Concurrence of overt Cushing’s syndrome and primary aldosteronism accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex: case report

Abstract Background Various adrenal disorders including primary aldosteronism and Cushing’s syndrome lead to the cause of hypertension. Although primary aldosteronism is sometimes complicated with preclinical Cushing’s syndrome, concurrence of overt Cushing’s syndrome and primary aldosteronism is very rare. In addition, it has been drawing attention recently that primary aldosteronism is brought about by the presence of aldosterone-producing cell cluster in adjacent adrenal cortex rather than the presence of aldosterone-producing adenoma. Case presentation A 67-year-old Japanese female was referred to our institution due to moon face and central obesity. Based on various clinical findings and data, we diagnosed this subject as overt Cushing’s syndrome and primary aldosteronism. Furthermore, in immunostaining for cytochrome P450 (CYP) 11B1, a cortisol-producing enzyme, diffuse staining was observed in tumorous lesion. Also, in immunostaining for CYP11B2, an aldosterone-producing enzyme, CYP11B2 expression was not observed in tumorous lesion, but strong CYP11B2 expression was observed in adjacent adrenal cortex, indicating the presence of aldosterone-producing cell cluster. Conclusions We should bear in mind the possibility that concurrence of overt Cushing’s syndrome and primary aldosteronism is accompanied by aldosterone-producing cell cluster in adjacent adrenal cortex.

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Combined Primary Aldosteronism and Preclinical Cushing's Syndrome: An Unusual Case Presentation of Adrenal Adenoma.

Hypertension Research ◽

10.1291/hypres.24.723 ◽

2001 ◽

Vol 24 (6) ◽

pp. 723-726 ◽

Cited By ~ 26

Author(s):

Tadaaki HONDA ◽

Tetsuya NAKAMURA ◽

Yuichiro SAITO ◽

Yoshio OHYAMA ◽

Hiroyuki SUMINO ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Primary Aldosteronism ◽

Unusual Case ◽

Adrenal Adenoma ◽

Cushing's Syndrome ◽

Case Presentation

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Significance of steroidogenic enzymes in the pathogenesis of adrenal tumour

Acta Endocrinologica ◽

10.1530/acta.0.1280235 ◽

1993 ◽

Vol 128 (3) ◽

pp. 235-242 ◽

Cited By ~ 26

Author(s):

Hirotaka Shibata ◽

Hiromichi Suzuki ◽

Tadashi Ogishima ◽

Yuzuru Ishimura ◽

Takao Saruta

Keyword(s):

Normal Control ◽

Cushing’S Syndrome ◽

Primary Aldosteronism ◽

Protein Level ◽

Cushing's Syndrome ◽

Adrenocortical Adenoma ◽

Adrenal Tumour ◽

Steroidogenic Enzymes ◽

Aldosterone Producing Adenoma ◽

Cytochrome P 450

We examined both activities and amounts of steroidogenic cytochrome P-450s at the posttranslational protein level and steroid contents in the adrenocortical adenoma from patients with primary aldosteronism and Cushing's syndrome. Aldosterone synthase cytochrome P-450 (human P-450aldo) was detected in the tumour portion of aldosterone-producing adenoma, but not in the normal control adrenals, at the protein level. Neither the activities nor the amounts of other P-450s in the tumour portion of aldosterone-producing adenoma were significantly different from those in the non-tumour portion in the adenoma and the normal control adrenals. The aldosterone content was significantly elevated, while the androstenedione content was significantly decreased in the tumour portion of the adenoma compared with that in the normal control adrenals. In Cushing's syndrome, both the activities and amounts of P-45017α and P-450c21 were significantly elevated in the tumour portion compared with the non-tumour portion of the adenoma and the normal control adrenals, while those of P-450scc and P-45011β in the tumour portion were not significantly different from the normal control adrenals. The cortisol content was significantly elevated, while the amounts of aldosterone and 18-hydroxydeoxycorticosterone in the tumour portion of the adenoma were significantly decreased compared with those in the normal control adrenals. These results demonstrate that overexpression of P-450aldo in aldosterone-producing adenoma, and those of P-45017α and P-450c21 in cortisol-producing adenoma may play some role in the pathogenesis of primary aldosteronism and Cushing's syndrome, respectively.

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Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome

Endocrine Journal ◽

10.1507/endocrj.k10e-402 ◽

2011 ◽

Vol 58 (7) ◽

pp. 543-551 ◽

Cited By ~ 47

Author(s):

Kiichiro Hiraishi ◽

Takanobu Yoshimoto ◽

Kyoichiro Tsuchiya ◽

Isao Minami ◽

Masaru Doi ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Primary Aldosteronism ◽

Cushing's Syndrome ◽

Clinicopathological Features ◽

Subclinical Cushing’S Syndrome

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Nycthemeral rhythm of plasma cortisol levels in the Cushing's syndrome associated with hyperplasia of adrenal cortex, before and after treatment of hypophyseal suppression with ultrasonic technique

Journal of Neural Transmission ◽

10.1007/bf01239886 ◽

1967 ◽

Vol 30 (1-4) ◽

pp. 129-135

Author(s):

G. Giusti ◽

R. Toccafondi ◽

B. Tarquini

Keyword(s):

Adrenal Cortex ◽

Cushing’S Syndrome ◽

Plasma Cortisol ◽

Cushing's Syndrome ◽

Ultrasonic Technique ◽

Before And After ◽

Cortisol Levels

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IN VIVO AND IN VITRO STUDIES OF ADRENAL SECRETIONS IN CUSHING'S SYNDROME AND PRIMARY ALDOSTERONISM*

