered to be positive on a screening test. A PAC ≥ 6 ng/dl on seated saline suppression test (SST) was used to confirm the diagnosis of PA. Results: Four hundred and eighty‐six patients were included in this study. Seventy‐six (15.6%, 95% confidence interval [CI]: 12.7%–19.1%) patients had a positive screening test with positive confirmatory test in 20 of the 36 (55.5%, 95% CI: 39.3%–71.7%) screen‐positive patients who underwent SST. Patients with positive screening test had a higher proportion of females (65.8% vs. 50%; p =.011), frequent history of hypertensive crises (21.1% vs. 8%; p =.001), uncontrolled blood pressure (51.3% vs. 34.6%; p =.006), diagnosis of hypertension before diabetes (32.9% vs. 21.7%; p =.035) and higher systolic (137.6 ± 6.9 vs. 131.2 ± 17.8 mmHg; p =.004) and diastolic (85.3 ± 11.1 vs. 81.7 ± 10.7 mmHg; p =.007) blood pressures. Patients with positive confirmatory test had longer duration of diabetes (108 [60–162] vs. 42 [24–87] months; p =.012), hypertension (84 [42–153] vs. 36 [15–81] months; p =.038) and higher creatinine (1.16 [1.02–1.42] vs. 0.95 [0.84–1.12] mg/dl; p =.021). Conclusions: PA is prevalent (at least 4.1%) in Asian Indian patients with T2DM and hypertension. Further studies are needed to assess the cost‐effectiveness of routine screening. [ABSTRACT FROM AUTHOR]

Context: Aldosterone has been recently characterized as a 'stress hormone'. Stress per se elicits a sizable rise in aldosterone secretion, which could be replicated by the administration of a low dose (0.03–1 μg, IV) of adrenocorticotropic hormone (ACTH). Whether or not the aldosterone response to ACTH could be selectively impaired, that is, in association with intact cortisol response, is presently unknown. Objective: To determine whether or not the aldosterone response to low dose of ACTH is impaired in subjects referred to assess the hypothalamic–pituitary–adrenal axis (HPA). Design: Retrospective analysis. Setting: Outpatient referral endocrine day care centre. Patients: One hundred and ninety‐five consecutive subjects who underwent the low dose (1 μg) ACTH test, in whom decreased cortisol reserve was suspected due to former/present glucocorticoid excess, pituitary disease or/and unexplained weakness. Main Outcome Measures: The outcome was the detection of lack of aldosterone response, defined as a rise <111 pmol/l. Results: In all, 46/195 subjects had subnormal aldosterone response as compared with 52/195 subjects showing diminished cortisol response. Nine subjects had combined deficient aldosterone and cortisol response. In the 37 subjects with isolated subnormal aldosterone response common associations were the use of exogenous glucocorticoids, mostly prednisone (n = 16); former Cushing disease (n = 2); nonfunctioning pituitary adenoma (n = 8); hypothyroidism (n = 11); the use of statins (n = 11), angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers (n = 6), sex steroids in transgenders and orthostatic hypotension (n = 3). Twenty‐seven percent (25/93) of the subjects with recent exposure to glucocorticoids had impaired aldosterone response to ACTH. Conclusion: Blunted aldosterone response to ACTH in the absence of hypoaldosteronism was seen in ~27% of subjects referred for HPA assessment using the low dose 1 μg ACTH test. Exposure to glucocorticoid excess was often linked to this impairment, independent of the cortisol response to ACTH. [ABSTRACT FROM AUTHOR]

Objective: Although renal impairments are observed in patients with primary aldosteronism (PA), the association between plasma aldosterone concentration (PAC) and specific structural kidney damage remains unknown. Thus, we analysed the association between PAC, and markers of glomerular and tubular damage. Design: This was a retrospective cross‐sectional study of 96 PA patients, in which we analysed the association between PAC and markers of kidney damage, including urinary albumin‐creatinine ratio (ACR) for glomerular damage, and urinary liver fatty acid‐binding protein (L‐FABP), N‐acetyl‐β‐D‐glucosaminidase (NAG) and β2‐microglobulin (β2‐MG) for tubular damage. In addition, we evaluated the association between PAC and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) as a marker for body fluid volume. Results: Urinary ACR, L‐FABP, NAG, β2‐MG and NT‐proBNP significantly correlated with PAC. PAC (<415 pmol/L, 415‐550, 550‐740, 740 <)‐based quartile analysis revealed that both elevated markers of kidney damage and NT‐proBNP could be observed in PA patients with a PAC over 550 pmol/L. Logistic regression analysis showed that PAC was significantly associated with a risk of both microalbuminuria and lowered eGFR (<60 mL/min/1.73 m2), with its optimal cut‐offs for predicting each, 558 and 594 pmol/L, respectively. Conclusions: Increased PAC, especially over 550 pmol/L, is associated with excessive damage to the tubule and glomerulus. [ABSTRACT FROM AUTHOR]

