The paper by Lim et al.  appearing in this issue of the Journal of Hypertension explores the hypothesis that so-called ‘essential hypertension', ‘low-renin essential hypertension’ (LREH) and ‘idiopathic hyperaldosteronism’ (a form of primary aldosteronism), represent progressive stages in individuals with hypertension. The underlying mechanism for this progression, they propose, is persistent stimulation of the adrenal by excessive angiotensin II, causing aldosterone overproduction, which eventually evolves into an autonomous phase; in other words, ‘tertiary hyperaldosteronism'. Although this idea is not new (a fact which is conceded by the authors), the paper approaches the hypothesis in several novel ways. For example, whereas previous investigators have explored the concept of tertiary hyperaldosteronism primarily in the context of renovascular or chronic renal parenchymal conditions known to be associated with elevated renin levels [2–4], the current paper proposes that tertiary hyperaldosteronism may develop in the absence of such conditions. Second, the authors incorporate new data concerning the ability of angiotensin II to paradoxically upregulate adrenocortical type 1 angiotensin II (AT1) receptors, and thereby to increase adrenal sensitivity to angiotensin II. Third, the authors discuss new information implicating polymorphisms of the aldosterone synthase gene in the development of hyperaldosteronism, and suggest that individuals with certain polymorphisms may be predisposed to the development of tertiary hyperaldosteronism.
In keeping with the authors’ primary hypothesis, increasing age is accompanied by a gradual fall in renin levels, a rise in aldosterone/renin ratios and increasing blood pressure sensitivity to salt . Of course, an age-related progressive decline in renal function and reduction in the number of functioning juxtaglomerular cells would be expected to produce similar changes. Indeed, elevated aldosterone/renin ratios are well-recognized to occur in patients with chronic renal impairment , in which renin levels tend to fall in response to reduced renin secretory mass and to salt and water retention, while any associated hyperkalaemia tends to elevate aldosterone. However, this does not rule out the possibility that, at least in some hypertensive individuals, ageing may also be accompanied by the gradual development of adrenal hypersensitivity to angiotensin II, and eventually autonomy, in terms of aldosterone production.
How could this postulated increase in adrenal sensitivity come about? The authors propose a ‘vicious cycle’ concept, the first half of which involves a paradoxical upregulation of adrenal AT1 receptors caused by excessive angiotensin II stimulation. Presumably then, the hypothesis of Lim et al. is only applicable to those individuals who have chronically elevated renin/angiotensin II levels; otherwise, the stimulus for AT1 receptor upregulation and development of eventual tertiary hyperaldosteronism would not exist. It is not entirely clear, however, as to how the authors believe high renin/angiotensin II levels may develop in this subset of hypertensive individuals in the first place. The presence of renovascular or chronic renal parenchymal conditions would be an obvious candidate, but these disorders do not appear to be particularly common among patients with established primary aldosteronism. In the study of Beevers et al. of 136 patients with primary aldosteronism, only 21 had evidence of such conditions . Sympathetic activation due to stress is cited as an alternative possible mechanism, but evidence that this can lead to chronic elevation of renin/angiotensin II levels is lacking.
In the second part of the ‘vicious cycle’ hypothesis, the authors suggest that the raised aldosterone secretion resulting from enhanced adrenal sensitivity to angiotensin II in turn promotes the production of angiotensin II. This is in conflict with our current concept of negative feedback regulation of renin/angiotensin II, and with the suppression of renin and angiotensin II levels that accompanies excessive aldosterone secretion in primary aldosteronism. According to our usual understanding, increased aldosterone production, by inducing suppression of angiotensin II, is likely to ‘break’ (rather than propagate) the cycle to which the authors refer. They have tried to address this by referring to the work of Sun and Weber , which has yielded evidence to suggest that aldosterone promotes tissue generation of angiotensin II. The implication of this is that increased tissue generation of angiotensin II may be capable of stimulating aldosterone production in the absence of any rise in circulating angiotensin II. Again, the actual evidence is slim. The tissue generation of angiotensin II observed in the study of Sun and Weber was, in fact, within rat heart and kidney and not within the adrenal cortex.
Thus, the two main weaknesses in the hypothesis relate to the following: (i) how does elevated renin/angiotensin II occur in the first place to initiate the ‘vicious cycle’ and (ii) how does elevated aldosterone exacerbate elevated angiotensin II and thereby propagate the ‘vicious cycle'? It would seem much simpler to explore more likely possibilities. For example, it may be that some aldosterone synthase polymorphisms cause enhanced sensitivity of the AS gene to normal levels of angiotensin II; this would at least obviate the need to propose elevated renin/angiotensin II levels as leading to excessive aldosterone production. The second weakness would remain, since the excessive aldosterone would still be expected to switch off (rather than switch on) angiotensin II, especially if, as the authors propose, the next stage is low (rather than high) renin essential hypertension. This weakness would be overcome in a model which allowed for the possibility that certain aldosterone synthase polymorphisms do not just cause enhanced sensitivity of aldosterone to angiotensin II, but in fact lead to aldosterone production that is autonomous of angiotensin II from the outset. An already recognized genetic defect (the hybrid 11β-hydroxylase/aldosterone synthase gene causing familial, glucocorticoid-remediable aldosteronism) does just that .
