This Article Abstract Full Text (PDF) All Versions of this Article: 91/7/2618    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted 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 Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mulatero, P. Articles by Maccario, M. Search for Related Content PubMed PubMed Citation Articles by Mulatero, P. Articles by Maccario, M. Related Collections Adrenal and Hypertension Endocrine Oncology

Comparison of Confirmatory Tests for the Diagnosis of Primary Aldosteronism

Division of Internal Medicine and Hypertension (P.M., A.M., F.V.), University of Torino, 10133 Torino, Italy; Division of Internal Medicine 3 (F.F.), University of Padova, 35128 Padova, Italy; Division of Internal Medicine (G.R.), Reggio Emilia Hospital, 42100 Reggio Emilia, Italy; Division of Internal Medicine B (F.P.), University of Verona, 37134 Verona, Italy; Division of Endocrinology (C.F., L.Mo.), P. Universitad Catolica de Chile, 114D Santiago, Chile; and Division of Endocrinology and Metabolism (L.Ma., F.V., M.M.), University of Torino, 10126 Torino, Italy

Address all correspondence and requests for reprints to: Paolo Mulatero, M.D., Centro Ipertensione Ospedale San Vito, Strada San Vito 34, 10133, Torino, Italy. E-mail: paolo.mulatero{at}libero.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Primary aldosteronism (PA) is the most frequent form of secondary hypertension, accounting for up to 5–10% of all hypertensive patients, and the diagnosis of PA can present an important challenge for the clinician. After a positive screening test, the diagnosis is confirmed by a suppression test, often an iv saline load test (SLT) or a fludrocortisone suppression test (FST). The FST is considered by many to be the most reliable but is more complex and expensive.

Objective and Design: Our objective was to compare the specificity of SLT with FST for the diagnosis of PA.

Patients and Setting: The study included 100 hypertensive patients referred to hypertension units with suspected PA after the screening test.

Intervention: All patients underwent FST and SLT.

Main Outcome Measures: We assessed plasma aldosterone concentrations (PAC) before and after FST and SLT.

Results: After iv SLT, 10.4% of the PA patients were negative and 16.1% of patients with essential hypertension were positive after SLT; that is, a correct diagnosis with SLT was obtained in 88% of patients compared with FST. PAC after SLT and PAC after FST were highly correlated (P < 0.0001). Receiver operator characteristic curve analysis demonstrated that the best cutoff for PAC after SLT was 5 ng/dl. Patients with aldosterone-producing adenoma displayed a smaller reduction of PAC compared with patients with bilateral adrenal hyperplasia; a PAC after SLT greater than 6 ng/dl identified all patients eventually diagnosed as having aldosterone-producing adenoma.

Conclusions: This study demonstrates that the iv SLT is a reasonably good alternative to the more expensive and complex FST for the diagnosis of PA after a positive screening test.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
PRIMARY ALDOSTERONISM (PA) is the most frequent form of secondary hypertension, accounting for up to 5–10% of all hypertensive patients (1). The rate of diagnosis of PA has dramatically increased after the widespread use of the plasma aldosterone concentration (PAC)/plasma renin activity (PRA) ratio as a screening test (2). The diagnosis of PA is an important challenge for the clinician because it has been recently demonstrated that patients with PA exhibit a higher rate of cardiovascular complications compared with matched essential hypertensives (3). It should be emphasized that an increased PAC/PRA ratio is not by itself a diagnosis of PA; a suppression test should always be performed to demonstrate that the aldosterone secretion is inappropriate for a high-salt diet and not normally suppressible; in fact, between 30 and 50% of patients with a positive PAC/PRA ratio will display aldosterone levels that are normally suppressed after confirmatory testing (1, 4, 5). The most widely used tests are the saline load (either oral or iv) and the fludrocortisone suppression test (FST), the latter of which is considered by some authors the most reliable test for the confirmation of PA (1, 6, 7). A third possibility is the oral saline load, which consists of the administration of salt supplementation for 3 d followed by urinary aldosterone and sodium measurements on the third day (patients are considered positive if urinary aldosterone is >12 µg/d and sodium is >200 mmol/d) (1, 6). The iv saline load test (SLT) is generally preferred to FST because it does not require hospitalization and therefore costs less and is more easily performed; in fact, FST requires 4-d hospitalization and the consumption of fludrocortisone tablets together with salt and potassium supplementation (1, 6, 7). Hypokalemia is frequent during FST, and so potassium levels need to be checked at least twice per day during the test and the doses of potassium supplementation adjusted to maintain normokalemia. Fludrocortisone with salt has been reported by Lim et al. (8) to be potentially responsible for adverse cardiac effects; however, that study used a much higher dose of fludrocortisone (1.5 mg/d) and salt (480 mmol/d) compared with the widely accepted protocols for FST (0.4 mg/d and 90 mmol/d, respectively). Finally, only small doses of potassium supplements were used, which may have been insufficient in many patients to prevent potassium loss.

