Is aldosterone the missing link in refractory hypertension?: aldosterone-torenin ratio as a marker of inappropriate aldosterone activity

(2002) 16, 153 158 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE Is aldosterone the missing link in refractory hypertension?: aldosterone-torenin ratio as a marker of inappropriate aldosterone activity PO Lim 1, RT Jung 2 and TM MacDonald 3 1 Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK; 2 Department of Endocrinology, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK; 3 Hypertension Research Centre, Department of Clinical Pharmacology and Therapeutics, University of Dundee, Dundee, UK Use of the random aldosterone-to-renin ratio (ARR) as a reliable marker of inappropriate aldosterone activity has led to primary aldosteronism (PA) being increasingly diagnosed in hypertensive patients. At least 10% of hypertensives have been found to have PA, the majority of whom presumably have bilateral adrenal hyperplasia or idiopathic hyperaldosteronism as an aetiology for PA. Whilst these patients clearly have excess aldosterone activity, they have in common many features that are found in hypertensive patients in general, amongst which include heightened angiotensin II adre- nal sensitivity. Whether these individuals belong within the spectrum of essential hypertension is being debated, but is probably irrelevant clinically since they appear to respond favourably to spironolactone treatment. In addition, there is recent evidence suggesting that these patients overexpress a key enzyme involved in aldosterone production, the aldosterone synthase, the activity of which appears to relate to its genotypic variation. (2002) 16, 153 158. DOI: 10.1038/sj/jhh/1001320 Keywords: primary aldosteronism; aldosterone-to-renin ratio; hypertension Background The prevalence of primary aldosteronism (PA) quoted in most standard medical textbooks is less than 2% within the hypertensive population. This figure is based on the small number of hypertensive patients who exhibit frank hyperaldosteronism with complete laboratory findings of hypokalaemic alkalosis, suppressed renin activity and excessive aldosterone production. The current debate relates to whether hyperaldosteronism could manifest without necessarily fulfilling the above-described triad. Conn 1 who first described PA as a distinct disease entity in 1964 proposed that PA might be diagnosed in the absence of low potassium levels. He enthused that the prevalence of PA could be as high as 20%, since nodules were commonly found in post-mor- Correspondence: Dr PO Lim, British Heart Foundation Clinical Lecturer in Cardiology, Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. E-mail: limpo cf.ac.uk This paper has been presented as a debate in the British Hypertension Society Annual Scientific Meeting, Oxford 1999. Received 20 August 2001; accepted 11 October 2001 tem examination of adrenal glands obtained from hypertensive subjects. 2 More recently, with the introduction of aldosterone-to-renin ratio (ARR) as a marker of inappropriate aldosterone activity, the need for laboratory excess aldosterone to diagnose PA has also been dropped by some investigators. 3 Furthermore, even within the normal population, plasma aldosterone levels varies widely according to age and salt intake, and subjects with PA may have plasma aldosterone levels falling within a range that is perceived to be normal. 4 To overcome this problem, a functional definition of PA has been adopted, ie the failure of plasma aldosterone to suppress in response to salt loading which confirms the diagnosis without the need to have clearly elevated levels of plasma or urinary aldosterone. 3,5 8 Not surprisingly, this broader definition has caused some controversy, as many more hypertensive patients are included within the bracket of PA, who would in the past have been labelled under the descriptive heading of low renin essential hypertension (LREH).

154 High prevalence of primary aldosteronism Previous efforts in using plasma potassium and renin levels to screen for PA were relatively unrewarding. 8 10 Since hypertension could be cured by removing a Conn s adenoma, the emphasis was to look for PA with this specific aetiology in mind. This ignored bilateral adrenal hyperplasia (or idiopathic hyperaldosteronism (IHA)) which was less amenable to surgical treatment unless functional lateralisation could be demonstrated, 11,12 despite being another common cause of PA. The bias against diagnosing IHA was that an obvious clinical syndrome of hyperaldosteronism had to be present followed by exclusion of an adrenal adenoma. 7 This explains the preponderance of PA cases due to Conn s adenoma by two-thirds to three-quarters over and above that of IHA in most PA series prior to the introduction of ARR as a screening test. 6,13 16 However, with the shift in PA definition to that of assessing the lack of aldosterone suppressibility, IHA is more readily diagnosed and the use of ARR 7,17,18 as a screening tool has precipitated this. In fact, hypertensive patients with poorly suppressible aldosterone secretion in response to salt loading were described nearly three decades ago. These subjects would now be diagnosed as having PA. 19 21 Equally important, it is now accepted that Conn s adenoma, which is predominantly made up of fasciculata type cells, is not the only cause of aldosterone-producing-adenoma (APA). APA of glomerulosa type cells has recently been described. 