Functional tests for primary aldosteronism: Value of captopril suppression

With the introduction of more simple screening tests such as the aldosterone/renin ratio, the detection rate of primary aldosteronism has increased considerably. Until now, no reference values have been available for reporting the aldosterone/renin ratio using plasma aldosterone values expressed in SI units (pmol/L) and plasma active renin (ng/L) measured by immunoradiometric assay. We studied 153 subjects who had either normal blood pressure, essential hypertension, or primary aldosteronism. Essential hypertensive patients usually have aldosterone/renin (pmol/ L/ng/L) ratios below 100, whereas ratios for patients with primary aldosteronism are above 140. Results that fall between 100 and 140 suggest a need for repeat testing. Patients with elevated aldosterone/renin ratios require confirmatory testing to demonstrate nonsuppressive autonomous aldosterone production. To this end, salt loading is widely used, but this approach may be contraindicated in patients with severe hypertension. The captopril suppression test appears as effective as salt loading in confirming a diagnosis of primary aldosteronism. In addition, the captopril test is safe, well tolerated, and cost-effective.     

Detection of primary aldosteronism by the 6-hour integrated aldosterone/renin ratio

An outpatient diagnostic procedure measuring the 6-hour integrated plasma concentration of aldosterone and plasma renin activity was used to detect primary aldosteronism in 12 patients with low renin hypertension, including six with mild hypertension and normal urinary excretion and spot plasma levels of aldosterone. The ratio of integrated plasma concentration of aldosterone to plasma renin activity in the 12 patients (mean, 339; range, 116-700; p less than 0.0001) did not overlap with that measured in 105 normotensive controls (mean, 27.8; range, 5-97) or in 87 subjects with essential hypertension (mean, 29.2; range, 4-67). Eight patients had surgically proven adenomas (3 of which measured less than 5 mm) with normalization of blood pressure following adrenalectomy. The four remaining patients had bilateral hyperplasia. The 6-hour integrated plasma concentration of aldosterone to plasma renin activity ratio was found to be a useful new outpatient diagnostic tool for evaluation of primary hyperaldosteronism.     

USE OF AN INTRAVENOUS SODIUM LOAD IN SCREENING FOR PRIMARY HYPERALDOSTERONISM

A sodium loading test was performed in 35 patients presenting with hypertension and hypokalemia. In 14 of these patients, intravenous administration of 0.9% saline (2 I in 4 h) on two consecutive days caused urinary aldosterone excretion to fall to values within the range for normal volunteers. The other 21 patients, in whom urinary aldosterone excretion did not decline following two days of saline loading, or in whom pronounced hypokalemia after the first day of loading precluded further saline infusion, were designated as having primary aldosteronism. Seventeen of this group underwent surgery and discrete adrenal adenomas were found in 16. When serum potassium concentration, plasma renin activity or the relationships of serum potassium to concurrent urinary potassium excretion or of urinary aldosterone excretion to plasma renin activity were used as alternative diagnostic criteria for primary aldosteronism, overlapping of the two groups occurred. It is concluded that measurement of urinary aldosterone excretion after intravenous sodium loading is a useful test in the identification of primary aldosteronism due to aldosterone-producing adenoma. In this series the saline loading test was more specific in diagnosis than criteria based on serum and urinary potassium, plasma renin activity or unsuppressed aldosterone excretion.     

Diagnostic value of the post-captopril test in primary aldosteronism

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.     

Importance of atrial natriuretic hormone in an exaggerated natriuresis during acute sodium load in primary aldosteronism.

To elucidate the factors which contribute to the exaggerated natriuresis in primary aldosteronism, hemodynamic and hormonal changes induced by saline infusion (at a rate of 0.5 l/h for 3 h) were examined in 6 patients with primary aldosteronism, 13 with essential hypertension, and 8 normotensive subjects. After saline infusion, increases in urinary sodium excretion, glomerular filtration rate, atrial natriuretic hormone, and urinary dopamine excretion along with suppression of plasma renin activity and aldosterone were compared in the three groups. All three groups demonstrated similar increases in glomerular filtration rate, but patients with primary aldosteronism did not show changes in urinary dopamine excretion, plasma renin activity, and aldosterone, despite their increased excretion of sodium. The increase in plasma atrial natriuretic hormone was significantly greater in primary aldosteronism than in essential hypertension or normotensive subjects. No changes in blood pressure or heart rate were seen. These findings suggest that atrial natriuretic hormone might play a role in the exaggerated excretion of sodium in patients with primary aldosteronism.     

