Different pathogenesis of glucose intolerance in two subtypes of primary aldosteronism: Aldosterone‐producing adenoma and idiopathic hyperaldosteronism

It is well known that primary aldosteronism (PA) due to aldosterone-producing adenoma (APA) is a surgically curable secondary hypertension. Thus, the differential diagnosis between unilateral hyperaldosteronemia due to APA and bilateral hyperaldosteronemia due to idiopathic hyperaldosteronism (IHA) is crucial to decide surgical indication for treatment in PA patients. Adrenal venous sampling (AVS) can diagnose the laterality of hypersecretion of aldosterone in those patients, while it is still impossible to differentiate bilateral hypersecretion of bilateral aldosterone-producing adenomas (Blt-APAs) from that of bilateral hyperplasia of IHA. To solve the problem, we try to develop a new method of supper-selective ACTH-stimulated adrenal venous sampling (SS-ACTH-AVS). We performed SS-ACTH-AVS by using a strip-tip type 2.2 Fr micro-catheter (Koshin Medical Inc. Japan). Adrenal effluents were sampled super-selectively at the central veins and at one or two tributaries of adrenal veins in each gland. We would like to emphasize that SS-ACTH-AVS can precisely analyze the situation of hyperfunction of steroidogenesis in each side of adrenals as well as in some tiny lesions inside the adrenal cortex which are not visible in the CT images. Moreover, we can differentiate Blt-APAs from IHA, and postulate the decision of surgical treatment, such as partial adrenalectomy. Thus, we should perform SS-ACTH-AVS especially in the case demonstrating the existence of bilateral adrenal lesions such as unilateral and bilateral tumors, or even no tumor in both sides in the patients with PA.

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Urinary excretion of 19-noraldosterone, 18, 19-dihydroxycorticosterone and 18-hydroxy-19-norcorticosterone in patients with aldosterone-producing adenoma or idiopathic hyperaldosteronism

Acta Endocrinologica ◽

10.1530/acta.0.1260484 ◽

1992 ◽

Vol 126 (6) ◽

pp. 484-488 ◽

Cited By ~ 8

Author(s):

Y Takeda ◽

I Miyamori ◽

K Iki ◽

R Takeda ◽

P Vecsei

Keyword(s):

Urinary Excretion ◽

Primary Aldosteronism ◽

Aldosterone Producing Adenoma ◽

Idiopathic Hyperaldosteronism

Urinary excretion of 19-noraldosterone. 18, 19-dihydroxycorticosterone (18, 19(OH)2-B), 18-hydroxy-19-norcorticosterone (18-OH-19-nor-B), 18-hydroxycorticosterone (18-OH-B), 18-hydroxycortisol (18-OH-F) and aldosterone were measured in 25 patients with primary aldosteronism, 16 with an aldosterone-producing adenoma and 9 with idiopathic hyperaldosteronism. In patients with idiopathic hyperaldosteronism, urinary 19-noraldosterone (207±51 pmol/day), 18, 19(OH)2-B (21±4.2 nmol/day) and 18-OH-19-nor-B (879±21 3 pmol/day) levels were lower but not significantly different from 19-noraldosterone (263±56 pmol/day), 18, 19(OH)2-B (40±8.7 nmol/day) and 18-OH-19-nor-B (1322±267 pmol/day) seen in patients with aldosterone-producing adenoma. Urinary aldosterone did not differ significantly between patients with idiopathic hyperaldosteronism and those with aldosterone-producing adenoma. Both urinary 18-OH-B and 18-OH-F excretion were significantly higher in aldosterone-producing adenoma (39±5.2 nmol/day, 1660±318 nmol/day, respectively) compared with patients with idiopathic hyperaldosteronism (19±3.3 nmol/day, 541±93 nmol/day. respectively) (p<0.05). Though urinary 18-OH-F and 18-OH-B concentrations were useful markers, the mineralocorticoid steroids which we can only now measure, 19-noraldosterone, 18, 19(OH)2-B and 18-OH-19-nor-B, could not be used to distinguish the two subsets of primary aldosteronism.