Context: The success rate of cannulation of the right adrenal vein is limited. The aldosterone gradient within the same adrenal vein branch is specific for aldosterone‐producing adenoma. Objective: This study was performed to investigate whether the absolute aldosterone gradient within the left adrenal vein (left‐AV absolute aldosterone gradient) indicates unilateral excess aldosterone. Design and setting: A retrospective cross‐sectional study in a single referral centre. Patients and methods: In total, 123 consecutive patients with primary aldosteronism who had successful adrenal vein sampling (AVS) data were examined. The left‐AV absolute aldosterone gradient was considered significant when a gradient of >4:1 in the aldosterone‐to‐cortisol ratio between the common trunk vein and central vein was found. Main outcome measure: The prevalence of the unilateral subtype in patients with a significant left‐AV absolute aldosterone gradient. Results: The prevalence of the unilateral subtype was higher in patients with than without a significant left‐AV absolute aldosterone gradient (88.2% [15/17] vs 21.7% [23/106], P <.001). Of 60 patients with spontaneous hypokalemia, left unilateral disease on computed tomography, or both, a significant left‐AV absolute aldosterone gradient was present only in patients with the unilateral subtype on AVS (42.9% [15/35]), but not in those with the bilateral subtype (0.0% [0/25]). These data were validated in an external cohort. Conclusion: The presence of a significant left‐AV absolute aldosterone gradient can be used to diagnose the left unilateral subtype of primary aldosteronism on AVS in patients with spontaneous hypokalemia, left unilateral disease on computed tomography or both. [ABSTRACT FROM AUTHOR]

Objective: Current Endocrine Society Clinical Practice Guidelines use a specific aldosterone/renin ratio (ARR) threshold to screen for primary aldosteronism (a treatable disease causing up to 15% of hypertension in primary care) in all patients. We sought to characterize demographic variations in the ARR, hypothesizing a need for age‐ and sex‐specific reference ranges to improve the accuracy of the test. Design: Retrospective cross‐sectional analysis of ARR measurements at a single tertiary hospital from December 2016 to June 2018. Patients: A total of 442 patients with clinically indicated ARR were included, after excluding those who were on spironolactone or the oral contraceptive pill, were pregnant or had an existing adrenal condition. Measurements: Aldosterone, renin and the ARR. Results: Among those aged 20‐39 years (n = 74), females had significantly higher median aldosterone (369 vs 244 pmol/L, P =.028), lower median renin (17.0 vs 27.6 mIU/L, P =.034) and higher median ARR (20.7 vs 10.3 (pmol/L)/(mIU/L), P =.001) than males, despite having lower systolic (135 vs 145 mmHg, P =.021) and diastolic (89 vs 96.5 mmHg, P =.007) blood pressure. The ≥ 60‐year age group (n = 157) also had significant sex differences in the ARR. With increasing age (20‐39 vs ≥ 60 years), there was a significant fall in plasma aldosterone in females (369 pmol/L vs 264 pmol/L, P =.005), with no change observed in males. Conclusions: For those 20‐39 years old, aldosterone and the ARR are significantly higher in females despite a lower systolic and diastolic BP, highlighting the potential for false‐positive results. Our findings indicate the need for prospective studies with a control population to define age‐ and sex‐specific ARR reference ranges. [ABSTRACT FROM AUTHOR]

Objective: Polycystic ovary syndrome (PCOS) is associated with an increased prevalence of dysglycaemia, which includes impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Patients with PCOS demonstrate abnormal patterns of steroid hormones. Here, we analyse the correlation between glucose metabolism and serum steroid hormones in PCOS. Design: Observational double‐centre study. Patients: 914 patients with PCOS. Measurements: We assessed the glucose metabolism status of all patients according to the 1999 WHO criteria. Serum steroid hormones were measured by liquid chromatography‐tandem mass spectrometry. Results: The median age of the patients was 26 years (interquartile range: 21‐30), and 40.6% (371/914) had abnormal glucose metabolism: 29.3% (268/914) had prediabetes, and 11.3% (103/914) had T2DM. Correlation analysis not adjusting for confounding factors revealed that serum aldosterone, androstenedione, oestrone, pregnenolone and the free androgen index were positively correlated, while progesterone was negatively correlated with the risk of abnormal glucose metabolism. After adjusting for age, body mass index and fasting insulin levels in the logistic regression model, only aldosterone (P =.013), androstenedione (P =.046) and oestrone (P =.014; in quartiles) were correlated with the risk of abnormal glucose metabolism. Conclusions: This study indicates a high prevalence of prediabetes and T2DM in patients with PCOS. Furthermore, there were positive correlations of serum aldosterone, androstenedione and oestrone with the risk of abnormal glucose metabolism after adjusting for confounding factors. [ABSTRACT FROM AUTHOR]

