Prevalence and diagnostic workup of primary aldosteronism: new knowledge and new approaches

Not long after Conn1 first described primary aldosteronism (PAL) in 1955, the true prevalence of this new syndrome as a potentially curable cause of hypertension became a matter of considerable debate. Although Conn's original patient, a 34-year-old woman with a 4-cm right adrenal aldosterone-producing adenoma (APA), was severely hypokalaemic, he soon recognized that PAL could cause hypertension without hypokalaemia, and thereby masquerade as ‘essential hypertension’.2 By 1968 he was able to report 14 APAs removed from patients with normokalaemic PAL.3 These observations and the findings of others that (1) 21% of 48 hypertensive patients had suppressed plasma levels of renin4 and (2) 20% of 220 autopsied hypertensive patients had adrenal cortical adenomas compared with only 1.8% of 220 age- and sex-matched autopsied normotensive patients5 led Conn2,3 to propose that up to 20% of patients with so-called ‘essential hypertension’ may have PAL. However, this view was contested strongly, especially by Kaplan.6 He found low levels of aldosterone in cortical adenomas removed from patients with ‘essential hypertension’ compared with those from patients with PAL and a low incidence of PAL among normokalaemic hypertensive patients. Kaplan concluded that PAL accounted for less than 1% of hypertension and was not worth looking for unless patients were hypokalaemic. However, it is likely that Kaplan frequently overlooked the diagnosis of PAL because it was excluded in patients who failed to demonstrate elevated secretion or urinary excretion of aldosterone, levels of which were subsequently demonstrated to be within the normal range in many patients with PAL.7 Other studies reporting low prevalence rates for PAL may also have underestimated the true rate for various reasons including: (1) insistence on elevated urinary or plasma aldosterone levels;8 (2) insistence on unprovoked hypokalaemia;9 (3) reliance on National Register reporting rates;10 or (4) failure to take into consideration the capability of medications to produce false-negative tests, such as the ability of diuretics to elevate levels of plasma renin activity (PRA) or angiotensin II (AII) and cause false-negative plasma aldosterone–PRA ratios (ARR).11 Nevertheless, Kaplan's views became the consensus and, thereafter, were propagated in textbooks of medicine. Several key observations made in more recent times have led to a reappraisal of this dogma regarding the incidence of PAL and raised the possibility that Conn may, in fact, have been closer to the truth than his disputants. In 1981, Hiramatsu and co-workers12 reported the use of the ARR to detect and remove APAs from 9 (2.6%) of 348 ‘unselected’ hypertensive patients. Only three of the nine were hypokalaemic. Using only adrenal venography and scintigraphy to confirm the diagnosis, all cases of bilateral adrenal hyperplasia (BAH) and most APAs less than 1 cm would have been missed, suggesting an even higher prevalence. McKenna et al.13 reported recognition of 10 patients with PAL using a single ratio, six of whom had normal plasma aldosterone levels. After initially screening only those hypertensive patients with hypokalaemia, Gordon from the Greenslopes Hospital Hypertension Unit (GHHU) began, in 1990, to also apply the ARR to patients with resistant hypertension who were normokalaemic. The proportion found to have PAL among this group was so high (about 50%) that in 1991 it became the policy of the unit to screen all hypertensive patients, regardless of the presence or absence of hypokalaemia or the severity of the hypertension. This change in screening policy was associated with a 10-fold increase in the annual rate of detection of PAL, which exceeded 90 patients in 1995 and has remained over 70 ever since. Of the 790 patients who have so far been diagnosed by the unit as having PAL, only 30% were known to have been hypokalaemic up until the time of referral. The GHHU reported confirmation of PAL using fludrocortisone suppression testing (FST) in 17 (8.5%) of 199 normokalaemic hypertensive patients screened for PAL by ARR testing over a period of 8 months.14 Although these patients were ‘selected’, in that they had been referred to a hypertension unit, none was known to be hypokalaemic or was referred with the diagnosis of PAL in mind, and fewer than half were taking two or more antihypertensive medications at the time of presentation. Among a group of 52 patients who answered an advertisement for volunteers for antihypertensive drug trials, six (12%) were found to have persistently elevated ARR levels and PAL confirmed by FST.15 All six were normokalaemic. In a recent study reported by Brown et al.,16 2 (2.7%) of 74 hypertensive subjects who had been previously diagnosed as having essential hypertension and who underwent ARR testing were found to have PAL (confirmed by FST). In that study, antihypertensive medications were withheld for only 3 days before ARR measurement and, therefore, it is probable that patients with PAL who had been receiving long-term diuretic treatment up until this time would have been missed because in similar individuals, investigated in the GHHU, a reduced ratio (within the normal range) has sometimes been observed to persist for prolonged periods after cessation of these agents. Comparison of the results obtained in the two studies is further complicated by the fact that Brown et al. measured ratios in recumbent rather than upright patients and, based on