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(Hypertension. 2002;39:935.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Diagnostic Value of the Post-Captopril Test in Primary Aldosteronism

Oscar L. Castro; Xichun Yu; David C. Kem

From the Department of Medicine, University of Oklahoma, and Veterans Administration Medical Center, Oklahoma City, Okla.

Correspondence to David C. Kem, MD, 3E107 (111B4), 921 NE 13^th Street, Oklahoma City, OK 73104. E-mail david-kem{at}ouhsc.edu

	Abstract

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Primary aldosteronism is a disorder with hypertension, hypokalemia, increased plasma aldosterone, and suppressed renin activity. A random plasma aldosterone/renin activity (PA/PRA) >65 (conventional units ratio [CUR] >30) has been proposed as a screening test. We have retrospectively determined the value of the post-captopril plasma aldosterone/renin activity (CAPT PA/PRA) test for the diagnosis of patients with primary aldosteronism whose PA/PRA was <65. We considered the CAPT PA/PRA test to be positive for primary aldosteronism if either the plasma aldosterone concentration did not drop below 0.33 nmol/L (12 ng/dL) or the ratio was >26 (CUR >12). We found 6 patients with a random PA/PRA of 21 to 60 (CUR 10 to 28), yet with an abnormal post-captopril test criteria for primary aldosteronism. Five had an abnormal saline suppression test, and all 6 were confirmed by a combination of diagnostic localization with computerized axial tomography, iodocholesterol scan, adrenal venous sampling, and/or surgery. Four had idiopathic adrenal hyperplasia, and 2 had an aldosterone-producing adenoma. One other patient had an abnormal random plasma aldosterone/renin activity ratio of 99 (CUR 46), a negative saline infusion study, and was determined to have essential hypertension. In summary, the CAPT PA/PRA, but not the random PA/PRA, correctly diagnosed 6 patients with primary aldosteronism in our institution. An additional patient with essential hypertension was incorrectly diagnosed as having primary aldosteronism by the PA/PRA test. We conclude that the simple addition of 25 mg of captopril, taken orally 2 hours before sampling, enhances the accuracy for diagnosing patients with primary aldosteronism.

Key Words: adrenal gland • hyperaldosteronism • renin • captopril • diagnostic testing

	Introduction

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Primary aldosteronism is a disorder characterized by hypertension, spontaneous hypokalemia, increased plasma aldosterone (PA), and suppressed plasma renin activity (PRA) and is often refractory to conventional medical treatment. Prevalence estimates in the past for primary aldosteronism have varied from 0.05% to 3% of the population with hypertension. Two groups working independently^1,2 reported that administration of captopril 2 to 3 hours before measuring the plasma PA/PRA (CAPT PA/PRA) response to acute blockade of renin/angiotensin II was helpful in confirming the diagnosis of primary hyperaldosteronism. The CAPT PA/PRA concentration was proposed as a simple tool for establishing a specific diagnosis of primary aldosteronism. Although these studies failed to demonstrate it to be useful for differentiating between an aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH), it was found to be quite specific for its original purpose of establishing the primary diagnosis. This was accomplished by comparing the CAPT PA/PRA test results to an accepted sodium loading "gold standard" test using saline suppression.

Since that time, several groups have proposed use of a random nonstimulated plasma aldosteronism/renin activity ratio (PA/PRA) with a range of values from 43 to108 (CUR 20 to 50) as a useful screening test for primary aldosteronism. This has become a popular approach and has been advocated by a number of authorities.^3–9 However, there are several drawbacks to this approach including the following: (1) the PA/PRA ratio alone is not regarded as a specific test and therefore a second, more specific test is recommended for confirmation;^10,11 (2) the ratio alone may vary considerably; and (3) preparation of the patient for both studies is generally recommended and/or required for consistent results. We have examined the PA/PRA ratio before and after captopril administration during the course of evaluation of our hypertensive patients at the University of Oklahoma Health Sciences Center.

