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

Abstract

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

Treatment of Familial Hyperaldosteronism Type I: Only Partial Suppression of Adrenocorticotropin Required to Correct Hypertension

“…Whereas an argument exists for attempting complete suppression of abnormally regulated aldosterone production in patients with FH-I (see below), this approach would also be expected to render patients at significant risk of Cushingoid side effects. Indeed, occasional reports (21) of glucocorticoidinduced side effects in treated patients have caused some investigators to express caution in the use of glucocorticoids (22,23) and, in the case of affected children, to favor the use of other agents (such as amiloride) to avoid the growthretarding effects of glucocorticoid treatment in this age group (24). In the current study of eight patients with genetically proven FH-I, glucocorticoid doses of 0.125-0.25 mg dexamethasone daily or 2.5-5 mg prednisolone daily were sufficient to maintain normal blood pressure throughout 0.5-3.8 yr of follow-up without the need for additional antihypertensive medication.…”

Why is plasma renin activity lower in populations of African origin?

“…79 The potential importance of abnormal renal tubular sodium reabsorption as a determinant of sodium balance and of blood pressure has been highlighted by genetic studies of renal sodium transporters in rare familial conditions. 80 For example, Liddle's syndrome is a rare autosomal dominant disorder caused by a molecular defect leading to increased activity of the renal epithelial sodium channel. The increased renal sodium reabsorption and sodium retention leads to high blood pressure and suppression of plasma renin activity.…”

Linkage of Gordon’s syndrome to the long arm of chromosome 17 in a region recently linked to familial essential hypertension

“…1 Until recently, however, there were no clues to the molecular basis of GS, another variety of salt-sensitive familial hypertension. Important progress was made in the recent study by Mansfield et al, 6 in which evidence for linkage to chromosomes 1 and 17 was found.…”