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Primary Aldosteronism, a Common Entity? the Myth Persists

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Primary Aldosteronism, a Common Entity? the Myth Persists Journal of Human Hypertension (2002) 16, 159–162 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE Primary aldosteronism, a common entity? the myth persists PL Padfield Department of Medical Sciences, Western General Hospital, University of Edinburgh, Scotland, UK Primary aldosterone excess or hyperaldosteronism is aldosterone is in fact inappropriately elevated if the an important cause of hypertension which, when asso- renin level is low. A single measurement of the ratio of ciated with an aldosterone secreting adenoma, is amen- aldosterone to renin levels is claimed to be highly pre- able to surgical cure. The biochemical hallmarks of the dictive of patients who will have primary aldosterone condition are a relative excess of aldosterone pro- excess. This paper examines the logic behind such duction with suppression of plasma levels of renin (a claims and presents evidence from the literature that an proxy for angiotensin II, the major trophic substance abnormal ratio is simply a different description of the regulating aldosterone secretion). This combination of low renin state and that such patients do not necessarily a high aldosterone and a low renin is however more have mineralocorticoid hypertension. Most patients ‘dis- commonly associated with ‘nodular hyperplasia’ of the covered’ by this test will have what many call low-renin adrenal glands, a condition not improved by surgery hypertension, a condition not amenable to specific ther- and variably responsive to the effects of the mineral- apy. Claims that they are peculiarly sensitive to the ocorticoid antagonist, spironolactone. Until recently the hypotensive effects of spironolactone have not been prevalence of either form of secondary hypertension tested in controlled trials. The test would however be has been thought to be low such that few clinicians expected to pick up those individuals with true Conn’s ‘hunted’ for it in the absence of hypokalaemia (the tra- syndrome but such patients remain too few in number ditional clue for the syndrome). This view has been chal- to justify widespread use of an expensive screening lenged, firstly by the realisation that no more than 50% test. of such patients will have a low plasma potassium and Journal of Human Hypertension (2002) 16, 159–162. DOI: secondly by the assumption that a ‘normal’ plasma 10.1038/sj/jhh/1001321 Keywords: primary aldosterone excess; Conn’s syndrome; low-renin; hyperaldosteronism; aldosterone/renin ratio Introduction single causative factor, the removal of which will cure hypertension. I have moved from a time when I have lived and worked throughout a quarter of a we investigated everybody1 to one where I investi- century where clinical hypertension research has gate few and I am not persuaded that this is the been both productive and exciting. This has been no wrong approach. more so that in the area of mineralocorticoid hyper- tension. Fashions change however and I well remember Background starting out in hypertension research in a unit where On 29 October 1954 Jerome Conn gave his presiden- every patient had a full assessment of the renin- tial address at the 27th Annual Meeting of the Cen- angiotensin-aldosterone system. This was only tral Society for Clinical Research in the United partly for research purposes as there was a genuine States of America.2 He described a patient with belief that this system was intimately concerned in hypertension who was cured by the removal of an the pathogenesis of high blood pressure. As the adrenal tumour. I was privileged to work in the years have passed my own philosophical approach institution where he investigated the index patient, to the hypertensive patient has changed. I no longer a middle-aged female, for many weeks before finally believe that most hypertensive patients harbour a persuading a surgeon that she must have an adrenal tumour and that he (the surgeon) had but to find it. Correspondence: Dr PL Padfield, Department of Medical It is worth remembering that Conn had none of the Sciences, Western General Hospital, University of Edinburgh, benefits of the modern clinician and indeed, at that Edinburgh, Scotland, UK. time, aldosterone had not even been discovered. It Based upon a paper presented at the Annual Scientific Meeting of the British Hypertension Society, held in Glasgow, Sep- was not long before electrocortin, as it was called by tember 1999. the Taits in London, became ‘aldosterone’ and it was Received 20 August 2001; accepted 11 October 2001 clear that what Conn had described was a benign Primary aldosteronism, a common entity? PL Padfield 160 aldosterone-producing adenoma of the adrenal identifying this or that adrenal steroid that might be gland. This condition has since been eponymously the cause of hypertension in such patients. In retro- named, Conn’s syndrome. Renin had been known spect it is clear of course that a relative aldosterone about for over 50 years and as assays