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.

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)

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.

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.