Idiopathic Hyperaldosteronism Patients Research Articles

Metabolic Outcomes of Primary Aldosteronism Patients Receiving Adrenalectomy or Spironolactone Treatments

To investigate the metabolic outcomes of primary aldosteronism (PA) patients receiving adrenalectomy (ADX) or spironolactone treatment and the contributing factors to the metabolic outcomes. The clinical data of 70 patients with aldosterone-producing adenoma (APA) and 86 patients with idiopathic hyperaldosteronism (IHA) were retrospectively analyzed. All subjects received confirmatory diagnosis of APA or IHA at the Department of Endocrinology and Metabolism, West China Hospital between March 2018 and October 2020. APA patients underwent ADX, while IHA patients were given spironolactone, a mineralocorticoid receptor antagonist (MRA). After ADX or spironolactone treatment, the outcomes of the metabolic indicators and the inter-group differences between the APA patients and IHA patients were studied. There was no significant difference between the baseline data of the APA group and those of the IHA group in terms of age, sex, duration of hypertension, maximum systolic blood pressure (SBP-max), maximum diastolic blood pressure (DBP-max), body mass index (BMI), fasting blood glucose (FBG), lipid parameters, and renal function. IHA patients had higher waist circumference, serum potassium, and plasma renin activity (PRA) than those of the APA patients (all P<0.05). All patients showed significant improvement in blood pressure, blood potassium, and plasma aldosterone at follow-up. However, they also showed increased triglycerides (TG) accompanied by deterioration in renal function (P≤0.001). Multiple regression showed that TG levels were associated with spironolactone treatment for IHA patients and post-treatment BMI and creatinine levels. Furthermore, APA patients showed improvement in their FBG after ADX (P=0.041), while IHA patients showed elevated levels of FBG after spironolactone treatment (P=0.037). After treatment, PA patients still may experience abnormal lipid metabolism and deteriorating renal function. Spironolactone therapy may give rise to worse glucolipid metabolism than ADX therapy does.

FRI186 Differences Of Body Composition And Comorbidities In Patients With Primary Aldosteronism According To Sex And Subtypes

Abstract Disclosure: S. Park: None. C. Ahn: None. S. Seo: None. S. Kim: None. J. Yoon: None. J. Kim: None. Background: Primary aldosteronism (PA) is associated with metabolic risks such as diabetes and obesity. However, controversy exists as to which subtype of PA has a higher metabolic risk between idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA). We aimed to assess the body composition of two PA subtypes according to sex and evaluate autonomous cortisol secretion (ACS) and its contribution to comorbidities. Methods: A total of 400 patients with PA and 1:10 age- and sex-matched healthy controls (n=4,000) were enrolled. Clinical and biochemical data were reveiwed. The skeletal muscle area (SMA), subcutaneous fat area, and visceral fat area (VFA) at the third lumbar spine were calculated using abdominal computed tomography-based body composition analysis. Results: In both sexes, a higher body mass index (BMI) was observed in patients with IHA than in those with APA (P&amp;lt;0.001 in men and P=0.049 in women). Hemoglobin A1c (HbA1c) level and the prevalence of diabetes were higher in female patients with IHA than in those with APA (6.0±0.9 vs. 5.6±0.5%, P=0.005 for HbA1c; 19.0% vs. 6.8%, P=0.016 for diabetes). The VFA/BMI ratio was significantly higher in patients with IHA than in patients with APA (5.77±2.69 vs. 4.56±2.35, P&amp;lt;0.001 in men; 4.03±2.58 vs. 2.53±2.05, P&amp;lt;0.001 in women). In subgroup analysis, decreased SMA was observed in PA patients with ACS compared with those without ACS. Compared with age- and sex-matched healthy controls, all patients with IHA and female patients with APA showed significantly higher VFA and VFA/BMI. Conclusion: Patients with IHA were more obese and had higher visercal adiposity than those with APA. This metabolically unfavorable body composition may contribute to a higher metabolic risk in patients with IHA. The role of adipose tissue in pathogenesis of IHA remains to be elucidated. Presentation: Friday, June 16, 2023

The metabolic phenotype of patients with primary aldosteronism: impact of subtype and sex - a multicenter-study of 3566 Caucasian and Asian subjects.

Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

Diurnal blood pressure pattern and cardiac damage in hypertensive patients with primary aldosteronism.

The aim of our study was to evaluate the relationship between the 24-h blood pressure (BP) profile, plasma NT-proBNP levels and left ventricular hypertrophy (LVH) in subjects with primary aldosteronism (PA) compared to patients with essential hypertension (EH). A total of 385 consecutive patients with PA [187 with aldosterone producing adenoma (APA) and 198 with idiopathic hyperaldosteronism (IHA)] and 385 patients with EH were matched based on age, sex, body mass index (BMI), BP values and duration of hypertension. Twenty-four-hour ambulatory BP monitoring (ABPM), plasma levels of NT-proBNP, left ventricular mass index (LVMI), and other clinical medical data were assessed in all patients. No differences in age, sex, BMI, clinical BP, 24-h mean BP, daytime BP, or duration of hypertension were found between groups. Nighttime systolic BP (130 ± 16 vs. 127 ± 17 mmHg, p < 0.05) and diastolic BP (82 ± 10 vs. 79 ± 11 mmHg, p < 0.01) were higher in PA patients than in EH patients. In addition, nocturnal BP decline was reduced, while median NT-proBNP (53.7 vs. 33.2 pg/ml, P < 0.001) and LVMI (113 ± 25 vs. 102 ± 26 g/m2, P < 0.001) were higher in PA patients than in EH patients. Moreover, the median NT-proBNP level was higher in APA patients than in IHA patients (68.0 vs. 42.4 pg/ml, P < 0.001). In stepwise multivariate regression analysis, LVMI was correlated with NT-proBNP, nighttime systolic BP and sex in PA patients. Patients with PA show higher nighttime BP and NT-proBNP levels and lower nocturnal BP decline than those with EH. In addition, higher nocturnal systolic BP has been shown to be strongly associated with cardiac damage in PA patients.

MON-161 Body Weight Reduction Not Always Reduced Adrenal Gland Volume in Obese Patients

Recent studies have shown that obesity is a major risk factor for idiopathic hyperaldosteronism (IHA). IHA patients have greater AGV than normal controls. However, it is unclear whether such changes are caused by obesity and whether losing weight could reverse the morphological and functional abnormalities of the adrenal gland. This study was to investigate the association of obesity with adrenal gland volume (AGV) and the effects of weight loss on AGV. This study recruited obese patients (N=25) who underwent sleeve gastrectomy and age- and sex-matched normal-weight (N=25) and overweight healthy volunteers (HV) (N=21). Thin-slice computed tomography was used to evaluate adrenal morphological changes. AGV was measured semiautomatically based on the digital imaging and communications in medicine (DICOM) image. The effects of weight loss on AGV were evaluated in patients for one year or more after sleeve gastrectomy. The results showed that left, right and total AGV were larger in obese patients than those in overweight and normal- weight HVs (6.77±0.36, 5.76±0.31, and 12.53±0.64 cm3 vs. 3.88±0.14, 3.09± 0.13 and 6.97± 0.24 cm3 vs. 3.38±0.23, 2.67±0.15 and 6.04±0.36 cm3). No statistically significant difference was identified between overweight and normal-weight HVs. Sleeve gastrectomy significantly reduced body weight (-27.1±2.5 kg), left AGV (-0.80±0.26 cm3), and right AGV (-0.88±0.20 cm2). However, the adrenal volume in five patients was not reduced, despite significant weight loss postsurgery. In brief, obesity leads to increased AGV, and in some cases, this effect seems to be irreversible. We speculate that obesity causes permanently adrenal morphological changes (increased volume or hyperplasia), and under certain circumstances, it results in excessive aldosterone secretion via altered adipokines (leptin, CTRP1, etc.).

