scholarly journals Analysis of Unilateral Adrenal Hyperplasia with Primary Aldosteronism from the Aspect of Messenger Ribonucleic Acid Expression for Steroidogenic Enzymes: A Comparative Study with Adrenal Cortices Adhering to Aldosterone-Producing Adenoma

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 999-1006 ◽  
Author(s):  
Kazuto Shigematsu ◽  
Kioko Kawai ◽  
Junji Irie ◽  
Hideki Sakai ◽  
Osamu Nakashima ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Zona Glomerulosa ◽  
Adrenal Hyperplasia ◽  
Steroidogenic Enzymes ◽  
Unilateral Adrenalectomy ◽  
Messenger Ribonucleic Acid ◽  
Unilateral Adrenal Hyperplasia ◽  
Aldosterone Production ◽  
Long Term Follow Up ◽  
Aldosterone Producing Adenoma

Unilateral adrenal hyperplasia with primary aldosteronism is very rare and shows similar endocrine features to aldosterone-producing adenoma and bilateral adrenal hyperplasia. In this study, the mRNA expression of steroidogenic enzymes in unilateral adrenal hyperplasia was examined by in situ hybridization. We found subcapsular micronodules composed of spironolactone body-containing cells, which showed intense expression for 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 18-hydroxylase, and 21-hydroxylase but not 17α-hydroxylase, indicating aldosterone production. This expression pattern was the same as that in unilateral multiple adrenocortical micronodules, reported recently. Additionally, it was noted that a nodule with active aldosterone production was closely adjacent to one showing intense 17α-hydroxylase expression. In the adrenal cortices adhering to aldosterone-producing adenoma, the majority of hyperplastic zona glomerulosa and hyperplastic nodules demonstrated a decreased steroidogenic activity. However, minute nodules indicative of active aldosterone production were found at high frequency. These results suggest that the subcapsular micronodules observed might be the root of aldosterone-producing adenoma. Furthermore, we emphasize the need for long-term follow-up after unilateral adrenalectomy or enucleation of the adenoma because of the possibility that buds with autonomous aldosterone production may still be present in the contralateral or remaining adrenal tissue.

scholarly journals Aldosterone-Producing Adenoma With a Somatic KCNJ5 Mutation Revealing APC-Dependent Familial Adenomatous Polyposis

2016 ◽  
Vol 101 (11) ◽  
pp. 3874-3878 ◽  
Author(s):  
Julien Vouillarmet ◽  
Fabio Fernandes-Rosa ◽  
Julia Graeppi-Dulac ◽  
Pierre Lantelme ◽  
Myriam Decaussin-Petrucci ◽  
...  
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Primary Aldosteronism ◽  
Clinical Symptoms ◽  
Point Of View ◽  
Severe Dysplasia ◽  
Adenomatous Polyposis ◽  
Adrenal Hyperplasia ◽  
Positron Emission ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma

Context: Recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 have been identified in aldosterone-producing adenomas (APAs). The question as to whether they are responsible for both nodulation and aldosterone production is not solved. Case Description: We describe the case of a young patient who was diagnosed with severe arterial hypertension due to primary aldosteronism at age 26 years, followed by hemorrhagic stroke 4 years later. Abdominal computed tomography showed bilateral macronodular adrenal hyperplasia. Identification of lateralized aldosterone secretion led to right adrenalectomy, followed by normalization of biochemical and hormonal parameters and amelioration of blood pressure. The resected adrenal showed three nodules, one of them expressing aldosterone synthase and harboring a somatic KNCJ5 mutation. A Weiss revisited index of 3 of the APA prompted us to perform a second 18F-2-fluoro-2-deoxy-D-glucose-positron emission tomography after surgery, which revealed abnormal rectal activity despite the absence of clinical symptoms. Gastrointestinal exploration showed multiple polyps with severe dysplasia, and the diagnosis of familial adenomatous polyposis was established in the presence of a germline heterozygous APC gene mutation. Sequencing of somatic DNA from the APA and a second adrenal nodule revealed biallelic APC inactivation due to loss of heterozygosity in both nodules. Conclusions: This case report underlines the need for establishing the frequency of germline APC variants in patients with primary aldosteronism and bilateral macronodular adrenal hyperplasia because their presence may predispose to APA development and severe hypertension well before the first familial adenomatous polyposis symptoms appear. From a mechanistic point of view, it supports a two-hit model for APA development, whereby the first hit drives increased cell proliferation whereas the second hit specifies the pattern of hormonal secretion.

