Adrenal venous sampling criteria for chemiluminescent enzyme immunoassay as a preferable alternative to radioimmunoassay in primary aldosteronism.

Plasma aldosterone concentration (PAC) was routinely measured using radioimmunoassay (RIA); however, the RIA kit was discontinued in March 2021 in Japan. This study examined PAC conversion in adrenal venous sampling (AVS) and AVS criteria when measured using chemiluminescent enzyme immunoassay (CLEIA). PAC of 415 adrenal venous blood samples from AVS (including segmental AVS) of 63 patients with primary aldosteronism was measured using RIA (Spac-S aldosterone kit; Fujirebio Inc.) and CLEIA (Lumipulse Presto Aldosterone; Fujirebio Inc.). PAC of 70 AVS samples was also measured using liquid chromatography-mass spectrometry (LC-MS/MS, ASKA Pharma Medical Co., Ltd.). PAC conversion formulas were determined for each AVS sample assay. PAC measured using CLEIA was significantly correlated with that measured using RIA (correlation coefficient = 0.971). The PAC conversion formula was PAC (CLEIA) = PAC (RIA) × 0.772 - 1,199 pg/mL. The PAC of 14,000 pg/mL in RIA was equivalent to 9,613 pg/mL in CLEIA. PAC measured using CLEIA was also correlated with that measured using LC-MS/MS, and the PAC conversion formula was PAC (CLEIA, pg/mL) = 0.97 × PAC (LC-MS/MS, pg/mL) + 211. The inter-assay coefficient of variability (CV) was 1.1-1.3% and intra-assay CV was 1.0-1.7%, measured using CLEIA. The PAC conversion formula for AVS samples was obtained using CLEIA and RIA, and the conversion formula was different from that for peripheral blood. PAC values measured by CLEIA showed preferable accuracy and high concordance with those measured by LC-MS/MS, even in AVS samples. The study outcomes are useful for interpreting AVS results using non-RIA measurement methods.

Anatomical Variations of the Left Adrenal Vein Encountered During Venous Sampling.

PURPOSE: To identify anatomical variations in the left adrenal vein (LAV) and to evaluate the role of preprocedural contrast-enhanced computed tomography (CT) planning. METHODS: The length of the left adrenal central vein (LACV), the vessel that receives blood from all tributaries of the left adrenal gland, was measured using venograms of patients who had undergone adrenal venous sampling (AVS) for the diagnosis of primary aldosteronism between October 2017 and December 2019. The anatomical variants of the LAV were described and classified. Contrast-enhanced CT was used to evaluate the detection rate of the following: (a) confluence of the left inferior phrenic vein and the LAV and (b) the last tributary flowing into the LAV. RESULTS: In total, 311 patients (143 men, 168 women; mean age: 49.3 years ± 11.0) were enrolled. Of them, 9 (2.9%) patients had anatomical variants lacking a LACV. In patients with a LACV (n = 302), the venographic LACV length was 9.0 mm ± 3.9 (<1 mm in 9 patients). The detection rate of the confluence of the left inferior phrenic vein and LAV, as determined using contrast-enhanced CT, was high (96.2%), whereas that of the last tributary flowing into the LAV was low (0.8%). In 4 of 18 patients with short or absent LACV, the variant was visualized using contrast-enhanced CT. CONCLUSIONS: In some patients, the LACV is absent or short, which is an anatomical variation. Understanding venographic anatomical variations can help avoid misleading results resulting from a suboptimal sampling site in AVS. For some subtypes, contrast-enhanced CT may also help in planning the AVS procedure.

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

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

Changes in glucose metabolism based on 75-g oral glucose tolerance tests before and after surgery for adrenal Cushing's syndrome.