Clinical Characteristics of Aldosterone Producing Adenoma and Idiopathic Hyperaldosteronism with Obstructive Sleep Apnea Hypopnea Syndrome

To investigate the clinical characteristics of aldosterone producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) complicated with obstructive sleep apnea hypopnea syndrome (OSAHS) and the effect of OSAHS on renin-angiotensin-aldosterone system (RAAS) in APA and IHA patients. The clinical data of 127 patients with primary aldosteronism (PA) diagnosed from May 2010 to Aug. 2019 were retrospectively analyzed. There were 70 cases of APA, 53 cases of IHA. Another 4 cases were primary adrenal hyperplasia (PAH), so not included into further analysis. According to the results of polysomnography, the 123 patients of APA or IHA were divided into OSAHS group (96 cases) and non-OSAHS group (27 cases ). The patients with OSAHS were divided into mild, moderate and severe subgroups based on apnea hypopnea index (AHI).The clinical characteristics, biochemical parameters, plasma renin activity, aldosterone levels, and the ratio of aldosterone to renin activity (ARR) in the patients of APA and IHA complicated with OSAHS were compared with those of the patients without OSAHS. There were 49 OSAHS cases (49/70, 70.0%) in APA patients. and 47 OSAHS cases (47/53, 88.7%) in IHA patients. The age, male ratio, body mass index (BMI), waist circumference, triglyceride, blood uric acid, and blood creatinine in APA patients with OSAHS were higher than those in APA patients without OSAHS ( P<0.05), while high-density lipoprotein and estimated glomerular filtration rate (eGFR) were lower ( P<0.05). Compared to the patients without OSAHS, IHA-OSAHS patients had higher BMI and waist circumference ( P<0.05). Moderate/severe OSAHS-APA patients exhibited higher plasma renin activity levels and lower ARR values than the APA patients with no/mild OSAHS ( P<0.05). There were no significant differences in plasma renin activity, aldosterone levels, and ARR values between moderate/severe OSAHS-IHA group and no/mild OSAHS-IHA group. The prevalence of OSAHS is significantly higher in the patients with PA than normal population, and OSAHS may aggravate glycose, lipid and uric acid metabolism in PA patients. Moderate/severe OSAHS can increase renin levels and decrease ARR values in APA patients, but has no significant effect on RAAS in IHA patients.

The Value of Postural Stimulation Test Combined with Adrenal CT in the Diagnosis of Aldosterone-producing Adenoma

Adrenal vein sampling (AVS) and pathological report were selected as gold standard to assess the value of adrenal CT scan combined with postural stimulation test in diagnosing aldosterone-producing adenoma. The clinical data of primary aldosteronism (PA) patients including aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were retrospectively collected in the West China Hospital of Sichuan University. The sensitivity and specificity of adrenal CT scan combined with postural stimulation test in diagnosing APA were studied. A total of 83 APA patients and 42 IHA patients were enrolled in this study. ROC curve was plotted with increase percentage of serum aldosterone in upright position compared with recumbent position. The optimal cutoff point for APA diagnosis by postural stimulation test was 11%, and the percentage less than 11% was taken as a positive result. The patients were diagnosed by postural stimulation test, with 60 cases positive and 23 cases negative in APA patients and 12 cases positive and 30 cases negative in IHA patients. When AVS and pathological report were selected as the gold standard, the sensitivity and specificity of postural stimulation test in diagnosing APA were 72.3% and 71.4% respectively. Among the 83 APA patients, 65 patients with unilateral nodules and 18 patients with bilateral nodules were diagnosed by CT scan. The coincidence rate in APA diagnosis between CT scan and AVS or pathological report was 78.3% (65/83). Among the 60 patients with positive result in postural stimulation test, who were diagnosed bilateral nodules by CT scan, 51 patients were diagnosed as APA by AVS or pathological report (51/60). Adrenal CT combined with postural test can increase the diagnostic accuracy of APA patients.

Cellular and Genetic Causes of Idiopathic Hyperaldosteronism.

Primary aldosteronism affects ≈5% to 10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral primary aldosteronism is caused by computed tomography-detectable aldosterone-producing adenomas, which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The cause of the most common bilateral form of primary aldosteronism, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of 15 IHA adrenals was examined with CYP11B2 immunohistochemistry and next-generation sequencing. CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2-expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least 1 CYP11B2-positive aldosterone-producing cell cluster (APCC) or micro-aldosterone-producing adenomas. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. Next-generation sequencing of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit α 1-D ( CACNA1D, n=57; 58%) and potassium voltage-gated channel subfamily J-5 ( KCNJ5, n=1; 1%). These data suggest that IHA may result from not only hyperplasia but also the accumulation or enlargement of computed tomography-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.

