Yuta Tezuka

Is there a role for segmental adrenal venous sampling and adrenal sparing surgery in patients with primary aldosteronism

OBJECTIVE AND DESIGN Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS)--that is, the collection of effluents from bilateral adrenal central veins (CV)--sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA. METHODS We performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens. RESULTS S-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV. CONCLUSIONS Compared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.

Histopathological Classification of Cross-Sectional Image–Negative Hyperaldosteronism

Context Approximately half of patients with primary aldosteronism (PA) have clinically evident disease according to clinical (hypertension) and/or laboratory (aldosterone and renin levels) findings but do not have nodules detectable in routine cross-sectional imaging. However, the detailed histopathologic, steroidogenic, and pathobiological features of cross-sectional image-negative PA are controversial. Objective To examine histopathology, steroidogenic enzyme expression, and aldosterone-driver gene somatic mutation status in cross-sectional image-negative hyperaldosteronism. Methods Twenty-five cross-sectional image-negative cases were retrospectively reviewed. In situ adrenal aldosterone production capacity was determined using immunohistochemistry (IHC) of steroidogenic enzymes. Aldosterone-driver gene somatic mutation status (ATP1A1, ATP2B3, CACNA1D, and KCNJ5) was determined in the CYP11B2 immunopositive areas [n = 35; micronodule, n = 32; zona glomerulosa (ZG), n = 3] using next-generation sequencing after macrodissection. Results Cases were classified as multiple adrenocortical micronodules (MN; n = 13) or diffuse hyperplasia (DH) of ZG (n = 12) based upon histopathological evaluation and CYP11B2 IHC. Aldosterone-driver gene somatic mutations were detected in 21 of 26 (81%) of CYP11B2-positive cortical micronodules in MN; 17 (65%) mutations were in CACNA1D, 2 (8%) in KCNJ5, and 1 each (4% each) in ATP1A1 and ATP2B. One of 6 (17%) of nodules in DH harbored somatic aldosterone-driver gene mutations (CACNA1D); however, no mutations were detected in CYP11B2-positive nonnodular DH areas. Conclusion Morphologic evaluation and CYP11B2 IHC enabled the classification of cross-sectional image-negative hyperaldosteronism into MN and DH. Somatic mutations driving aldosterone overproduction are common in micronodules of MN, suggesting a histological entity possibly related to aldosterone-producing cell cluster development.

A case of bilateral aldosterone-producing adenomas differentiated by segmental adrenal venous sampling for bilateral adrenal sparing surgery

Primary aldosteronism due to unilateral aldosterone-producing adenoma (APA) is a surgically curable form of hypertension. Bilateral APA can also be surgically curable in theory but few successful cases can be found in the literature. It has been reported that even using successful adrenal venous sampling (AVS) via bilateral adrenal central veins, it is extremely difficult to differentiate bilateral APA from bilateral idiopathic hyperaldosteronism (IHA) harbouring computed tomography (CT)-detectable bilateral adrenocortical nodules. We report a case of bilateral APA diagnosed by segmental AVS (S-AVS) and blood sampling via intra-adrenal first-degree tributary veins to localize the sites of intra-adrenal hormone production. A 36-year-old man with marked long-standing hypertension was referred to us with a clinical diagnosis of bilateral APA. He had typical clinical and laboratory profiles of marked hypertension, hypokalaemia, elevated plasma aldosterone concentration (PAC) of 45.1 ng dl−1 and aldosterone renin activity ratio of 90.2 (ng dl−1 per ng ml−1 h−1), which was still high after 50 mg-captopril loading. CT revealed bilateral adrenocortical tumours of 10 and 12 mm in diameter on the right and left sides, respectively. S-AVS confirmed excess aldosterone secretion from a tumour segment vein and suppressed secretion from a non-tumour segment vein bilaterally, leading to the diagnosis of bilateral APA. The patient underwent simultaneous bilateral sparing adrenalectomy. Histopathological analysis of the resected adrenals together with decreased blood pressure and PAC of 5.2 ng dl−1 confirmed the removal of bilateral APA. S-AVS was reliable to differentiate bilateral APA from IHA by direct evaluation of intra-adrenal hormone production.