Minireview: primary aldosteronism--changing concepts in diagnosis and treatment

Primary aldosteronism affects 5-13% of patients with hypertension. Patients with hypertension and hypokalemia and most patients with treatment-resistant hypertension should undergo screening for primary aldosteronism with a plasma aldosterone concentration to plasma renin activity ratio. A high plasma aldosterone concentration to plasma renin activity ratio is a positive screening test result, a finding that warrants confirmatory testing. For those patients that want to pursue a surgical cure, the accurate distinction between the subtypes (unilateral vs. bilateral adrenal disease) of primary aldosteronism is a critical step. The subtype evaluation may require one or more tests, the first of which is imaging the adrenal glands with computed tomography, followed by selective use of adrenal venous sampling. Because of the deleterious cardiovascular effects of aldosterone, normalization of circulating aldosterone or aldosterone receptor blockade should be part of the management plan for all patients with primary aldosteronism. Unilateral laparoscopic adrenalectomy is an excellent treatment option for patients with unilateral aldosterone-producing adenoma. Bilateral idiopathic hyperaldosteronism should be treated medically. In addition, aldosterone-producing adenoma patients may be treated medically if the medical treatment includes mineralocorticoid receptor blockade.     

QT interval in patients with primary aldosteronism and low-renin essential hypertension

INTRODUCTION: QT interval prolongation increases the risk of sudden death in several medical conditions. Patients with primary aldosteronism and salt-sensitive hypertension experience more cardiovascular events than those with normal-renin essential hypertension. QT interval prolongation might represent one of the risk factors for cardiovascular events in these patients. The aim of the present study was to evaluate the QT interval in patients with primary aldosteronism and low-renin essential hypertension (LREH). METHODS: Twenty-seven patients with primary aldosteronism, 17 patients with LREH, 117 patients with essential hypertension and 25 healthy individuals were studied. Plasma aldosterone, plasma renin activity, and aldosterone to plasma renin activity ratio (ARR) were determined. Corrected QT intervals (QTcs) were measured from a 12-lead electrocardiogram. RESULTS: The QTc was longer in primary aldosteronism (434 +/- 23 ms) and LREH (430 +/- 18 ms) compared with essential hypertension (419 +/- 22 ms) and healthy controls (412 +/- 19 ms) (P = 0.0004). The prevalence of QTc longer than 440 ms was higher in primary aldosteronism (48%) and LREH (23%) compared with essential hypertension (11%) and healthy controls (4%) (P < 0.0001). QTc correlated with plasma aldosterone (P = 0.01), ARR (P = 0.02), and diastolic blood pressure (P = 0.01). ARR (P = 0.01) and systolic blood pressure (P = 0.01) were identified as independent predictors of QTc. CONCLUSIONS: We postulate that the elevated aldosterone secretion contributes to the prolongation of the QT interval in patients with primary aldosteronism and LREH through both a depletion of intracellular potassium concentration and higher blood pressure values. QTc measurement might represent one simple, non-invasive and reproducible index to characterize the cardiovascular risk in patients with primary aldosteronism and LREH.     

Influence of antihypertensive medication on aldosterone and renin concentration in the differential diagnosis of essential hypertension and primary aldosteronism

OBJECTIVE: Antihypertensive drugs influence the neurohumoral cardiovascular system and the concentration of hormones involved in blood pressure regulation. Little is known, however, about the extent to which various antihypertensive drugs influence cardiovascular hormone concentrations and thus disturb the differential diagnosis of hypertension in clinical practice. In this study we compare the impact of different antihypertensive medicaments on the renin-angiotensin-aldosterone system in patients with essential hypertension who are screened for primary aldosteronism. DESIGN AND SUBJECTS: We analysed serum aldosterone (SAC) and plasma renin concentration (PRC) in 37 normotensive controls, 144 hypertensive patients with essential hypertension, and 19 patients with primary aldosteronism. Patients were on different treatment regimens such as single drug or combination therapy with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II subtype 1 (AT1) receptor antagonists, calcium channel blockers, spironolactone and no treatment. RESULTS: In patients with essential hypertension, beta-blocker therapy (n = 47) led to a highly significant suppression of renin, whereas serum levels of aldosterone were not significantly altered. ACE inhibitors and AT1 receptor antagonists (n = 55) decreased aldosterone levels only to a minor extent. Calcium channel blockers (n = 23) had no significant influence on SAC or PRC. In patients with primary aldosteronism treated with spironolactone (n = 8), renin escaped suppression and reached very high levels. CONCLUSION: Beta-blockers and aldosterone antagonists have the strongest impact on the renin-angiotensin system. The decrease in renin concentration by beta-blockers leads to an increase in the ratio of aldosterone to renin, and thus to false-positive results in patients with essential hypertension. Calcium channel blockers, and probably also ACE inhibitors and AT1 receptor antagonists alone or in combination, may be continued during screening for primary aldosteronism by determination of renin and aldosterone concentration.     