Abstract 057: Cellular and Genetic Causes of Idiopathic Hyperaldosteronism

Background: Primary aldosteronism (PA) affects ~10% of hypertensive patients and has unilateral and bilateral forms (30%:70%). Unilateral PA is caused by aldosterone-producing adenomas (APA), which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone regulating genes ( KCNJ5&gt;&gt;CACNA1D ). We recently demonstrated that adrenals from normotensive patients present with pockets of cell expressing aldosterone synthase (CYP11B2). These aldosterone-producing foci (APF) have somatic gene mutations similar to those found in APA ( CACNA1D &gt;&gt; KCNJ5 ). Bilateral PA, which is typically treated by mineralocorticoid receptor (MR) blockade rather than surgery, is termed idiopathic hyperaldosteronism (IHA). Its pathobiology is largely unknown but has been thought to be due to zona glomerulosa (ZG) hyperplasia. Methods: We studied 11 IHA patients (7 males, 4 females) who had unilateral adrenalectomy. Immunohistochemistry for CYP11B2 and next generation sequencing (NGS) targeting genes found in APA were performed on formalin fixed paraffin embedded adrenal tissue. Results were compared to previously described cohorts of 53 age-matched normotensive patients (29 males, 24 females) which were evaluated similarly. Results: CYP11B2 expression was absent from intervening ZG cells in 8/11 (73%) IHA adrenals, but all adrenals harbored at least one APF. The median number and size of APF per case were significantly larger in IHA than normotensive controls (6.1 vs 0 APF/cm 2 of adrenal cortex and 0.25 vs. 0.16 mm 2 , respectively; p&lt;0.0001 and p&lt;0.006). In this IHA cohort, NGS identified CACNA1D and KCNJ5 somatic mutations in 44/71 (62%) and 1/71 (1%) of APF, respectively. Interpretations. Diffuse CYP11B2 expression in adrenal ZG cells was only observed in 3/11 IHA cases, arguing against ZG hyperplasia as the major underlying pathobiology. Rather, we demonstrated increased and enlarged APF in IHA adrenals compared to normotensive controls, supporting potential contribution to the clinical manifestations of hyperaldosteronism. The frequent occurrence of aldosterone-dysregulating CACNA1D somatic mutations in APF support CACNA1D as a potential therapeutic target in IHA to complement current MR blockade approaches.

The application of captopril challenge test in the diagnosis of primary aldosteronism

Objective: To evaluate the value of captopril challenge test (CCT) in the diagnosis of primary aldosteronism (PA). Methods: A total of 674 patients [(45.0±13.7) years, men 341, women 333] admitted to Peking Union Medical College Hospital from 2000 to 2015 were analyzed. Among them, 222 subjects were with essential hypertension (EH), 28 were with pheochromocytoma (PHEO), 246 were with idiopathic hyperaldosteronism (IHA) and 178 were with aldosterone producing adenoma (APA). All patients received CCT. 24 h urine sodium was measured in partial patients. Plasma renin activity (PRA), aldosterone (ALD) were detected. Results: Compared with EH [PRA: before 0.5(0.2, 0.9) μg·L(-1)·h(-1,) after 0.8(0.4, 1.5) μg·L(-1)·h(-1;) ALD: before (393±122) pmol/L, after (360±97) pmol/L] and PHEO [PRA: before 0.3(0.1, 0.9) μg·L(-1)·h(-1,) after 0.4(0.1, 1.6) μg·L(-1)·h(-1;) ALD: before (396±108) pmol/L, after (374±114) pmol/L], lower levels of PRA and higher levels of ALD before and after CCT were observed in PA patients [PRA: before 0.1 (0.1, 0.2) μg·L(-1)·h(-1,) after 0.1 (0.1, 0.2) μg·L(-1)·h(-1;) ALD: before (468±216) pmol/L; after (457±199) pmol/L]. After CCT, the suppression rate of ALD [2.8% (-8.8%, 15.4%) vs 6.6% (-4.3%, 17.6%)] and increasing rate of PRA [0(0, 50%) vs 50%(0, 200%)] in PA patients were lower than those in EH patients. The ALD/PRA ratio (ARR) were higher in PA than that in EH or PHEO patients. In the EH subjects, ALD levels of seated posture were higher than those of recumbent posture both before and after receiving captopril, but with no changes in ARR after CCT. No significant differences in ALD and ARR (before and after receiving captopril) were observed between seated and recumbent position in the PA group. The ARR after CCT tended to decrease in EH subjects with elevated urine-sodium compared with those with normal urine-sodium. No changes could be viewed in ALD and PRA levels between normal urine-sodium and elevated urine-sodium groups among APA, IHA and EH patients either before or after CCT. Among patients with APA, the ALD levels before CCT and the ARR after CCT were lower in the patients with AngiotensionⅡ(AngⅡ) reactive than those without. A ROC curve analysis suggested that the optimal cutoff value was 46.2 (ALD unit: ng/dl; PRA unit: μg·L(-1)·h(-1)) for ARR after challenge in diagnosing PA, with the sensitivity of 88.7% and specificity of 84.8%. Conclusions: ARR after 25 mg captopril had high sensitivity and specificity in diagnosis of PA with the cutoff of 46.2. Seated CCT could replace recumbent CCT as a more confirmatory test. The PRA increasing rate should be taken into consideration when diagnosis of PA.