became avail- excess (for a given level of renin) was present in able for the measurement of both renin activity in those patients with low renin hypertension. The plasma and aldosterone in urine, and subsequently absence of a suppressed aldosterone level was plasma, it became clear that Conn’s syndrome of against a role for an alternative mineralocorticoid aldosterone excess resulted in sodium retention and (see Padfield et al9). suppression of renin. The hallmark of Conn’s syn- Through the 1970s it became clear to us in Glas- drome was high aldosterone production with a sup- gow that the differences between so-called idio- pressed renin. Initially all patients investigated had pathic hyperplasia and low renin hypertension were hypokalaemia but it became apparent that not all quantitative rather than qualitative. Seminal studies patients with low renin aldosterone excess had an performed around that time showed quite clearly adrenal adenoma.3 In early series it seemed clear that: that about a quarter of such patients had what came • Patients with true Conn’s syndrome had plasma to be called idiopathic hyperplasia or pseudo hyper- aldosterone levels that were insensitive to changes aldosteronism. These patients did not have a dis- 4 in circulating angiotensin II (induced by assump- creet tumour but had nodular adrenal glands. Some tion of the erect posture or by infusion of the pep- nodules could be large being indistinguishable from 10 5 tide itself). true tumours in a variety of imaging techniques. • Patients with the idiopathic hyperplastic variety While the removal of an aldosterone producing of primary aldosteronism had an enhanced aldos- adrenal adenoma resulted in cure of hypertension in terone response to such manoeuvres.11,12 at least 70% of cases, surgery for nodular hyper- plasia did not.6 There were even examples in the Idiopathic hyperplasia of the adrenal glands asso- literature of patients who had both adrenal glands ciated with aldosterone excess was not primary removed but who remained hypertensive following aldosteronism at all but some form of secondary replacement therapy. This is not surprising if it is aldosteronism whereby the adrenal gland was appreciated that the nodules from hyperplastic exquisitely sensitive to small changes in circulating glands do not make aldosterone; whereas of course angiotension II. The coup de grace for those who tumours do.7 This observation threw into question believed in qualitative differences was the obser- the whole notion of what so-called primary aldos- vation that when patients with low renin hyperten- teronism meant. The optimism of the 1960s where sion (a low circulating renin with a normal it was genuinely believed by some that up to 20% aldosterone) were infused with angiotensin II they of patients with hypertension might have primary behaved exactly as did the hyperplastic patients aldosteronism gradually subsided throughout the with an exaggerated aldosterone response. 1970s and most of the 1980s to a belief that primary We wrote in several papers around the middle aldosterone excess was a rare cause of hypertension. 1970s that idiopathic hyperaldosteronism and low Most textbooks and recent reviews now give it a renin hypertension were simply a continuum in the prevalence rate of probably less than 1% of the spectrum of essential hypertension (see Padfield et hypertensive population.8 al4, Davies et al10). There was much other circumstantial evidence to support this view. Pathophysiology • In patients with tumerous Conn’s syndrome a plot The measurement of plasma renin was always more of circulating renin or angiotensin II against readily available to clinicians than was the measure- aldosterone produced a negative correlation ment of aldosterone and in the search for aldos- (aldosterone induced sodium retention sup- terone excess it was found that a significant pro- pressing renin) whereas in those with the hyper- portion of patients (who otherwise had essential plastic form of the disease the relationship was hypertension) had a low or suppressed plasma renin positive (see Davies et al10). This is exactly what activity. While working at the MRC BP unit in Glas- would be expected if the aldosterone was high as gow 25 years ago, I showed that plasma renin levels, a result of angiotensin II. just like blood pressure itself, were normally distrib- • Patients with Conn’s syndrome had other evi- uted in hypertensive patients and therefore any sub- dence of mineralocorticoid excess in that division of hypertension based on the renin level exchangeable sodium was always elevated; it was was as arbitrary as the definition of hypertension not in the hyperplastic variety being on a par with 9 itself. Nonetheless, there was a flurry of literature those patients with low renin hypertension.10 in the 1970s describing the condition of low renin hypertension. These patients did not have aldos- terone excess but because low renin was a hallmark Clinical consequences of mineralocorticoid effect a search ensued for other Arguing as a purist for a particular disease entity, or mineralocorticoids.
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