Context: Previous studies suggested that plasma aldosterone (PAC) response to ACTH stimulation could predict the subtypes of primary aldosteronism (PA) and avoid adrenal venous sampling (AVS). Objective: Assess the usefulness of peripheral (P) PAC response to ACTH stimulation during AVS to identify the source of aldosterone in patients with PA. Methods: Two hundred and fifteen patients were assigned to four different lateralization ratio (LR) groups based on different combinations of basal (≥ or <2) and post‐ACTH LR (≥ or <4). The P vein parameters analysed included as follows: mean basal PAC, maximal PAC (PACmax), and PAC/C ratio (PACmax/C), PAC absolute increase, PAC relative increase following ACTH bolus (250 mcg IV) and maximal variation of PAC/C ratio between post‐ACTH and basal measures. Results: Mean basal PAC was significantly higher in group 1 (basal LR > 2 and post‐ACTH > 4) than in group 2 (basal LR > 2, post‐ACTH < 4) or group 4 (basal LR < 2 post‐ACTH < 4) (P <.001). PACmax, PACmax/C and PAC absolute increase following ACTH were higher in group 1 than the others (P <.017). Using receiver operating characteristic (ROC) curves analysis of groups 1 and 4, best AUC were obtained with mean basal PAC (AUC: 0.757 95% IC: 0.653‐0.861), PACmax (AUC: 0.753 95% IC: 0.646‐0.860) and PACmax/C (AUC: 0.750 95% IC: 0.646‐0.853). Conclusion: P mean basal PAC and PACmax and PACmax/C are higher in basal and ACTH lateralized PA than in other groups. Peripheral PAC cut‐off values fail to adequately distinguish all groups and cannot replace the requirement to conduct AVS. [ABSTRACT FROM AUTHOR]

Context: Although saline infusion test is widely used as a confirmatory test for primary aldosteronism (PA), it is reportedly less sensitive in patients in whom aldosterone is responsive to the upright position by performing it in recumbent position. Based on a single‐centre experience, seated saline infusion test (SSIT) has been reported to be highly sensitive and superior to recumbent testing in identifying both unilateral and bilateral forms of PA. However, due to limited participants number, the utility of SSIT needs to be validated in other series. Objective: This study aimed to evaluate the accuracy of SSIT in determining the PA subtypes compared with adrenocorticotropic hormone stimulation test under dexamethasone suppression (Dex‐AT). Patients and Setting: Sixty‐four patients with PA who underwent both SSIT and Dex‐AT were included. Subtype diagnosis of PA was determined by adrenal venous sampling (AVS) (16 unilateral and 48 bilateral forms). Main Outcome Measure: Plasma aldosterone concentrations (PACs) were measured after SSIT and Dex‐AT. Results: The area under the receiver operating characteristic (ROC) curve for diagnosing unilateral PA was greater in SSIT than that in Dex‐AT (0.907 vs. 0.755; P = .023). ROC curve analysis predicted optimal cut‐off PACs of 13.1 ng/dL (sensitivity, 93.8%; specificity, 79.2%) for SSIT and 34.2 ng/dL (sensitivity, 75.0%; specificity, 68.8%) for Dex‐AT. Conclusions: Seated saline infusion test has superior accuracy in subtype diagnosis of PA compared with Dex‐AT. SSIT can be a sensitive test for determining patients who require AVS prior to surgery. [ABSTRACT FROM AUTHOR]

Objective: This study aimed at comparing precursors of endogenous corticosteroid production in patients with primary adrenal insufficiency and in secondary adrenal insufficiency. Design: Twenty patients with primary adrenal insufficiency and matched controls and 19 patients with secondary adrenal insufficiency participated in this ancillary analysis of two different studies. Patients and measurements: Patients with primary adrenal insufficiency were on stable hydrocortisone and fludrocortisone therapy. Patients with secondary adrenal insufficiency received two different doses of hydrocortisone in a randomized crossover study. Main outcome measures were concentrations of precursors of cortisol and aldosterone measured by LC‐MS/MS Results: Compared to controls, progressively lower concentrations of the glucocorticoid precursors 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone concentrations were found in patients with secondary adrenal insufficiency on lower hydrocortisone dose, secondary adrenal insufficiency on higher hydrocortisone dose and primary adrenal insufficiency, respectively. Half of the primary adrenal insufficient patients showed evidence of residual endogenous cortisol or aldosterone synthesis, as determined by quantifiable 11‐deoxycortisol, 11‐deoxycorticosterone and corticosterone conce ntrations. In secondary adrenal insufficient patients with higher endogenous cortisol production, as indicated by 11‐deoxycortisol concentrations above the median, no increased cortisol exposure was observed both by plasma pharmacokinetic parameters and 24‐hour free cortisol excretion in urine. Conclusions: Adrenal corticosteroid production is likely to continue during treatment in a considerable percentage of patients with both primary and secondary adrenal insufficiency. In patients with secondary adrenal insufficiency, this synthesis appears to be sensitive to the dose of hydrocortisone. However, the residual corticosteroid concentrations were quantitatively low and its clinical significance remains therefore to be determined. [ABSTRACT FROM AUTHOR]