22 The pathophysiology differs depending whether hyperaldosteronism is due to APA made up of fasciculata or glomerulosa type cells. The fasciculata cell type APA is corticotropin-responsive and is associated with production of high levels of hybrid steroids such as 18-hydroxy-cortisol/corticosterone and 18- oxocortisol/corticosterone. 23,24 This is also seen in the much rarer form of PA, the glucocorticoidremediable aldosteronism (GRA). 25 However, the APA of glomerulosa cell type is angiotensin II sensitive, a feature which it shares with IHA and essential hypertension. The ARR is increasingly being adopted to help identify hypertensive patients with possible PA, and its use is the reason why a higher prevalence of PA is being recognised worldwide. 26 29 The use of ARR to detect PA was first proposed in a National of Health Conference in Bethesda, Maryland, USA in 1976. At this meeting, Mitchell et al 4 reported that in five patients with PA, the mean ARR was grossly elevated to 2235 (plasma aldosterone pmol/l, plasma renin activity (PRA) ng/ml/hr) in comparison with other hypertension subgroups and normotensive volunteers who had ARRs well below 600 on ad libitum dietary salt intake. Volume loading with 2 litres of saline 0.9% over 4 hours did not significantly alter the ARRs in the control groups, whilst elevating the mean ARR in patients with PA to nearly 7500 thus further increasing the discriminative power of ARR in detecting PA. Hiramatsu et al 30 introduced into clinical practice the use of ARR in screening for PA. They screened 348 untreated hypertensive patients and found that nine patients had ARRs greater than 2085 who proved to have APA with subsequent tests. The ARR in these patients were persistently greater than 1668 despite changes to dietary salt intake and repeat blood tests at different times of the day. In comparison, in 323 patients with essential hypertension, ARRs were persistently less than 556 despite changes in salt intake and drug therapy (hydralazine, methyldopa and -blocker). Gordon et al 31 extended the use of this index to screen for PA and reported that PA might be much more prevalent. This had obvious clinical implications. When ARR was used in an unselected hypertension clinic population, this group was picking up 52 cases of PA per year from 1992. Our group in Dundee, like others, initially thought that this high prevalence of PA might be restricted to the Australian population, however between May 1995 and January 1997, we screened 495 hypertension clinic referrals using an ARR threshold of 750. We found 16.6% (77) of 465 patients with complete data for ARR had an elevated ratio. One patient had previously had an APA resected and presented with recurrent hyperaldosteronism. We hospitalised 45 of these patients for the salt loading with fludrocortisone (FST) over 4 days, and 41 out of 45 (91%) had plasma aldosterone 140 pmol/l following FST suggesting PA. One patient with a negative FST was subsequently proved to have a right-sided APA detected on CT scanning and confirmed by adrenal scintigraphy. This screening exercise thus suggested a minimum PA prevalence of 9.2% (43/465) in the Dundee hypertension clinic population. We carried out a further exercise in a general practice and found that 14.4% had ARR 750, and these were the patients with worse blood pressure control despite being on multiple antihypertensive therapy. 32 Others have since reported similarly high prevalence of PA. 29 See Table 1. The controversy of idiopathic hyperaldosteronism Some studies have shown that the body sodium is not expanded in patients with IHA in contrast to those with Conn s adenomas. 33 This finding questioned the validity of IHA as a distinct diagnostic entity, 34 and there was even a suggestion that hyperaldosteronism plays no part in maintaining hypertension in this PA subgroup. 35 Whilst it is undeniable that at one end of the spectrum of IHA cases, the clinical and laboratory features of hyperaldosteronism are clearly present, the lack of an expanded body sodium in some IHA cases is an apparent paradox which can be explained. Experimental studies have shown that sodium retention and volume

Table 1 Screening for primary aldosteronism in the hypertensive population using the aldosterone-to-renin ratio 155 Study reference n K + ARR Raised Proven PA Comments threshold ARR (minimum prevalence) Hiramatsu 30 348 whole range 2085 2.6% 2.6% Minimum ARR threshold 556 Hamlet 64 61 whole range 695 24.6% 8.2% Medical therapy continued Gordon 18 199 normal 834 20.0% 8.5% 79% on treatment when ARR was measured. 26 with raised ARR with repeat testing. Brown 26 74 normal 2000 8.0% 2.7% Therapy stopped for 3 days Lim 17 465 whole range 750 16.6% 9.2% Medical therapy continued, single random ARR Rayner 29 214 whole range 1000 32.0% 8.0% 5 APA Loh 65 350 whole range 556 18.0% 4.6% Plasma aldosterone 417 pmol/l at screening expansion are short-term phenomena with aldosterone excess. The maintenance of hypertension relates more to a raised systemic vascular resistance in the longer term following mineralocorticoid escape. 36 39 Excess sodium would thus eventually be eliminated via pressure natriuresis 40 and the release of natriuretic factors. 41,42 It is likely that the aldosterone effects in IHA are more insidious, allowing these adaptive mechanisms to take place leading to a new body sodium and fluid equilibrium. 