PS 14-79 ROLE OF ENDOGENOUS ADRENOCORTICOTROPIC HORMONE ON CIRCADIAN ALDOSTERONE RHYTHM IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: We recently reported that stimulation with high-dose adrenocorticotropin (ACTH) caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Design and Method: Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. Patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 09.00 (PAC0900), 23.00 (PAC2300), and after 1 mg dexamethasone suppression (PACdex) were measured and compared among the three groups. The PAC2300/PAC0900, and PACdex/PAC0900 ratios were also analyzed. Results: PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. Conclusions: The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients.

OS 35-09 LONG-TERM OUTCOME OF SURGICALLY- AND MEDICALLY-TREATED PATIENTS OF THE PRIMARY ALDOSTERONISM PREVALENCE IN HYPERTENSIVES (PAPY) STUDY

Abstract PA causes excess cardiovascular (CV) damage, but whether it worsens prognosis remained uncertain as there are no prospective studies. To compare long-term outcome of the 1125 patients recruited in the PAPY study. 11.2% of the PAPY study patients had PA: 6.4% idiopathic hyperaldosteronism (IHA) received medical therapy; 4,8% aldosterone-producing adenoma (APA) required adrenalectomy. Endpoints were total and CV mortality, major adverse cardiovascular events (MACE) and total CV events. Kaplan-Meier and Cox's analysis were used to compare IHA and APA with essential hypertensives (EH). In 2015 outcome data were gathered blindly to final diagnosis. After 11.9 years (median) 65% of the patients had follow-up data. Overall the baseline features of available patients were similar to those lost at follow-up. Compared to EH, IHA patients showed worse death-free survival (88.6% vs 96.8%; p = 0.015), while adrenalectomized APA patients did not. At multivariate analysis IHA independently predicted overall mortality (hazard ratio: 3.02; 95% CI: 1.03-8.85; p = 0.044). With a robust prospective design and the strength of a high power we showed that medically-treated IHA patients remained at a higher risk than EH patients at a long-term follow-up while adrenalectomized APA patients did not. Hence, accurate PA subtyping to achieve early identification of those that need adrenalectomy is key to improve outcome.

Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism

We recently reported that stimulation with high-dose ACTH caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. The patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 0900h (PAC0900), 2300h (PAC2300), and after 1-mg dexamethasone suppression test (PACdex) was measured and compared among the three groups. The PAC2300/PAC0900 and PACdex/PAC0900 ratios were also analyzed. PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients.

Role of endogenous ACTH on circadian aldosterone rhythm in patients with primary aldosteronism.