Adrenal Cushing's syndrome (CS) is caused by cortisol-producing adrenal adenoma and is frequently accompanied by glucose metabolism disorders, which are characterized by increased insulin resistance and insufficient ß-cell compensation. However, considering the rarity of CS, few studies have assessed whether the glucose metabolism disorders could be ameliorated by surgical treatment. In this case series, we evaluated glucose metabolism before and after surgery in 11 patients (10 women and 1 man) who underwent unilateral adrenalectomy for overt adrenal CS between 2005 and 2016. Patients with pre-diagnosed diabetes mellitus (DM) were excluded. Pre- and post-operative 75-g oral glucose tolerance tests were performed. Cortisol secretion decreased significantly after surgery (median 24-h urinary free cortisol: 582.0 µg/day [interquartile range: 321.0-743.0 µg/day] to 31.3 µg/day [23.6-40.6 µg/day], p = 0.001). The results of the OGTT generally improved after surgery (normal glucose tolerance/impaired glucose tolerance/DM: 2/8/1 to 8/3/0), with significant decreases in the immunoreactive insulin and glucose levels. We also found a decrease in the median homeostatic model assessment of insulin resistance (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and increases in the median Matsuda index (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001), median insulinogenic index (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.08), and median disposition index (609.1 [237.8-1,095.2] to 1,286.0 [1,034.6-1,857.6], p = 0.002). These findings indicate that adrenalectomy for adrenal CS without overt DM may help ameliorate glucose metabolism disorders, and improve both insulin resistance and insulin secretion.

Comparative study of the effects of ipragliflozin and sitagliptin on multiple metabolic variables in Japanese patients with type 2 diabetes: A multicentre, randomized, prospective, open-label, active-controlled study.

In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of ß-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on ß-cell function.

Evaluation of Cortisol Production in Aldosterone-Producing Adenoma.

Aldosterone-producing adenoma (APA) is sometimes accompanied with subclinical hypercortisolism. We investigated the ability of cortisol production in APA, both clinically and pathologically. A retrospective cohort study was conducted at Yokohama Rosai Hospital from 2009 to 2016. Thirty patients with APA and serum cortisol levels during the 1 mg dexamethasone suppression test (F-DST)<3.0 µg/dl were included. We evaluated the 1) difference between pre-adrenalectomy F-DST (pre-F-DST) and post-adrenalectomy F-DST (ΔF-DST), 2) correlation between ∆F-DST and pre-F-DST, tumour size determined by CT, and type of adrenalectomy (total or partial), and 3) relationship between the ratio of F-DST divided by tumour size (ΔF-DST/pre-F-DST/mm) and immunoreactivity of CYP17A1, CYP11B1, and CYP11B2. The median [interquartile range] age was 48 [38-58] years. We found a significant decrease in F-DST after adrenalectomy [before: 1.4 (1.1-1.8); after: 0.9 (0.6-1.2); p<0.001]. Additionally, a significant correlation was found for ΔF-DST and both pre-F-DST (Spearman, ρ=-0.68, p<0.001) and tumour size (ρ=-0.51, p 0.005). No significant difference was found in ΔF-DST between total and partial adrenalectomy. CYP17A1 and CYP11B1 were positive in 21 (100%) and 17 (81%) adenomas, respectively. CYP17A1 immunoreactivity in the tumour was significantly related with ΔF-DST/pre-F-DST/mm (p 0.049). F-DST significantly decreased after adrenalectomy, and most of the adenomas were immunohistochemically positive for CYP17A1 and CYP11B1 as well as CYP11B2. We should consider the possibility of autonomous cortisol production as well as hyperaldosteronism in the evaluation and treatment of APA patients.

Aldosterone excess may inhibit insulin secretion: A comparative study on glucose metabolism pre- and post-adrenalectomy in patients with primary aldosteronism.