43 In an observational study, 39 a patient with IHA who previously responded to spironolactone had this treatment stopped. It was clearly demonstrated that his blood pressure rose together with an expansion in body fluid volume and increased exchangeable sodium as similarly observed in patients with APA. Thus, the lack of demonstrable increased body sodium is of little relevance in deciding whether hyperaldosteronism is present or not. Furthermore, the positive correlation between blood pressure and exchangeable sodium observed in patients with APA 33 reverses if these patients are left untreated for a more prolonged period. 43 Another argument was that, in contrast to resected Conn s adenoma, hyperplastic nodules obtained from patients with IHA do not produce aldosterone in vitro. 33,44 This point is again of little relevance in practice as inappropriate hyperaldosteronism is clearly present in some patients with IHA. This might be related to an enhanced degree of adrenal angiotensin II sensitivity. Furthermore, aldosterone production in Conn s adenoma in vivo relates to corticotropin secretion and this fact could question the autonomous nature of aldosterone secretion which would explain why plasma aldosterone may not always be persistently elevated in some patients with APA. 14 Aldosterone-to-renin ratio as a marker of inappropriate aldosterone activity A single random ARR greater than 1500 almost certainly indicates the presence of hyperaldosteronism. The issue is whether hyperaldosteronism varies in degree within the hypertensive population in general and whether ARR could also be a marker of this. It is known that, within the hypertensive population, the degree of plasma aldosterone suppression in response to salt loading is impaired compared with the normotensive population. 45 Beretta-Piccoli et al 46 reported that body sodium in hypertensive patients changed with age and correlated with blood pressure. Interestingly, these findings had some parallels with regard to ARR when applied to the hypertensive population. Komiya et al 47 observed that ARR related positively to age and plasma sodium concentration in 741 patients with essential hypertension, relationships which were not detectable using plasma aldosterone levels. 48 A recent study reported by Schlaich et al 49 involving young adults with mild hypertension suggested that there was a linear relationship between poor plasma aldosterone suppression with deterioration of left ventricular diastolic function in response to salt loading. This is consistent with the view that the blood pressure effect, 38,50 as well as cardiac adverse effects 51 of aldosterone are salt dependent, or are unmasked only in the presence of excess salt. As mentioned above, plasma aldosterone in itself does not correlate with blood pressure in hypertension. However, we have data that suggest that ARR does correlate with blood pressure in the hypertensive population. 52 In 119 (66 males) hypertensive subjects with mean age of 48 (s.d. 12) years assessed off drug therapy, ARR (log transformed) significantly and positively correlated with 24-h systolic ambulatory blood pressure (r = 0.22, P 0.05) and clinic systolic blood pressure (r = 0.19, P 0.05). As an indicator of inappropriate aldosterone activity the ARR may allow the effect of aldosterone on blood pressure to be evaluated and perhaps guide drug therapy. Aldosterone-to-renin ratio as a guide for drug therapy The PRA response to oral frusemide has been used to guide drug treatment in the past. 53 55 Further

156 studies however failed to consistently relate blood pressure lowering effect of many drugs; spironolactone, 56 thiazide diuretics, 57,58 nifedipine, 59 and methydopa 60 to renin status. ARR might be more reliable in this respect in isolating patients with inappropriate aldosterone activity who would respond favourably to aldosterone antagonists. Many patients with PA retain their renin responsiveness, thus the frusemide stimulation test, though specific, lacks sensitivity in detecting PA. This perhaps explains the above conflicting data. 61 We have treated with spironolactone 28 (12 males) hypertensive subjects with a mean age of 55 (s.d. 10) years and ARR greater than 750 who failed to suppress their plasma aldosterone in response to salt loading. 62 These subjects were followed up for a mean period of 12.9 (7) months. Spironolactone in doses of 25 to 50 mg significantly reduced the need for antihypertensive drugs by 0.5 (95% CI 0.1 to 1.0), P = 0.02, as well as reducing blood pressure (systolic blood pressure 15 mm Hg (CI 5 to 25), P = 0.007 and diastolic blood pressure (mm Hg) by 8 mmhg (CI 4 to 13), P = 0.001). Forty-eight per cent achieved blood pressure 140/90 mm Hg and 13/27 (48%) were treated with spironolactone monotherapy. Three patients complained of breast tenderness and only one patient was intolerant of spironolactone at the doses used. The favourable blood pressure lowering effects of spironolactone in hypertensive patients with a raised ARR has similarly been observed by others. 63 Nevertheless, the results of these observational studies will need to be confirmed in a larger randomised trial. The introduction of more specific mineralocorticoid receptor blockers will perhaps improve drug tolerance for this group of patients in the near future. 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