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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.

Background: Hypertension is one of the most common and distinguishing clinical features of patients with overt Cushing’s syndrome (CS) and subclinical Cushing’s syndrome (SCS). Although hypertension can be triggered by excess cortisol levels, it is unclear whether the cortisol is sufficient to explain the hypertension among these diseases (particularly SCS in which cortisol is slightly elevated) indicating the potential contribution of aldosterone to the elevated blood pressure. In this study, we aimed to examine the aldosterone biosynthesis among patients with CS or SCS. Methods: We conducted the prospective study enrolling 90 patients (21 CS and 69 SCS) from 2016 to 2019 at Yokohama Rosai Hospital. We diagnosed patients with CS when they showed clinical features of CS and serum cortisol levels (F) after 1 mg dexamethasone (1-mg DST) was >5 μg/dl. SCS was defined as F after 1-mg DST was >1.8 μg/dl. For patients who are considered to be appropriate for adrenalectomy, we performed the segment-selective ACTH-loading adrenal venous sampling (AVS) to find the laterality of cortisol producing adenoma (CPA). The resolution of hypertension was assessed 1-year after the adrenalectomy. Results: The median [interquartile range] age was 51 [46–62] years and males were 28%. Hypertension was observed in 21 (100%) CS and 58 (84%) SCS patients. Median F after 1mg-DST were 16.4 [14.3–18.7] mg/dl and 5.1 [3.4–7.5] mg/dl among CS and SCS patients, respectively. Median plasma renin activity among CS and SCS patients were 0.7 [0.4–1.3] ng/ml/h and 0.5 [0.2–0.9] ng/ml/h, respectively. Median plasma aldosterone concentrations (PAC) among CS and SCS patients were 8.3 [7.2–9.8] ng/dl and 9.3 [7.2–17.0] ng/dl at baseline, rising to 24.7 [18.6–32.3] ng/dl and 32.9 [25.8–48.3] ng/dl after ACTH stimulation. During the AVS, all SCS cases with hypertension showed the aldosterone excess (i.e. effluent aldosterone concentrations ≥1400 ng/dl after ACTH stimulation) in at least one adrenal segmental tributary vein. All CS cases showed the hypertension resolution after the resection of CPA except one case showing aldosterone excess on the opposite side of CPA. Among 39 SCS cases who underwent adrenalectomy, hypertension remained in 10 cases, and all of them showed aldosterone excess on the opposite side of CPA. Conclusion: We found that aldosterone was likely to be elevated (or hyper-responsive to ACTH) among CS or SCS patients with hypertension. The proportion of the hypertension resolution after the CPA resection was lower when patients showed aldosterone excess on the opposite side of CPA. These findings indicate that elevated aldosterone may contribute to the high prevalence of hypertension and its resolution rate after adrenalectomy for patients with CPA. Further studies are needed to examine the clinical effectiveness of the intervention targeting aldosterone among patients with CS and SCS.

Background and Aim: Glycated albumin (GA) reflects a short-term glycemic control (about 2 weeks) in comparison to glycated hemoglobin (HbA1c) which reflects a long-term glycemic control. Thus, if the dietary, exercise, or medication therapy before the educational admission is effective, a rapid improvement in GA can be observed. However, the impact of the improvement in GA on the subsequent glycemic control is not well understood. This retrospective study analyzed the association between the change of GA before educational admission and glycemic control one year after the discharge of patients with type 2 diabetes mellitus (T2DM). Method: We analyzed data from 114 T2DM patients who were admitted to our hospital from 2011 to 2016. The GA data within 30 days before admission and on the day of admission were available for all patients. The change of GA per day (ΔGA/day) was calculated as [(GA on admission) - (GA before admission)/number of days between the two measurements of GA]. Patients with renal dysfunction (eGFR < 30 mL/min/1.73 m2) or insulin deficiency [fasting C-peptide (CPR) < 0.5 ng/mL or two-hour postprandial CPR < 1.0 ng/mL] were excluded. Patients achieving an HbA1c of < 7.0 % at one year after discharge were defined as achievers, and the rest were defined as non-achievers. Multiple baseline factors including the ΔGA/day between the two groups were compared. Results: Of the 114 patients, 68 were achievers and 46 were non-achievers. GA significantly declined during before and just after the admission to hospital (median [interquartile range]: 26.0 [22.2 - 32.7] to 25.0 [21.4 - 29.8] %, p < 0.001). The range of the ΔGA/day was between -1.14 and 0.28, with a median value of -0.08 [-0.26 - 0.002]. The age, body mass index, and HbA1c levels at admission were not significantly different between the two groups. The increase in CPR after the glucagon loading test was higher in the achievers than in the non-achievers (1.85 [1.32 - 2.87] vs 1.21 [0.53 - 1.92] ng/ml, p = 0.004). The ΔGA/day was lower in the achievers than in the non-achievers (-0.14 [-0.39 - -0.006] vs -0.04 [-0.13 - 0.03], p = 0.002). A logistic regression analysis demonstrated that the ΔGA/day was the factor associated with achieving an HbA1c of < 7.0% at one year after discharge (Odds ratio: 0.037, 95 % confidence interval: 0.004 - 0.267, p < 0.001). In the receiver operating characteristic curve analysis, the ΔGA/day had an area under the curve of 0.67 in the achievement group and the cutoff value was set as -0.146 for predicting the achievement, with a sensitivity of 0.50 and a specificity of 0.85. Conclusion: Our results suggest that the change in GA before the educational admission can predict the glycemic control one year after the discharge of T2DM patients.