We recently reported that stimulation with high-dose ACTH caused different responses in terms of aldosterone secretion in aldosterone-producing adenomas (APAs) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism (PA). However, the role of endogenous ACTH in aldosterone secretion in PA has not been systematically evaluated. In this study, we examined diurnal changes in plasma aldosterone concentration (PAC), and changes in PAC after dexamethasone administration in patients with suspected PA, in order to evaluate the effect of endogenous ACTH on aldosterone secretion. Seventy-three patients admitted to Kyoto University Hospital with suspected PA were included. The patients were classified into non-PA, IHA, and APA groups according to the results of captopril challenge test and adrenal venous sampling. PAC at 0900 h (PAC0900), 2300 h (PAC2300), and after 1-mg dexamethasone suppression test (PACdex) was measured and compared among the three groups. The PAC2300/PAC0900 and PACdex/PAC0900 ratios were also analyzed. PAC2300 and PACdex were lower than PAC0900 in all three groups. There were no significant differences in PAC2300/PAC0900 among the three groups. However, PACdex/PAC0900 was significantly lower in the APA group compared with the non-PA and IHA groups. The results of this study indicate that aldosterone secretion in APA patients is more strongly dependent on endogenous ACTH than in IHA and non-PA patients. The results also suggest that factors other than ACTH, such as clock genes, may cause diurnal changes in aldosterone secretion in IHA and non-PA patients.

Abstract 008: Novel Pathological Diagnosis Between Aldosterone Producing Adenoma And Idiopathic Hyperaldosteronism

The expressions of steroidogenic enzymes to produce aldosterone like CYP11B1, CYP11B2, 3BHSD1 and 3BHSD2 remain to be clarified to confirm pathological subclassification between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Furthermore, we examined the correlation between APA tumor size and the status of intratumoral steroidogenic enzymes involved in aldosterone biosynthesis using immunohistochemistry. Surgically proven forty APA patients and ten IHA patients were retrospectively studied. Multi-detector computed tomography, AVS, and laparoscopic adrenalectomy were performed in all of the patients studied. The tumor area of APA at the maximum diameter of the sections was precisely measured by ImageJ software. The status of steroidogenic enzymes was immunohistochemically analyzed using monoclonal antibodies for CYP11B1, CYP11B2, 3BHSD1 and 3BHSD2, and the findings were evaluated according to the H-score system, based on both the number of immunopositive cells and relative immunointensity. Adrenal masses were not detected by computed tomography in 20 APA patients.In all of 10 IHA patients, hyperplastic zona glomerulosa was accompanied by an expression of HSD3B1. In contrast, tumor cells in all 40 APA patients were not immunopositive to HSD3B1, but strongly and dominanty expressed HSD3B2. Perhaps, due to compensatory responses to excess aldosterone, APA had an adjacent zona glomerulosa whose immunoreactivities to HSD3B1 and HSD3B2 were profoundly reduced in all 40 APA patients. Maximum tumor area obtained in the specimens was significantly correlated with preoperative plasma aldosterone concentration, urinary aldosterone excretion, the H-score of CYP11B1, and was inversely correlated with the H-score of CYP11B2. These results demonstrated that small adenomas could produce sufficient aldosterone to cause clinically overt primary aldosteronism because of the significantly higher CYP11B2 expression per tumor area. Monoclonal antibodies against HSD3B1 and HSD3B2 could be useful for immunohistochemical differentiation between APA and IHA. In addition, the relatively higher CYP11B2 expression per area in smaller APA could clinically cause PA despite their CT-undetectable tumor size.

Elevation of Angiotensin-II Type-1-Receptor Autoantibodies Titer in Primary Aldosteronism as a Result of Aldosterone-Producing Adenoma

The mechanisms of excess aldosterone secretion in primary aldosteronism (PA) remain poorly understood, although a role for circulating factors has been hypothesized for decades. Agonistic autoantibodies against type-1 angiotensin-II receptor (AT1AA) are detectable in malignant hypertension and preeclampsia and might play a role in PA. Moreover, if they were elevated in aldosterone-producing adenoma (APA) and not in idiopathic hyperaldosteronism (IHA), they might be useful for discriminating between these conditions. To test these hypotheses, we measured the titer of AT1AA in serum of 46 patients with PA (26 with APA, 20 with IHA), 62 with primary hypertension (PH), 13 preeclamptic women, and 45 healthy normotensive blood donors.We found that the AT1AA titer was higher (P<0.05) in both PA and PH patients (2.65 ± 1.55 and 1.86 ± 0.63, respectively) than in normotensive subjects (1.00 ± 0.20). In APA, it was 2-fold higher than in IHA patients (3.43 ± 1.20 versus 1.64 ± 1.39, respectively, P<0.001), despite similar blood pressure values. Of note, it allowed effective discrimination of APA from either PH or IHA, as shown by Receiver Operator Characteristics curve analysis. Moreover, after captopril challenge, plasma aldosterone concentration fell more in AT1AA-positive than in AT1AA-negative PA patients (-32.4% [21.1-42.9] versus 0.0% [0.0-22.6], P=0.015), suggesting an agonistic role for these autoantibodies. Thus, a higher serum AT1AA titer in patients with APA than in IHA and PH patients can be useful in differentiating APA patients from either PH or IHA, and thus in selecting PA patients to be submitted to adrenal vein sampling.