Saline load requires only a 4-h infusion of 0.9% NaCl solution (1, 2, 9) but carries a potential risk for acute volume overload, especially in individuals rendered predisposed by preexisting left ventricular or renal dysfunction. Furthermore, SLT can potentially promote potassium wasting, which is usually not monitored during this test. To the best of our knowledge, only one study over 20 yr ago compared the two tests in patients with suspected PA (10). However, in that study, the FST was performed using more than double the dose that is currently suggested as ideal for the correct application of the test (1 mg/d instead of 0.4 mg/d) (1, 6, 10).

In this study, we compared FST and iv SLT as a confirmatory test in 100 patients with suspected PA after the screening test.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
One hundred patients were positive for the PA screening test performed in the six units participating in the study in the period from January to December 2004. Patients were enrolled after written informed consent and approval of the study protocol by the local ethics committees. The reasons for patient referral were onset of hypertension at a young age, resistance of hypertension to conventional antihypertensive therapy, hypertension with unexplained spontaneous or diuretic-induced hypokalemia, high plasma aldosterone, low PRA, and/or adrenal incidentaloma. The screening tests were performed according to the conditions and cutoffs considered to be optimal in the single centers and as published previously; in particular, in the centers from Torino and Padova, the screening test was considered to be positive when the PAC/PRA ratio was higher than 40 (PAC in ng/dl and PRA in ng/ml·h) together with PAC higher than 15 ng/dl (2), whereas the centers from Reggio Emilia and Santiago considered the screening test to be positive when the PAC/PRA ratio was higher than 35 and 25, respectively, without a cutoff for PAC (5, 11), and finally, the center from Verona considered a PAC/renin ratio higher than 32 pg/ml as positive, because in their hands, this corresponded to a PAC/PRA ratio of 50 (12). In all centers, unless otherwise specified, PAC and PRA were determined by RIA (Sorin Biomedical Diagnostics, Vercelli, Italy). The intra- and interassay coefficients of variation (CV) for aldosterone were 7.9 and 9.6%, respectively; the normal range is 2–12 ng/dl supine and 5–0 ng/dl upright. The intra- and interassay CV for PRA were 5.4 and 9.1%, respectively; the normal range is 0.4–3 ng/ml·h supine and 1.5–6 ng/ml·h upright. In Verona, instead of PRA, renin was measured as direct active renin (DAR) by the Nichols Diagnostics (San Juan Capistrano, CA) chemiluminescent immune assay performed on the automated Nichols Advantage System. The intra- and interassay CV were less than 5 and 8%, respectively. The cutoff of the aldosterone/DAR ratio was chosen according to the data of a previous study where DAR was compared with PRA (12). In that study, PRA and DAR were closely correlated (r = 0.87; P < 0.0001). In Santiago, PAC was measured by RIA using a commercial kit from Diagnostic Products Corp. (Los Angeles, CA). The intra- and interassay CV for PAC were 5.1 and 5.9%, respectively. The PRA was determined as previously described by Kreft et al. (13). The intra- and interassay CV for PRA were 7.5 and 9.1%, respectively. Both methods demonstrated a high correlation with the PAC and PRA RIAs used by the Italian groups.