Introduction: Primary aldosteronism (PA) is associated with an increased risk of impaired glucose tolerance or type 2 diabetes mellitus. Previous studies have reported that impaired insulin secretion and insulin sensitivity in PA may lead to impaired glucose tolerance. However, the relationship between PA and glucose tolerance, and the factor associated with these glucose metabolism abnormalities is not well understood. In particular, few studies have analyzed the association between aldosterone excess and insulin sensitivity or resistance after the adjustment for other clinical variables. In this study, we analyzed the associations between multiple clinical variables observed in PA and the indices of insulin sensitivity and resistance, using the result of 75 g oral glucose tolerance test (OGTT).Method: This was a retrospective observational study that analyzed the data of 646 patients with PA who underwent adrenal venous sampling and 75 g OGTT. The insulinogenic index and Matsuda index, indices of insulin secretion and sensitivity, respectively, were calculated from the results of a 75 g OGTT. Correlations between these indices and the multiple clinical variables were analyzed. In addition, we performed multiple regression analyses to identify the independent explanatory variables of these indices.Results: Insulinogenic index had positive correlations with the body mass index (BMI), alanine aminotransferase (ALT) level, triglyceride (TGL) level, and potassium level, and negative correlations with both age and plasma aldosterone concentration (PAC). In a multiple regression analysis, both the age (β = -0.231, p < 0.001) and potassium level (β = 0.175, p = 0.002) were selected as the independent explanatory factors. The Matsuda index had positive correlations with the PAC and cortisol level after a 1 mg dexamethasone suppression test (DST), and negative correlations with BMI, ALT level, TGL level, plasma renin activity (PRA), and potassium level. In a multiple regression analysis, BMI (β = -0.216, p < 0.001), ALT level (β = -0.290, p < 0.001), TGL level (β = -0.225, p < 0.001), the cortisol level after 1 mg DST (β = 0.124, p = 0.009), and PRA (β = -0.119, p = 0.019) were selected as the independent explanatory factors.Conclusion: In PA patients, older age and decreased potassium levels were associated with impaired insulin secretion. An increase in the variables associated with metabolic abnormalities such as BMI, ALT, and TGL were associated with decreased insulin sensitivity. In addition, we found that decreased PRA was associated with increased insulin sensitivity.