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

Hypertension ◽  
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.

scholarly journals Disordered CYP11B2 Expression in Primary Aldosteronism

2017 ◽  
Vol 49 (12) ◽  
pp. 957-962 ◽  
Author(s):  
Celso Gomez-Sanchez ◽  
Maniselvan Kuppusamy ◽  
Martin Reincke ◽  
Tracy Williams
Keyword(s):  
Primary Aldosteronism ◽  
Secondary Hypertension ◽  
Zona Glomerulosa ◽  
Common Type ◽  
Older Individuals ◽  
Cell Clusters ◽  
Cellular Expression ◽  
Normal Individuals ◽  
Aldosterone Producing Adenoma

AbstractPrimary aldosteronism is the most common type of secondary hypertension affecting 6–10% of patients with primary hypertension. PA is mainly caused by unilateral hyperaldosteronism due to an aldosterone-producing adenoma, unilateral hyperplasia with or without micronodules or bilateral zona glomerulosa hyperplasias with or without macro or micronodules. The development of antibodies against the terminal enzyme of aldosterone biosynthesis (CYP11B2) has permitted the further characterization of normal adrenals and resected adrenals from patients with primary aldosteronism. Normal adrenals exhibit two different patterns of cellular expression of CYP11B2: young individuals display a relatively uniform expression of the enzyme throughout the zona glomerulosa while the adrenals of older individuals have dispersed CYP11B2-expressing cells but have more groups of cells called aldosterone-producing cell clusters (APCC). APAs exhibit different patterns of CYP11B2 staining that vary from uniform to homogeneous. There are also a proportion of cells within the APA that co-express different enzymes that are not normally co-expressed in normal individuals. Approximately 30% of patients with unilateral hyperaldosteronism do not have an APA, but either have an increased number of CYP11B2 expressing micronodules or hyperplasia of the zona glomerulosa. In summary, the studies reported in this review are shedding new light on the pathophysiology of primary aldosteronism. The wide variation in histopathological features of the adenomas and concurrent presence of APCCs raises the possibility that most cases of unilateral production of aldosterone actually might represent bilateral asymmetric hyperplasia with nodules frequently due to the development of somatic aldosterone-driving mutations.

scholarly journals Analysis of mRNA expression for steroidogenic enzymes in the remaining adrenal cortices attached to adrenocortical adenomas.

2008 ◽  
Vol 158 (6) ◽  
pp. 867-878 ◽  
Author(s):  
Kazuto Shigematsu ◽  
Takehiro Nakagaki ◽  
Naohiro Yamaguchi ◽  
Kioko Kawai ◽  
Hideki Sakai ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Zona Fasciculata ◽  
Steroidogenic Enzymes ◽  
Steroidogenic Enzyme ◽  
Adrenocortical Adenomas ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma ◽  
Cortical Nodules ◽  
Design And Methods

Design and methodsWe have recently demonstrated that the adrenal cortices attached to aldosterone-producing adenoma (APA) contained microscopic subcapsular micronodules suggestive of active aldosterone production. In this study, we used in situ hybridization to investigate the mRNA expression of steroidogenic enzymes in the adrenal cortices attached to cortisol-producing adenoma (CPA) and clinically silent adenoma (non-functioning adenoma; NFA), in addition to APA.ResultsMicroscopic subcapsular micronodules, which were several hundreds of micrometers in size and spheroid in shape, were observed in the cortices attached to CPA and NFA, as well as APA, at high frequency. Most of the cortical nodules in zona fasciculata to zona reticularis showed a suppressed steroidogenesis in the cortices attached to adenoma, but some expressed intensely all necessary steroidogenic enzyme mRNAs for cortisol synthesis.ConclusionsIt is thus necessary to keep in mind, on the occasion of subtotal adrenalectomy, that lesions with the potential to later develop into functional adrenocortical nodules may be present in other parts of the ipsilateral or contralateral adrenal cortices.

