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Caution About the Overdiagnosis of Primary Aldosteronism

  • Norman M. Kaplan
    Correspondence
    Address reprint requests and correspondence to Norman M. Kaplan, MD, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235–8899
    Affiliations
    University of Texas Southwestern, Medical Center at Dallas
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      Montori and colleagues
      • Montori VM
      • Schwartz GL
      • Chapman AB
      • Boerwinkle E
      • Turner ST
      Validity of the aldosterone-renin ratio used to screen for primary aldosteronism.
      begin their article in this issue of the Proceedings by stating, “Primary aldosteronism may be more common in patients with presumed essential hypertension than previously thought.” Whereas the consensus had been that primary aldosteronism was present in less than 1% of all patients with hypertension,
      • Kaplan NM
      Commentary on the incidence of primary aldosteronism: current estimations based on objective data.
      a steady stream of articles, many written by Stowasser
      • Stowasser M
      Primary aldosteronism: rare bird or common cause of secondary hypertension?.
      from Brisbane, Australia, has reincarnated Conn's original claim
      • Conn JW
      Plasma renin activity in primary aldosteronism: importance in differential diagnosis and in research of essential hypertension.
      that primary aldosteronism could be present in 20% of patients.
      Most of the recent high estimates of the prevalence of primary aldosteronism derive from the application of the plasma aldosterone-renin ratio, based on the known excess of plasma aldosterone concentration (PAC) and the subsequent suppression of plasma renin activity (PRA) that are seen in patients with this disease. The premise underlying this test is based on autonomous hypersecretion of aldosterone, from either a solitary adenoma or bilateral adrenal hyperplasia, totally independent of the usual control exerted by the renin-angiotensin mechanism. The suppression of PRA occurs as a consequence of the hyperaldosteronism that causes volume expansion and elevated blood pressure, which in turn inhibit release of renin from the juxtaglomerular cells in the kidneys. The aldosterone-renin ratio combines the measurement of aldosterone and renin into a single value that is intended to magnify the autonomous nature of aldosterone in patients with primary aldosteronism.
      Montori et al provide data from a meticulous study of 497 patients previously diagnosed as having essential hypertension who had aldosterone-renin ratios measured under different conditions: supine before diuretic therapy, seated before diuretic therapy, and seated after diuretic therapy. Their purpose was to determine whether the aldosterone-renin ratio provides a measure of hyperaldosteronism that is totally independent from plasma renin levels, a relationship that must hold true if an elevated aldosteronerenin ratio is to serve as a marker for primary aldosteronism.
      Their data clearly show that the aldosterone-renin ratio is dependent on variations in PRA levels; thus, “elevation of the aldosterone-renin ratio was predominantly a sign of low PRA, rather than a measure of elevated PAC relative to PRA.” Montori et al note further that “elevation of the aldosterone-renin ratio … can be more appropriately characterized as an indication of low PRA … than as a sign of an inappropriately elevated PAC.”
      The study by Montori et al may have included some patients with unrecognized primary aldosteronism since no details were provided about the certainty of the diagnosis of “essential hypertension.” Moreover, one of the principal findings, that the aldosterone-renin ratio decreased after diuretic therapy (shown in their Figure 2), could reflect a suppression of aldosterone secretion due to the degree of diuretic-induced reduction in serum potassium.
      Neither of these possibilities negates the major findings of Montori et al. However, these data do not, by themselves, negate the value of the aldosterone-renin ratio as a screening test for primary aldosteronism if, as Montori et al point out, there is a requirement for an absolute elevation in PAC. Unfortunately, most recent studies that use the aldosterone-renin ratio simply require an elevated ratio without regard for the necessity of an elevated PAC.
      Many patients with hypertension, particularly elderly or black patients or those with renal damage, have extremely low PRA levels, often as low as 0.1 ng·mL−1·h−1. Obviously, such a low PRA with even a low PAC of 5 μg/dL would produce a high aldosterone-renin ratio. Therefore, the major clinical message of the analysis by Montori et al must be to demand both a low PRA and a high PAC. As Stewart
      • Stewart PM
      Mineralocorticoid hypertension.
      noted, the better approach would be to express the data as a subnormal PRA and an elevated PAC rather than as a ratio.
      As I have written previously,
      • Kaplan NM
      Cautions over the current epidemic of primary aldosteronism.
      numerous reasons exist for being cautious about the current epidemic of primary aldosteronism. Since the enthusiasts
      • Stowasser M
      Primary aldosteronism: rare bird or common cause of secondary hypertension?.
      claim that neither hypertension nor hypokalemia is necessarily seen in patients who presumably have primary aldosteronism, promiscuous and misguided overuse of the aldosterone-renin ratio could lead to unnecessary work-ups that are expensive, possibly harmful, and sometimes misleading. Moreover, more patients likely have adrenal “incidentalomas” than aldosterone-producing adenomas; thus, there is a strong possibility of unnecessary surgery if an elevated aldosteronerenin ratio is the only basis for the diagnosis. Finally, the largest proportion of patients with an elevated aldosteronerenin ratio who are subsequently found to have autonomous hyperaldosteronism have bilateral adrenal hyperplasia that must be treated medically, rather than an aldosterone-producing adenoma in which surgery is usually appropriate.
      All in all, I believe the data from Montori et al should help squelch some of the current overenthusiasm in diagnosing primary aldosteronism that is based on inappropriate use and interpretation of the aldosterone-renin ratio.

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        Validity of the aldosterone-renin ratio used to screen for primary aldosteronism.
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        Commentary on the incidence of primary aldosteronism: current estimations based on objective data.
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        Primary aldosteronism: rare bird or common cause of secondary hypertension?.
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        Plasma renin activity in primary aldosteronism: importance in differential diagnosis and in research of essential hypertension.
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        Mineralocorticoid hypertension.
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        Cautions over the current epidemic of primary aldosteronism.
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