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EXPLORATION OF THE SEATED SALINE SUPPRESSION TEST FOR THE DIAGNOSIS OF PRIMARY ALDOSTERONISM IN THE CHINESE POPULATION

Endocrine Practice ◽

10.4158/ep-2020-0064 ◽

2020 ◽

Vol 26 (8) ◽

pp. 891-899 ◽

Cited By ~ 1

Author(s):

Dan Zhang ◽

Tao Chen ◽

Haoming Tian ◽

Yuanmei Li ◽

Dan Mo ◽

...

Keyword(s):

Essential Hypertension ◽

Receiver Operating Characteristic ◽

Primary Aldosteronism ◽

Operating Characteristic ◽

Plasma Aldosterone ◽

Youden Index ◽

Plasma Aldosterone Concentration ◽

Suppression Test ◽

Aldosterone Producing Adenoma ◽

Idiopathic Hyperaldosteronism

Objective: We prospectively investigated the accuracy of the seated saline suppression test (SSST) in 113 patients with hypertension (including 93 primary aldosteronism [PA] and 20 essential hypertension patients) in the Department of Endocrinology and Metabolism. Methods: Each patient underwent a recumbent saline suppression test (RSST) and SSST. The accuracy of the SSST for a confirmative PA diagnosis and subtype classification was evaluated and compared with the RSST. Results: The area under the receiver operating characteristic (ROC) curve of plasma aldosterone concentration (PAC) for the SSST was significantly greater than that for the RSST (0.945 ± 0.0199 vs. 0.828 ± 0.0404; P<.05). The ROC analysis showed that the optimal PAC cut-off values were 12.94 ng/dL for the SSST (sensitivity 86.02%, specificity 95%; Youden index [YI] 0.810) and 12.04 ng/dL for the RSST (sensitivity 83.15%, specificity 57%; YI 0.401). The optimal PAC cut-off value for classifying aldosterone-producing adenoma and idiopathic hyperaldosteronism was 18.12 ng/dL for the SSST (sensitivity 73.5%, specificity 79.5%). No patients experienced adverse events during the SSST. Conclusion: The SSST is safe and convenient for PA diagnosis. The accuracy of the SSST for a confirmatory diagnosis of PA was better than that of the RSST. The SSST is a reliable alternative for PA confirmation in Chinese individuals. Abbreviations: APA = aldosterone-producing adenoma; ARR = aldosterone to renin ratio; AVS = adrenal vein sampling; CT = computed tomography; EH = essential hypertension; IHA = idiopathic hyperaldosteronism; MRI = magnetic resonance imaging; PA = primary aldosteronism; PAC = plasma aldosterone concentration; PRA = plasma renin activity; ROC = receiver operating characteristic; RSST = recumbent saline suppression test; SSST = seated saline suppression test; YI = Youden index

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Update on Genetics of Primary Aldosteronism

Biomedicines ◽

10.3390/biomedicines9040409 ◽

2021 ◽

Vol 9 (4) ◽

pp. 409

Author(s):

Kiyotaka Itcho ◽

Kenji Oki ◽

Haruya Ohno ◽

Masayasu Yoneda

Keyword(s):

Genetic Analysis ◽

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Secondary Hypertension ◽

Voltage Gated ◽

Intracellular Calcium Signaling ◽

Recent Developments ◽

Aldosterone Producing Adenoma ◽

Idiopathic Hyperaldosteronism ◽

Ca2 Channels

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5–10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, and CTNNB1 in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca2+ channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.

