Apparent Mineralocorticoid excess Apparent mineralocorticoid excess (AME) is an autosomal recessive disease first described in a 3- years old boy with hypertension, hypokalaemia, low plasma renin activity, and aldosterone concentration, and responsiveness to spironolactone, with a decreased rate of conversion of active cortisol to cortisone suggesting a defect in the oxidation of cortisol. AME is caused by inactivating mutations in the HSD11B2 gene encoding 11β- hydroxysteroid de hydrogenase type 2 (HSD11B2). Given that plasma free cortisol levels are ∼1000- fold those of aldosterone and cortisol binds with high affinity to MR, lack of HSD11B2 is responsible for cortisol binding to MR in the distal nephron of the kidney and a phenotype of pseudohyperaldosteronism.
In early life, AME is characterized by severe hypertension, sup pressed renin and plasma aldosterone, and an elevated ratio of urinary cortisol to cortisone metabolites. Affected children may also exhibit lower birth weight, polydipsia, polyuria, failure to thrive, poor growth, hypokalaemia, and persistent metabolic alkalosis. AME is associated with variable organ damage, potentially affecting kidneys, retina, heart, and central nervous system. A milder phenotype has been described in adults with hypertension and milder biochemical abnormalities. The phenotypic variability is associated with different extents of impairment of HSD11B2 activity with distinct mutations. Differential diagnosis includes excessive ingestion of liquorice, which contains glycyrrhetinic and glycyrrhizic acid, both being po tent competitive inhibitors of HSD11B2 activity. Inadvertent overexposure to potent synthetic mineralocorticoids also mimics AME. AME treatment is based on MR antagonism with spironolactone or eplerenone. Other antihypertensive drugs such as amiloride, calcium channel blockers, and thiazides, which can help to normalize blood pressure and lower hypercalciuria, may be associated. The importance of early diagnosis and treatment was reinforced by the description of significant improvement in end- organ damage in patients who had undergone two to 13 years of treatment.
Activating Mutations of the Mineralocorticoid Receptor
A Mendelian form of human hypertension was described by Geller et al. in 2000, caused by an activating mutation of the NR3C2 gene, coding for the MR. The heterozygous MR p.Ser810Leu mutation was identified in a 15- year- old boy with severe hypertension associated with suppressed plasma renin and low aldosterone levels. Screening of his family showed that the p.Ser810Leu mutation was transmitted as an autosomal dominant trait and cosegregated with early- onset hypertension (before age 20) in 11 subjects. Two female carriers of the mutation had their pregnancies complicated by marked exacerbation of hypertension, accompanied by low serum potassium levels and undetectable aldosterone levels, but without signs of preeclampsia.
The MR p.Ser810Leu mutation is located in the MR ligand binding pocket, inducing a major change in its conformation and ligand specificity. While there is no difference in mutant or wild- type MR activity in response to aldosterone, both progesterone and spironolactone, two MR antagonists, are able to activate transcription via the p.Ser810Leu MR mutant. These findings suggest that progesterone may contribute to the exacerbation of hypertension during pregnancy. The endogenous steroids responsible for hypertension in men and non- pregnant women carrying the p.Ser810Leu mutation were identified to be cortisone and 11- dehydrocorticosterone, the main cortisol and cortico sterone metabolites produced by the action of HSD11B2 in the distal nephron, which bind with high affinity to the mutant MR and are potent activators of mutant MR- dependent transcription [98]. Given the much higher concentration of plasma cortisol than corticosterone, the authors suggested that cortisone is the endogenous steroid binding and activating the mutant MR. While one study reported a high frequency of MR p.Ser810Leu in hypertensive pregnant women from Mexico, no further family carrying this mutation was described. Furthermore, the mutation is not listed in the large database of genetic variants ExAC (The Exome Aggregation Consortium, http:// exac.broadinstitute. org) and its frequency is not described on the 1000 genomes project (http:// www.internationalgenome.org). The use of MR antagonists such as spironolactone or eplerenone should be avoided in patients carrying the p.Ser810Leu mutation as they act as agonists on the mutant MR. In contrast, the third- generation MR antagonists BR- 4628 and finerenone, both derived from dihydropyridines, are also antagonists on the mutant receptor. Finrenone, currently approved for clinical use, might be an option to treat carriers of the MR p.Ser810Leu mutation.
