Abnormal neonatal sodium handling in skin precedes hypertension in the SAME rat.

We discovered high Na+ and water content in the skin of newborn Sprague-Dawley rats, which reduced ~ 2.5-fold by 7 days of age, indicating rapid changes in extracellular volume (ECV). Equivalent changes in ECV post birth were also observed in C57Bl/6 J mice, with a fourfold reduction over 7 days, to approximately adult levels. This established the generality of increased ECV at birth. We investigated early sodium and water handling in neonates from a second rat strain, Fischer, and an Hsd11b2-knockout rat modelling the syndrome of apparent mineralocorticoid excess (SAME). Despite Hsd11b2-/- animals exhibiting lower skin Na+ and water levels than controls at birth, they retained ~ 30% higher Na+ content in their pelts at the expense of K+ thereafter. Hsd11b2-/- neonates exhibited incipient hypokalaemia from 15 days of age and became increasingly polydipsic and polyuric from weaning. As with adults, they excreted a high proportion of ingested Na+ through the kidney, (56.15 ± 8.21% versus control 34.15 ± 8.23%; n = 4; P < 0.0001), suggesting that changes in nephron electrolyte transporters identified in adults, by RNA-seq analysis, occur by 4 weeks of age. Our data reveal that Na+ imbalance in the Hsd11b2-/- neonate leads to excess Na+ storage in skin and incipient hypokalaemia, which, together with increased, glucocorticoid-induced Na+ uptake in the kidney, then contribute to progressive, volume contracted, salt-sensitive hypertension. Skin Na+ plays an important role in the development of SAME but, equally, may play a key physiological role at birth, supporting post-natal growth, as an innate barrier to infection or as a rudimentary kidney.

Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome.

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 11ßHSD2 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.

Liquorice-induced apparent mineralocorticoid excess presenting in the emergency department.

A 65-year-old woman with a background of myalgic encephalitis, who was taking alternative medicines and dietary supplements, presented with hypokalaemia and hypertension. After a thorough history it became apparent that this was most likely secondary to regular consumption of liquorice tea. The patient was advised to discontinue drinking this tea and was discharged. Follow-up showed normalising blood pressure and hypokalaemia, with a normal aldosterone:renin ratio.

Conditional Deletion of Hsd11b2 in the Brain Causes Salt Appetite and Hypertension.

BACKGROUND: The hypertensive syndrome of Apparent Mineralocorticoid Excess is caused by loss-of-function mutations in the gene encoding 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2), allowing inappropriate activation of the mineralocorticoid receptor by endogenous glucocorticoid. Hypertension is attributed to sodium retention in the distal nephron, but 11ßHSD2 is also expressed in the brain. However, the central contribution to Apparent Mineralocorticoid Excess and other hypertensive states is often overlooked and is unresolved. We therefore used a Cre-Lox strategy to generate 11ßHSD2 brain-specific knockout (Hsd11b2.BKO) mice, measuring blood pressure and salt appetite in adults. METHODS AND RESULTS: Basal blood pressure, electrolytes, and circulating corticosteroids were unaffected in Hsd11b2.BKO mice. When offered saline to drink, Hsd11b2.BKO mice consumed 3 times more sodium than controls and became hypertensive. Salt appetite was inhibited by spironolactone. Control mice fed the same daily sodium intake remained normotensive, showing the intrinsic salt resistance of the background strain. Dexamethasone suppressed endogenous glucocorticoid and abolished the salt-induced blood pressure differential between genotypes. Salt sensitivity in Hsd11b2.BKO mice was not caused by impaired renal sodium excretion or volume expansion; pressor responses to phenylephrine were enhanced and baroreflexes impaired in these animals. CONCLUSIONS: Reduced 11ßHSD2 activity in the brain does not intrinsically cause hypertension, but it promotes a hunger for salt and a transition from salt resistance to salt sensitivity. Our data suggest that 11ßHSD2-positive neurons integrate salt appetite and the blood pressure response to dietary sodium through a mineralocorticoid receptor-dependent pathway. Therefore, central mineralocorticoid receptor antagonism could increase compliance to low-sodium regimens and help blood pressure management in cardiovascular disease.

