Apparent mineralocorticoid excess syndrome: an overview

Abstract

Apparent mineralocorticoid excess (AME) syndrome results from defective 11 -hydroxysteroid dehydrogenase type 2 (11 -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 11 -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 11 -HSD2. Reduced 11 -HSD2 activity may explain the increased sodium retention in preeclampsia, renal disease and liver cirrhosis. Relative deficiency of 11 -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 11 -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 11 -HSD2; although AME is a genetic disorder, several exogenous compounds can bring about the symptoms by inhibiting 11 -HSD2 enzyme. Substrate excess as seen in Cushing's syndrome and ACTH ectopic production can overwhelm the capacity of 11 -HSD2 to convert F to E, leading up to an acquired form of AME. A síndrome do excesso aparente de mineralocorticóides (SEAM) resulta de defeito na 11 -hidroxisteróide desidrogenase tipo 2 (11 -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 11 -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 11 -HSD2. Redução na atividade da 11 -HSD2 pode explicar o aumento da retenção de sódio na pré-eclâmpsia, na doença renal e na cirrose hepática. Deficiência relativa de atividade da 11 -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 11 -HSD2 poderia justificar a ligação entre baixo peso ao nascer e hipertensão no adulto. Variabili-

11β-Hydroxysteroid Dehydrogenase Type 1 and the Metabolic Syndrome

“…Cortisol and 11 -HSDs have been implicated in hypertension (Anagnostis et al, 2009;Andrews et al, 2003;Campino et al, 2010;Cicala & Mantero, 2010;Edwards et al, 1988;Ferrari, 2010;Franks et al, 2004;Funder et al, 1988;Gathercole & Stewart, 2010;Y. Liu et al, 2008;Malavasi et al, 2010;Millis, 2011;Monder et al, 1989;Morales et al, 2008;Mune et al, 1995;Palermo et al, 2004;Paterson et al, 2004;Quinkler & Stewart, 2003;Raff & Findling, 2003;Stewart et al, 1996;Walker & Andrew, 2006;Walker et al, 1993;Wallerath et al, 1999;White et al, 1997). The fact that 11 -HSD2 is important in protecting MR in the distal nephron from stimulation by GCs revealed its role in the regulation of arterial blood pressure.…”

“…The fact that 11 -HSD2 is important in protecting MR in the distal nephron from stimulation by GCs revealed its role in the regulation of arterial blood pressure. Pharmacological inhibition or genetic deficiency of 11 -HSD2 leads to the development of hypertension (Anagnostis et al, 2009;Andrews et al, 2003;Edwards et al, 1988;Ferrari, 2010;Funder et al, 1988;Gathercole & Stewart, 2010;Palermo et al, 2004;Walker et al, 1993;White et al, 1997). HSD11B2 can be epigenetically regulated, what is also involved in hypertension development (Millis, 2011).…”

“…After both a single dose and posterior 72 h of continuous treatment with carbenoxolone, in healthy male volunteers, Tomlinson et al observe a decrease not only on serum cortisol generation, after oral administration of cortisone acetate (although only significantly for continuous treatment), but also on cortisol concentrations, after oral cortisone acetate, and glycerol concentrations, after oral prednisone, both within SAT interstitial fluid (in the latter location being indicative of inhibition of GC-mediated lipolysis) . It is important to mention that 11-HSD2 inhibition, with licorice or carbenoxolone, can lead to cortisol-dependent mineralocorticoid excess, with hypertension, sodium retention, hypokalemia and fluid retention (Andrews et al, 2003;Edwards et al, 1988;Ferrari, 2010;Gathercole & Stewart, 2010;Palermo et al, 2004;Stewart et al, 1990;Stewart et al, 1987). 11 -HSD2 is expressed principally in the distal nephron, where it inactivates cortisol to cortisone and thereby protects MR from cortisol (Andrews et al, 2003;Edwards et al, 1988;Ferrari, 2010;Funder et al, 1988;Palermo et al, 2004).…”

“…It is important to mention that 11-HSD2 inhibition, with licorice or carbenoxolone, can lead to cortisol-dependent mineralocorticoid excess, with hypertension, sodium retention, hypokalemia and fluid retention (Andrews et al, 2003;Edwards et al, 1988;Ferrari, 2010;Gathercole & Stewart, 2010;Palermo et al, 2004;Stewart et al, 1990;Stewart et al, 1987). 11 -HSD2 is expressed principally in the distal nephron, where it inactivates cortisol to cortisone and thereby protects MR from cortisol (Andrews et al, 2003;Edwards et al, 1988;Ferrari, 2010;Funder et al, 1988;Palermo et al, 2004). PF-915275 is a potent and selective 11 -HSD1 inhibitor, without adverse side effects in a wide range of orally tested doses, that is selective for the human and primate enzymes (Bhat et al, 2008;Courtney et al, 2008).…”

Sambucus nigra Extracts Inhibit Infectious Bronchitis Virus at an Early Point during Replication

“…The range of plants that have been surveyed for their potential as anti-IBV agents is also limited, although, purified compounds isolated from Glycyrrhiza radix (licorice root) [25] and Forsythia suspensa (weeping forsythia) [26] have shown effectiveness against IBV in vitro. However, the use of these extracts or the active ingredients from these extracts for long-term treatment or prevention strategies poses some toxicity concerns [27][28][29]. These concerns, combined with the difficulties often encountered when translating in vitro research into in vivo treatments [30], suggest that in vitro identification of a number of different antiviral plants for future in vivo studies is important.…”