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.

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 Angiotensin II Type 1 Receptor Autoantibodies in Primary Aldosteronism

2020 ◽  
Vol 52 (06) ◽  
pp. 379-385
Author(s):  
Lucie S. Meyer ◽  
Siyuan Gong ◽  
Martin Reincke ◽  
Tracy Ann Williams
Keyword(s):  
Angiotensin Ii ◽  
Primary Aldosteronism ◽  
Functional Role ◽  
Adrenal Hyperplasia ◽  
Endocrine Hypertension ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma ◽  
Agonistic Autoantibodies

AbstractPrimary aldosteronism (PA) is the most common form of endocrine hypertension. Agonistic autoantibodies against the angiotensin II type 1 receptor (AT1R-Abs) have been described in transplantation medicine and women with pre-eclampsia and more recently in patients with PA. Any functional role of AT1R-Abs in either of the two main subtypes of PA (aldosterone-producing adenoma or bilateral adrenal hyperplasia) requires clarification. In this review, we discuss the studies performed to date on AT1R-Abs in PA.

Fludrocortisone suppression test in normal subjects, in patients with essential hypertension and in patients with various forms of aldosteronism

1980 ◽  
Vol 93 (1) ◽  
pp. 100-107 ◽  
Author(s):  
Jens Otto Lund ◽  
Meta Damkjær Nielsen
Keyword(s):  
Essential Hypertension ◽  
Primary Aldosteronism ◽  
Single Case ◽  
Plasma Renin ◽  
Normal Subjects ◽  
High Plasma ◽  
Significant Suppression ◽  
Control Value ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma

Abstract. The response of urinary diurnal tetrahydroaldosterone (TH-aldo) excretion to fludrocortisone administration (0.3 mg q.i.d. for 3 days) was studied. In normal subjects (n = 13) and in patients with essential hypertension (n = 8), urinary TH-aldo decreased to 36 per cent (range 19–48) and to 51 per cent (range 33–61) of the control value, respectively. Twenty-four patients with primary aldosteronism were studied. Twenty-two of these showed no significant suppression of urinary TH-aldo in that the excretion of TH-aldo was 79 per cent of the control value or more. Nineteen of these patients were submitted to operation, and an adrenal aldosterone-producing adenoma was disclosed in every single case. Two patients with primary aldosteronism demonstrated a significant suppression of aldosterone production to 62 and 68 per cent, respectively. Adrenal micronodular hyperplasia was verified in one case and suspected in the other. A significant suppression of aldosterone production was observed in 4 of 5 patients with aldosteronism and normal or high plasma renin levels. The combination of low plasma renin and autonomy of aldosterone production offers a high degree of certainty for the presence of an aldosterone-producing adenoma.

scholarly journals Mouse Models of Primary Aldosteronism: From Physiology to Pathophysiology

Endocrinology ◽  
2017 ◽  
Vol 158 (12) ◽  
pp. 4129-4138 ◽  
Author(s):  
Leticia Aragao-Santiago ◽  
Celso E Gomez-Sanchez ◽  
Paolo Mulatero ◽  
Ariadni Spyroglou ◽  
Martin Reincke ◽  
...  
Keyword(s):  
Mouse Models ◽  
Primary Aldosteronism ◽  
Genetic Basis ◽  
Plasma Renin ◽  
Adrenal Hyperplasia ◽  
Endocrine Hypertension ◽  
Bilateral Adrenal Hyperplasia ◽  
Human Disorder ◽  
Aldosterone Producing Adenoma ◽  
Functional Mechanisms

Abstract Primary aldosteronism (PA) is a common form of endocrine hypertension that is characterized by the excessive production of aldosterone relative to suppressed plasma renin levels. PA is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. Somatic mutations have been identified in several genes that encode ion pumps and channels that may explain the aldosterone excess in over half of aldosterone-producing adenomas, whereas the pathophysiology of bilateral adrenal hyperplasia is largely unknown. A number of mouse models of hyperaldosteronism have been described that recreate some features of the human disorder, although none replicate the genetic basis of human PA. Animal models that reproduce the genotype–phenotype associations of human PA are required to establish the functional mechanisms that underlie the endocrine autonomy and deregulated cell growth of the affected adrenal and for preclinical studies of novel therapeutics. Herein, we discuss the differences in adrenal physiology across species and describe the genetically modified mouse models of PA that have been developed to date.