The Diagnostic Value of the 24 Hour Integrated Concentration of Plasma Aldosterone

The 24-hour urinary excretion rate of aldosterone, the 24-hour integrated concentration of plasma aldosterone (IC-ALDO) and the morning plasma aldosterone levels from a single, discrete venipuncture of 92 subjects (30 normal subjects, 62 patients with mild, essential hypertension) were compared, using the variance ratio method, to 12 patients with primary aldosteronism.

The variance of the IC-ALDO was significantly lower than the respective variances of the 24-hour urinary excretion of aldosterone (P < 0.01) and of the discrete, morning plasma levels of aldosterone (P < 0.01).

The clinical usefulness of this diagnostic procedure depends on its ability to discriminate between healthy subjects and various hypertensive patients. Because of its narrower variance and enhanced discriminatory ability, the 24-hour IC-ALDO may have useful application in diagnosis of various disorders of aldosterone secretion. We have found the IC-ALDO completely separated 11 of 12 primary aldosteronism patients (mean 36±17) from essential hypertensive controls (mean 9.6±4.1)(P < 0.01). When IC-ALDO was combined with integrated concentration of plasma renin activity in an ALDO/RENIN ratio, all 12 primary aldosteronism patients were diagnosed.     

Ratio of serum aldosterone to plasma renin concentration in essential hypertension and primary aldosteronism.

The ratio of serum aldosterone to plasma renin activity (PRA) has been proposed as sensitive screening method in the diagnosis of primary aldosteronism under random conditions. However, the method for determination of renin activity is hampered by the necessity of ice cooling during storage and transport. The present study was therefore conducted to examine the ratio of serum aldosterone to plasma renin concentration (ARR) and its usefulness in diagnosis of primary aldosteronism under ambulatory conditions and given antihypertensive medication. 146 patients with arterial hypertension who consecutively attended the outpatient clinic were studied prospectively. Patients with secondary hypertension besides primary aldosteronism were not included in the series. 37 normotensive patients served as control. Also, 17 patients with known primary aldosteronism were retrospectively examined. Among the hypertensive group 2 patients with Conn's syndrome were newly detected (1.4%). ARR was 7.92 +/- 6.04 [pg/ml]/[pg/ml] in normotensive controls (range from 2.03 to 26.98), 14.61 +/- 18.50 [pg/ml]/[pg/ml] in patients with essential hypertension (n = 144, range from 0.41 to 115.45) and 155.92 +/- 127.84 [pg/ml]/[pg/ml] in patients with primary aldosteronism (n = 19, range from 6.75 to 515). 17 of the 19 patients with Conn's syndrome had an ARR of more than 50. Under ongoing drug treatment this represents a sensitivity of 89% and a specificity of 96%. Sensitivity decreased to 84% and specificity increased to 100% when a second criteria (aldosterone > or = 200 pg/ml) was included. In summary, ARR using renin concentration is a useful screening parameter for primary aldosteronism.     

血浆醛固酮/肾素活性比值在诊断原发性醛固酮增多症患者的价值

目的采用血浆醛固酮/肾素活性比值(ARR)在高血压患者中筛选原发性醛固酮增多症(原醛)病例,治疗和随访患者、分析其临床特点,从而探讨原醛的临床特点和 ARR 在原醛诊断中的价值。方法收集门诊和住院的高血压患者902例(其中3级高血压609例),空腹采血并用放射免疫方法测定血浆肾素和醛固酮水平及血生化指标,计算 ARR。对比值大于25(ng/dl 比ng·ml~(-1)·h~(-1))的126例疑诊为原醛的病例进行肾上腺薄层 CT 扫描,分析其临床特点、用抗醛固酮药物治疗并进行随访。结果原醛在高血压人群中占14%(126/902),肾上腺 CT 见54例单侧或双侧增生和25例腺瘤;原醛合并低血钾占39%(49/126);25例患者接受外科治疗,有效率100%,其中48%(12/25)能达到治愈;用螺内酯治疗有效率为89%(48/54),单药控制率为24%(13/54)。结论中国人原醛占高血压10%以上,ARR 应作为高血压尤其是重度和难治性高血压患者的常规检查,ARR 在原醛诊断中有重要意义,可以提高原醛的诊断率。     