In primary aldosteronism (PA), it is reported that secondary hyperparathyroidism (SHPT) is caused by increased urinary Ca excretion due to excessive aldosterone, which may decrease bone mineral density and increase fracture risk. However, there have been few reports that evaluated changes in bone metabolism markers in detail before and after the treatment for PA. In this retrospective study, we evaluated changes in multiple bone metabolism markers before and after adrenalectomy. We analyzed 16 patients who underwent adrenalectomy for unilateral aldosterone-producing adenoma (APA) in our hospital from April 2009 to November 2017 and compared various bone metabolism markers before and after surgery. All patients were diagnosed with unilateral hyperaldosteronism by segmental adrenal venous sampling. Patients with bilateral hyperaldosteronism and bone disease were excluded. We compared changes in levels of serum Ca, 24-hour urinary Ca excretion (u-Ca), intact parathyroid hormone (iPTH), tartrate-resistant acid phosphatase 5b (TRACP-b5), bone-specific alkaline phosphatase (BAP), and undercarboxylated osteocalcin (ucOC) before and one year after surgery. Sixteen patients consisted of 8 males and 8 females (Mean age =49.6 years old, BMI =23.7 kg/m2, hypertension duration =10.9 years, blood pressure =135/84 mmHg, eGFR =86.6 mL/min/1.73 m2). After surgery, aldosterone hypersecretion improved markedly (plasma aldosterone (PAC); 278.4 ± 167.5 to 96.9 ± 47.1 pg/mL, urinary aldosterone; 28.6 ± 22.7 to 5.6 ± 3.9 μg/day). Significant increase in serum Ca (8.74 ± 0.24 to 9.31 ± 0.80 mg/dL, P < 0.001) and decreases in u-Ca (0.23 ± 0.10 to 0.09 ± 0.07 g/day, P = 0.002) and iPTH (86.7 ± 40.8 to 54.4 ±16.3 pg/mL, P < 0.001) were observed. In addition, significant decreases in TRACP-b5 (373.0 ± 180.1 to 211.9 ± 101.2 mU/dL, P < 0.001), BAP (16.6 ± 7.06 to 10.8 ± 3.73 μg/L, P < 0.001), and ucOC (7.56 ± 5.0 to 4.04 ± 2.3 ng/mL, P = 0.004) levels were observed. The change in iPTH had significant positive correlation with the change in PAC (r = 0.55, P = 0.026), while it had no correlation with the change in u-Ca. The correction of hyperaldosteronism by adrenalectomy decreased urinary Ca excretion, iPTH level, and bone tune over. In addition, our results suggest that the increase in iPTH was caused by hyperaldosteronism, independent from the excess in urinary calcium excretion.

Introduction: Primary aldosteronism (PA), characterized by a hypersecretion of aldosterone from the adrenal gland, increases the risks of cardiovascular disease. However, there is limited report on the changes of echocardiographic parameters after adrenalectomy in patients with PA. This study aimed to assess the multiple changes of echocardiographic parameters, including left atrial (LA) enlargement, diastolic dysfunction, left ventricular (LV) systolic function, and LV hypertrophy, pre- and post-adrenalectomy. Methods: In a retrospective cohort study, we analyzed a total of 122 patients with aldosterone-producing adenoma who underwent unilateral adrenalectomy from 2009 to 2016. All patients were diagnosed with unilateral hyperaldosteronism on the basis of segmental adrenal venous sampling (S-AVS). We excluded patients with a history of myocardial infarction, atrial fibrillation, or bilateral hyperaldosteronism. Echocardiography was performed before and 1-year after adrenalectomy and we evaluated multiple echocardiographic parameters. Results: After surgery, blood pressure, plasma aldosterone concentration and 24-hour urinary aldosterone excretion declined significantly (all P < 0.001). In echocardiography, LA diameter (LAD) decreased significantly (34.3 [30.9-37.5] to 33.8 [30.5-36.0] mm; P = 0.001). Early diastolic filling velocity to septal early diastolic mitral annular tissue velocity ratio tended to decrease (8.25 [6.99-9.58] to 7.9 [6.8-9.4], P = 0.22). LV diastolic internal dimension (48.3 [45.3-51.3] to 46.8 [42.6-49.5] mm), LV posterior wall thickness (8.5 [7.5-9.4] to 7.9 [7.4-9.0] mm), and LV mass index (LVMI) (101.17 [84.3-123.2] to 87.4 [77.0-103.2] g/m2) decreased significantly (all P < 0.001). Ejection fraction, fractional shortening, cardiac index did not change significantly. The most influencing factors to changes in LAD and LVMI were pre-operative values of each echocardiographic parameter. Conclusion: Our results indicate that correction of hyperaldosteronism by adrenalectomy improves LA enlargement and LV hypertrophy in patients with aldosterone-producing adenoma. The improvement effects on these parameters may be exerted depending on pre-operative abnormality. Adrenalectomy could be an effective treatment for decreasing risks of cardiovascular disease by improving blood pressure and cardioprotective effect.