Rapid Screening of Primary Aldosteronism by a Novel Chemiluminescent Immunoassay

Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results when measured by radioimmunoassay and development of more rapid assays has been long expected. We have developed chemiluminescent enzyme immunoassays enabling the simultaneous measurement of both aldosterone and renin concentrations in 10 minutes by a fully automated assay using antibody-immobilized magnetic particles with quick aggregation and dispersion. We performed clinical validation of diagnostic ability of this newly developed assay-based screening of 125 patients with primary aldosteronism from 97 patients with essential hypertension. Results of this novel assay significantly correlated with the results of radioimmunoassay (aldosterone, active renin concentration, and renin activity) and liquid chromatography–tandem mass spectrometry (aldosterone). The analytic sensitivity of this particularly novel active renin assay was 0.1 pg/mL, which was better than that of radioimmunoassay (2.0 pg/mL). The ratio of aldosterone-to-renin concentrations of 6.0 (ng/dL per pg/mL) provided 92.0% sensitivity and 76.3% specificity as a cutoff for differentiating primary aldosteronism from essential hypertension. This novel measurement is expected to be a clinically reliable alternative for conventional radioimmunoassay and to provide better throughput and cost effectiveness in diagnosis of hyperaldosteronism from larger numbers of hypertensive patients in clinical settings.

Surgical strategy for an adult patient with a catecholamine-producing ganglioneuroblastoma and a cerebral aneurysm: a case report

BackgroundGanglioneuroblastomas, particularly those that produce catecholamine, are extremely rare in adults. Here, we report an interesting surgical case of an adult patient with a catecholamine-producing ganglioneuroblastomas in her adrenal gland, suspected to be a pheochromocytoma, and with a cerebral aneurysm.Case presentationThe patient was a 73-year-old woman under treatment for hypertension. During a health check-up, a cystic retroperitoneal tumor was incidentally found in the superior pole of her right kidney. Her blood adrenaline level was slightly elevated, and her urinary adrenaline, noradrenaline, and dopamine levels were above the upper reference limits. In addition, 24-h urinary excretion of metanephrine, normetanephrine, and vanillylmandelic acid were all increased. 123I-Meta-iodobenzylguanidine scintigraphy showed an abnormal accumulation of the marker in the cyst wall. She was, therefore, diagnosed with a pheochromocytoma and scheduled for tumor resection. However, preoperatively, 8-mm-diameter cerebral aneurysm was incidentally found in her basilar artery. This required careful preoperative discussion. The aneurysm was difficult to approach and treat, and based on its position, shape, and size, the risk of rupture was low. Because hypertension is a major risk factor for aneurysmal rupture, we decided to proceed with the tumor resection. A lumbar catheter was placed to monitor the cerebral aneurysm for intraoperative rupture, and her transcranial motor-evoked potential and somatosensory-evoked potentials were monitored to track her intraoperative neurological function. During surgery, we carefully monitored fluctuations in blood pressure and resected the tumor with minimal mobilization. Postoperatively, head computed tomography confirmed that there was no sign of rupture. Histopathologically, the tumor was diagnosed as a catecholamine-producing ganglioneuroblastoma. The postoperative course was good, and the patient’s blood pressure improved.ConclusionsCareful perioperative management is needed for a patient with both a catecholamine-producing tumor and cerebral aneurysm.

Image quality and radiation dose of low-tube-voltage CT with reduced contrast media for right adrenal vein imaging

OBJECTIVES To compare image quality and radiation dose of right adrenal vein (RAV) imaging computed tomography (CT) among conventional, low kV, and low kV with reduced contrast medium protocols. METHODS One-hundred-and-twenty patients undergoing adrenal CT were randomly assigned to one of three protocols: contrast dose of 600mgI/kg at 120-kV tube voltage setting (600-120 group), 600mgI/kg at 80kV (600-80 group), and 360mgI/kg at 80kV (360-80 group). Iterative reconstruction was used for 80-kV groups. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the RAV and size-specific dose estimates (SSDE) were measured. Three radiologists evaluated 4-point visualisation scores of RAV by consensus reading. RESULTS The RAV detectability was 95%, 97.2%, and 97.3% for 600-120, 600-80, and 360-80 groups, respectively (p=1.000). Visualisation scores were not significantly different among the groups (p=0.152). There were no significant differences in CNR or SNR between the 600-120 and 360-80 groups. SSDE of the 360-80 group was significantly lower than that of the 600-120 group (5.86mGy±1.44 vs. 7.27mGy±1.81, p<0.001). CONCLUSIONS 80-kV scans with 360 mgI/kg contrast media showed comparable detectability of RAV to conventional scans, while reducing 19% of SSDE.

