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Endocrinology and Metabolism Clinics of... Sep 1995Apparent mineralocorticoid excess is a congenital syndrome of sodium retention and hypertension with suppressed renin and aldosterone and normal cortisol levels.... (Review)
Review
Apparent mineralocorticoid excess is a congenital syndrome of sodium retention and hypertension with suppressed renin and aldosterone and normal cortisol levels. Patients with the syndrome have, however, highly abnormal levels of urinary cortisol to cortisone metabolites, indicating a reduced or absent activity of 11 beta-hydroxysteroid dehydrogenase 2, the enzyme responsible for conversion of cortisol to receptor-inactive cortisone. Very recently, the gene for 11 beta-hydroxysteroid dehydrogenase 2 was cloned, and mutations leading to absent or markedly reduced enzyme activity were found in 10 or 11 patients to date.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hypertension; Hypokalemia; Mineralocorticoids; Renin; Syndrome
PubMed: 8575412
DOI: No ID Found -
Steroids Apr 1996Pseudohypoaldosteronism was first described in 1958 by Cheek and Perry, who reported an infant with severe salt wasting in the absence of any renal or adrenal defect.... (Review)
Review
Pseudohypoaldosteronism was first described in 1958 by Cheek and Perry, who reported an infant with severe salt wasting in the absence of any renal or adrenal defect. Since then several reports have described patients affected by symptoms consistent with resistance to mineralocorticoid action. The clinical picture is characterized by salt wasting and failure to thrive and is resistant to the administration of exogenous mineralocorticoids. Biological features are invariably high plasma and urinary aldosterone levels and elevated plasma renin activity associated with hyponatremia, hyperkalemia, and metabolic acidosis. The discovery of abnormal binding of aldosterone to the mineralocorticoid receptor (MR) in lymphocytes from affected patients, by analogy to findings in other syndromes of steroid hormone resistance, led to the hypothesis that the disease reflected a molecular defect in MR, which has prompted a series of molecular studies to characterize the defect. In this paper we review mechanisms of mineralocorticoid action, discuss the clinical features of mineralocorticoid resistance, overview the molecular characterization of the MR, and close with some pathophysiological hypotheses and questions.
Topics: Aldosterone; Drug Resistance; Humans; Mineralocorticoids; Pseudohypoaldosteronism; Receptors, Mineralocorticoid
PubMed: 8732998
DOI: 10.1016/0039-128x(96)00011-6 -
The Journal of Clinical Endocrinology... Apr 2020Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels... (Review)
Review
CONTEXT
Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation.
EVIDENCE ACQUISITION
This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism.
EVIDENCE SYNTHESIS
The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists.
CONCLUSION
NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.
Topics: Cortisone; Humans; Hydrocortisone; Mineralocorticoid Excess Syndrome, Apparent; Mineralocorticoids; Phenotype; Prognosis
PubMed: 31909799
DOI: 10.1210/clinem/dgz315 -
Journal of Molecular Endocrinology Jan 2017The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling of electrolytes, and induces diverse effects on other tissues. Traditionally, the... (Review)
Review
The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects of MR were ascribed to ligand-receptor binding and activation of gene transcription. However, the MR also utilises a number of intracellular signalling cascades, often by transactivating unrelated receptors, to change cell function more rapidly. Although aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. Tissue-selective and mineralocorticoid-specific effects are conferred through the enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER. This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex interactions in physiology and disease.
Topics: Aldosterone; Animals; Disease Susceptibility; Gene Expression Regulation; Homeostasis; Humans; Ligands; MAP Kinase Signaling System; Mineralocorticoids; Organ Specificity; Oxidation-Reduction; Oxidative Stress; Protein Binding; Protein Serine-Threonine Kinases; Receptors, Mineralocorticoid; Signal Transduction; Structure-Activity Relationship; Transcription, Genetic
PubMed: 27821439
DOI: 10.1530/JME-15-0318 -
Circulation Research Jul 2020
Topics: Aldosterone; Extracellular Matrix; Humans; Mineralocorticoids; Mitral Valve Prolapse; Receptors, Mineralocorticoid
PubMed: 32673533
DOI: 10.1161/CIRCRESAHA.120.317424 -
The Journal of Clinical Investigation Jan 2024Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to...
Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.