Summary: Objective: Emerging evidence supports a positive, bidirectional and clinical relevant interaction between parathyroid hormone (PTH) and the renin‐angiotensin‐aldosterone‐system (RAAS). A beneficial effect of the widely used RAAS inhibitors might include a PTH‐lowering effect, as high PTH levels may be harmful to cardiovascular health. We aimed to investigate whether PTH levels are lowered by short‐term treatment with an angiotensin 2 receptor blocker (valsartan) independently of coadministration of vitamin D3. Secondary end‐points included effects on blood pressure, cardiac conduction and concentrations of renin and aldosterone. Design and Methods: In a double‐blind placebo‐controlled trial, we included 81 otherwise healthy postmenopausal women with high PTH levels (>6.9 pmol/L) and vitamin D insufficiency (25(OH)D < 50 nmol/L). Participants received 2 weeks of treatment with valsartan 80 mg/d, vitamin D3 70 μg/d, valsartan plus vitamin D3 or double placebo. Results: Valsartan treatment did not affect plasma PTH, although treatment reduced diastolic blood pressure (P = .01) and the aldosterone/renin ratio (P < .001). We found no associations between calciotropic hormones and RAAS markers. Vitamin D3 supplementation reduced PTH by 3.4% (25th, 75th −9.0 to 8.7) compared to a 7.1% increase (25th, 75th −2.4 to 30.9) in the placebo group (P = .01), but did not affect blood pressure, cardiac conduction or concentrations of renin and aldosterone. Conclusions: Independently of vitamin D3, short‐term valsartan treatment did not reduce PTH. Vitamin D3 reduced PTH but did not affect blood pressure, cardiac conduction or the RAAS. The study does not support a direct association between PTH and aldosterone or a blood pressure‐lowering effect of vitamin D3. [ABSTRACT FROM AUTHOR]

Summary: Renin‐angiotensin‐aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the “classical” RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low‐renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low‐renin levels are expression of a physiological response to sodium‐volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low‐renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low‐renin hypertension, enlightening the novelties in genetics of the familial forms. [ABSTRACT FROM AUTHOR]

Summary: Background: The saline suppression test (SST) serves to confirm the diagnosis of primary aldosteronism (PA) whilst adrenal vein sampling (AVS) is used to determine whether the aldosterone hypersecretion is unilateral or bilateral. An accurate prediction of bilateral PA based on SST results could reduce the need for AVS. Aim: We sought to identify SST parameters that reliably predict bilateral PA. Methods: The results from 121 patients undergoing SSTs at Monash Health from January 2010 to January 2018 including screening blood tests, imaging, AVS and histopathology results were evaluated. Patients were subtyped into unilateral or bilateral PA based on AVS and surgical outcomes. Results: Of 113 patients with confirmed PA, 33 had unilateral disease whilst 42 had bilateral disease. In those with bilateral disease, plasma aldosterone concentration (PAC) was significantly lower post‐SST, together with a significant fall in the aldosterone‐renin ratio (ARR). The combination of PAC < 300 pmol/L and a reduction in ARR post‐SST provided 96.8% specificity in predicting bilateral disease. Eighteen of 39 patients (49%) with bilateral PA could have avoided AVS using these criteria. Conclusion: A combination of PAC < 300 pmol/L and a lower ARR post‐SST could reliably predict bilateral PA. An independent cohort will be needed to validate these findings. [ABSTRACT FROM AUTHOR]

Summary: Background and Aim: Hypoaldosteronism is associated with either insufficient aldosterone production or aldosterone resistance (pseudohypoaldosteronism). Patients with aldosterone defects typically present with similar symptoms and findings, which include failure to thrive, vomiting, hyponatremia, hyperkalemia and metabolic acidosis. Accurate diagnosis of these clinical conditions therefore can be challenging. Molecular genetic analyses can help to greatly clarify this complexity. The aim of this study was to obtain an overview of the clinical and genetic characteristics of patients with aldosterone defects due to biosynthesis defects or aldosterone resistance. Design and Patients: We investigated the clinical and molecular genetic features of 8 consecutive patients with a clinical picture of aldosterone defects seen in our clinics during the period of May 2015 through October 2017. We screened CYP11B2 for aldosterone synthesis defects and NR3C2 and the three EnaC subunits (SCNN1A, SCNN1B and SCNN1G) for aldosterone resistance. Results: We found 4 novel and 2 previously reported mutations in the genes CYP11B2, NR3C2, SCNN1A and SCNN1G in 9 affected individuals from 7 unrelated families. Conclusion: Molecular genetic investigations can help confidently diagnose these conditions and clarify the pathogenicity of aldosterone defects. This study may expand the clinical and genetic correlations of defects in aldosterone synthesis or resistance. [ABSTRACT FROM AUTHOR]