[OP.6D.06] THE ACCURATE NOVEL TEN MINUTES MEASUREMENTS OF ALDOSTERONE AND ACTIVE RENIN CONCENTRATIONS WILL BE USEFUL AT OUTPATIENT OFFICE

Objective: The measurement of plasma aldosterone concentration (PAC) and renin activity (PRA) or active renin concentration (ARC) is clinically important not only for detection of primary aldosteronism but also for the selection of antihypertensive agents to treat patients successfully. However, it has taken approximately 7 days for clinicians to get the results. Of late, we developed the novel rapid non-RIA assays of PAC and ARC, which are measurable in 10 minutes. This study is intended to investigate the utility and accuracy of this new methods. Design and method: Both PAC and ARC were simultaneously measured by chemiluminescent enzyme immunoassay (CLEIA) system machine with their specific monoclonal antibodies and were automatically washed by the immobilized magnetic particles. We retrospectively compared RIA-assayed PAC, PRA, ARC and LC-MS/MS-measured PAC with CLEIA-measured PAC and ARC in 290 patients with aldosterone producing adenoma (APA, n = 100), bilateral idiopathic hyperaldosteronism (IHA, n = 100) and essential hypertension (EH, n = 90). Results: CLEIA-measured PAC were significantly correlated with RIA-assayed PAC (y = 0.9846 x + 2.5708, Spearmans r = 0.9072, P < 0.0001), and also significantly correlated with LC-MS/MS PAC (y = 1.039 x + 8.0, Spearmans r = 0.997, P < 0.0001). Rapid CLEIA-measured ARC with the lower detection limit of 0.25 pg/mL, which is very small as compared to that of 2 pg/mL in conventional RIA-assayed ARC, were significantly correlated with RIA-assayed ARC (y = 1.0103 x + 0.9156, Spearmans r = 0.8166, P < 0.0001), and also significantly correlated with RIA-assayed PRA (Spearmans r = 0.8091 y = 4.4331 x + 0.4456, P < 0.0001). ARR-A and ARR-C of APA patients were 206 ± 21.7 and 64.5 ± 5.1 (Mean ± SEM), respectively. ARR-A and ARR-C of IHA patients were 42.8 ± 4.7 and 13.2 ± 0.9, and those of EH patients 15.4 ± 3.1 and 3.0 ± 0.5, respectively. Conclusions: Our ten minutes CLEIA-assay of PAC and ARC were proved to be accurate and might be clinically very useful, not only for detecting primary aldosteronism but also for choosing antihypertensive drugs in EH patients. Clinicians will be able to get the simultaneously measured results during patients’ waiting for a short time at their first visits.

PS 14-70 THE DEVELOPMENT OF ACCURATE 10 MINUTE MEASUREMENT OF ACTIVE RENIN AND ALDOSTERONE CONCENTRATION AND ITS CLINICAL SIGNIFICANCE

Objective: The measurement of plasma aldosterone concentration (PAC) and renin activity (PRA) or active renin concentration (ARC) is clinically important not only for detection of primary aldosteronism but also for the selection of antihypertensive agents to treat patients successfully. .However, it has taken approximately 7 days for clinicians to get the results. Of late, we developed the novel rapid non-RIA assays of PAC and ARC, which are measurable in 10 minutes. This study is intended to investigate the utility and accuracy of this new methods. Design and Method: Both PAC and ARC were simultaneously measured by chemiluminescent enzyme immunoassay (CLEIA) system machine with their specific monoclonal antibodies and were automatically washed by the immobilized magnetic particles. We retrospectively compared RIA-assayed PAC, PRA, ARC and LC-MS/MS-measured PAC with CLEIA-measured PAC and ARC in 290 patients with aldosterone producing adenoma (APA, n = 100), bilateral idiopathic hyperaldosteronism (IHA, n = 100) and essential hypertension (EH, n = 90). Results: CLEIA-measured PAC were significantly correlated with RIA-assayed PAC (y = 0.9846 x + 2.5708, Spearmans r = 0.9072, P < 0.0001), and also significantly correlated with LC-MS/MS PAC (y = 1.039x + 8.0, Spearmans r = 0.997, P < 0.0001). Rapid CLEIA-measured ARC with the lower detection limit of 0.25 pg/mL, which is very small as compared to 2 pg/mL in RIA-assayed ARC, were significantly correlated with RIA-assayed ARC (y = 1.0103 x + 0.9156, Spearmans r = 0.8166, P < 0.0001), and also significantly correlated with RIA-assayed PRA (Spearmans r = 0.8091 y = 4.4331 x + 0.4456, P < 0.0001). ARR-A and ARR-C of APA patients were 206 ± 21.7 and 64.5 ± 5.1 (Mean ± SEM), respectively. ARR-A and ARR-C of IHA patients were 42.8 ± 4.7 and 13.2 ± 0.9, and those of EH patients 15.4 ± 3.1 and 3.0 ± 0.5, respectively. Conclusions: Our ten minute measurement of PAC and ARC were proved to be very accurate and might be clinically useful.