Cardiac structural changes in idiopathic hyperaldosteronism and treatment with spironolactone

Objective To analyze the cardiac structural changes of patients with primary aldosteronism(PA),to observe cardiac structural remodeling of idiopathic hyperaldosteronism(IHA) patients after treatment with spironolactone,and to discuss the association of the remodeling with blood pressure and blood aldosterone levels.Methods A total of 172 PA patients were taken as experimental group and 100 patients with essential hypertension(EH) served as control group.The clinical data of patients in the two groups were collected.The general information,biochemical data,hormone levels and echocardiographic parameters,including the aortic opening(AO),left atrium diameter(LAd),diastolic left ventricular diameter(DVLd),systolic left ventricular diameter(SVLd),interventricular spetal thickness(IVST),left ventricular posterior wall thickness(LVPW),and left ventricular mass index(LVMI) were compared between the two groups.Thirty-eight patients with IHA were followed up,and changes of the above-mentioned echocardiographic parameters were observed.We also analyzed the relationship between the parameters of cardiac structural remodeling with the blood pressure and plasma aldosterone levels.Results The AO,LAd,DVLd,SVLd,IVST,LVPW,and LVMI in PA group were significantly increased compared with those in EH group(P0.01),and these parameters were positively correlated with the systolic pressure(P0.05).The cardiac hypertrophy parameters,such as IVST and LVMI,were significantly improved after treatment with spironolactone(P0.01);and the cardiac volume parameters,such as AO,LAd,DVLd,and SVLd,had no noticeable changes,and were correlated with plasma aldoterone level.Conclusion PA patients have a more severe cardiac remodeling compared with EH patients,which has a closer relationship with systolic blood pressure.Treatment with spironolactone can ameliorate the cardiac structural changes,especially the cardiac hypertrophy,in IHA patients.

Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study

Primary aldosteronism (PA) is characterized by the onset of both cardiac and gluco-metabolic alterations. The aim of this study was to evaluate the impact of aldosterone excess on the development of such complications, and the effects of surgical and pharmacological treatment on their long-term outcome. We prospectively re-examined 61 patients: 25 with aldosterone-producing adenoma (APA), after surgery, and 36 patients with idiopathic hyperaldosteronism (IHA) on pharmacological treatment. The lipid, fasting and dynamic glucose profiles and the echocardiographic parameters were evaluated at diagnosis and at follow-up. After adrenalectomy all patients had normalization of aldosterone levels and were cured of hypokalaemia, and a resolution of hypertension was achieved in 12 of 25 patients. APA patients showed a significant reduction of both plasma glucose (P=0.017) and insulin levels (P=0.001) after 75 g oral glucose tolerance test. Stabilization of glucose metabolism complications was observed in IHA patients. Multiple regression analysis at diagnosis showed a positive correlation between homeostasis model assessment (HOMA) insulin resistance index and HOMA beta cell and serum aldosterone levels in both APA and IHA. Echocardiographic parameters were improved in both APA and IHA at follow-up and the difference was statistically significant for left ventricular mass index (P=0.017) and interventricular septum thickness (P=0.007) in APA patients. The removal of aldosterone excess in APA patients induces the regression of both cardiac and gluco-metabolic complications, indicating aldosterone as a main determinant of such alterations. In IHA patients the medical treatment seems to avoid the possible progression of the these alterations that appear to be stable.