values obtained in 147 apparently healthy volunteers, the upper limit of normal for the ratio was taken to be approximately twice used in the GHHU study in upright subjects. Nevertheless, the prevalence rate for PAL reported by these authors was still substantially greater than that which is generally accepted. In 1997, Young17 reported that the introduction of improved screening methodologies at the Mayo Clinic was associated with a ‘more than 10-fold’ increase in the rate of diagnosis of PAL over the preceding 5 years compared with that between 1960 and 1991. Lim and co-workers18 reported elevated ARR levels in 77 (15.5%) of 495 consecutive patients referred to their hypertension unit in Dundee, UK. PAL was confirmed in 40 of the 43 patients who were assessed further using fludrocortisone and salt loading, suggesting the ARR to be highly specific for PAL. When they applied the ARR to 125 hypertensive patients randomly selected from a UK family physician practice database, they found high levels in 18 patients (14.4%), most of whom probably had PAL.18 Loh et al.19 reported ARR levels to be elevated in 63 (18%) of 350 unselected hypertensive patients attending primary care clinics in Singapore. Only 13 of these 63 patients were hypokalaemic. Saline infusion testing, which was used to confirm PAL among 56 of those with elevated ratios, was positive in 16 patients, only six of whom were hypokalaemic. Based on these diagnostic criteria and results, the authors estimated a prevalence of PAL of at least 5% among the adult Asian hypertensive population. As discussed below, this figure would probably have been much higher if FST (rather than saline infusion testing, which demonstrated a high false-negative rate when assessed at the GHHU) had been used to establish the diagnosis. Whatever the true prevalence of PAL, it is clear that this condition is far more common than was previously thought and that most patients with PAL are normokalaemic and are therefore likely to be misdiagnosed as having ‘essential hypertension’ unless subjected to a specific screening test. An understanding of factors affecting aldosterone and renin secretion is a requisite for the correct interpretation of levels measured during a diagnostic workup for PAL. The major chronic regulator of aldosterone is plasma AII, which in turn is regulated by the plasma level of active renin. Renin levels are raised by manoeuvres that stimulate sympathetic nervous system activity, acting through beta-adrenoceptors on juxtaglomerular cells. Thus, renin levels rise in response to upright posture, hypovolaemia, fear and pain. Levels fall with recumbency, volume expansion and administration of β-adrenoceptor blocking drugs20 and drugs that interfere with sympathetic transmission, such as α-methyl-dopa21 and clonidine.22 Increases and decreases in body sodium status suppress and stimulate renin secretion, respectively, both through volume-dependent means and by varying sodium delivery to the macula densa. The brisk rise in renin that occurs after administration of calcium channel blockers, particularly those of the dihydropyridine variety,22 may result from reflex sympathetic stimulation, natriuretic effects or from direct effects on calcium-dependent renin regulatory pathways induced by these agents. Renin (and aldosterone) levels, in continuously recumbent subjects follow a circadian rhythm that peaks between 02.00 h and 08.00 h and demonstrates a trough between 12.00 h and 18.00 h.23,24 Although of relatively modest amplitude, this rhythm can influence the response of renin and aldosterone to other factors, such as upright posture, which shows its greatest effect on first awakening in the morning.23 These observations dictate that for normal ranges to be established, samples should always be collected at the same time of day and after the same length of time in a particular posture and that the effects of dietary salt intake and antihypertensive medications should be taken into account. Potassium plays an important chronic positive regulatory role in aldosterone secretion, and hypokalaemia should be corrected before the diagnosis of PAL is excluded on the basis of normal ARR levels or normal suppression of aldosterone during FST. The stimulatory effect of adrenocortrophic hormone (ACTH) on aldosterone is probably only short-lived but nevertheless needs to be borne in mind when evaluating aldosterone responses to various manoeuvres. Demonstration of falling morning cortisol levels helps exclude an acute rise in ACTH (e.g. induced by stress) as being the predominant stimulus for aldosterone levels to rise on moving to an upright posture or during AII infusion, or to remain above the threshold of normal suppression during FST. Negative regulators of aldosterone, which include atrial natriuretic peptide25 (levels of which are increased in PAL26) and dopamine,25 could, in theory, also exert influences sufficient to interfere with interpretation of test results during the diagnostic workup of PAL. Further work in this area would be worthwhile. The plasma ARR is widely regarded as the being the most reliable available screening test for PAL.13,17,27 However, both false-positive and false-negative results can occur (see Table 1 for list). β-Adrenoceptor blocking agents,20α-methyl-dopa21 and clonidine28 tend to suppress renin to a greater extent than aldosterone, presumably because of the continuing effects of potassium and ACTH on aldosterone secretion. Therefore, they frequently cause false-positive ARR levels. In patients with renal