Optimal use and interpretation of the aldosterone renin ratio to detect aldosterone excess in hypertension

With the introduction of the aldosterone/renin ratio as a screening test, the detection rate of primary aldosteronism has increased considerably. Nevertheless, no consensus has so far been reached regarding the cutoff points, operating characteristics or indeed even the reference values for reporting the aldosterone/renin ratio using plasma active renin (ng/l or mU/l) measured by immunoradiometric assay. We review the characteristics of this ratio in normal individuals, essential hypertension and primary hyperaldosteronism in an attempt to reach an agreement regarding its optimum use and interpretation - both using the renin activity or concentration. It seems that the optimal cutoff for patients with primary aldosteronism is above 30 ng/dl per mug/l/h or 800 pmol/l per mug/l/h or 130 pmol/ng or 80 pmol/mU. We explore enhancing measures such as captopril loading or use with a plasma aldosterone cutoff as well as pitfalls with the test such as confounding medications or the need for confirmatory testing. For the latter, demonstration of autonomous aldosterone production via salt loading is widely used, but may not be most advantageous and may even be contraindicated in patients with severe hypertension. The renin stimulation test may be an alternative being safe, well tolerated, and cost effective.     

Single dose captopril as a diagnostic test for primary aldosteronism

Most diagnostic tests for primary aldosteronism use maneuvers to expand the extracellular fluid volume, thereby suppressing the renin-angiotensin system. This results in a decline in plasma aldosterone concentrations in normal subjects and essential hypertension (EH) patients, but not in patients with primary aldosteronism. Captopril blocks angiotensin II synthesis and might be used as a diagnostic test for primary aldosteronism. We have measured plasma aldosterone concentrations 2 h after the administration of 25 mg captopril in 9 normotensive subjects, 10 patients with EH, and 12 patients with primary aldosteronism while they were ingesting an unrestricted diet. The plasma aldosterone concentration decreased to less than 15 ng/dl in all normotensive subjects and in 9 of 10 patients with EH, but remained greater than 15 ng/dl in 4 of 5 patients with idiopathic hyperaldosteronism and in all patients with an aldosterone-producing adenoma. The aldosterone to renin ratio was greater than 50 in 4 of 5 patients with idiopathic hyperaldosteronism and in all adenoma patients, but less than 50 in all normotensive subjects and EH patients. A nomogram comparing the plasma aldosterone concentration with the aldosterone to renin ratio clearly separated primary aldosteronism patients from EH patients.     

Urinary tetrahydroaldosterone as a screening method for primary aldosteronism: a comparative study

BACKGROUND: The major aldosterone metabolite 3 alpha,5 beta tetrahydroaldosterone reflects up to 45% of the aldosterone secretion. Its 24-h urinary excretion is likely to provide an accurate index of the daily aldosterone production and to be an indicator for primary aldosteronism (PA). METHODS: In a prospective study, the validity of tetrahydroaldosterone as a screening test for PA was evaluated in comparison to serum potassium, plasma aldosterone, plasma renin activity, plasma aldosterone/renin activity ratio (PARR), as well as 24-h urinary aldosterone-18-glucuronide and free aldosterone. A total of 111 normotensive individuals, 412 PA patients and 1453 essential hypertensive patients, were studied. The effect of blood sampling technique on potassium level was also investigated. RESULTS: Tetrahydroaldosterone differentiated PA from essential hypertension with a sensitivity of 96% and a specificity of 95%. The sensitivity was 89% for plasma aldosterone, 87% for free aldosterone, 85% for PARR, 71% for aldosterone-18-glucuronide and 51% for renin activity. Specificities varied between 91% and 85%. The combined use of the parameters plasma aldosterone > or =9.0 ng/dL and PARR > or =25 resulted in a sensitivity of 82% and specificity of 95%. Forearm exercise proved to be a source of erroneous elevations of potassium sufficient to obscure the suspicion of PA. CONCLUSION: The data suggest that tetrahydroaldosterone is the most reliable screening test for PA. Tetrahydroaldosterone determination in combination with aldosterone-18-glucuronide and free aldosterone increases diagnostic specificity for PA. Potassium, renin, plasma aldosterone, and basal PARR are inadequate screening procedures because they are subject to high rates of false-positive and false-negative results.     