scholarly journals Subtyping of Patients with Primary Aldosteronism: An Update

2017 ◽  
Vol 49 (12) ◽  
pp. 922-928 ◽  
Author(s):  
Jacques Lenders ◽  
Graeme Eisenhofer ◽  
Martin Reincke
Keyword(s):  
Functional Imaging ◽  
Primary Aldosteronism ◽  
Non Invasive ◽  
Positron Emission ◽  
Choice Of Treatment ◽  
Bilateral Adrenal Hyperplasia ◽  
Potential Alternative ◽  
Aldosterone Producing Adenoma ◽  
Excessive Secretion ◽  
Diagnostic Work

AbstractPrimary aldosteronism (PA) comprises two main subtypes: unilateral aldosteronism, mainly caused by aldosterone-producing adenoma; and bilateral adrenal hyperplasia. Establishing the correct subtype in patients with PA is indispensible for choice of treatment. In addition to established methods, alternative tests are evolving for subtyping. Computed tomography (CT) and adrenal venous sampling (AVS) are currently recommended in the guidelines for the diagnostic work-up of patients with PA. CT cannot be used as a stand-alone test for subtyping because of its limited accuracy but may be used in combination with other tests such as AVS or functional imaging. Nevertheless CT remains mandatory to exclude adrenocortical carcinoma. AVS provides the most accurate test to detect excessive secretion of aldosterone from an adrenal mass but has several practical limitations and disadvantages. Therefore, alternative non-invasive and patient-friendly methods are required to determine the need for adrenalectomy. Functional imaging with specific molecular positron emission tomographic ligands is a potential alternative method that may replace AVS for subclassifying patients with PA. The results of preliminary studies of 11C-metomidate are promising but ligands incorporating radionuclides with longer half-lives that selectively bind to CYP11B2 are needed. Steroid profiling provides another method for subtyping and selecting patients for adrenalectomy, but this technology is in its infancy and prospective outcome-based studies are required to determine if this technique may provide an alternative to AVS.

scholarly journals Molecular mechanisms in primary aldosteronism

2019 ◽  
Vol 242 (3) ◽  
pp. R67-R79 ◽  
Author(s):  
Kelly De Sousa ◽  
Alaa B Abdellatif ◽  
Rami M El Zein ◽  
Maria-Christina Zennaro
Keyword(s):  
Arterial Hypertension ◽  
Adrenal Cortex ◽  
Primary Aldosteronism ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Type I ◽  
Adrenal Hyperplasia ◽  
New Genes ◽  
Aldosterone Production ◽  
Bilateral Adrenal Hyperplasia

Primary aldosteronism (PA) is the most common form and an under-diagnosed cause of secondary arterial hypertension, accounting for up to 10% of hypertensive cases and associated to increased cardiovascular risk. PA is caused by autonomous overproduction of aldosterone by the adrenal cortex. It is mainly caused by a unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Excess aldosterone leads to arterial hypertension with suppressed renin, frequently associated to hypokalemia. Mutations in genes coding for ion channels and ATPases have been identified in APA, explaining the pathophysiology of increased aldosterone production. Different inherited genetic abnormalities led to the distinction of four forms of familial hyperaldosteronism (type I to IV) and other genetic defects very likely remain to be identified. Somatic mutations are identified in APA, but also in aldosterone-producing cell clusters (APCCs) in normal adrenals, in image-negative unilateral hyperplasia, in transitional lesions and in APCC from adrenals with bilateral adrenal hyperplasia (BAH). Whether these structures are precursors of APA or whether somatic mutations occur in a proliferative adrenal cortex, is still a matter of debate. This review will summarize our knowledge on the molecular mechanisms responsible for PA and the recent discovery of new genes related to early-onset and familial forms of the disease. We will also address new issues concerning genomic and proteomic changes in adrenals with APA and discuss adrenal pathophysiology in relation to aldosterone-producing structures in the adrenal cortex.