impairment, renin levels tend to fall in response to reduced renin-secretory mass and to salt and water retention, whereas any associated hyperkalaemia will tend to elevate aldosterone, making false-positive ARR results common in this condition.13 False-negative plasma ARR results may be encountered among patients with PAL who are hypokalaemic or in the presence of coexisting conditions that release plasma renin activity (PRA) from chronic suppression (such as severe dietary salt restriction, renovascular hypertension,29 pregnancy30 and malignant hypertension31) and in patients treated with diuretics17 or dihydropyridine calcium channel antagonists.27 In a study by Nakamura and co-workers26 some patients with PAL demonstrated renin levels that remained unsuppressed for at least 6 days after withdrawal of spironolactone. Our own experience suggests that PRA can remain unsuppressed and ARR levels within the normal range for several weeks after cessation of chronic diuretic (including spironolactone) treatment in patients with PAL. Cappuccio and colleagues22 reported sustained rises in PRA (but not plasma aldosterone) in patients administered amlodipine, which were still apparent 3 days after withdrawing this drug. Renin levels may rise modestly after commencement of verapamil (a non-dihydropyridine calcium antagonist)32 or hydralazine33 (which is associated with reflex sympathetic stimulation) but, in our experience, rarely to an extent that significantly affects the ARR. Most studies have found no significant effect of prazosin on plasma aldosterone or renin levels.33 Whereas angiotensin-converting enzyme (ACE) inhibitors usually increase PRA significantly, and often to very high levels, in patients without PAL, they appear to be much less able to stimulate PRA and, thereby, cause a false-negative plasma ARR in patients with PAL.34 Early experience with AII receptor antagonists suggests that they may produce similar effects, and it is probably safest to assume that they are capable of causing false-negative ARR results until such time as more definitive information becomes available. At the GHHU, hypokalaemia is corrected by potassium supplements and patients are advised to maintain a liberal dietary salt intake prior to ARR testing and throughout the subsequent diagnostic workup for PAL. Diuretics are ceased for at least 4 weeks and β-adrenoceptor blockers, α-methyl-dopa, clonidine and dihydropyridine-type calcium channel antagonists are withheld for at least 2 weeks before ARR testing, substituting other agents (such as hydralazine, prazosin or slow-release forms of verapamil) that have a lesser effect on the ratio in order to maintain control of hypertension. However, useful information can sometimes be obtained even when patients are still taking medications known to interfere. For example, a raised ARR in a patient taking a diuretic or dihydropyridine calcium channel blocker is strongly suggestive of PAL, whereas a normal ARR in a patient taking a β-adrenoceptor blocker would render the diagnosis highly unlikely. At the GHHU, blood is collected for ARR measurement mid-morning from patients who have been seated for at least 10 min after 2–4 h of upright posture (sitting, standing or walking; Table 2). If measured mid-morning in ambulant patients on uncontrolled diets, it would be expected to be most sensitive for AII-responsive forms of PAL (most patients with BAH and all with AII-responsive APA35). On the other hand, in the early morning after overnight recumbency, when ACTH levels are higher and PRA and AII levels lower than later in the morning after changing to an upright posture, the plasma ARR should be most sensitive for AII-unresponsive forms (AII-unresponsive APA and The AII-responsive approximately of patients with PAL in our and AII-unresponsive APA (which up most of the in our experience, generally associated with higher ARR levels than in other forms of PAL and, therefore, less likely to be As a have found that a mid-morning upright is for screening to an recumbent and, in it is more these an ARR of greater than aldosterone in PRA in is regarded as raised and suggestive of PAL. of PAL the of aldosterone that is other aldosterone that is of its normal chronic At the GHHU, PAL is confirmed using FST. In this failure of upright plasma aldosterone to suppress to less than 6 during administration of fludrocortisone 6 and slow-release sodium three times with is regarded as (1) upright PRA on day 4 is suppressed to less than 1 and (2) of plasma cortisol levels at h and h on day 4 not the of an acute rise in ACTH which may have suppression of the slow-release potassium is in sufficient to plasma potassium at h and within the normal thereby the possibility of a missed diagnosis to suppression of aldosterone or a false-positive FST to of aldosterone by The of a dietary salt intake of at least 3 (confirmed by urinary sodium helps that suppression of is and is by having the patient a within h of because often hypertensive patients have previously on a as of their and PAL in patients urinary aldosterone levels, measured in a obtained on the day of a sodium excretion with potassium to maintain use saline infusion such as 2 over 4 with plasma aldosterone levels at the of the infusion of more than 10 being regarded as This has the of only a However, at the GHHU, saline infusion only 17 of patients confirmed as having PAL using FST and only 3 of 10 patients who were subsequently of PAL after In of to urinary aldosterone levels measured in obtained on the day of the FST the detection of