Summary: Context: The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. Objective: We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. Design and patients: We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35‐40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. Main outcome measure: Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. Results: Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35‐40 years and 69% (198/289) in those aged ≥40 years (trend for P < .01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35‐40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35‐40 years. Conclusion: Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS. [ABSTRACT FROM AUTHOR]

Objective The only reliable method for subtyping primary aldosteronism (PA) is adrenal venous sampling (AVS), which is costly and time-consuming. Considering the limited availability of AVS, it would be helpful to obtain information on the diagnosis of bilateral hyperaldosteronism (BHA) from routine tests. We aimed to establish new, simple criteria for outpatients to diagnose BHA from PA before AVS. Design We retrospectively analysed 82 patients who were diagnosed with PA and underwent AVS. Thirty-seven patients were diagnosed with unilateral hyperaldosteronism (UHA), and 36 with BHA and nine were undetermined. Among the variables that were significantly different between UHA and BHA in the univariate analysis, we chose three variables to be included in multivariate logistic regression models and constructed a subtype prediction score. Results The subtype prediction score was calculated as follows: 3 points for no adrenal nodules on computed tomography imaging, 2 for serum potassium of ≥3·5 mmol/l and 2 for aldosterone-to-renin ratio of <490 after a captopril challenge test. Receiver operating characteristic curve analysis for the ability to discriminate BHA from UHA showed that a score of 7 points had 50% sensitivity and 100% specificity and a score of 5 points had 67% sensitivity and 94% specificity (area under the curve: 0·922; 95% CI: 0·863-0·980). Conclusions Our new, simple criteria specifically distinguished BHA from UHA in the outpatient setting before AVS. Furthermore, not only endocrinologists but also general internists can use this convenient, safe scoring system. [ABSTRACT FROM AUTHOR]

Objective To evaluate volumetric and densitometric properties of the adrenal glands in patients with unilateral and bilateral disease in comparison with normal controls. Design A total of 77 patients (56 males and 21 females) diagnosed with primary aldosteronism ( PA) with a mean age of 53 ± 10 years were prospectively enrolled. Unenhanced and contrast-enhanced computed tomography scans were analysed for adrenal volumes and mean densities. These values were compared with normal controls and between PA subtypes. Results Adrenals containing an aldosterone-producing adenoma ( APA, n = 56) had on average higher attenuation values as compared to adrenals with bilateral adrenal hyperplasia ( n = 21). Mean adrenal gland volume in PA patients was not significantly different between PA subtypes. In comparison with normal adrenal glands, volumes were significantly higher in PA patients ( P < 0·0001) including adrenals contralateral to APAs, which were significantly larger in comparison with controls. Conclusion Independent of subtype differentiation, adrenal volumetry reveals higher adrenal volumes in PA patients in comparison with normal controls. These findings provide indirect evidence for a general adrenal growth dysregulation in the context of PA. [ABSTRACT FROM AUTHOR]

Complete resolution of hypertension (CRH) after adrenalectomy for primary aldosteronism is far from a certainty. Although several prognostic models have been proposed to predict outcome after adrenalectomy, studies have not clarified which of the available models can be used reliably in clinical practice. To identify, describe and appraise all prognostic models developed to predict CRH, and meta-analyse their predictive performances. We searched MEDLINE, Embase and Web of Science for development and validation studies of prognostic models. After selection, we extracted descriptive statistics and aggregated area under the receiver operator curve (AUC) using meta-analysis. From 25 eligible studies, we identified 12 prognostic models used for predicting CRH after total adrenalectomy in primary aldosteronism. We report the results for 3 models that had available data from at least 3 external validation studies: the primary aldosteronism surgical outcome (PASO) score (AUC: 0.81; 95% confidence interval [CI]: 0.74-0.86; 95% predictive interval [PI]: 0.04-1.00), Utsumi nomogram (AUC: 0.79; 95% CI: 0.72-0.85; 95% PI: 0.03-1.00) and the aldosteronoma resolution score (ARS) model (AUC: 0.77; 95% CI: 0.74-0.80; 95% PI: 0.59-0.86 for all studies and AUC: 0.80; 95% CI: 0.75-0.85; 95% PI: 0.57-0.93 for the studies with the same adrenal vein sampling-guided adrenalectomy rate compared to the models meta-analysed). The PASO score, Utsumi nomogram and ARS model showed comparable discrimination performance to predict CRH in primary aldosteronism. Unlike the ARS model, the number of external validation studies for the PASO score and the Utsumi nomogram was relatively low to draw definite conclusions., (© 2023 John Wiley & Sons Ltd.)

