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Monogenic Forms of Mineralocorticoid Hypertension: Insights Into the Pathogenesis of ‘Essential’ Hypertension?

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Monogenic Forms of Mineralocorticoid Hypertension: Insights Into the Pathogenesis of ‘Essential’ Hypertension? Journal of Human Hypertension (1998) 12, 7–12 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 REVIEW ARTICLE Monogenic forms of mineralocorticoid hypertension: insights into the pathogenesis of ‘essential’ hypertension? M Petrelli and PM Stewart Department of Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK Keywords: hyperaldosteronism; mineralocorticoid; Liddle’s syndrome; inheritance; cortisol; 11␤-hydroxysteroid dehydrogen- ase Hypertension is a common condition, which, mary aldosteronism due to an adrenocortical tumour depending on its definition, affects 10–25% of the (Conn’s Syndrome).1 Both subjects had a mineral- population. Because it is an established risk factor ocorticoid excess syndrome, characterised by pot- for coronary and cerebrovascular disease, hyperten- assium deficiency, suppressed plasma renin activity sion has, quite rightly, been targeted as an important (PRA) and increased aldosterone secretion rate, factor in determining the health of the nation. which, in contrast to tumorous aldosteronism, Despite this we can explain the underlying cause of responded to treatment with the synthetic glucocort- a patient’s hypertension in Ͻ5% of cases; the icoid, dexamethasone. Shortly afterwards, an remainder are labelled ‘essential’ hypertension, an additional, well-documented case was described, elegant way of stating that the aetiology is unknown. confirming the existence of this new ‘glucocorticoid As a result, in the vast majority of cases treatment remediable’ aldosteronism syndrome.2 Sub- is given on an empirical basis. sequently it was shown to be inherited in an autoso- In the last 5 years, significant advances have been mal dominant fashion and approximately 100 cases made in our understanding of the pathogenesis of were reported in the world literature up to the early hypertension with the characterisation of three 1990’s.3–9 forms of inherited hypertension. All arise because The most common presentation of GRA used to be of distinct, single gene mutations but can result in the discovery of asymptomatic severe hypertension, the same phenotype, that of mineralocorticoid especially in infancy or early adulthood. With the hypertension. The purpose of this article is to ability to identify individuals by genetic or bio- review these ‘monogenic’ forms of mineralocort- chemical testing, much milder or earlier clinical icoid hypertension, glucocorticoid-remediable hyp- forms are being described. A strong family history of eraldosteronism, Liddle’s syndrome and apparent hypertension, often associated with premature death mineralocorticoid excess, and to discuss their sig- due to cerebrovascular accident is characteristically nificance to the broader population with essential seen in some GRA kindreds.10 In some cases control hypertension. of blood pressure (BP) has been unsatisfactory with common antihypertensive agents. Routine biochem- Glucocorticoid remediable aldosteronism istry may reveal hypokalaemia, which is often sev- (GRA) (also referred to as ere if patients are taking potassium-wasting diuretics. However, the clinical spectrum of this dis- dexamethasone suppressible order is heterogeneous, with up to 50% of all cases hyperaldosteronism or glucocorticoid- having normal serum potassium levels, and others suppressible hyperaldosteronism) having apparently ‘normal’ BP.4,7,10 In GRA, the In 1966 a hypertensive father and son were renin-angiotensin system is suppressed; aldosterone described with a new disorder that mimicked pri- levels are either elevated or normal and is exclus- ively regulated by ACTH, rather than the normal principal secretogogue, angiotensin II. As a result, plasma aldosterone levels do not increase and Correspondence: PM Stewart, Professor of Medicine, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham plasma renin activity (PRA) remains suppressed in B15 2TH, UK response to upright posture or to an infusion of Received 3 May 1997; revised and accepted 22 June 1997 angiotensin II.6,8,11–14 In establishing the differential Inheritance of mineralocorticoid hypertension M Petrelli and PM Stewart 8 diagnosis of primary aldosteronism, patients should by Lifton and colleagues in 1992,20,21 following the have supine PRA, aldosterone and cortisol measured cloning and characterisation of the P450 11␤- at 08.00 h and again erect at 12.00 h. A fall in plasma hydroxylase genes involved in the final pathways of cortisol (and by inference ACTH) together with a glucocorticoid and mineralocorticoid biosynth- concomitant fall in plasma aldosterone across the esis22,23 (Figure 1). 