	Methods

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We reviewed all random PA/PRA and CAPT PA/PRA studies available to us in patients suspected of having primary aldosteronism. During this retrospective analysis of data from our university and Veterans Administration Medical Center Endocrinology and Hypertension Clinics, 6 patients had a baseline PA/PRA ratio of less than 65 (CUR 30), and therefore, a diagnosis of primary aldosteronism would have been excluded on the basis of this value alone. Their subsequent CAPT PA/PRA test ratio indicated a diagnosis of primary aldosteronism. These patients had a 5- to 7-year history of elevated blood pressure and occasional hypokalemia. An additional patient was initially believed to have primary aldosteronism on the basis of an elevated random PA/PRA ratio but was subsequently demonstrated to have a diagnosis of essential hypertension. The present study examines the details of these patients’ diagnoses and compares the usefulness of the CAPT PA/PRA test with that of the PA/PRA ratio for the diagnosis of primary aldosteronism.

Our protocol for both the random and the CAPT PA/PRA tests involves discontinuation of all medications known to affect the plasma PA/PRA level for a minimum of 1 week before study, except for potassium supplements and 1 blockers or clonidine. Spironolactone had not been taken by any patient for at least 3 months. The baseline PA/PRA ratio and a subsequent captopril suppression test (PA and PA/PRA ratio 2 hours after 25 mg of oral captopril) were obtained in all patients. The PA/PRA ratio is expressed in SI units for this journal. This ratio is also calculated using conventional units (provided in parentheses) because several of the cited publications use the CUR for their calculated ratios. Saline infusion studies were performed on 5 of the patients as previously described for confirmation of the diagnosis.¹²

Etiologic distinctions between APA and IAH were subsequently made using a combination of computerized axial tomography (CAT) scan, NP59 iodocholesterol imaging, adrenal venous sampling, and/or surgery.¹³

Permission to review the patients’ records was obtained from the University of Oklahoma Health Sciences Center Institutional Review Board.

	Results

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Our institutions include the Veterans Administration Medical Center and University of Oklahoma Hospitals Endocrinology and Hypertension Clinics. There was no specific hypertension registry, but our fellows average 90 to 100 hypertensive evaluations per year, and a review of our records indicates 36 PA/PRA ratios were obtained last year. Last year, 8 patients were newly diagnosed with primary aldosteronism, 2 having surgery for resection of an APA and the remainder having IAH. For previous years, the number of patients screened for primary aldosteronism by PA/PRA or CAPT PA/PRA testing averaged less than 20, and we identified only 2 to 3 patients per year with primary aldosteronism during this period. Approximately 200 to 220 patients were evaluated for a diagnosis of primary hyperaldosteronism during the previous 7-year period. A diagnosis of primary aldosteronism was established in 18 to 20 of these patients, who were either referred specifically for this diagnosis or were screened for this entity on the basis of intermittent or sustained hypokalemia and hypertension.

The clinical laboratory data for each of the 7 patients identified in this retrospective study are shown in Table 1. It is apparent that hypokalemia was prevalent, and sometimes marked, in these patients. The individual baseline PA, PRA, and PA/PRA ratios before and after CAPT for these patients are shown in Table 2. The PA/PRA ratio of patient 16 was 99 (CUR 46), and the baseline PA was 0.38 nmol/L. The PA/PRA ratios in the other 6 patients were less than 65, including 3 who were 54 (CUR 25) or less. All would be considered to have a negative or questionable screening test for primary aldosteronism depending on the cutoff employed for the PA/PRA ratio. We have chosen the 65 ratio as a cutoff value as recommended by Weinberger et al⁵ because this represents a relatively conservative value that is used by a number of other investigators. Each patient was subsequently identified as having primary aldosteronism based on a positive 2-hour CAPT PA/PRA ratio >26 and a post-captopril plasma aldosterone concentration >0.33 nmol/L. These data are shown in Table 2 and in Figure 1. Patient 16, with an elevated PA/PRA ratio suggesting a diagnosis of primary aldosteronism, had a normal post-captopril study and subsequent confirmation by a negative saline infusion test. It was determined that his mild intermittent hypokalemia was associated with concomitant diuretic administration. He therefore had an established diagnosis of essential hypertension. Five of the other 6 patients had a saline infusion test that was confirmatory of the diagnosis of primary aldosteronism (Table 3). The other patients had a combination of diagnostic studies (Table 4) leading to a definitive diagnosis of either an APA or IAH.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics in Patients With Hypertension and Hypokalemia at the Time of Presentation