In all centers, blood samples were obtained in the sitting position between 0800 and 1000 h. All antihypertensive drugs were stopped at least 3 wk before the PAC and PRA measurements (at least 6 wk before for diuretics and at least 8 wk before for spironolactone). Patients were advised to maintain a diet with normal and constant sodium intake (120 mmol sodium and 60 mmol potassium per day).

All patients underwent both iv SLT and FST. Patients not in washout during the screening period and therefore taking an -blocker (doxazosin) and/or a calcium channel blocker (verapamil or amlodipine) maintained the same therapy during and for the period between the two tests. For the period between the screening and the end of the second confirmatory test, patients were advised to maintain the same diet and sodium intake, as described above. The second test was performed after at least 4 wk from the first. The two tests were performed as described previously (1, 2): in particular, iv SLT was performed by infusing 2 liters of 0.9% NaCl over 4 h, and the test was considered positive if posttest PAC levels were more than 5 ng/dl (1, 9, 10). In the FST, upright PAC was measured at 1000 h after 4 d fludrocortisone acetate (0.1 mg every 6 h) administration and sodium chloride supplementation (slow-release sodium chloride given after meals, 30 mmol thrice daily) and with patients consuming sufficient dietary salt to achieve a urinary excretion rate of 3 mmol/kg·d. The FST was considered positive if the posttest upright (1000 h) PAC levels were more than 5 ng/dl (1, 2, 6, 7). Potassium levels were carefully monitored during FST to minimize changes of plasma potassium levels, and potassium supplementation was modified accordingly. Plasma potassium levels were monitored during SLT in a subgroup of 61 patients after which we did not perform this assay anymore because of the small variation observed during this test (potassium variations during the test were –0.05 ± 0.2 mmol/liter). All patients underwent a computed tomography (CT) scan with fine cuts (2.5–3 mm) of the adrenal. Adrenal venous sampling (AVS) was not available in all centers and was performed in 37 (55%) of 67 patients with confirmed PA. Criteria for cannulation and for lateralization were considered as described previously (2). Two patients were excluded from the final evaluation, because they had PRA more than 1 ng/ml·h at the end of the FST. All adenomas were surgically removed and confirmed by histological examination. All patients with PA were screened for glucocorticoid remediable aldosteronism (GRA) using a long-PCR technique, as described previously (14, 15, 16).

Statistical analysis

All evaluated parameters are expressed as mean ± SD or median (25–75th percentile) where appropriate. The normal distribution of the various parameters was investigated using the Kolmogorov-Smirnov test. Values between groups were compared by the Student’s t test and the Mann-Whitney U test. Receiver operator characteristic (ROC) analysis was used to determine the test characteristics of the different variables predicting the diagnosis.

Correlations were evaluated by Spearman’s correlation coefficient.

The positive predictive value of the test was defined as the ratio between subjects that were true positives (defined by FST) and all subjects that were positive for the test.

The negative predictive value was defined as the ratio between subjects that were true negatives (defined by FST) and all the subjects that were negative for the test. The different ROC curves were compared by the area under the curves (AUC) and by the method of Hanley and McNeil (17) A value of z above the critical level of 1.96 was used to accept the hypothesis that the two areas were different. A P value of <0.05 was considered statistically significant.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
The characteristics of the population studied are shown in Table 1. Seven (10.4%) of 67 patients with PA, as confirmed by FST, were negative after iv SLT and 5 (16.1%) of 31 patients with essential hypertension (EH) after FST were positive after iv SLT; that is, SLT gave a correct diagnosis in 86 of 98 patients (88%). Therefore, the iv SLT resulted in 90% sensitivity and 84% specificity with a positive predictive value of 92% and a negative predictive value of 79% (Table 2). Of the seven false-negative diagnoses of PA with SLT, one displayed a nodule on the CT scan, but AVS revealed bilateral adrenal hyperplasia (BAH), and the remaining six displayed normal adrenals on CT scan but did not undergo AVS because it was unavailable in the centers of diagnosis. Interestingly, the patients who were positive with iv SLT and negative with FST also displayed normal adrenals on CT scan [none underwent AVS and therefore the presence of micro-aldosterone-producing adenoma (micro-APA) in some of these patients cannot be excluded]. We did not observe major variations of plasma potassium concentrations during FST (no more than 0.2 mmol/liter) because it was carefully monitored and promptly corrected with supplements. In a subgroup of 61 patients, we measured potassium during SLT (although is not currently done in the test), and we did not observe significant variation of the plasma potassium levels (mean reduction, –0.05 mmol/liter). Therefore, we did not measure potassium levels during SLT in the remaining patients.