of patients with a positive FST and 8 of 10 subsequently by at the of the of work is to to definitive for patients with PAL on the of work in order to the In of PAL by the of an and hypertension are with the administration of in (e.g. of that not cause of hypertension is highly in with some patients severely hypertensive from whereas others remain normotensive into testing for the presence of the in blood using a described by et or a at the has the diagnosis of the of only a single blood which can be as blood or to a this The of sustained suppression of plasma aldosterone during administration of 6 is the most reliable being highly sensitive and specific for However, this test or and blood over several and is not without and At GHHU, the of patients with PAL have for the and further to between forms associated with adrenal of aldosterone, which may be curable by and those associated with bilateral The only reliable to this is by adrenal the of this has been by its in particularly with to of the right adrenal Therefore, many on adrenal with or For example, at the Mayo is the primary means by which APAs are is for selected such as those in which the is or or in patients over the of 40 years in whom the of an adrenal may be less clear than in However, from in the of APAs and can be in patients with PAL, not all mass in this may be At the GHHU, using to in only of patients with APA diagnosed with PAL between and than a of APAs less than 1 cm in which accounted for half of APAs were and was in 10 patients, a or probable mass in the but not the adrenal aldosterone levels demonstrate normal to upright posture and to AII infusion in most patients with BAH but not in those with AII-unresponsive However, these manoeuvres BAH from AII-responsive a of APA first described by the GHHU in and which for over half of all APAs removed by the urinary levels of the and which are usually elevated in patients with AII-unresponsive APAs but not in patients with are usually normal in patients with AII-responsive Thus, these patients masquerade as BAH but, those with AII-unresponsive can be of In the Greenslopes Hospital is in all patients with PAL of by in order to BAH from and to APAs the all patients which has useful in the adrenal and will detect any that may based on the of are in by in an to patient and effects of on hormone is in the morning after overnight to the effects of in posture on aldosterone levels in patients with AII-responsive of PAL and to take of the effect of ACTH on aldosterone in all of samples are collected from of the right and adrenal by a highly in this so as to the of and a is collected with adrenal of adrenal venography helps the of adrenal associated with of all at of is assessed by the between adrenal and cortisol levels, with of at least 3 of between 2 and 3 may useful but those with of less than 2 should always be excluded from further consideration when evaluating An on only the but an as to the adrenal is suppressed with but not diagnostic of or significant of aldosterone with APA or The right adrenal is often to and than the as it is usually and more often to into the rather than the renal and is more in However, at Greenslopes the right adrenal rate has improved over the in of both adrenal was in of the patients who had this as of their diagnostic workup between and for this high rate include the high and experience, the use of only two and insistence on the of more than from adrenal rates of of of and right adrenal during adrenal for at the Greenslopes Hospital Hypertension was regarded as being if samples demonstrated an cortisol of at least in the to which samples are with blood are corrected for by the ratio for care is in the measurement of aldosterone and cortisol levels in adrenal because may be very high and in and may have a major effect on If adrenal is the aldosterone will be suppressed on that to suppression of renin. The ratio on that will be the same as or less than If the ratio on is significantly least two higher than the ratio, with a ratio no higher than on the other the study is to that should or the hypertension. Hypertension is in the of these patients and significantly improved in all of the The to a and a than the The GHHU FST as a means of a has been or is aldosterone by the Although only of patients were after the the were with much lower aldosterone and much higher PRA In patients with PAL, hypertension to the introduction of or in (e.g. and For patients in whom aldosterone not on treatment with or can be without by using low initially and these medications measured in to demonstrate treatment is also for patients in whom results but who for those to be an high or those who would from a period of control of their hypertension prior to by the or associated with FST and have these in patients with a high to a of treatment with an aldosterone and such testing for those who to However, this to take into the of effects (including hyperkalaemia and renal associated with aldosterone treatment and the and associated with treatment in those patients the of a In our experience, patients who a or a improved hypertension control after are for the in their of by the In the of the ARR to a of hypertensive patients has led to a increase in detection of PAL and the recognition that PAL is common in most normokalaemic patients. These findings strongly for the screening of all hypertensive patients for PAL, regardless of plasma potassium This would that patients with less normokalaemic are not overlooked and of specific the of which a to definitive testing and