View this table: [in this window] [in a new window]   Table 2. Basal and Post-Captopril (CAPT), PA, PRA, and PA/PRA Ratios

View larger version (10K): [in this window] [in a new window]   Plasma aldosterone concentration and plasma aldosterone to plasma renin activity ratio (PA/PRA) at baseline (open symbols; different shapes identify each patient in Table 2) and 2 hours after ingestion of 25 mg captopril (closed symbols) in the 7 patients. The top line (- - -) is the critical ratio for interpretation of the basal data (PA/PRA <65) and the bottom line () for interpretation of the CAPT PA/PRA data (<26).

View this table: [in this window] [in a new window]   Table 3. Results of Saline Infusion Test

View this table: [in this window] [in a new window]   Table 4. Localization Studies

	Discussion

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Several recent reviews of primary aldosteronism have recommended the use of the PA/PRA ratio obtained under a variety of conditions to screen for patients likely to demonstrate this entity.^10,11 Different cutoff levels for the ratio have been proposed, and variable results have been reported (Table 5). Most authors recommend that the diagnosis be confirmed using one of several "gold standard" tests that have been developed over the years. Weinberger, however, recommends that a PA/PRA ratio >65 with an absolute PA >0.42 nmol/L does not need a confirmatory study.⁵ These confirmatory tests include aldosterone/renin profiling,¹⁴ use of deoxycorticosterone or fludrocortisone¹⁵ and/or high sodium intake for 3 days,¹⁶ rapid infusion of 2 L of normal saline for 4 hours after a brief upright period,¹² or saline followed by furosemide diuresis.¹⁷ In 1983, we compared the use of the PA/PRA ratio obtained 2 hours after a dose of captopril with results obtained using the "gold standard" saline infusion.² We found that the acute suppression of aldosterone and removal of any negative feedback on circulating levels of renin using the CAPT PA/PRA ratio were as efficacious as the more cumbersome infusion of saline over a 4-hour period. Since that time, some investigators have reported either no improvement in the diagnostic value of the post-captopril test or a slight decrease in its sensitivity compared with a variety of other tests.^7,8 Thibonnier et al, ¹ however, found an increase in sensitivity after administration of captopril compared with the baseline PA/PRA ratio. Unfortunately, there are potential difficulties in interpreting several of these studies because of differences in their experimental designs. Recently, Agharazii et al¹⁸ published a detailed comparison of the captopril test and 3 days of high-salt loading in 49 patients with a presumed diagnosis of primary aldosteronism. These investigators demonstrated that the captopril test is as efficacious in confirming the diagnosis as is the "gold standard" test of 3 days of oral salt loading. Thus, the captopril-stimulated PA/PRA ratio has been now confirmed using 2 different "gold-standard" salt-loading tests.^2,18

View this table: [in this window] [in a new window]   Table 5. Random Morning PA/PRA Cutoff Values Proposed by Other Authors

Using criteria suggested by others to screen patients for primary aldosteronism, we have found 6 patients in a retrospective study whose final diagnosis of primary hyperaldosteronism was based on specific criteria, including the captopril suppression test, but who were incorrectly diagnosed using only the PA/PRA ratio. In addition, we found 1 patient whose PA/PRA screening test suggested a diagnosis of primary aldosteronism, yet who turned out to have essential hypertension on further testing. This was a retrospective study, and no registry was in place during this time interval to allow us to compare estimates of the sensitivity of the PA/PRA ratio with and without CAPT.