Conflicting data have been published on the effects of aldosterone excess on glucose metabolism. Specifically, there are limited data on whether adrenalectomy in patients with aldosterone-producing adenomas (APA) can improve glucose metabolism. In this study we evaluated changes in glucose metabolism, before and after surgery for APA. The subjects were 61 patients treated with unilateral adrenalectomy, localized by adrenal venous sampling. A 75g-oral glucose tolerance test (OGTT) was performed before and 1 year after adrenalectomy. Patients with diabetes mellitus or a serum cortisol level >3 µg/dL after a 1 mg dexamethasone suppression test, were excluded. Using the 75g-OGTT data, insulin secretion and insulin resistance (or sensitivity) indices were calculated. The results showed that immunoreactive insulin levels during the OGTT increased significantly after adrenalectomy, whereas plasma glucose levels, before and after surgery, were comparable. The insulinogenic index significantly increased after surgery (0.5 [0.4-0.8] to 0.8 [0.4-1.1], p < 0.001). The disposition index remained largely unchanged (806.2 [489.4-1,138.9] to 686.6 [479.4-922.1], p = 0.25). The homeostatic model assessment of insulin resistance increased significantly (1.0 [0.6-1.5] to 1.5 [1.0-2.2], p < 0.001) and the ISImatsuda decreased significantly (6.9 [4.5-10.4] to 5.2 [3.4-7.9], p < 0.001). Changes in these indices were not correlated with changes in potassium and aldosterone levels before and after surgery. In conclusion, insulin secretion increased after adrenalectomy for APA, indicating that aldosterone excess inhibits insulin secretion. However, because of a parallel increase in insulin resistance, plasma glucose levels remained unchanged.

Clinical Utility of the Adrenocorticotropin Stimulation Test with/without Dexamethasone Suppression for Definitive and Subtype Diagnosis of Primary Aldosteronism.

The adrenocorticotropin (ACTH) stimulation test (AST) has been reported to be useful for diagnosing primary aldosteronism (PA), particularly for differentiating PA subtypes under 1-mg dexamethasone suppression (DS). The aim of our study was to clarify the effect of 1-mg DS on AST results. A retrospective cohort study was conducted using data for 48 patients (PA: 30/48). We estimated the difference in plasma aldosterone concentration (PAC) responsiveness to ACTH stimulation with single (AST alone) and combined (AST under 1-mg DS) tests within the same patient. We compared the diagnostic accuracy of these two tests for PA and the laterality of hyperaldosteronism. We found no differences in PAC responsiveness to ACTH stimulation between single and combined tests, and observed a significant positive linear relationship (30 min, R² = 0.75, p-value < 0.01). Both tests showed the highest diagnostic accuracy for PA following 30 min of ACTH stimulation. The ability to detect the laterality of hyperaldosteronism was inconsistent and differed according to the two definitions: lateralization ratio and the absolute aldosterone levels in adrenal venous sampling. PAC responsiveness to ACTH stimulation was similar for AST with and without 1-mg DS. AST can be performed under both conditions with similar accuracy to detect PA.

Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on Atherosclerosis, ß-Cell Function, and Glycemic Control in Japanese Patients with Type 2 Diabetes Mellitus Who are Treatment Naïve or Poorly Responsive to Antidiabetes Agents: A Multicenter, Prospective Observational, Uncontrolled Study.

BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used in patients with type 2 diabetes. However, the pleiotropic effects of sitagliptin is not well understood. OBJECTIVE: To assess the clinical efficacy and safety of sitagliptin on atherosclerosis, ß-cell function, and glycemic control in Japanese patients with type 2 diabetes. METHODS: A prospective observational study of 270 patients with type 2 diabetes mellitus was carried out. Patients (aged 64.3 [12.4] years, body mas index 25.2 [4.3]) with glycated hemoglobin >6.9% (52 mmol/mol) or fasting plasma glucose >130 mg/dL were treated with sitagliptin for 12 months. The primary end point was glycated hemoglobin level changes from baseline to 3 months. The secondary end points included changes in several biomarkers related to inflammation and ß-cell function from baseline to 3 months, as well as changes in glycated hemoglobin level from baseline to 12 months. RESULTS: Glycated hemoglobin levels were significantly lower in patients treated with sitagliptin for 3 months than at baseline (8.1% [1.4%]-7.3% [1.2%]) (65 [16.9]-56 [13.1] mmol/mol]) (P < 0.0001), which continued after 12 months (7.4% [1.3%]) (56 [15.2] mmol/mol) (P < 0.0001). In addition, a marker of vascular-specific inflammation, pentraxin-3, and a marker of ß-cell function (proinsulin/insulin ratio), respectively, were lower after treatment with sitagliptin for 3 months than at baseline (1.88 [0.78]-1.65 [0.63] ng/mL [P = 0.0038] and 0.20 [0.14]-0.17 [0.11] [P = 0.01], respectively). On the other hand, a biomarker reflecting whole body inflammation; that is, high-sensitivity C-reactive protein level, was unchanged. Adverse events occurred in 14 patients (5.18%). CONCLUSIONS: Sitagliptin may have beneficial effects on vascular inflammation and ß-cell function in Japanese patients with type 2 diabetes. Pentraxin-3 may be an early predictive marker for detecting the antiatherosclerotic effects of dipeptidyl peptidase-4.