OS 35-01 THE PREVALENCE OF SLEEP APNEA SYNDROME IN PRIMARY ALDOSTERONISM.

Objective: Primary aldosteronism (PA) and sleep apnea syndrome (SAS) are common form of secondary hypertension. Some papers reported the group of high risk of SAS was higher rate of complication with PA than that of low risk of SAS. However, there are few reports which evaluated CPAP implementation rate of the PA patients with SAS diagnosing by Polysomnography (PSG). We aim to clarify clinical characteristics of patients of PA with SAS. Design and Method: We screened with Apnomonitor 284 PA patients who underwent adrenal venous sampling (AVS). 144 cases with high score of apnea hypopnea index (AHI) or oxygen desaturation index (ODI) were examined by PSG to decide application of CPAP. We compared systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma aldosterone concentration (PAC), plasma renin activity (PRA), PAC/PRA ratio (ARR) body mass index (BMI) and AHI. Results: AHI: 30.7 ± 2.3/hr(Average ± SEM). 68 PA patients were severe SAS (302, was significantly correlated with AHI (r = 0.3568, P < 0.001). SBP: 150.2 ± 1.2 mmHg, DBP: 94.0 ± 0.9 mmHg, PAC: 26.5 ± 1.1 ng/dl, PRA: 0.35 ± 0.02 ng/ml/hr and ARR: 164.6 ± 11.1 ng/dl per ng/ml/hr were not significantly correlated with AHI. Conclusions: This study demonstrated the high prevalence rate of SAS in PA patients. To detect a SAS complication, the screening by apnomonitor and PSG should be performed in PA patients.

OS 19-08 THE ACTIVATED INTRARENAL RENIN-ANGIOTENSIN SYSTEMS AND OXIDATIVE STRESS IN TUBULAR CAN BE THE ORIGINAL MECHANISM OF RENAL DAMAGE IN PRIMARY ALDOSTERONISM.

Objective: High prevalence of renal damage has been demonstrated in patients with primary aldosteronism (PA). However, the original mechanism and onset still be elucidated. The purpose of this study is to investigate the possible original mechanisms of renal damages in PA. Design and Method: Consecutive 72 patients with aldosterone producing adenoma (APA) and 70 patients with essential hypertension (EH) participated. No patients had renal damages defined as eGFR (based on Cystatin C) < 60 ml/min/1.73m2 and/or urinary albumin (UACR) ≥ 30 mg/g Creatinine and diabetes mellitus defined as HbA1c (NGSP) ≥ 6.5 % and/or medical treatments. All APA patients had taken sufficient mineralocorticoid receptor antagonists (MRAs) until the day of adrenalectomy. Urine samples were collected in the morning at the day of diagnosis (as baseline) and at that of adrenalectomy. Urine total angiotensinogen (UAGTN, &mgr;g/gCreatinine) and liver-type fatty acid-binding protein (L-FABP, &mgr;g/gCreatinine) were measured. The former indicates the activated intrarenal renin-angiotensin system (RAS) due to podocyte injury in the glomerular and megalin dysfunction on the proximal tubular, and the latter is the antioxidant derived from proximal tubular in human. Results: Age, sex distribution, blood pressure, eGFR, UACR, and plasma total AGTN were similar between two groups at baseline. Meanwhile, UAGTN and L-FABP were higher in APA than in EH (10.2 vs. 2.9, p < 0.0005; 5.1 vs. 2.8, p < 0.05). UAGTN and L-FABP in APA showed the correlation (r = 0.6212, p < 0.0001). In multivariate analysis limited to non-renal parameters, plasma aldosterone and plasma AGTN were correlated with UAGTN in APA. UAGTN and L-FABP were decreased after MRAs treatment (10.2 vs. 3.9, p < 0.05; 5.1 vs. 3.7, p < 0.005) and the declines of these markers were correlated with each other (r = 0.3097, p = 0.0102). Conclusions: Activated intrarenal RAS due to podocyte injury in the glomerular and megalin dysfunction and oxidative stress in the proximal tubular which occur before microalbuminuria can be the original mechanisms of renal damage in PA.