We believe the PA/PRA screening test lacks precision because of its inordinate dependence on the reliability and reproducibility of the PRA determination as the denominator of the ratio. As an example, the mean±2 SD for a commercially available low PRA standard is 0.015±0.006 nmol/L per minute. If a patient has a PA value of 0.42 nmol/L and such a low PRA, the PA/PRA ratio would vary from 27 to 65 depending only on the reported PRA determination. It is well established that PRA values <0.026 nmol/L per minute have such variation in most assays.

The specificity of the CAPT PA/PRA test is more dependent on demonstrating that the post-captopril PRA is relatively fixed, despite the loss of the inhibitory levels of angiotensin II (Ang II), and the PA fails to be suppressed to less than a definable level (<0.33 nmol/L). These data support the use of the CAPT PA/PRA test when PA and PRA values are near the normal range. If the PRA rises significantly, it is not fixed or suppressed and would therefore be considered "normal." At the same time, if the PA drops below the established absolute criterion, its dependency on circulating Ang II is probable and a diagnosis of primary aldosteronism is unlikely. Thus, it would seem likely that the simple addition of 25 mg of oral captopril and obtaining the PA/PRA ratio 2 hours later will provide a definitive diagnosis of primary aldosteronism in the majority of patients without the need for an additional confirmatory test at a later date.

The reproducibility of the CAPT PA/PRA test has not been rigorously tested in a significant number of patients or volunteers. To date, we have not observed any falsely positive studies. One patient with an abnormal CAPT PA/PRA ratio, an adrenal adenoma on computed tomography (CT), and a negative urinary metanephrines study was found unexpectedly at surgery to have a pheochromocytoma. An elevated urinary vanillylmandelic acid (VMA), taken at the same time as the metanephrines, had not been reported before the time of surgery. Our concern that this was a falsely positive CAPT PA/PRA test was relieved when subsequent evaluation demonstrated an abnormal saline infusion test and a persistently abnormal CAPT PA/PRA test. It was concluded that the patient had IAH and a concurrent pheochromocytoma. We have observed one patient with a "negative" CAPT PA/PRA test (the original criteria required a ratio of >108 [CUR>50] and an absolute PA value >0.42 nmol/L [>15 ng/dL])² to have primary aldosteronism using our current CAPT PA/PRA criteria. This patient has a borderline-abnormal saline infusion test (post-saline PA of 0.22 nmol/L (8 ng/dL).

The recent use of the PA/PRA ratio in 2 studies that have suggested a prevalence of primary aldosteronism of up to 10% of the hypertensive population is provocative.^19,20 Both studies used fludrocortisone over 3 days to suppress PA as the "gold standard" confirmatory test. The captopril-PA/PRA test has not been compared directly with the fludrocortisone "gold standard" test, and this would be of interest because use of a single test, such as the captopril-PA/PRA test, would simplify such studies in at-risk populations. Several of the patients were referred to us with a possible diagnosis of primary hyperaldosteronism based on outside laboratory tests or by demonstrated hypokalemia. The diagnostic testing was therefore directed toward patients more likely to have such a diagnosis than would be found in the general hypertensive population. Thus, we cannot provide a reasonable estimate of the frequency of this diagnosis in our clinic population. Such a study has just been initiated in our institution and will require 2 years for completion based on current power estimates.

In conclusion, we believe there is evidence that a significant number of patients with primary aldosteronism will be either misdiagnosed or inconclusively diagnosed using a morning random PA/PRA ratio with cutoff values of 54 or 65. The simple addition of 25 mg oral captopril 2 hours before obtaining a second set of blood samples, therefore, not only serves as a screening test but also establishes a definitive diagnosis of primary aldosteronism. Finally, this test saves time and money and leads directly to definitive studies localizing the lesion.

Received November 30, 2001; first decision January 16, 2002; accepted February 8, 2002.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Castro, O. L. Articles by Kem, D. C. Search for Related Content PubMed PubMed Citation Articles by Castro, O. L. Articles by Kem, D. C. Related Collections Clinical Studies Other diagnostic testing