Guanosine triphosphate can directly regulate cortisol production by activating Ca(2+)-messenger systems in bovine adrenal fasciculata cells.

Adenosine triphosphate (ATP) is known to stimulate cortisol production in vitro, however, the effect of guanosine triphosphate (GTP) on cortisol production is not known. We studied the effect of GTP on cortisol production and investigated the regulation of intracellular signal transduction systems, including the cyclic AMP-dependent and Ca(2+)-messenger systems, in bovine adrenal fasciculata cells. GTP clearly induced cortisol biosynthesis but only to a level less than half the adrenocorticotropic hormone (ACTH)-induced maximum. The binding site for [γ-(35)S]-GTPγS was shown to differ completely from that for ATP and also from those for Gs and Gi, as indicated by the fact that binding was not influenced by pretreatment with cholera toxin and pertussis toxin. GTP significantly increased cytosolic calcium ([Ca(2+)]i) and inositol 1, 4, 5-triphosphate without affecting cyclic AMP formation. GTP-induced cortisol production was suppressed by H-9 and Calphostin C (specific protein kinase C inhibitors) but not by H-8 and KT5720 (specific inhibitors of cyclic AMP-dependent protein kinase), suggesting that GTP activates cortisol biosynthesis possibly via a protein kinase C-dependent pathway. Extracellular calcium may be essential for GTP activity since GTP-induced cortisol production was almost completely suppressed in its absence. In conclusion, it can be postulated that GTP-induced steroid secretion in bovine adrenal fasciculata cells is under paracrine or autocrine control.

Calibration and evaluation of routine methods by serum certified reference material for aldosterone measurement in blood.

We attempted to study the standardization of aldosterone measurement in blood. The serum certified reference material (serum CRM) was established by spiking healthy human serum with pure aldosterone. ID-LC/MS/MS as a reference measurement procedure was performed by using the serum CRM. LC-MS/MS as a comparison method (CM) was routinely used for clinical samples, and the values with and without calibration by the serum CRM were compared. The serum CRM demonstrated similar reactivity with peripheral blood plasma as clinical samples in routine methods (RM) of RIA, ELISA, and CLEIA. In comparison between RM and CM, the results in regression analysis indicated that the range of the correlation coefficient (r) was 0.913 - 0.991, the range of y intercept was 0.9 - 67.3 pg/mL and the range of slope was 0.869 - 1.174. The values by RM in 100 - 150 pg/mL for the diagnostic level, had a significant calibration effect, and the relative difference between calibrated value in RM and result by CM was within ±20%. Furthermore, the calibrated value using the serum CRM was 10,187 pg/mL, which corresponds to measured value of 14,000 pg/mL using RIA for the adrenal venous sampling. Measured values between plasma and serum as a sample for the aldosterone measurement from clinical samples showed no significant differences. In conclusion, we succeeded to prepare the certified reference material of aldosterone for RM. Then, we can accurately calculate corrected values by using our equation for four RMs of determination of aldosterone.

Characterization of steroidogenic enzyme expression in aldosterone-producing adenoma: a comparison with various human adrenal tumors.