Background Germline mutations of the KCNJ5 gene encoding Kir3·4, a member of the inwardly rectifying K+ channel, have been identified in 'normal' adrenal glands, patients with familial hyperaldosteronism ( FH) type III, aldosterone-producing adenomas ( APAs) and sporadic cases of primary aldosteronism ( PA). Objective To present two novel KCNJ5 gene mutations in hypertensive patients without PA, but with Adrenocorticotropic hormone (ACTH)-dependent aldosterone hypersecretion. Design and Patients Two hypertensive patients without PA, who exhibited enhanced ACTH-dependent response of aldosterone secretion, underwent genetic testing for the presence of the CYP11B1/ CYP11B2 chimeric gene and KCNJ5 gene mutations. Genomic DNA was isolated from peripheral white blood cells, and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials. Structural biology studies were also carried out. Results Two novel germline heterozygous KCNJ5 mutations, p.V259M and p.Y348N, were detected in the two subjects. Electrophysiological studies showed that the Y348N mutation resulted in significantly less negative reversal potentials, suggesting loss of ion selectivity, while the V259M mutation did not affect the Kir3.4 current. In the mutated structural biology model, the N348 mutant resulted in significant loss of the ability for hydrogen bonding, while the M259 mutant was capable of establishing weaker interactions. The CYP11B1/ CYP11B2 chimeric gene was not detected. Conclusions These findings expand on the clinical spectrum of phenotypes associated with KCNJ5 mutations and implicate these mutations in the pathogenesis of hypertension associated with increased aldosterone response to ACTH stimulation. [ABSTRACT FROM AUTHOR]

Context Recent studies have identified that the somatic PRKACA L206R mutation can cause cortisol-producing adenomas ( CPAs). This study investigated the prevalence and characteristics of PRKACA, GNAS and CTNNB1 mutations in adrenal lesions in patients from a single centre in China. Design, Patients and Measurements We sequenced PRKACA, GNAS and CTNNB1 genes in 108 patients, including 60 patients with CPAs (57 with unilateral and three with bilateral adenomas), 13 with nonfunctional adenomas, 12 with adrenocortical carcinomas ( ACCs), 15 with primary bilateral macronodular hyperplasia ( PBMAH) and eight with aldosterone and cortisol cosecreting adenomas. Mutations in PRKACA, GNAS and CTNNB1 were examined, and clinical characteristics were compared. Results Among the unilateral CPAs, we identified somatic mutations in PRKACA (L206R) in 23 cases (40·4%), GNAS (R201C and R201H) in six cases (10·5%), CTNNB1 (S45C, L46P and S45P) in six cases (10·5%) and CTNNB1 plus GNAS in two cases (3·5%). PRKACA and GNAS mutations were mutually exclusive. Among the patients with nonfunctional adenoma, two carried CTNNB1 mutations. Among the patients with ACC, two carried GNAS and CTNNB1 mutations but none carried PRKACA mutations. One patient showed bilateral CPA, and one PBMAH patient carried PRKACA mutations. No mutations in PRKACA, GNAS or CTNNB1 were identified in the eight patients with aldosterone and cortisol cosecreting adenomas. PRKACA-mutant adenomas were associated with young age, overt Cushing's syndrome and high cortisol levels compared with non- PRKACA-mutant or CTNNB1-mutant lesions. Conclusions PRKACA mutations are present in CPAs and bilateral adrenal macronodular hyperplasia. PRKACA mutation is associated with more severe autonomous cortisol secretion. [ABSTRACT FROM AUTHOR]

Objectives: Human physiology and epidemiology studies have demonstrated complex interactions between the renin-angiotensin-aldosterone system, parathyroid hormone and calcium homeostasis. Several of these studies have suggested that aldosterone inhibition may lower parathyroid hormone (PTH) levels. The objective of this study was to assess the effect of 4 weeks of maximally tolerated mineralocorticoid receptor antagonist therapy with eplerenone on PTH levels in patients with primary hyperparathyroidism (P-HPT) when compared to amiloride and placebo. We also investigated the synergistic effect of these interventions when combined with cinacalcet for an additional 2 weeks., Design: Randomized, double-blinded, three parallel-group, placebo-controlled trial., Patients: Patients with P-HPT., Results: Most patients were women (83%) and White (76%). Maximally tolerated doses of eplerenone and amiloride induced significant reductions in blood pressure and increases in renin and aldosterone production; however, despite these physiologic changes, neither intervention induced significant changes in PTH or calcium levels when compared to the placebo. Both eplerenone and amiloride therapy induced significant reductions in procollagen type 1 N-terminal propeptide levels when compared to placebo. When cinacalcet therapy was added, PTH and calcium levels were markedly reduced in all groups; however, there was no significant difference in PTH or serum calcium reductions between groups., Conclusions: Although maximally tolerated therapy with eplerenone and amiloride induced expected changes in renin, aldosterone and blood pressure, there were no meaningful changes in PTH or serum calcium levels in P-HPT patients. These results suggest that inhibition of aldosterone action does not have a clinically meaningful role in medical therapy for P-HPT., (© 2022 John Wiley & Sons Ltd.)