Pseudohipoaldosteronismo y aparente exceso de mineralocorticoides: cara y ceca en dos pacientes pediátricos / Pseudohypoaldosteronism and apparent mineralocorticoid excess: two faces, two pediatric patients

Los síndromes endocrinológicos con hipofunción o hiperfunción con niveles paradójicos de dosajes hormonales han sido bien caracterizados en los últimos años del siglo XX, a partir del desarrollo de técnicas genéticas y moleculares. Presentamos dos pacientes con pseudohipoaldosteronismo y aparente exceso de mineralocorticoides como síndromes en espejo, con la intención de alertar al médico clínico respecto de su consideración como entidad diagnóstica en niños con alteraciones hidroelectrolíticas. (AU)

Endocrinological syndromes with underactive or overactive hormonal levels with paradoxical dosages have been well characterized over the years of the twentieth century, from the development of genetic and molecular techniques. We present two patients with pseudohypoaldosteronism and apparent mineralocorticoid excess as mirror syndromes, with the aim to alert the clinician regarding their consideration as a diagnostic entity in children with fluid and electrolyte disturbances. (AU)

Apparent mineralcorticoid excess syndrome, an often forgotten or unrecognized cause of hypokalemia and hypertension: case report and appraisal of the pathophysiology.

The glicyrrhizic acid, contained in licorice, has a mineralcorticoid-like effect. Chronic excess intake of licorice induces the rare syndrome of "apparent mineralcorticoid excess", due to the inhibitory effect of glicyrrhizic acid on 11 ß-hydroxysteroid dehydrogenase type 2 determining clinical/biochemical manifestations as resistant hypertension, metabolic alkalosis and severe hypokalemia. We report a typical clinical case of licorice abuse to emphasize the importance of a detailed anamnesis, which is essential for the diagnosis, avoid unnecessary and expensive investigations, and reduce the duration of hospitalization. We also provide an appraisal of the pathophysiology of "apparent mineralcorticoid excess" syndrome, still an often forgotten or unrecognized cause of hypokalemia and hypertension.

11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension.

Hypertension represents a major public and global health problem, most of which likely can be improved by lifestyle changes including changing dietary habits with less consumption of processed and preserved foods, which generally contain higher amounts of salt than freshly prepared food items. Among causes for endocrine hypertension are syndromes of mineralocorticoid excess. This group of mostly monogenic and acquired disorders typically causes hypertension through activation of the mineralocorticoid receptor either directly or indirectly via hormonal mediators and from overactive amiloride-sensitive epithelial sodium channels located in the distal tubule and collecting ducts of the kidneys. Apart from primary aldosteronism, mineralocorticoid excess can be caused by congenital adrenal hyperplasia (CAH) due to mutations of the 11beta-hydroxylase and 17alpha-hydroxylase genes, by inactivating mutations of the glucocorticoid receptor gene (Chrousos syndrome), endogenous hypercortisolism (Cushing's syndrome), by mutations of the 11beta-hydroxysteroid dehydrogenase type 2 gene (apparent mineralocorticoid excess/AME) or licorice/carbenoxolone intake, mutations of the epithelial sodium channel genes (Liddle syndrome), mutations of the mineralocorticoid receptor gene (Geller syndrome), and by mutations in the WNK1, WNK4, KLHL3, CUL3 genes (pseudohypoaldosteronism type 2 or Gordon syndrome). Most of these conditions are treated by restricting dietary salt intake. However, some require special therapies including dexamethasone/hydrocortisone (CAH), spironolactone/eplerenone (AME), epithelial sodium channel inhibitors amiloride/triamterene (Liddle and Gordon syndrome), while in others spironolactone and MR antagonists may be contraindicated due to an abnormally structured MR (Geller syndrome). We here review the pathophysiology, diagnosis, and therapy of these rare conditions including the presentation of a patient with 11beta-hydroxylase deficiency.

Low-renin hypertension of childhood.

Low-renin hypertension occurs in children as a result of several genetic mutations that cause mineralocorticoid excess or excess stimulation of the mineralocorticoid receptor. This article discusses the genetic disorders that cause low-renin hypertension.

Genetics of hypertensive syndrome.

The knowledge of the genetic bases of hypertension has improved over the last decade; this area of research has high priority due to the high incidence of hypertension and its impact on public health. Monogenetic mineralocorticoid hypertension syndromes are associated with suppressed plasma renin activity due to excessive activation of the mineralocorticoid pathway. We review the pathophysiology, phenotype, and method of diagnosis for familial hyperaldosteronism type I and type II, hypertensive forms of congenital adrenal hyperplasia, 11beta-hydroxysteroid dehydrogenase type 2 deficiency, Liddle's syndrome, an activating mutation of the MR, and glucocorticoid resistance. We also review some genes that could contribute to essential hypertension.

Effects of endocrine-disrupting chemicals on adrenal function.