We analyzed the expression profiles of several steroidogenic enzymes in normal adrenals, aldosterone-producing adenomas (APA), cortisol-producing adenomas combined with Cushing's syndrome (CPA) or with subclinical Cushing's syndrome (SCPA), and nonfunctioning adrenal adenomas (NFA) to clarify the nature and characteristics of steroidogenesis in APA. Clinical data were collected for all subjects. In resected adrenal glands (normal adrenals, APA, CPA, SCPA, and NFA), the mRNA expression levels of the CYP17, HSD3B2, CYP11B1, and CYP11B2 genes were studied using real-time quantitative PCR and immunohistochemistry. The CYP11B2 mRNA level in APA was significantly higher than that in other groups. The CYP17/HSD3B2 ratio for mRNA in APA was significantly lower than those in the other groups. Low ratio of CYP17/HSD3B2 with high expression of CYP11B2 seems to explain steroidogenic characteristics of APA.

Vascular aldosterone production at the pre-diabetic stage of young Otsuka Long-Evans Tokushima Fatty (OLETF) rats, compared with Long-Evans Tokushima Otsuka (LETO) rats.

We examined the ability of aortic smooth muscle cells (AoSMC) prepared from spontaneously diabetic rats to produce aldosterone (Aldo) and the regulatory mechanism that controls their Aldo production. AoSMC of 6 week-old Long-Evans Tokushima Otsuka (LETO: the control group) and 6 week-old Otsuka Long-Evans Tokushima Fatty (OLETF: the type 2 diabetes group) rats were used in the present experiments. CYP11B2 (Aldo synthetase) mRNA expression was detected in both the LETO and OLETF AoSMC. Basal Aldo production was significantly greater (4-5 fold higher) in the OLETF AoSMC culture medium than in the LETO AoSMC culture medium. When AoSMC were co-incubated with high-density lipoproteins (HDL), supplying cholesterol as a substrate for steroidogenesis in rats, angiotensin II (AII) significantly increased greater Aldo production in the OLETF AoSMC than in the LETO AoSMC. The present data suggested that future onset of diabetic vascular dysfunction is partly caused by excess Aldo production by AoSMC in young OLETF rats. Concomitant stimulation by HDL and AII resulted in elevated Aldo production in the OLETF and the LETO AoSMC, and also demonstrated that AII-induced Aldo production is greatly enhanced by HDL in OLETF, rather than in LETO. In conclusion, our data clearly demonstrated that Aldo production in the OLETF AoSMC was significantly higher than in the LETO AoSMC, suggesting possible future onset of vascular dysfunction in diabetes, induced by local Aldo production in the AoSMC.

Feasibility of single-port laparoscopic partial adrenalectomy with selective adrenal venous sampling and high-resolution ultrasound for unilateral aldosterone-producing adenomas.

BACKGROUND: The surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy for patients with aldosterone-producing adenomas are unknown. Precise diagnosis of intra-adrenal aldosterone activity and a precise surgical procedure may improve outcomes. In this study, we aimed to determine the surgical and endocrinological outcomes of single-port laparoscopic partial adrenalectomy with preoperative segmental selective adrenal venous sampling and intraoperative high-resolution laparoscopic ultrasound in patients with unilateral aldosterone-producing adenomas. We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. METHODS: A single-center, retrospective cohort study. All patients with unilateral aldosterone-producing adenomas diagnosed by selective adrenal venous sampling and treated surgically between January 2012 and February 2015 were included. Follow-up with biochemical and clinical assessments was set at 1 year after surgery for short-term outcomes and was performed every 3 months after surgery. RESULTS: We identified 53 patients with partial adrenalectomy and 29 patients with laparoscopic total adrenalectomy. Single-port surgery was performed for 37 and 19 patients, respectively. Single-port surgery was associated with shorter operative and laparoscopic times (odds ratio, 0.14; 95% confidence interval, 0.039-0.49; P = .002 and odds ratio, 0.13; 95% confidence interval, 0.032-0.57; P = .006, respectively). All single-port and multi-port partial adrenalectomy cases showed complete short-term (median 1 year) biochemical success, and 92.9% (26 of 28 patients) who underwent single-port partial adrenalectomy and 100% (13 of 13 patients) who underwent multi-port partial adrenalectomy showed complete long-term (median 5.5 years) biochemical success. No complications were observed with single-port adrenalectomy. CONCLUSION: Single-port partial adrenalectomy is feasible after selective adrenal venous sampling for unilateral aldosterone-producing adenomas, with shorter operative and laparoscopic times and a high rate of complete biochemical success.