View larger version (18K): [in this window] [in a new window]   FIG. 1. A, ROC curve analysis of PAC, PAC/PRA, PAC recumbent, PAC post SLT. B, Sensitivity and specificity for PAC post SLT. A cutoff value of 5.0 ng/dl corresponded to specificity and sensitivity of 88%.

PAC were reduced significantly after both tests in patients with PA and EH; however, patients with EH displayed greater reduction of PAC compared with patients with PA, as expected (Table 1 and Fig. 2).

View larger version (15K): [in this window] [in a new window]   FIG. 2. PAC before and after FST and SLT. A clustering box plot summarizes the differences in PAC before and after FST and SLT in patients with EH and PA. Median value is indicated by the thick line. Box plot and bar indicate 75th and 95th percentiles, respectively. PAC is significantly higher in patients with PA compared with patients with EH before and after the two tests (P < 0.0001 for all comparisons). There is no statistically significant difference between PAC after FST and PAC after SLT in patients with EH and in patients with PA.

View larger version (16K): [in this window] [in a new window]   FIG. 3. PAC before and after FST and SLT in patients with APA and BAH. A clustering box plot summarizes the differences in PAC before and after FST and SLT in patients with APA and BAH in whom the diagnosis has been made by AVS. Median value is indicated by the thick line. Box plot and bar indicate 75th and 95th percentiles, respectively. There is no statistically significant difference between PAC after FST and PAC after SLT in patients with APA and in patients with BAH. PAC was significantly higher both after FST and SLT in patients with APA compared with patients with BAH (P < 0.01 for both comparisons).

View larger version (26K): [in this window] [in a new window]   FIG. 4. Linear regression analysis of PAC post iv SLT and PAC post FST. There was a strong association between PAC after SLT and PAC after FST both in patients with EH and PA (P < 0.0001; r=0.784). Gray dots indicate patients with PA, black dots patients with EH.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Over the last decade, several studies have demonstrated that PA is the most frequent cause of secondary hypertension1, 5, 11, 16, 18, 19, 20, 21 . Hence, the diagnostic work-up for PA is highly relevant to current clinical practice. To date, the accepted approach for the diagnosis of PA is based on a screening test, the measure of the PAC/PRA ratio, followed by a confirmatory test in subjects who are positive by the screening test (1). The FST has been considered by some authors as the most reliable confirmatory test for PA (1, 6, 7). However, the FST requires hospitalization, which is time-consuming for both patients and healthcare providers and is highly costly. Although many centers use the iv SLT as an alternative to the FST, a direct comparison between these two tests has not been performed to date. Herein, we report a comparison between FST and iv SLT in a large population of hypertensive subjects with a positive PA screening test. The results of the present study support the SLT test as a reasonably reliable alternative to the more expensive and complex FST for the diagnosis of PA.

In our study, both SLT and FST proved to be safe and generally well tolerated, with a small percentage of patients displaying a significant increase in blood pressure, which was controlled in all cases. The SLT resulted in a correct diagnosis in most cases (88%) and gave a high positive predictive value (92%) with high sensitivity and specificity (90% and 84%, respectively). Seven (10.4%) of 67 PA patients were overall misdiagnosed by SLT. One was shown to have BAH by AVS. The exact proportion of APA missed by SLT cannot be determined by this study because 45% of the patients with PA did not undergo AVS, and CT lacks reliability in differentiating APA from BAH. Hence, it can only be said that, at worst, SLT may have missed six of 27 (22%) of APA, and at best, it did not miss any. However, none of the patients with a final diagnosis of APA were misdiagnosed by SLT, which is of particular importance, because this subtype of PA benefits from and indicates unilateral adrenalectomy. Furthermore, our study shows that a few patients with BAH may be missed with the use of the SLT and thus considered as low-renin essential hypertensives. However, low-renin essential hypertension and BAH may in fact belong to a common pathophysiological continuum, and both conditions have been shown to benefit from low doses of spironolactone (22), which successfully controls hypertension in patients who are positive at the screening test for PA (23, 24).