Topics: Rats; Humans; Animals; Mineralocorticoid Receptor Antagonists; Chromatin; Amiloride; Mineralocorticoids; Kidney; Hypertension; Kidney Diseases; Gene Expression Profiling
PubMed: 37906287
DOI: 10.1172/JCI157165 -
Journal of Hypertension. Supplement :... May 2003About 3% of our hypertensive patients have high blood pressure induced by corticosteroids. Muscle weakness, tiredness, polyuria and polydipsia may indicate hypokalaemia.... (Review)
Review
About 3% of our hypertensive patients have high blood pressure induced by corticosteroids. Muscle weakness, tiredness, polyuria and polydipsia may indicate hypokalaemia. Hypokalaemic hypertension in the presence of a low plasma renin activity is the typical finding of corticosteroid hypertension. The most frequent cause of corticosteroid hypertension is primary aldosteronism (Conn's syndrome) due to an adrenal adenoma or bilateral hyperplasia of the adrenal glands. The plasma concentration of aldosterone and the ratio between plasma aldosterone and renin concentrations are high, and the kaliuresis exceeds 30 mmol/24 h in the presence of hypokalaemia. Adrenal carcinomas are rare and very malignant. The localization of an adrenal tumour is made by computer tomography (CT-scan) or nuclear magnetic resonance imaging and by measurement of the aldosterone/cortisol concentrations in the adrenal venous blood. Adenomas are removed under laparoscopy, and adrenal hyperplasias are treated with spironolactone (50-400 mg daily) or amiloride (5-30 mg daily). In rare cases (<1%), excessive stimulation of the mineralocorticoid receptor is due to cortisol (apparent mineralocorticoid excess, Cushing's disease, liquorice, or hereditary deficiency of 11beta-hydroxysteroid dehydrogenase) or to a chimeric gene coding for 11beta-hydroxylase (CYP11B1/CYP11B2). In these rare cases, the synthesis of aldosterone is under the control of the adrenocorticotrophic hormone, so treatment with glucocorticoids (dexamethasone 0.25-1.0 mg daily) is therefore possible (glucocorticoid-remediable aldosteronism). Excessive deoxycorticosterone (DOC) causes the same symptoms and signs as hyperaldosteronism. Excessive DOC is found in patients with adrenal tumours that secrete DOC, in those with hereditary or acquired disorders with dysfunctioning glucocorticoid receptors, or in those with congenital hyperplasia of the adrenal glands (deficiency of 17alpha-hydroxylase or 11beta-hydroxylase). Liddle's syndrome is a constitutive hyperactivity of the transepithelial transport of sodium, which under normal conditions is controlled by the mineralocorticoid receptor. Plasma renin and aldosterone concentrations are suppressed and the plasma potassium concentration may be normal. In contrast, plasma aldosterone and renin concentrations are increased in patients with hypokalaemic hypertension which represents secondary aldosteronism. The increased aldosterone is the consequence of stimulated renin activity due to renal or renovascular or other disorders, antihypertensive drugs or other medications. In conclusion, a work-up for corticosteroid-induced hypertension is indicated in patients with hypokalaemic hypertension and in those with severe hypertension even in the absence of hypokalaemia, and in hypertensive patients with a family history of cardiovascular diseases.
Topics: Adrenal Gland Diseases; Humans; Hypertension; Mineralocorticoids
PubMed: 12929904
DOI: 10.1097/00004872-200305002-00005 -
Medicine Jul 2017Mineralocorticoid responsive hyponatremia of the elderly (MRHE) is an emerging concept of hyponatremia in aged people. Diagnosis of MRHE requires exclusion of syndrome... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Mineralocorticoid responsive hyponatremia of the elderly (MRHE) is an emerging concept of hyponatremia in aged people. Diagnosis of MRHE requires exclusion of syndrome of inappropriate antidiuresis and adrenal dysfunction. Thus we aimed to evaluate the characteristics of all patients with suspected MRHE available for a review.
METHODS
We conducted a systematic review using MEDLINE and Google scholar. We included published case reports of adult patients diagnosed as MRHE, written by English and Japanese language. Serum and urine electrolytes as well as the levels of antidiuretic hormone (ADH), cortisol, plasma renin activity (PRA), and aldosterone were analyzed.
RESULTS
A total of 27 MRHE patients were identified in 9 reports. In these patients, average age was 79 years, median serum sodium was 117 mEq/L. The median levels of ADH, cortisol, PRA, and aldosterone were 0.9 pg/mL, 18.7 μg/dL, 0.37 ng/mL/h, and 39.6 pg/mL, respectively. Water restriction test was conducted in 7 patients. Random sample cortisol measurements did not exceed satisfactory levels to rule out adrenal dysfunction in four cases. No cases underwent low-dose adrenocorticotropic hormone stimulation test. Only 27 patients from 9 case reports in Japanese were eligible for inclusion in our study.
CONCLUSION
All published cases of MRHE as a cause of hyponatremia are described for the first time. In these cases, latent adrenal sufficiency might have been hidden and should have been excluded.
Topics: Aged; Hematologic Agents; Humans; Hyponatremia; Mineralocorticoids
PubMed: 28682868
DOI: 10.1097/MD.0000000000007154 -
Hypertension (Dallas, Tex. : 1979) Feb 2019
Topics: Fibrosis; Heart Atria; Humans; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 30595119
DOI: 10.1161/HYPERTENSIONAHA.118.11604 -
Molecular and Cellular Endocrinology Mar 2021The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct... (Review)
Review
The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.
Topics: Animals; Antifungal Agents; Azoles; Drug Monitoring; Humans; Mineralocorticoids; Syndrome
PubMed: 33484741
DOI: 10.1016/j.mce.2021.111168