Considering the wide range of chemicals known to disrupt adrenal function and the physiological importance of the adrenal cortex, it is surprising that endocrine disruption of the adrenal gland has not been more widely researched. The chemical nature of adrenal disruptors is highly varied, and there are features of the adrenal structure and function, which render it particularly vulnerable to toxic attack. However, the homeostatic mechanisms inherent in the hypothalamo-pituitary-adrenal axis mean that only the most catastrophic effects are recognized as adrenal disruption, such as in the case of etomidate. In order to detect potentially significant but milder forms of toxic disruption of adrenal function a new approach is needed; this requires the use of more sophisticated approaches than simply measuring one hormone at one time point. New methodologies are also needed, such as the use of human adrenal cell lines for the screening of toxins and for mechanistic investigation of adrenal disruptors. This review focuses on mechanisms of adrenal toxicity and on the challenges facing researchers in this important field.

Apparent mineralocorticoid excess syndrome: an overview

A síndrome do excesso aparente de mineralocorticóides (SEAM) resulta de defeito na 11b-hidroxisteróide desidrogenase tipo 2 (11b-HSD2). Esta enzima é co-expressa com o receptor mineralocorticóide (RM) nos rins e converte cortisol (F) em cortisona (E), seu metabólito inativo. Deficiência desta enzima permite que o cortisol não metabolizado se ligue ao RM, induzindo retenção de sódio, hipocalemia, supressão da APR e hipertensão. Mutações no gene que codifica a 11b-HSD2 são responsáveis pela forma herdada, mas um quadro clínico semelhante de SEAM ocorre durante ingestão dos bioflavonóides, alcaçuz e carbenoxolona, que são inibidores competitivos da 11b-HSD2. Redução na atividade da 11b-HSD2 pode explicar o aumento da retenção de sódio na pré-eclâmpsia, na doença renal e na cirrose hepática. Deficiência relativa de atividade da 11b-HSD2 pode ocorrer na síndrome de Cushing devido à saturação da enzima e explicar o estado de excesso mineralocorticóide que caracteriza a síndrome do ACTH ectópico. Redução da expressão placentária da 11b-HSD2 poderia justificar a ligação entre baixo peso ao nascer e hipertensão no adulto. Variabilidade polimórfica no gene HSD11B2 determina, em parte, a sensibilidade ao sódio, um preditor do surgimento da hipertensão no adulto. A SEAM representa um espectro de hipertensão mineralocorticóide cuja severidade reflete o defeito genético de base na 11b-HSD2; embora a SEAM seja uma doença genética, vários compostos exógenos podem provocar os sintomas pela inibição da 11b-HSD2. O excesso de substrato, visto na síndrome de Cushing e na produção ectópica de ACTH, pode sobrepujar a capacidade da 11b-HSD2 de converter F em E, levando a uma forma adquirida de SEAM.

Apparent mineralocorticoid excess syndrome: an overview.

Apparent mineralocorticoid excess (AME) syndrome results from defective 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). This enzyme is co-expressed with the mineralocorticoid receptor (MR) in the kidney and converts cortisol (F) to its inactive metabolite cortisone (E). Its deficiency allows the unmetabolized cortisol to bind to the MR inducing sodium retention, hypokalemia, suppression of PRA and hypertension. Mutations in the gene encoding 11beta-HSD2 account for the inherited form, but a similar clinical picture to AME occurs following the ingestion of bioflavonoids, licorice and carbenoxolone, which are competitive inhibitors of 11beta-HSD2. Reduced 11beta-HSD2 activity may explain the increased sodium retention in preeclampsia, renal disease and liver cirrhosis. Relative deficiency of 11beta-HSD2 activity can occur in Cushing's syndrome due to saturation of the enzyme and explains the mineralocorticoid excess state that characterizes ectopic ACTH syndrome. Reduced placental 11beta-HSD2 expression might explain the link between reduced birth weight and adult hypertension. Polymorphic variability in the HSD11B2 gene in part determines salt sensitivity, a forerunner for adult hypertension onset. AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2; although AME is a genetic disorder, several exogenous compounds can bring about the symptoms by inhibiting 11beta-HSD2 enzyme. Substrate excess as seen in Cushing's syndrome and ACTH ectopic production can overwhelm the capacity of 11beta-HSD2 to convert F to E, leading up to an acquired form of AME.

Hypertension and adrenal disorders.

Adrenal disorders causing hypertension can be related to the dysfunction of either the adrenal cortex or the adrenal medulla. These disorders, including congenital adrenal hyperplasia (CAH), owing to 11B-hydroxylase deficiency and to 17alpha-hydroxylase deficiency; apparent mineralocorticoid excess; familial hyperaldosteronism type I; primary aldosteronism; Cushing's syndrome; and familial glucocorticoid resistance, primarily affect the adrenal cortex and cause low-renin hypertension. The classic disorder of the adrenal medulla resulting in hypertension is pheochromocytoma, although hypertension in obesity might also be associated with catecholamine secretion. In this review, we discuss these etiologies and the most recent advances in our knowledge of their pathophysiology, diagnosis, and treatment.