scholarly journals Update in diagnosis and management of primary aldosteronism

2018 ◽  
Vol 56 (3) ◽  
pp. 360-372 ◽  
Author(s):  
Sofia M. Dick ◽  
Marina Queiroz ◽  
Bárbara L. Bernardi ◽  
Angélica Dall’Agnol ◽  
Letícia A. Brondani ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Metabolic Alkalosis ◽  
Adrenal Adenoma ◽  
Adrenal Hyperplasia ◽  
Appropriate Treatment ◽  
Common Causes ◽  
Confirmatory Tests ◽  
Aldosterone Producing Adenoma ◽  
Aldosterone To Renin Ratio ◽  
Oral Sodium

AbstractPrimary aldosteronism (PA) is a group of disorders in which aldosterone is excessively produced. These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis. The prevalence of PA ranges from 5% to 12% around the globe, and the most common causes are adrenal adenoma and adrenal hyperplasia. The importance of PA recognition arises from the fact that it can have a remarkably adverse cardiovascular and renal impact, which can even result in death. The aldosterone-to-renin ratio (ARR) is the election test for screening PA, and one of the confirmatory tests, such as oral sodium loading (OSL) or saline infusion test (SIT), is in general necessary to confirm the diagnosis. The distinction between adrenal hyperplasia (AH) or aldosterone-producing adenoma (APA) is essential to select the appropriate treatment. Therefore, in order to identify the subtype of PA, imaging exams such as computed tomography or magnetic ressonance imaging, and/or invasive investigation such as adrenal catheterization must be performed. According to the subtype of PA, optimal treatment – surgical for APA or pharmacological for AH, with drugs like spironolactone and amiloride – must be offered.

scholarly journals The syndromes of low-renin hypertension: "separating the wheat from the chaff"

2004 ◽  
Vol 48 (5) ◽  
pp. 674-681 ◽  
Author(s):  
Claudio E. Kater ◽  
Edward G. Biglieri
Keyword(s):  
Receptor Antagonist ◽  
Myocardial Fibrosis ◽  
Cardiac Remodeling ◽  
Primary Aldosteronism ◽  
Renin Activity ◽  
Adrenal Hyperplasia ◽  
Test Characteristics ◽  
Low Renin Hypertension ◽  
Bilateral Adrenal Hyperplasia ◽  
Aldosterone Producing Adenoma

Primary aldosteronism (PA) is characterized by hypertension and suppressed renin activity with or without hypokalemia and comprises the aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia or idiopatic hyperaldosteronism (IHA). In recent series employing the aldosterone (aldo, ng/dL):renin (ng/mL·h) ratio (ARR) for screening, prevalence of PA among hypertensives soars to 8-20%; current predominance of IHA (>80%) over APA suggests the inclusion of former low-renin essential hypertensives (LREH), in whom plasma aldo can be reduced by suppressive maneuvers. We evaluated the test characteristics of the ARR obtained retrospectively from 127 patients with PA (81 APA; 46 IHA) and 55 with EH (30 LREH; 25 NREH) studied from 1975 to 1990. Using the combined ROC-defined cutoffs of 27 for the ARR and 12ng/dL for aldo, we obtained 89.8% sensitivity (Ss) and 98.2% specificity (Sp) in discriminating PA from EH: all APA and 72% of the IHA patients had values above these limits, but only one (3%) with LREH. Among the 46 IHA patients, 10 (21.7%) had ARR <27, four of whom with aldo <12ng/dL, virtually indistinguishable from LREH. Use of higher cutoff values (ARR >100; aldo >20) may attain 84%Ss and 82.6%Sp in separating APA from IHA. Because IHA and LREH ("the chaff") may be spectrum stages from the same disease, definite discrimination between these entities seems immaterial. However, precise identification of the APA ("the wheat") is critical, since it is the only surgically curable form of PA. Thus, while patients who may harbor an APA must be thoroughly investigated and surgically treated, non-tumoral disease (IHA and LREH) may be best treated with an aldo-receptor antagonist that will also prevent the aldo-mediated inflammatory effects involved in myocardial fibrosis and abnormal cardiac remodeling.

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