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Evaluation of a test using saralasin to differentiate primary aldosteronism due to an aldosterone-producing adenoma from idiopathic hyperaldosteronism

Metabolism ◽

10.1016/0026-0495(84)90214-2 ◽

1984 ◽

Vol 33 (8) ◽

pp. 734-738 ◽

Cited By ~ 3

Author(s):

Ronald D. Brown ◽

David C. Kem ◽

Michael J. Hogan ◽

Rebecca L. Hegstad

Keyword(s):

Primary Aldosteronism ◽

Aldosterone Producing Adenoma ◽

Idiopathic Hyperaldosteronism

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Primary aldosteronism in Klinefelter’s syndrome: two cases

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-19-0126 ◽

2019 ◽

Vol 2019 ◽

Author(s):

Yasufumi Seki ◽

Satoshi Morimoto ◽

Naohiro Yoshida ◽

Kanako Bokuda ◽

Nobukazu Sasaki ◽

...

Keyword(s):

Luteinizing Hormone ◽

Primary Aldosteronism ◽

Luteinizing Hormone Receptor ◽

List Type ◽

Klinefelter’S Syndrome ◽

Klinefelter's Syndrome ◽

Plasma Aldosterone Concentration ◽

Lh Receptor ◽

Serum Lh ◽

Aldosterone Producing Adenoma

Summary Primary aldosteronism (PA) is more common than expected. Aberrant adrenal expression of luteinizing hormone (LH) receptor in patients with PA has been reported; however, its physiological role on the development of PA is still unknown. Herein, we report two unique cases of PA in patients with untreated Klinefelter’s syndrome, characterized as increased serum LH, suggesting a possible contribution of the syndrome to PA development. Case 1 was a 39-year-old man with obesity and hypertension since his 20s. His plasma aldosterone concentration (PAC) and renin activity (PRA) were 220 pg/mL and 0.4 ng/mL/h, respectively. He was diagnosed as having bilateral PA by confirmatory tests and adrenal venous sampling (AVS). Klinefelter’s syndrome was suspected as he showed gynecomastia and small testes, and it was confirmed on the basis of a low serum total testosterone level (57.3 ng/dL), high serum LH level (50.9 mIU/mL), and chromosome analysis. Case 2 was a 28-year-old man who had untreated Klinefelter’s syndrome diagnosed in his childhood and a 2-year history of hypertension and hypokalemia. PAC and PRA were 247 pg/mL and 0.3 ng/mL/h, respectively. He was diagnosed as having a 10 mm-sized aldosterone-producing adenoma (APA) by AVS. In the APA, immunohistochemical analysis showed co-expression of LH receptor and CYP11B2. Our cases of untreated Klinefelter’s syndrome complicated with PA suggest that increased serum LH levels and adipose tissues, caused by primary hypogonadism, could contribute to PA development. The possible complication of PA in hypertensive patients with Klinefelter’s syndrome should be carefully considered. Learning points: The pathogenesis of primary aldosteronism is still unclear. Expression of luteinizing hormone receptor has been reported in aldosterone-producing adenoma. Serum luteinizing hormone, which is increased in patients with Klinefelter’s syndrome, might contribute to the development of primary aldosteronism.

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Abstract 12591: Impact of Aldosterone Producing Adenoma on Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism

Circulation ◽

10.1161/circ.130.suppl_2.12591 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Takeshi Matsumoto ◽

Yukihito Higashi ◽

Nozomu Oda ◽

Akimichi Iwamoto ◽

Yumiko Iwamoto ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Primary Aldosteronism ◽