Background: In our hospital, we perform segmental adrenal venous samplings (S-AVS) to detect the exact locations of causative lesions of primary aldosteronism (PA), and adrenalectomy for localized lesion. In this study, we investigated the influence of laboratory values in the tributary veins of unresected adrenal glands to surgical outcomes. Methods: A total of 102 PA patients who underwent S-AVS (collected blood samples from 3 or more tributary veins in each adrenal gland) and unilateral adrenalectomy were analyzed. All patients were assessed on the biochemical success of Primary Aldosteronism Surgical Outcomes (PASO) one year after adrenalectomy, by performing saline infusion tests. We divided the patients into two groups; complete success (Com) and incomplete (partial and absent) success (Inc), and compared maximum aldosterone values (Ald max) and Ald max to cortisol ratio (Ald max/Cort ratio) in tributary veins of unresected side, and Ald and Ald/Cort ratio in the central veins of unresected side. Results: Eighty-seven patients had complete biochemical success and fifteen had incomplete success. Inc group had higher Ald max (11000 [7950-22300] pg/mL vs 7030 [4260-11900] pg/mL, p < 0.05) and Ald max/Cort ratio (18.05 [12.77-34.15] vs 9.13 [6.27-14.25], p < 0.05) in the tributary veins, and Ald (9260 [5480-15100] pg/mL vs 5800 [3410-8060] pg/mL, p < 0.05) and Ald/Cort (13.67 [9.51-21.87] vs 8.08 [5.88-10.96], p < 0.05) in the central veins of unresected side, compared to Com group. In logistic analyses for PASO results as an objective variable, Ald max/Cort ratio in the tributary veins had the highest AUC (0.780) as a subjective variable. When the cutoff values were set as 20.92 or 12.77, their sensitivities / specificities were 47% / 85% and 80% / 70%, respectively. On the other hand, lateralized ratio had no significant differences between Com and Inc groups. Conclusion: Biochemical PASO results are influenced by aldosterone values in tributary veins or central veins of unresected side, but not lateralized ratio.

Introduction: Primary aldosteronism (PA) is a common cause of secondary hypertension. It is characterized by excess production of aldosterone from the adrenal glands resulting in suppressed plasma renin activity (PRA) by a negative feedback regulation. Thus, if a patient with hypertension had an unsuppressed PRA, the possibility of PA might be excluded. However, we have observed some PA patients with unsuppressed PRA in our hospital. Here, we report clinical characters of PA patients with unsuppressed PRA. Methods: We searched for PA patients with unsuppressed PRA (Escaped PRA group) from 969 patients who underwent segmental adrenal venous sampling (S-ATS) in our hospital between April 2009 and March 2018. Escaped PRA group were those with PRA level of >1.0 ng/mL/hr in any two or more blood samples obtained in resting position, and had aldosterone producing adenomas (APAs) in which CYP11B2 expression was confirmed histopathologically. We also enrolled patients with APAs with suppressed PRA as a control group (34 females, 35 females ). All patients in the control group had PRA level of < 1.0 ng/mL/hr in any two or more blood samples obtained in resting position and had macroadenomas in which CYP11B2 expression was confirmed. We compared clinical characteristics between Escaped PRA group and Control group. Results: We found that 7 cases (3 males, 4 females) were in the Escaped PRA group (PRA; 2.3±0.8 ng/mL/hr). One of them showed a gap between PRA and Active Renin Concentration (ARC). Compared to the control group (PRA; 0.3±0.2 ng/mL/hr), the escaped PRA group had no significant difference in body mass Index, blood pressure, urinary aldosterone, and serum potassium. The escaped PRA group tended to be younger compared to control group (53.0±4.4 years-old vs 47.4±10.8 years-old, P = 0.12) and have decreased eGFR Escaped (74.4±20.0 mL/min/1.73 m2 vs 86.3±19.3 mL/min/1.73 m2, P = 0.088). Only serum cortisol level after 1 mg dexamethasone suppression test showed a significant difference (Escaped PRA group; 1.9±0.5 mg/dL, Control group 1.4±3.0 mg/dL, P = 0.011). Conclusion: Excess cortisol has been reported to increase PRA through increasing renin substrate and suppressing ACTH-dependent aldosterone secretion. We should not exclude the possibility of PA in patients without suppressed plasma renin activity, especially who had a cortisol excess.