Primary Aldosteronism due to Unilateral Adrenal Hyperplasia. Report of Two Cases and Review of the Literature.

2000 ◽  
Vol 47 (4) ◽  
pp. 443-449 ◽  
Author(s):  
MASAAKI MORIOKA ◽  
TATSUYA KOBAYASHI ◽  
ATSUSHI SONE ◽  
YOJI FURUKAWA ◽  
HIROYOSHI TANAKA
Keyword(s):  
Primary Aldosteronism ◽  
Review Of The Literature ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenal Hyperplasia

scholarly journals A Case of Primary Aldosteronism Due to Unilateral Adrenal Hyperplasia

2005 ◽  
Vol 28 (4) ◽  
pp. 379-384 ◽  
Author(s):  
Yasuyuki KATAYAMA ◽  
Nobuki TAKATA ◽  
Taiji TAMURA ◽  
Akemi YAMAMOTO ◽  
Fumihiko HIRATA ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenal Hyperplasia

scholarly journals Familial Hyperaldosteronism Type 3 with a Rapidly Growing Adrenal Tumor: An In Situ Aldosterone Imaging Study

2021 ◽  
Vol 44 (1) ◽  
pp. 128-138
Author(s):  
Nae Takizawa ◽  
Susumu Tanaka ◽  
Koshiro Nishimoto ◽  
Yuki Sugiura ◽  
Makoto Suematsu ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Primary Aldosteronism ◽  
Germ Line ◽  
Imaging Study ◽  
Adrenal Tumors ◽  
Adrenal Hyperplasia ◽  
Unilateral Adrenalectomy ◽  
Familial Hyperaldosteronism ◽  
Type 3

Primary aldosteronism is most often caused by aldosterone-producing adenoma (APA) and bi-lateral adrenal hyperplasia. Most APAs are caused by somatic mutations of various ion channels and pumps, the most common being the inward-rectifying potassium channel KCNJ5. Germ line mutations of KCNJ5 cause familial hyperaldosteronism type 3 (FH3), which is associated with severe hyperaldosteronism and hypertension. We present an unusual case of FH3 in a young woman, first diagnosed with primary aldosteronism at the age of 6 years, with bilateral adrenal hyperplasia, who underwent unilateral adrenalectomy (left adrenal) to alleviate hyperaldosteronism. However, her hyperaldosteronism persisted. At the age of 26 years, tomography of the remaining adrenal revealed two different adrenal tumors, one of which grew substantially in 4 months; therefore, the adrenal gland was removed. A comprehensive histological, immunohistochemical, and molecular evaluation of various sections of the adrenal gland and in situ visualization of aldosterone, using matrix-assisted laser desorption/ionization imaging mass spectrometry, was performed. Aldosterone synthase (CYP11B2) immunoreactivity was observed in the tumors and adrenal gland. The larger tumor also harbored a somatic β-catenin activating mutation. Aldosterone visualized in situ was only found in the subcapsular regions of the adrenal and not in the tumors. Collectively, this case of FH3 presented unusual tumor development and histological/molecular findings.

scholarly journals Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism

2021 ◽  
Vol 28 (1) ◽  
pp. 1-13
Author(s):  
Marcela Rassi-Cruz ◽  
Andrea G Maria ◽  
Fabio R Faucz ◽  
Edra London ◽  
Leticia A P Vilela ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Early Onset ◽  
Zona Glomerulosa ◽  
Unilateral Adrenalectomy ◽  
Transfected Cells ◽  
Functional Studies ◽  
Protein Levels ◽  
Whole Exome ◽  
Hyperplastic Tissue ◽  
Bilateral Adrenal Hyperplasia

Abstract Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

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