Association Between Aldosterone and Hypertension Among Patients With Overt and Subclinical Hypercortisolism.

Introduction: Hypertension is one of the most common clinical features of patients with overt and subclinical hypercortisolism. Although previous studies have shown the coexistence of autonomous cortisol and aldosterone secretion, it is unclear whether aldosterone plays a role in hypertension among patients with hypercortisolism. Therefore, we examined the associations of plasma aldosterone concentrations (PACs) with hypertension among patients with overt and subclinical hypercortisolism. Methods: This single-center retrospective cohort study included patients with adrenal tumor and serum cortisol levels after 1-mg dexamethasone suppression test >1.8 µg/dL (50 nmol/L). Using multivariable regression models adjusting for baseline characteristics, we investigated the association of PACs with systolic blood pressure and postoperative improvement of hypertension after the adrenalectomy. Results: Among 89 patients enrolled in this study (median age, 51 years), 21 showed clinical signs of Cushing syndrome (overt hypercortisolism) and 68 did not show clinical presentations (subclinical hypercortisolism). We found that higher PACs were significantly associated with elevated systolic blood pressure among patients with subclinical hypercortisolism (adjusted difference [95% CI] = +0.59 [0.19-0.99], P = 0.008) but not among those with overt hypercortisolism. Among 33 patients with subclinical hypercortisolism and hypertension who underwent adrenalectomy, the postoperative improvement of hypertension was significantly associated with higher PACs at baseline (adjusted risk difference [95% CI] = +1.45% [0.35-2.55], P = 0.01). Conclusion: These findings indicate that aldosterone may contribute to hypertension among patients with subclinical hypercortisolism. Further multi-institutional and population-based studies are required to validate our findings and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Characteristics of aldosterone-producing adenomas in patients without plasma renin activity suppression.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] µg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] µ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.

Safety and feasibility of radiofrequency ablation using bipolar electrodes for aldosterone-producing adenoma: a multicentric prospective clinical study.

Evaluation of feasibility and safety of percutaneous radiofrequency ablation using bipolar radiofrequency devices in a prospective multicenter cohort of patients with benign aldosterone-producing adenoma. A total of five institutions participated. CT-guided percutaneous RFA was performed for patients diagnosed as APA. The safety of the procedure was evaluated using the Common Terminology Criteria for Adverse Events. During the 84-day follow-up period, serial changes in plasma aldosterone concentration and plasma renin activity were measured. The percentage of patients with normalized hormonal activity after the procedure, was calculated with 95% confidence intervals. Forty patients were enrolled, and two patients were excluded for cerebral hemorrhage and no safe puncture root. In another patients, RFA was tried, but an intraprocedural intercostal arterial injury occurred. Consequently, RFA was completed in thirty-seven patients (20 men, 17 women; mean age, 50.4 ± 10.0 year). The tumor size was 14.8 ± 3.8 mm. The treatment success rate of the ablation was 94.6% (35/37), and a 2nd session was performed in 2.7% (1/37) patients. Grade 4 adverse events were observed in 4 out of 38 sessions (10.5%). The normalization of plasma aldosterone concentration or aldosterone-renin ratio was 86.5% (72.0-94.1: 95% confidence interval) on day 84. Percutaneous CT-guided RFA for APA using a bipolar radiofrequency system was safe and feasible with clinical success rate of 86.5% on day 84.