11␤-hydroxylase (CYP11B1) is same period is highly suggestive of GRA. A single responsible for the conversion of 11-deoxycortisol to measurement may not be representative, and this cortisol and, as such is regulated by ACTH. In con- procedure should be repeated on at least two trast, aldosterone synthase (CYP11B2) mediates 11␤- occasions. In addition, the administration of hydroxylation, 18-hydroxylation and 18-oxidation ACTH1–24 (Synacthen, Ciba-Geigy) to patients with of 11-deoxycorticosterone to aldosterone and is GRA results in aldosterone hyper-responsiveness regulated by angiotensin II.24 CYP11B2 is expressed compared to normal subjects12,13 and is sustained as only in the zona glomerulosa of the adrenal gland, long as ACTH is infused.14 Adrenal computerised defining the functional zonation of aldosterone tomography is usually normal in patients with GRA secretion within the adrenal. The two genes are though Pascoe et al15 have described a French family found in close proximity on human chromosome 8, with seven affected members, two of which had are 95% homologous in nucleotide sequence, and adrenal masses and another two adrenal hyperplasia have identical intron-exon structure.22,23 GRA is pre- on CT. Further information is required on the mor- sumed to result from the production of a chimeric phology of the adrenals in GRA since most cases are gene formed due to unequal cross-over and genetic treated medically and the adrenals are not removed. recombination at meiosis. Such a CYP11B1/ There are two important consequences of the CYP11B2 hybrid gene contains 3Ј sequences of aldo- regulation of aldosterone production solely by sterone synthase and 5Ј sequences of 11␤- ACTH. Firstly, there is dysregulation of aldosterone hydroxylase. So long as the breakpoint of the hybrid secretion because there is no negative feedback loop; gene is in or 5Ј to exon 4, the resultant protein can aldosterone does not suppress ACTH secretion from synthesise aldosterone but is under the regulatory the pituitary. Secondly, the exogenous adminis- control by ACTH, explaining the phenotype of tration of a glucocorticoid such as dexamethasone, GRA.20,21,25 In an adrenal gland removed from an by decreasing the secretion of ACTH, results in a affected case of GRA, this chimeric gene was indeed profound suppression of aldosterone levels, a con- shown to be expressed throughout the adrenal cor- comitant natriuresis, and correction of the biochemi- tex and was stimulated by ACTH in vitro.15 This cal and hormonal abnormalities seen in this dis- abnormal gene duplication can be detected by order. Prolonged treatment with glucocorticoids Southern blotting,26 or by faster and cheaper long leads to reactivation of the renin-angiotensin system polymerase chain reaction (PCR)27 allowing for and restoration of the normal regulation of aldos- direct genetic screening for this disorder and pre- terone secretion.16 However, careful examination of natal diagnosis. Hypertensive patients with primary aldosterone regulation in chronically treated indi- aldosteronism without demonstrable adenomata, as viduals suggests that aldosterone secretion may well as those with suppressed levels of PRA remain relatively insensitive to angiotensin, com- (especially children and young adults with positive pared with ACTH (Stowasser and Gordon, per- family history of hypertension/CVA), are candidates sonal communication). who should be screened. Although the condition is A further characteristic feature of GRA is the pro- inherited as an autosomal dominant trait, BP is duction of large quantities of the normally rare, 18- reported to be higher in offspring inheriting GRA hydroxylated steroids, 18 hydroxy-cortisol and from the mother compared to the father.28 It is poss- corticosterone (18-OHF, 18-OHB) and 18 oxo-cor- ible that the higher aldosterone levels in pregnancy tisol and corticosterone (18-OXOF, 18-OXOB).17–19 in the former scenario results in ‘programming’ of This abnormal pattern of corticosteroid biosynthesis hypertension in the developing fetus. was an important observation, providing a sensitive diagnostic test for patients with GRA (plasma and/or urinary assays), but also providing further insights into the pathogenesis of the condition. The syn- thesis of these steroids requires the simultaneous presence of two enzymes, 17␣-hydroxylase and 18- hydroxylase/oxidase. 17␣-hydroxylase is required for normal glucocorticoid biosynthesis and is expressed in the zona fasciculata/reticularis, whilst the combined 18-hydroxylation/oxidation step is the final pathway for aldosterone synthesis and as such would be predicted to be localised in the nor- mal adrenal only to the zona glomerulosa. However, like aldosterone itself, these 18-hydroxylated ster- oids were also shown to be ACTH-regulated and suppressed by dexamethasone, suggesting aberrant Figure 1 Adrenal steroidogenesis outlining the pathogenesis
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