Objective: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false-positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine-learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone., Design: A retrospective cross-sectional study in referral centres., Patients: This study included 615 patients with PA randomly assigned to the training and test data sets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516)., Measurements: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test data set., Results: The AUCs for the combination of SIT and CCT, SIT alone and CCT alone were 0.850, 0.813 and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT and combined with both SIT and CCT were 0.868, 0.854 and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis., Conclusions: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS., (© 2022 John Wiley & Sons Ltd.)

Background and Objective: Adrenalectomy for primary aldosteronism (PA) has been associated with decreased kidney function after surgery. It has been proposed that elimination of excess aldosterone unmasks an underlying failure of the kidney function. Contralateral suppression (CLS) is considered a marker of aldosterone excess and disease severity, and the purpose of this study was to assess the hypothesis that CLS would predict change in kidney function after adrenalectomy in patients with PA., Design and Patients: Patients with PA referred for adrenal venous sampling (AVS) between May 2011 and August 2021 and who were subsequently offered surgical or medical treatment were eligible for the current study., Results: A total of 138 patients were included and after AVS 85/138 (61.6%) underwent adrenalectomy while 53/138 (38.4%) were treated with MR-antagonists. In surgically treated patients the estimated glomerular filtration rate (eGFR) was reduced by 11.5 (SD: 18.5) compared to a reduction of 5.9 (SD: 11.5) in medically treated patients (p = .04). Among surgically treated patients, 59/85 (69.4%) were classified as having CLS. After adrenalectomy, patients with CLS had a mean reduction in eGFR of 17.5 (SD: 17.6) compared to an increase of 1.8 (SD: 12.8) in patients without CLS (p < .001). The association between CLS and change in kidney function remained unchanged in multivariate analysis. Post-surgery, 16/59 (27.1%) patients with CLS developed hyperkalemia compared to 2/26 (7.7%) in patients without CLS (p = .04)., Conclusion: This retrospective study found that CLS was a strong and independent predictor of a marked reduction of eGFR and an increased risk of hyperkalemia after adrenalectomy in patients with PA., (© 2022 John Wiley & Sons Ltd.)

Objective: Primary aldosteronism (PA) is a major cause of secondary hypertension and is associated with chronic renal injury. The glomerular filtration rate (GFR) in PA rapidly decreases after the removal of glomerular hyperfiltration due to aldosterone excess by adrenalectomy (ADX) or mineralocorticoid receptor antagonist (MRA) treatment and is stable in the long term. However, the effects of these treatments on the long-term renal function of PA patients with chronic kidney disease (CKD) is not well understood., Design and Patients: In this single-center, retrospective study, acute and chronic changes in the estimated GFR (eGFR) were examined in 107 patients with PA, including 49 patients with post-treatment CKD　defined as eGFR < 60 ml/min/1.73 m 2 ., Results: The reduction in eGFR observed 1 month after ADX in the CKD group (N = 31) was -20.1 ± 8.2 ml/min/1.73 m 2 . Multivariate analysis showed that pre-treatment eGFR and plasma aldosterone concentration were independent predictive factors of the acute reduction in eGFR after ADX. The reduction of eGFR observed 1 month after MRA administration in the post-treatment CKD group (N = 18) was -9.2 ± 5.9 ml/min/1.73 m 2 . Multivariate analysis showed that the duration of hypertension and pre-treatment eGFR were independent predictive factors of the acute reduction in eGFR after ADX administration. In 20 patients with CKD (N = 12 ADX and N = 8 MRA) followed for more than 5 years post-treatment, there was no further significant decline in eGFR over a follow-up period of 7 (6, 8) years nor any difference between the two treatment modalities., Conclusions: Our study suggests that treatment of PA in stage 3 CKD is safe and useful in preventing renal injury., (© 2022 John Wiley & Sons Ltd.)