Guidelines for the diagnosis and treatment of primary aldosteronism--the Japan Endocrine Society 2009.

The Japan Endocrine Society (JES) attempted to develop guidelines for the diagnosis and treatment of primary aldosteronism (PA). The Task Force Committee (TFC) was composed of a chair, selected by the JES, and additional experts. Systematic reviews of available evidence for Japanese patients were used to recommend the key treatment and prevention. We have evaluated the methods of screening, confirmatory tests and imaging, plus adrenal vein sampling (AVS). Consensus was guided by systematic review of evidence and discussion during each annual meeting of the JES, plus its related meetings, and by e-mail communication. The drafts prepared by TFC were reviewed successively by the members of Research on Intractable Diseases provided by the Japanese Ministry of Health, Labour and Welfare, and in comments from the JES's councilors. At each stage of review, TFC received written comments and incorporated suggested changes. In conclusion, all patients with hypertension should be screened for PA, because of the high prevalence of cardiovascular disease and the current low case-detection rate in Japan. Case detection can be performed in hypertensive patients and those with hypokalemia by determining the aldosterone/renin ratio, and the diagnosis of PA can be confirmed by two of three confirmatory tests. The presence of a unilateral aldosterone-producing adenoma should be established/excluded by AVS by an experienced radiologist, optimally followed by laparoscopic adrenalectomy. In contrast, patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, are optimally treated medically with mineralocorticoid receptor antagonists.

[Recent progress of diagnosis and treatment of primary aldosteronism].

In primary aldosteronism, cardio-cerebro-renal complication is higher in cases diagnosed after 5 years of onset of hypertension than those diagnosed before 5 years. Moreover, prognosis of hypertension and renal function after unilateral adrenalectomy for aldosterone-producing microadenoma with short-term exposure of hypertension is better than those for CT-detectable aldosterone-producing adenoma with long standing hypertension. Therefore, we should accurately diagnose PA among newly-onset hypertensive patients by simultaneous measurement of aldosterone and renin, and treat patients with aldosterone-producing microadenoma, which has been sometimes misdiagnosed as essential hypertension for a long time, by unilateral adrenalectomy, based on the diagnosis of adrenal venous sampling.

Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies.

The hypothalamus-pituitary-adrenal (HPA) axis plays an important role in primary aldosteronism. Aldosterone biosynthesis is regulated not only by angiotensin II in the renin-angiotensin-aldosterone system, but also by adrenocorticotropic hormone (ACTH), one of the key components of the HPA axis. Although previous studies have reported cortisol cosecretion in primary aldosteronism, particularly aldosterone-producing adenoma (APA), the clinical relevance of such aldosterone and cortisol cosecretion from APA and hypertension or other metabolic disorders has not been fully established. Several somatic mutations including KCNJ5 and CACNA1D are known to induce autonomous production of aldosterone in APA, and the aldosterone responsiveness to ACTH may vary according to each mutation. The ACTH stimulation test has been reported to be a useful tool to distinguish the subtypes of primary aldosteronism (e.g., unilateral vs bilateral) in some studies, but it has not been commonly applied in clinical practice due to limited evidence. Given the recent advancement of imaging, omics research, and computational approach, it is important to summarize the most updated evidence to disentangle the potential impact of cortisol excess in primary aldosteronism and whether the ACTH stimulation test needs to be considered during the diagnostic process of primary aldosteronism. In this article, we conducted a systematic review of epidemiological studies about (i) cortisol cosecretion in primary aldosteronism and (ii) the ACTH stimulation test for the diagnosis of primary aldosteronism (including subtype diagnosis). Then, we discussed potential biases (e.g., confounding bias, overadjustment, information bias, selection bias, and sampling bias) in the previous studies and introduced some advanced epidemiological/statistical methods to minimize these limitations. A better understanding of biases and epidemiological perspective on this topic would allow us to produce further robust evidence and balanced discussion about the causal mechanisms involving the HPA axis and clinical usefulness of the ACTH stimulation test among patients with primary aldosteronism.