Immunohistochemistry of the Human Adrenal CYP11B2 in Normal
                    Individuals and in Patients with Primary Aldosteronism

AbstractThe CYP11B2 enzyme is the terminal enzyme in the biosynthesis of aldosterone. Immunohistochemistry using antibodies against CYP11B2 defines cells of the adrenal ZG that synthesize aldosterone. CYP11B2 expression is normally stimulated by angiotensin II, but becomes autonomous in primary hyperaldosteronism, in most cases driven by recently discovered somatic mutations of ion channels or pumps. Cells expressing CYP11B2 in young normal humans form a continuous band beneath the adrenal capsule; in older individuals they form discrete clusters, aldosterone-producing cell clusters (APCC), surrounded by non-aldosterone producing cells in the outer layer of the adrenal gland. Aldosterone-producing adenomas may exhibit a uniform or heterogeneous expression of CYP11B2. APCC frequently persist in the adrenal with an aldosterone-producing adenoma suggesting autonomous CYP11B2 expression in these cells as well. This was confirmed by finding known mutations that drive aldosterone production in adenomas in the APCC of clinically normal people. Unilateral aldosteronism may also be due to multiple CYP11B2-expressing nodules of various sizes or a continuous band of hyperplastic ZG cells expressing CYP11B2. Use of CYP11B2 antibodies to identify areas for sequencing has greatly facilitated the detection of aldosterone-driving mutations.

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Disordered CYP11B2 Expression in Primary Aldosteronism

Hormone and Metabolic Research ◽

10.1055/s-0043-122238 ◽

2017 ◽

Vol 49 (12) ◽

pp. 957-962 ◽

Cited By ~ 18

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.

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Gonadotropin-Releasing Hormone Stimulate Aldosterone Production in a Subset of Aldosterone-Producing Adenoma

Medicine ◽

10.1097/md.0000000000003659 ◽

2016 ◽

Vol 95 (20) ◽

pp. e3659 ◽

Cited By ~ 9

Author(s):

Rui Kishimoto ◽

Kenji Oki ◽

Masayasu Yoneda ◽

Celso E. Gomez-Sanchez ◽

Haruya Ohno ◽

...

Keyword(s):

Gonadotropin Releasing Hormone ◽

Releasing Hormone ◽

Aldosterone Production ◽

Aldosterone Producing Adenoma

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CO-33: Different somatic mutations in multinodular adrenals with aldosterone-producing adenoma

Annales de Cardiologie et d Angéiologie ◽

10.1016/s0003-3928(16)30033-6 ◽

2015 ◽

Vol 64 ◽

pp. S16

Author(s):

F. Fernandes-Rosa ◽

I. Giscos-Douriez ◽

L. Amar ◽

C. Gomez-Sanchez ◽

T. Meatchi ◽

...

Keyword(s):

Somatic Mutations ◽

Aldosterone Producing Adenoma

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Amyloid Accumulation and Cognitive Decline in Clinically Normal Older Individuals: Implications for Aging and Early Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-179928 ◽

2018 ◽

Vol 64 (s1) ◽

pp. S633-S646 ◽

Cited By ~ 8

Author(s):

Elizabeth C. Mormino ◽

Kathryn V. Papp

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Older Individuals ◽

Clinically Normal ◽

Amyloid Accumulation ◽

Early Alzheimer’S Disease

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Studies of T-lymphocytes in preleukemic disorders and acute nonlymphocytic leukemia: in vitro radiosensitivity, mitogenic responsiveness, colony formation, and enumeration of lymphocytic subpopulations

Blood ◽

10.1182/blood.v61.3.449.449 ◽

1983 ◽

Vol 61 (3) ◽

pp. 449-455 ◽

Cited By ~ 30

Author(s):

SJ Knox ◽

BR Greenberg ◽

RW Anderson ◽

LS Rosenblatt

Keyword(s):