Genetic Study of Patients with Dexamethasone-Suppressible Aldosteronism without the Chimeric CYP11B1/CYP11B2 Gene

Glucocorticoid-remediable aldosteronism is an inherited disorder caused by a chimeric gene duplication between the CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes. The disorder is characterized by hyperaldosteronism and high levels of 18-hydroxycortisol and 18-oxocortisol, which are under ACTH control. The diagnosis of glucocorticoid-remediable aldosteronism had been traditionally made using the dexamethasone suppression test; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene. The aim of this work was to evaluate whether other genetic alterations exist in CYP11B genes (gene conversion in the coding region of CYP11B1 or in the promoter of CYP11B2) that could explain a positive dexamethasone suppression test and to determine another genetic cause of glucocorticoid-remediable aldosteronism. We also evaluated the role of 18-hydroxycortisol as a specific biochemical marker of glucocorticoid-remediable aldosteronism. We studied eight patients with idiopathic hyperaldosteronism, a positive dexamethasone suppression test, and a negative genetic test for the chimeric gene. In all patients we amplified the CYP11B1 gene by PCR and sequenced exons 3–9 of CYP11B1 and a specific region (−138 to− 284) of CYP11B2 promoter. We also measured the levels of 18-hydroxycortisol, and we compared the results with those found in four subjects with the chimeric gene. None of eight cases showed abnormalities in exons 3–9 of CYP11B1, disproving a gene conversion phenomenon. In all patients a fragment of 393 bp corresponding to a specific region of the promoter of CYP11B2 gene was amplified. The sequence of the fragment did not differ from that of the wild-type promoter of the CYP11B2 gene. The 18-hydroxycortisol levels in the eight idiopathic hyperaldosteronism patients and four controls with chimeric gene were 3.9 ± 2.3 and 21.9 ± 3.5 nmol/liter, respectively (P < 0.01). In summary, we did not find other genetic alterations or high levels of 18-hydroxycortisol that could explain a positive dexamethasone suppression test in idiopathic hyperaldosteronism. We suggest that the dexamethasone suppression test could lead to an incorrect diagnosis of glucocorticoid-remediable aldosteronism.

Genetic study of patients with dexamethasone-suppressible aldosteronism without the chimeric CYP11B1/CYP11B2 gene.

Glucocorticoid-remediable aldosteronism is an inherited disorder caused by a chimeric gene duplication between the CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) genes. The disorder is characterized by hyperaldosteronism and high levels of 18-hydroxycortisol and 18-oxocortisol, which are under ACTH control. The diagnosis of glucocorticoid-remediable aldosteronism had been traditionally made using the dexamethasone suppression test; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene. The aim of this work was to evaluate whether other genetic alterations exist in CYP11B genes (gene conversion in the coding region of CYP11B1 or in the promoter of CYP11B2) that could explain a positive dexamethasone suppression test and to determine another genetic cause of glucocorticoid-remediable aldosteronism. We also evaluated the role of 18-hydroxycortisol as a specific biochemical marker of glucocorticoid-remediable aldosteronism. We studied eight patients with idiopathic hyperaldosteronism, a positive dexamethasone suppression test, and a negative genetic test for the chimeric gene. In all patients we amplified the CYP11B1 gene by PCR and sequenced exons 3-9 of CYP11B1 and a specific region (-138 to -284) of CYP11B2 promoter. We also measured the levels of 18-hydroxycortisol, and we compared the results with those found in four subjects with the chimeric gene. None of eight cases showed abnormalities in exons 3-9 of CYP11B1, disproving a gene conversion phenomenon. In all patients a fragment of 393 bp corresponding to a specific region of the promoter of CYP11B2 gene was amplified. The sequence of the fragment did not differ from that of the wild-type promoter of the CYP11B2 gene. The 18-hydroxycortisol levels in the eight idiopathic hyperaldosteronism patients and four controls with chimeric gene were 3.9 +/- 2.3 and 21.9 +/- 3.5 nmol/liter, respectively (P < 0.01). In summary, we did not find other genetic alterations or high levels of 18-hydroxycortisol that could explain a positive dexamethasone suppression test in idiopathic hyperaldosteronism. We suggest that the dexamethasone suppression test could lead to an incorrect diagnosis of glucocorticoid-remediable aldosteronism.