Autonomous aldosterone production could result from a number of different genetic mutations, involving either biosynthetic or growth-regulating genes. In linkage studies involving a family with familial hyperaldosteronism type II (FH-II, a non-glucocorticoid suppressible familial variety of primary aldosteronism), the primary aldosteronism phenotype showed no cosegregation with polymorphisms of aldosterone synthase, AT1 receptor or multiple endocrine neoplasia type 1 loci . A genome-wide search, however, has revealed linkage with a locus situated in the short arm of chromosome 7 , and an analysis of candidate genes in this region is underway. The fact that FH-II is clinically, biochemically and morphologically indistinguishable from apparently non-familial primary aldosteronism raises the possibility that genetic mutations responsible for FH-II may also be operative in the much larger group of patients with apparently sporadic primary aldosteronism. The identification of such mutations could go a long way towards understanding the pathogenesis of primary aldosteronism and so-called ‘LREH', and facilitate the detection of individuals with specifically treatable and potentially curable forms of hypertension.
The link between primary aldosteronism and LREH is not a new concept. Both Grim  and our own group [12,13] have proposed that LREH represents an early stage of primary aldosteronism in many, if not most cases. Primary aldosteronism is defined as aldosterone production which is excessive and autonomous of its normal chronic regulator, renin/angiotensin II. The term ‘LREH’ has been used to describe forms of hypertension in which renin levels are suppressed, but aldosterone levels are normal, leading most investigators to exclude the diagnosis of primary aldosteronism. However, if the adrenal cortex is functioning normally, aldosterone levels should be suppressed in the presence of renin suppression, and not within normal limits (in which case they should be regarded as ‘inappropriately normal'). It is now well known that many patients with primary aldosteronism have aldosterone levels that are within the wide normal range. The Greenslopes Hospital Hypertension Unit  and, subsequently, other investigators [14–17], have demonstrated primary aldosteronism (detected by measuring the aldosterone/renin ratio in all hypertensives and confirmed by suppression testing with fludrocortisone, oral salt or intravenous saline) to be a much more common cause of hypertension than was previously thought. Most recently, detected patients have been normokalemic and therefore masquerade as if they have essential hypertension. Because the great majority of patients labelled as having ‘LREH’ have not been subjected to further study (such as fludrocortisone suppression testing), it is difficult to say how many of them might have had primary aldosteronism.
Finally, the leap from hypothesis to management recommendations should be viewed with caution. The management approach suggested in the paper by Lim et al. is restricted to medical treatment only, guided entirely by measurement of aldosterone and renin levels, without regard to the many factors that can complicate interpretation of results, or to the existence of potentially curable forms of primary aldosteronism. They describe aldosterone-producing adenoma (APA) (but not idiopathic hyperaldosteronism) as a ‘distinct diagnostic entity’ from essential hypertension, citing its adrenocorticotrophic hormone responsiveness and excess production of so-called ‘hybrid’ steroids (18-oxo- and 18-hydroxy-cortisol) as evidence for this. The angiotensin II-responsive variety of APA (which makes up one-half of APAs removed in the Greenslopes Hospital series), however, lacks these distinguishing characteristics . Angiotensin II-responsive APA masquerades biochemically as idiopathic hyperaldosteronism, with normal responsiveness of aldosterone to angiotensin II and normal hybrid steroid levels. Furthermore, since many patients with this type of APA are normokalemic (as in idiopathic hyperaldosteronism), it is frequently misdiagnosed as essential hypertension. Unlike idiopathic hyperaldosteronism, however, the hypertension associated with angiotensin II-responsive APA is potentially curable by unilateral adrenalectomy, making it important that the two forms of primary aldosteronism be differentiated during diagnostic work-up. Since they have similar biochemical features, and since many APAs are too small to be detected on computed tomography scanning, the only reliable way to do this is by adrenal venous sampling. The authors appear to have overlooked this point in their concluding remarks about tailoring medical treatment to hormonal profile. Their approach would miss potentially surgically curable hypertension, and this may help to explain why, in their experience, idiopathic hyperaldosteronism patients outnumber APA patients by a factor of 5 : 1, whereas other groups, which carefully try to separate these two subtypes (using adrenal venous sampling), find a ratio of more like 2 : 1 [13,16]. Because the use of spironolactone is not without risk of potentially troublesome (gynecomastia and menstrual irregularities) or even life-threatening (uremia and hyperkalemia, especially in patients with renal dysfunction) adverse effects, the issue of careful subtype differentiation is an important one.
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