Whole Blood ◽

Colony Formation ◽

Tritiated Thymidine ◽

Lymphocyte Stimulation Test ◽

Acute Nonlymphocytic Leukemia ◽

Clinically Normal ◽

Normal Individuals ◽

Increased Risk ◽

X Irradiation

Abstract Tritiated thymidine incorporation in a whole blood lymphocyte stimulation test (LST) and lymphocyte colony formation (CFU-L) from whole blood were measured following in vitro x-irradiation. Lymphocytes from patients with myelodysplastic disorders, acute nonlymphocytic leukemia, and patients at increased risk for leukemia because of their primary disease and/or cytotoxic therapy were found to be significantly more sensitive to in vitro x-irradiation than lymphocytes from clinically normal individuals. Cloning efficiencies and mitogenic responsiveness of patient lymphocytes were significantly depressed as compared to normal values. Using monoclonal antibodies to specific surface markers, quantitative abnormalities in lymphocytic subpopulations from myelodysplastic patients also were observed. These findings are suggestive of a defect at the T-cell level that may directly or indirectly affect hematopoiesis.

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O4-01-03: Entorhinal tau deposition is associated with parietal association cortex hypometabolism in clinically normal older individuals

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.07.347 ◽

2015 ◽

Vol 11 (7S_Part_6) ◽

pp. P266-P267

Author(s):

Bernard J. Hanseeuw ◽

Aaron P. Schultz ◽

Jorge Sepulcre ◽

Reisa A. Sperling ◽

Keith A. Johnson

Keyword(s):

Association Cortex ◽

Older Individuals ◽

Clinically Normal ◽

Parietal Association Cortex

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Aldosterone-Producing Cell Clusters in Normal and Pathological States

Hormone and Metabolic Research ◽

10.1055/s-0043-122394 ◽

2017 ◽

Vol 49 (12) ◽

pp. 951-956 ◽

Cited By ~ 13

Author(s):

Kei Omata ◽

Scott Tomlins ◽

William Rainey

Keyword(s):

Somatic Mutations ◽

Adrenal Glands ◽

Normal Subjects ◽

Cardiovascular Complications ◽

Cell Clusters ◽

Key Factor ◽

Aldosterone Producing Adenoma ◽

Next Generation Sequencing Ngs ◽

Small Clusters ◽

Generation Sequencing

AbstractPrimary aldosteronism (PA) significantly increases the risk of cardiovascular complications, and early diagnosis and targeted treatment based on its pathophysiology is warranted. Next-generation sequencing (NGS) has revealed recurrent somatic mutations in aldosterone-driving genes in aldosterone-producing adenoma (APA). By applying CYP11B2 (aldosterone synthase) immunohistochemistry and NGS to adrenal glands from normal subjects and PA patients, we and others have shown that CYP11B2-positive cells make small clusters, termed aldosterone-producing cell clusters (APCC), beneath the adrenal capsule, and that APCC harbor somatic mutations in genes mutated in APA. We have shown that APCC are increased in CT-negative PA adrenals, while others showed potential progression from APCC to micro APA through mutations. These results suggest that APCC are a key factor for understanding the origin of PA, and further investigation on the relation between APCC and PA is highly needed.

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Prevalence and Characterization of Somatic Mutations in Chinese Aldosterone-Producing Adenoma Patients

Medicine ◽

10.1097/md.0000000000000708 ◽

2015 ◽

Vol 94 (16) ◽

pp. e708 ◽

Cited By ~ 39

Author(s):

Baojun Wang ◽

Xintao Li ◽

Xu Zhang ◽

Xin Ma ◽

Luyao Chen ◽

...

Keyword(s):

Somatic Mutations ◽

Aldosterone Producing Adenoma

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

Acta Endocrinologica ◽

10.1530/eje-07-0626 ◽

2008 ◽

Vol 158 (6) ◽

pp. 867-878 ◽

Cited By ~ 9

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.

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