Journal of Clinical Investigation ◽

10.1172/jci104740 ◽

1963 ◽

Vol 42 (4) ◽

pp. 516-524 ◽

Cited By ~ 84

Author(s):

Edward G. Biglieri ◽

Satoshi Hane ◽

Paul E. Slaton ◽

Peter H. Forsham

Keyword(s):

Cushing’S Syndrome ◽

Primary Aldosteronism ◽

Cushing's Syndrome ◽

In Vitro Studies

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PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2016-1700 ◽

2016 ◽

Vol 101 (8) ◽

pp. 3010-3017 ◽

Cited By ~ 20

Author(s):

Yara Rhayem ◽

Luis G. Perez-Rivas ◽

Anna Dietz ◽

Kerstin Bathon ◽

Christian Gebhard ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Primary Aldosteronism ◽

Molecular Mechanisms ◽

Somatic Mutations ◽

Functional Characterization ◽

Cushing's Syndrome ◽

Antihypertensive Medications ◽

Unilateral Adrenalectomy ◽

Vitro Analysis

Context: Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol. Objective: The objective of the study was to investigate PRKACA somatic variants identified in APA cases. Design: Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues. Setting and Patients: APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution. Results: PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels. Conclusions: We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.

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Relationship between Adrenal Cortex Pathology in Cushing's Syndrome and its Response to the Dexamethasone Suppression Test

Journal of International Medical Research ◽

10.1177/030006059602400307 ◽

1996 ◽

Vol 24 (3) ◽

pp. 278-283

Author(s):

G Akçay ◽

Y Orhan ◽

F Aral ◽

N Özbey ◽

A Azezli ◽

...

Keyword(s):

Adrenal Cortex ◽

Cushing’S Syndrome ◽

Plasma Levels ◽

Cushing's Syndrome ◽

High Dose ◽

Cell Adenoma ◽

Unilateral Adrenalectomy ◽

High Dose Dexamethasone ◽

Suppression Test ◽

Dexamethasone Suppression

Cushing's syndrome is a severely disabling condition which can cause death if left untreated. Endogenous Cushing's syndrome can be ACTH-dependent or ACTH-independent. The ACTH-dependent type is more common and is usually caused by diffuse hyperplasia on the adrenal cortex. This study investigated the response to low- and high-dose dexamethasone suppression testing of 30 adrenalectomized patients with Cushing's syndrome, average age 37.3 ± 9.7 years. Twenty-four (79.3%) patients were female, and six (20.7%) were male. Bilateral adrenalectomy was performed in 14 (48.2%) patients and unilateral adrenalectomy (nine and seven right adrenalectomy) in 16 (51.8%). Two of the bilateral adrenalectomies were applied via endoscopic surgical approach. In the histopathological evaluation, diffuse hyperplasia was diagnosed in 13 (44.8%) patients and nodular hyperplasia in eight (26.6%), three macronodular and five micronodular hyperplasia. Adrenal cell adenoma was diagnosed in nine (28.6%) patients. Classic dexamethasone suppression testing was performed on all patients. Plasma levels of cortisol were not significantly decreased after low-dose testing, but plasma levels of cortisol were significantly decreased after high-dose testing in the diffuse hyperplasia group. In summary, due to the pathological changes of the adrenal cortex, dexamethasone suppression testing can differentiate between the two types of Cushing's syndrome.

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Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours

Acta Endocrinologica ◽

10.1530/eje.0.1500345 ◽

2004 ◽

pp. 345-349 ◽

Cited By ~ 13

Author(s):

S Zacharieva ◽

I Atanassova ◽

M Orbetzova ◽

E Nachev ◽

K Kalinov ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cushing’S Syndrome ◽

Primary Aldosteronism ◽

Cushing's Syndrome ◽

Prostaglandin E ◽

Vascular Endothelial ◽

Active Renin ◽

Adrenal Tumours ◽

Endothelial Growth Factor

OBJECTIVES: The aim of the present study was to determine vascular endothelial growth factor (VEGF), prostaglandin E(2) (PGE(2)) and active renin levels in patients with hormonally active adrenal tumours. DESIGN: The study was comprised of 16 patients with primary aldosteronism, 13 patients with active Cushing's syndrome due to adrenal adenomas, 8 patients with adrenal carcinomas, 19 patients with phaeochromocytoma and 19 healthy volunteers. METHODS: Active renin in plasma was determined by a two-site immunoradiometric assay. VEGF in sera samples and PGE(2) in 24-h urine were measured by ELISA. RESULTS: VEGF was significantly elevated in all the four groups of patients as compared with the controls. VEGF levels in patients with Cushing's syndrome were higher than those in patients with primary aldosteronism. Patients with adrenal carcinomas had the highest VEGF levels and the differences reached significance as compared with patients with primary aldosteronism and phaeochromocytoma. PGE(2) levels were not significantly different among groups. Active renin was significantly the lowest in patients with primary aldosteronism and significantly the highest in patients with phaeochromocytoma compared with the controls. Active renin in patients with primary aldosteronism was significantly lower than in those with Cushing's syndrome, phaeochromocytoma and adrenal carcinoma. CONCLUSIONS: Our data indicated that the mean level of VEGF in patients with all investigated adrenal tumours was significantly higher than in healthy controls. The cortisol-producing tumours appear to have increased angiogenic potential. Angiogenesis is probably associated not only with malignancy but also with functional activity of the adrenal tumors.

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