The difference between FST and SLT may be because of the different types of volume expansion, i.e. acute in the iv SLT and subacute in the FST, and/or to the different effects of posture or ACTH rhythm (25). In fact, patients were steadily recumbent during the iv SLT, whereas patients were in the upright position during the FST. This may increase the likelihood of SLT missing angiotensin II (AII)-responsive forms of PA, such as BAH and AII-responsive APA (26). On the other hand, in patients who underwent the iv SLT, the final measurement of aldosterone was performed around noon, when ACTH is lower than the morning baseline; this may have increased the chance of SLT missing forms of PA in which aldosterone is primarily regulated by ACTH and not responsive to AII (e.g. GRA and AII-unresponsive APA) (27).

A potential limitation of our study is that the different centers used slightly different screening cutoffs before the confirmatory test because we preferred to maintain the diagnostic screening strategy optimized in each center. However, the use of a relatively high PAC/PRA cutoff in some centers could have resulted in a lower detection of PA and possibly in decreased false-negative SLT results. Furthermore, because calcium channel blockers can rarely be responsible for a false-negative screening test (1.8% in a previous study) (4), we cannot rule out the possibility that a few patients with a mild form of PA could have been excluded from the study or have had a false-negative result with FST and SLT. Finally, because we did not perform a systematic study of the reproducibility of the two tests, we cannot rule out the possibility that a test would give different results if repeated.

Since the demonstration of a high prevalence of PA in the hypertensive population and especially in patients with grade 3 and resistant hypertension (28), the wide application of the screening test has resulted in a large increase in the diagnosis of PA (2). Consequently, this has also determined an increase in the costs related to the necessary diagnostic procedures. In this respect, when carefully performed, the iv SLT appears to be a reasonable alternative for definitive diagnosis of PA where insufficient resources and experience are available to carry out FST, which should still be regarded as the most reliable approach. In our hands, the best cutoff for the PAC post iv SLT is 5 ng/dl, which confirms the findings of two previous studies (9, 10). However, most confirmed APA (95%) had a PAC post iv SLT higher than 7.5 ng/dl, and therefore, this cutoff may be considered to further reduce the costs by reducing the number of CT scans and AVS.

In conclusion, this study demonstrates that the iv SLT is a reasonably reliable alternative to the FST for the confirmation of the diagnosis of primary aldosteronism in patients who are positive after the screening test.

	Footnotes

 
Author disclosure summary: P.M., A.M., F.F., G.R., F.P., C.F., L.Mo., L.Ma., F.V., and M.M. have nothing to declare.

First Published Online May 2, 2006

Abbreviations: AII, Angiotensin II; APA, aldosterone-producing adenoma; AUC, area under the curve; AVS, adrenal venous sampling; BAH, bilateral adrenal hyperplasia; CT, computed tomography; CV, coefficients of variation; DAR, direct active renin; EH, essential hypertension; FST, fludrocortisone suppression test; PA, primary aldosteronism; PAC, plasma aldosterone concentration; PRA, plasma renin activity; ROC, receiver operator characteristic; SLT, saline load test.

Received January 13, 2006.

