New Findings in Apparent Mineralocorticoid Excess

Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11␤-hydroxysteroid dehydrogenase type 2 enzyme (11␤-HSD2) cause AME. Typical patients with AME have defective 11␤-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11-3 H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0-6% in typical patients with AME whereas the normal conversion is 90-95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C3T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the K m (300 nM) over normal (54 nM). Because Ϸ40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.

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“…Cortisol secretion rate and cortisol half-life were determined as described (1,2,22,44). To establish the (45).…”

Section: Methodsmentioning

confidence: 99%

A genetic defect resulting in mild low-renin hypertension

Wilson

Dave-Sharma

Wei

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

130

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“…Mineralocorticoids were previously shown to induce hypercalcuria (37). The occurrence of hypercalcuria in the syndrome of apparent mineralocorticoid excess is suggested by the high incidence of nephrocalcinosis in previous reports (3,(38)(39)(40) and in patient E. A relationship between hypercalcuria, demineralization, and mineralocorticoid excess was demonstrated in a child with the type 1 variant of the syndrome and rickets (41). Spironolactone was effective in correcting the hypertension and hypokalemic alkalosis as well as the hypercalcuria and also led to healing of the rickets and resumption of linear growth.…”

Section: Mineralocorticoids and Calcium Balancementioning

confidence: 85%

Pathogenesis of the Type 2 Variant of the Syndrome of Apparent Mineralocorticoid Excess*

Ulick

Tedde

Mantero

1990

The Journal of Clinical Endocrinology & Metabolism

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The syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxydehydrogenation of cortisol to cortisone. Studies in this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. This view reconciled developing evidence that the mineralocorticoid receptor itself could not distinguish between mineralocorticoids and glucocorticoids. The syndrome occurs in two forms. In both forms there is decreased turnover of a normal level of plasma cortisol, consistent with the view that delayed removal of the glucocorticoid from strategic receptor sites unmasks its potential mineralocorticoid agonism. In the type 1 variant, impaired 11 beta-hydroxydehydrogenation is reflected by an elevated cortisol/cortisone metabolite ratio. In three patients with the type 2 variant, this ratio was normal, suggesting that the rate of 11 beta-hydroxydehydrogenation was unimpaired. The hypertension and hypokalemic alkalosis of both forms are improved by spironolactone, but patients with the type 2 variant have responded somewhat better to the suppression of cortisol by dexamethasone.

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“…Groups had searched extensively for unidentified circulating mineralocorticoids before it was appreciated that the implicated mineralocorticoid in AME was cortisol itself. 44,45 Liquorice, of which the active principal is glycyrrhetinic acid, together with its synthetic derivative carbenoxolone had been known to act as mineralocorticoids for several years. It was subsequently shown that these compounds exert their mineralocorticoid effects, not directly, but by inhibiting 11␤-HSD, [46][47][48][49] resulting in an acquired form of AME.…”

Section: Liddle's Syndromementioning

confidence: 99%

Monogenic forms of mineralocorticoid hypertension: insights into the pathogenesis of ‘essential’ hypertension?

Petrelli

Stewart

1998

J Hum Hypertens

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Hypertension is a common condition, which, depending on its definition, affects 10-25% of the population. Because it is an established risk factor for coronary and cerebrovascular disease, hypertension has, quite rightly, been targeted as an important factor in determining the health of the nation. Despite this we can explain the underlying cause of a patient's hypertension in Ͻ5% of cases; the remainder are labelled 'essential' hypertension, an elegant way of stating that the aetiology is unknown. As a result, in the vast majority of cases treatment is given on an empirical basis.In the last 5 years, significant advances have been made in our understanding of the pathogenesis of hypertension with the characterisation of three forms of inherited hypertension. All arise because of distinct, single gene mutations but can result in the same phenotype, that of mineralocorticoid hypertension. The purpose of this article is to review these 'monogenic' forms of mineralocorticoid hypertension, glucocorticoid-remediable hyperaldosteronism, Liddle's syndrome and apparent mineralocorticoid excess, and to discuss their significance to the broader population with essential hypertension.Glucocorticoid remediable aldosteronism (GRA) (also referred to as dexamethasone suppressible hyperaldosteronism or glucocorticoidsuppressible hyperaldosteronism)In 1966 a hypertensive father and son were described with a new disorder that mimicked priCorrespondence: PM Stewart, Professor

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New Findings in Apparent Mineralocorticoid Excess

Cited by 47 publications

References 18 publications

A genetic defect resulting in mild low-renin hypertension

A genetic defect resulting in mild low-renin hypertension

Pathogenesis of the Type 2 Variant of the Syndrome of Apparent Mineralocorticoid Excess*

Monogenic forms of mineralocorticoid hypertension: insights into the pathogenesis of ‘essential’ hypertension?

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