Vascular Function ◽

Cardiovascular Events ◽

Plasma Renin ◽

Secondary Hypertension ◽

Plasma Aldosterone Concentration ◽

Significant Difference ◽

Aldosterone Producing Adenoma ◽

Rock Activity

Background: Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs) activity. Primary aldosteronism (PA) is a most common cause of secondary hypertension. Recent studies have shown that risk of cardiovascular events is higher in patients with PA than in patients with essential hypertension (EH). However, there is little information on the relationship between subtype of PA and the grade of atherosclerosis. The purpose of this study was to evaluate the vascular function and ROCK activity in patients with PA. Methods: Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone producing adenoma (APA) group (50.7±14.3 years, 9 males), 23 patients with idiopathic hyperaldosteronism (IHA) group (55.8±9.9 years, 12 males), and 33 age-, gender-, and blood pressure-matched EH group (54.9 ± 10.7 years, 18 males). Results: FMD was significantly lower in the APA group than in the IHA group and EH group (3.2±2.0% vs. 4.6±2.3% and 4.4±2.2%, P<0.05, respectively), whereas there was no significant difference in FMD between the IHA group and EH group. There was no significant difference in the response of nitroglycerine in three groups. ROCK activity was significantly higher in the APA group than in the IHA group and EH group (1.29±0.57 vs. 1.00±0.46 and 0.81±0.36, P<0.05 and P<0.001, respectively), whereas there was no significant difference in ROCK activity between the IHA group and EH group. FMD correlated with age (r=-0.31, P<0.01), brachial arterial diameter (r=-0.44, P<0.01), plasma aldosterone concentration (PAC) (r=-0.35, P<0.01) and plasma renin activity ratio (ARR) (r=-0.34, P<0.01). ROCK activity correlated with age (r=-0.24, P=0.04), PAC (r=0.33, P<0.01) and ARR (r=0.46, P<0.01). Conclusions: APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EH. These findings suggest that APA may have a higher risk of future cardiovascular events.

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

Hypertension ◽

10.1161/hyp.64.suppl_1.008 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Fumitoshi Satoh ◽

Yoshikiyo Ono ◽

Ryo Morimoto ◽

Masataka Kudo ◽

Yoshitsugu Iwakura ◽

...

Keyword(s):

Computed Tomography ◽

Monoclonal Antibodies ◽

Tumor Size ◽

Zona Glomerulosa ◽

Maximum Diameter ◽

Steroidogenic Enzymes ◽

The Status ◽

Aldosterone Producing Adenoma ◽

Idiopathic Hyperaldosteronism ◽

Tumor Area

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.

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Study on clinical and endocrine characteristics of dexamethasone-suppressible hyperaldosteronism compared with those in primary aldosteronism owing to aldosterone-producing adenoma

Acta Endocrinologica ◽

10.1530/acta.0.1210334 ◽

1989 ◽

Vol 121 (3) ◽

pp. 334-344 ◽

Cited By ~ 1

Author(s):

Noriyoshi Yamakita ◽

Keigo Yasuda ◽

Nobuyasu Noritake ◽

Leilani B. Mercado-Asis ◽

Hiroshi Murase ◽

...

Keyword(s):

Blood Pressure ◽

Primary Aldosteronism ◽

Blood Pressure Response ◽

Laboratory Data ◽

Japanese Patients ◽

Pressure Response ◽

Plasma Aldosterone ◽

Vascular Damage ◽

Aldosterone Producing Adenoma

Abstract. The clinical and endocrine characteristics of 12 Japanese patients with dexamethasone-suppressible hyperaldosteronism were compared with those in 49 Japanese patients with primary aldosteronism due to aldosteronoma. The results were as follows: 1. Most of the laboratory data in the two groups were almost the same. 2. The grade of vascular damage in both uncontrolled (3) and well-controlled (9) patients with dexamethasonesuppressible hyperaldosteronism did not correlate with blood pressure response. 3. The responsiveness of plasma aldosterone to exogenous ACTH in 6 patients with dexamethasone-suppressible hyperaldosteronism was not different from that in 9 patients with aldosteronoma. Even in 3 well-controlled patients in the former group, the plasma aldosterone response was as low as in all the 3 patients with small aldosteronomas. 4. In 4 patients with small aldosteronomas, plasma aldosterone was continuously suppressed with daily dexamethasone to the same degree as in dexamethasone-suppressible hyperaldosteronism. 5. The blood pressure, however, did not improve even in the patients with small aldosteronomas. The possible indistinguishable mechanism in dexamethasone-suppressible hyperaldosteronism and primary aldosteronism with small adenomas and the role of unknown hypertensinogenic steroid(s) other than aldosterone in inducing hypertension in dexamethasone-suppressible hyperaldosteronism are discussed.

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