Accepted April 21, 2006.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Mulatero P, Dluhy RG, Giacchetti G, Boscaro M, Veglio F, Stewart PM 2005 Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab 16:114–119[CrossRef][Medline]
2. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young Jr WF 2004 Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 89:1045–1050[Abstract/Free Full Text]
3. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ 2005 Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 45:1243–1248[Abstract/Free Full Text]
4. Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, Veglio F 2002 Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension 40:897–902[Abstract/Free Full Text]
5. Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F, Montero J, Huete A, Gederlini A, Fardella CE 2003 Primary aldosteronism and hypertensive disease. Hypertension 42:161–165[Abstract/Free Full Text]
6. Gordon RD, Stowasser M, Klemm SA, Tunny TJ 1994 Primary aldosteronism and other forms of mineralocorticoid hypertension. In: Swales JD, ed. Textbook of hypertension. London: Blackwell Scientific; 865–892
7. Stowasser M, Gordon RD, Rutherford JC, Nikwan NZ, Daunt N, Slater GJ 2001 Diagnosis and management of primary aldosteronism. J Renin Angiotensin Aldosterone Syst 2:156–169[Medline]
8. Lim PO, Farquharson CA, Shiels P, Jung RT, Strithers AD, MacDonald TM 2001 Adverse cardiac effects of salt with fludrocortisone in hypertension. Hypertension 37:856–861[Abstract/Free Full Text]
9. Kem DC, Weinberger MH, Mayes DM, Nugent CA 1971 Saline suppression of plasma aldosterone in hypertension. Arch Intern Med 128:380–386[CrossRef][Medline]
10. Holland OB, Brown H, Kuhnert L, Fairchild C, Risk M, Gomez-Sanchez CE 1984 Further evaluation of saline infusion for the diagnosis of primary aldosteronism. Hypertension 6:717–723[Abstract/Free Full Text]
11. Rossi E, Regolisti G, Negro A, Sani C, Davoli S, Perazzoli F 2002 High prevalence of primary aldosteronism using postcaptopril plasma aldosterone to renin ratio as a screening test among Italian hypertensives. Am J Hypertens 15:896–902[CrossRef][Medline]
12. Olivieri O, Ciacciarelli A, Signorelli D, Pizzolo F, Guarini P, Pavan C, Corgnati A, Falcone S, Corrocher R, Micchi A, Cressoni C, Blengio G 2004 Aldosterone to renin ratio in a primary care setting: the Bussolengo study. J Clin Endocrinol Metab 89:4221–4226[Abstract/Free Full Text]
13. Kreft C, Menard J, Corvol P 1979 Value of renin measurement, saralasin test, and acelretolol treatment in hypertension. Kidney Int 15:176–183[Medline]
14. Mulatero P, Curnow KM, Aupetit-Faisant B, Foekling M, Gomez-Sanchez C, Veglio F, Jeunemaitre X, Corvol P, Pascoe L 1998 Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. J Clin Endocrinol Metab 83:3996–4001[Abstract/Free Full Text]
15. Mulatero P, Veglio F, Pilon C, Rabbia F, Zocchi C, Limone P, Boscaro M, Sonino N, Fallo F 1998 Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 83:2573–2575[Abstract/Free Full Text]
16. Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L, Pinto M, Huete A, Oestreicher E, Foradori A, Montero J 2000 Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 85:1863–1867[Abstract/Free Full Text]
17. Hanley JA, McNeil BJ 1982 The meaning and use of the area under the receiver operating characteristic (ROC) curve. Radiology 143:29–36[Abstract/Free Full Text]
18. Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, Klemm SA 1993 Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol 20:296–298[Medline]
19. Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young Jr WF 2000 Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 85:2854–2859[Abstract/Free Full Text]
20. Stowasser M, Gordon RD, Gunasekera TG, Cowley DC, Ward G, Archibald C, Smithers BM 2003 High rate of detection of primary aldosteronism, including surgically treatable forms, after ‘non-selective’ screening of hypertensive patients. J Hypertens 21:2149–2157[CrossRef][Medline]
21. Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky Jr J 2003 Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens 17:349–352[CrossRef][Medline]
22. Laragh J 2001 Abstract, closing summary, and table of contents for Laragh’s 25 lessons in pathophysiology and 12 clinical pearls for treating hypertension. Am J Hypertens 14:1173–1177[CrossRef][Medline]
23. Mahmud A, Feely J 2005 Aldosterone-to-renin ratio, arterial stiffness, and the response to aldosterone antagonism in essential hypertension. Am J Hypertens 18:50–55[CrossRef][Medline]
24. Hood S, Cannon J, Foo R, Brown M 2005 Prevalence of primary hyperaldosteronism assessed by aldosterone/renin ratio and spironolactone testing. Clin Med 5:55–60[CrossRef][Medline]
25. Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM, Kong AP 2005 The use of aldosterone-renin ratio as diagnostic test for primary aldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab 90:72–78[Abstract/Free Full Text]
26. Wisgerhof M, Brown RD, Hogan MJ, Carpenter PC, Edeis AJ 1981 The plasma aldosterone response to angiotensin II infusion in aldosterone-producing adenoma and idiopathic aldosteronism. J Clin Endocrinol Metab 52:195–198[Abstract]
27. Wenting GJ, Man in’t Veld AJ, Derkx FH, Brummelen PV, Schalekamp MA 1978 ACTH-dependent aldosterone excess due to adrenocortical adenoma: a variant of primary aldosteronism. J Clin Endocrinol Metab 46:326–335[Medline]
28. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P 2002 Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 40:892–896[Abstract/Free Full Text]