Context In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). Objectives To investigate the prevalence of BAS in AVS and how to resolve this condition. Design and setting Retrospective study involving nine referral centres. Patients Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. Measurements The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. Results In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. Conclusions BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure. [ABSTRACT FROM AUTHOR]

Objective Adrenal vein sampling ( AVS) is used for determining treatment options for primary aldosteronism ( PA), but is a difficult procedure. Adrenocorticotropic hormone ( ACTH) infusion or bolus has been reported to improve AVS success rates by increasing cortisol secretion, but effects on lateralization are controversial. We therefore assessed the effects of ACTH in regard to AVS success and lateralization in our unit, after a change in protocol to ACTH-stimulated AVS. Setting AVS was performed after overnight recumbency in patients with PA confirmed by fludrocortisone suppression testing. Bilateral sequential sampling was performed before and after an intravenous bolus of 250 mcg of ACTH. Lateralization was defined as an aldosterone/cortisol ratio in one adrenal vein at least twice peripheral, combined with a contralateral adrenal ratio no higher than peripheral (contralateral suppression). Results In 47 AVS procedures, the median adrenal/peripheral cortisol gradient increased on the left (11·6 vs 18·2 μg/100 ml, P < 0·001) and right (15·6 vs 31·5 μg/100 ml, P < 0·001) after ACTH. A total of 34 of 47 studies were diagnostic pre- ACTH (six failing because of low aldosterone levels bilaterally and seven failing to cannulate one or both sides) vs 44 of 47 ( P = 0·011) studies diagnostic post- ACTH (failure to cannulate one or both sides in 3). Concordance between diagnostic studies pre- and post- ACTH was 91%, but two bilateral cases became unilateral after ACTH and one unilateral case before ACTH was bilateral afterwards. Conclusions ACTH improved cortisol gradients and aldosterone secretion, resulting in a reduction in the proportion of nondiagnostic studies. There was a low proportion of discordance between pre- and post- ACTH diagnoses, the significance of which is unclear. [ABSTRACT FROM AUTHOR]

Context Congenital adrenal hyperplasia ( CAH) is caused most often by mutations in the CYP21A2 gene, resulting in cortisol and aldosterone deficiency and increased production of androgens. Objective To describe how women with CAH experience their condition and the care given. Design, setting and participants Semi-structured interviews with 13 adult Swedish women with CAH were transcribed. Data were analysed by qualitative content analysis to describe the variability in the experiences. Main outcome measures Qualitative evaluation of the participants' life experiences. Results The participants' experiences of having CAH are described in four different categories. 1. Information comprises the experiences of interaction with healthcare providers, knowledge acquisition and information disclosure. 2. Exposure encompasses the experiences of genital examinations, the medical focus on the genitalia and of being photographed repeatedly. 3. Health covers the self-perceived experiences of having a medical condition that requires pharmacological treatment and sometimes surgery. 4. Research comprises the experiences of having a scientifically well-studied condition. Different experiences of shame reoccur in all categories, thus forming the latent theme. Conclusion The experience of living with congenital adrenal hyperplasia can be facilitated by increased information and by acknowledging that women with CAH are a heterogeneous group with individual needs. Shame may be counterbalanced by increased parental support and increased knowledge among healthcare personnel aimed at providing children with continuous support and coping strategies during their upbringing. Based on the identified themes in this study, there are several research avenues to pursue in the future. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effects of β-adrenoreceptor antagonists (β-blockers) on the aldosterone-renin ratio (ARR) in the context of antihypertensive polypharmacy in chronic hypertension. To determine the optimal duration of β-blocker withdrawal required to normalize the ARR. Design A prospective, longitudinal study design was employed investigating two groups whom either remained on or withdrew from β-blocker therapy. Methods Hypertensive individuals taking β-blockers and a combination of thiazide diuretics, α1-blockers, calcium channel antagonists and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were recruited and followed over 10-12 weeks. β-Blockers were withdrawn at the first visit. Blood pressure (BP) was measured at each visit and blood drawn serially for measurement of plasma renin activity (PRA), direct renin concentration (DRC) and aldosterone. BP was optimized by maximizing non-renin-suppressing antihypertensives. Main outcomes were ARR, DRC, PRA and aldosterone. Plasma renin activity was calculated from angiotensin I measured using radioimmunoassay (RIA), DRC was measured using chemiluminescent immunoassay assay, and aldosterone was measured using both RIA and Chemilluminescence Assay (CIL). Results False-positive ARR for primary aldosteronism ( PA) occurred in 31% of patients taking β-blockers. ARR returned to normal following β-blocker withdrawal resulting from an increase in the DRC and PRA without affecting aldosterone. The optimum time for β-blocker withdrawal was 2 weeks when using DRC and 3 weeks for PRA. β-Blocker withdrawal did not adversely affect blood pressure. Conclusion Raised ARR consequent to β-blocker therapy causes false-positive screening for PA. Where β-blockers can be safely withdrawn, this effect is reversed within 2-3 weeks depending on whether DRC or PRA is used to calculate ARR. [ABSTRACT FROM AUTHOR]

The article reports on a case of primary aldosteronism (PA) in a 53-yea-old man. Topics covered include distinguishing the main subtypes of endocrine hypertension caused by PA, adrenal vein sampling (AVS) procedures conducted to reassess whether the patient was eligible for adrenalectomy, details of the extra adrenal origin of the PA, and role of the aldosterone-producing tumour in PA.