This article has been cited by other articles:

				B Rayner Primary aldosteronism and aldosterone-associated hypertension J. Clin. Pathol., July 1, 2008; 61(7): 825 - 831. [Abstract] [Full Text] [PDF]

				P. Mulatero, C. Bertello, D. Rossato, G. Mengozzi, A. Milan, C. Garrone, G. Giraudo, G. Passarino, D. Garabello, A. Verhovez, et al. Roles of Clinical Criteria, Computed Tomography Scan, and Adrenal Vein Sampling in Differential Diagnosis of Primary Aldosteronism Subtypes J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1366 - 1371. [Abstract] [Full Text] [PDF]

				C. Catena, G. Colussi, E. Nadalini, A. Chiuch, S. Baroselli, R. Lapenna, and L. A. Sechi Cardiovascular Outcomes in Patients With Primary Aldosteronism After Treatment Arch Intern Med, January 14, 2008; 168(1): 80 - 85. [Abstract] [Full Text] [PDF]

				G. Mengozzi, D. Rossato, C. Bertello, C. Garrone, A. Milan, R. Pagni, F. Veglio, and P. Mulatero Rapid Cortisol Assay during Adrenal Vein Sampling in Patients with Primary Aldosteronism Clin. Chem., November 1, 2007; 53(11): 1968 - 1971. [Abstract] [Full Text] [PDF]

				P. Mulatero, C. Bertello, C. Garrone, D. Rossato, G. Mengozzi, A. Verhovez, F. Fallo, and F. Veglio Captopril Test Can Give Misleading Results in Patients With Suspect Primary Aldosteronism Hypertension, August 1, 2007; 50(2): e26 - e27. [Full Text] [PDF]

				G. P. Rossi, A. Belfiore, G. Bernini, G. Desideri, B. Fabris, C. Ferri, G. Giacchetti, C. Letizia, M. Maccario, F. Mallamaci, et al. Comparison of the Captopril and the Saline Infusion Test for Excluding Aldosterone-Producing Adenoma Hypertension, August 1, 2007; 50(2): 424 - 431. [Abstract] [Full Text] [PDF]

				S. J. Hood, K. P. Taylor, M. J. Ashby, and M. J. Brown The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double-Blind Crossover Trial in Patients With Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio Circulation, July 17, 2007; 116(3): 268 - 275. [Abstract] [Full Text] [PDF]

				C. Catena, G. Colussi, E. Nadalini, A. Chiuch, S. Baroselli, R. Lapenna, and L. A. Sechi Relationships of Plasma Renin Levels with Renal Function in Patients with Primary Aldosteronism Clin. J. Am. Soc. Nephrol., July 1, 2007; 2(4): 722 - 731. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 91/7/2618    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted 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 Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mulatero, P. Articles by Maccario, M. Search for Related Content PubMed PubMed Citation Articles by Mulatero, P. Articles by Maccario, M. Related Collections Adrenal and Hypertension Endocrine Oncology