The changing clinical spectrum of primary aldosteronism

In a prospective study of 80 patients with primary aldosteronism (70 with adenoma and 10 with hyperplasia), "refractory" hypertension, hyperkinetic circulation, and hypovolemia were frequent occurrences. We found that measurements of serum potassium concentration and plasma renin activity were inadequate screening tests because of high rates of false-positive and false-negative results. The demonstration of excessive aldosterone production after three days of salt loading provided the best sensitivity (96 percent) and specificity (93 percent) in identifying patients with primary aldosteronism. Severe, persistent hypokalemia, increased plasma 18-hydroxycorticosterone values, and an anomalous postural decrease in the plasma aldosterone concentration, when present, provided the best indicators of the presence of an adenoma. Of three localizing procedures (selective adrenal venography, adrenal computed tomographic scan, and adrenal venous sampling for plasma aldosterone concentration) the measurement of adrenal venous plasma aldosterone concentration yielded 100 percent accuracy. These results indicate a wider clinical spectrum in primary aldosteronism than previously described. They also show that nonsuppressible aldosterone production is its most important diagnostic hallmark and the single best diagnostic screening procedure, and that adrenal venous sampling for plasma aldosterone concentration remains the most precise technique for identification and localization of tumors.     

The pattern of plasma renin activity and aldosterone secretion in normal and hypertensive subjects before and after saline infusions

The pattern of plasma renin activity and aldosterone secretion was studied in 56 unselected patients with essential hypertension and in 10 hypertensive patients with renal complications. The results were compared to responses found in 17 normal subjects and 6 patients with verified primary aldosteronism. In all cases, plasma renin activity and aldosterone secretion rates were measured under precise conditions of metabolic balance, initially during dietary salt restriction and then after physiologic saline infusions.

Abnormally low responses in plasma renin activity to salt restriction were found in 13 patients with essential hypertension (25 percent), and in 4 there was no significant increase with standing. The expected increase in aldosterone secretion also failed to occur in 9 patients, 6 of whom demonstrated low plasma renin activity. The great majority of patients with essential hypertension responded normally to saline infusions with decreased plasma renin activity and aldosterone secretion, but in 4 patients the latter was greater than 300 μg/day after saline infusion. The response of hypertensive patients with renal complications was not different from that seen in uncomplicated cases.

Although there was great variation in the responses seen in individual patients with essential hypertension, the combination of suppressed plasma renin activity and autonomous, excessive aldosterone secretion was found in only 1 patient. In this unselected series, the maximal incidence of primary aldosteronism (using the currently accepted criteria) was less than 5 percent.     

Reliability of screening methods for the diagnosis of primary aldosteronism.

An attempt has been made in studies on 1,036 consecutive, referred, hypertensive patients to determine the reliability of four measurements, as screening tests for primary aldosteronism: serum sodium, serum potassium, stimulated plasma renin activity (PRA) (after furosemide administration, 40 mg intravenously, and ambulation for 2 hours) and the plasma aldosterone concentration after a 2 liter infusion of 0.9 per cent saline solution, all performed during an 8 hour outpatient study. Based on the results of subsequent tests in selected patients, which showed failure of deoxycorticosterone (DOC) and fludrocortisone to produce normal suppression of plasma levels and excretion of aldosterone, 22 of the 1,036 patients were considered to have primary aldosteronism. Adrenal scans and adrenal vein aldosterone measurements revealed that primary aldosteronism was caused by a unilateral adrenal adenoma in five patients, probably by an adrenal adenoma in three other patients and by excessive aldosterone release from both adrenals in 14 patients.Serum sodium and serum potassium measurements were inadequate screening procedures because of unacceptably high rates of false-positive and false-negative results. A low PRA alone failed to differentiate patients with primary aldosteronism from 14 times the number of patients with “low-renin hypertension.” The saline suppression test yielded an encouragingly high sensitivity (0.77) when a plasma aldosterone concentration of 8.5 ng/dl after the saline infusion was used as the criterion of hyperaldosteronism. This diagnostic yield was improved to give a sensitivity of 0.95 by combining this saline suppression criterion with the alternative requirement that the patients have a low stimulated PRA, a fasting serum potassium concentration below 3.5 meq/liter and no depressor response to the administration of saralasin. It is concluded that this combination of laboratory procedures provides a safe, efficient and highly reliable means of discovering patients with primary aldosteronism among unselected hypertensive patients.     

Urinary Excretion of Kallikrein before and after Operation for Aldosterone-producing Adenoma

ABSTRACT. Hesse B, Rasmussen S, Lund JO, Christensen P, Damkjær Nielsen M. (Department of Clinical Physiology, Glostrup Hospital, and Institute for Experimental Medicine, Copenhagen, Denmark.) Urinary excretion of kallikrein before and after operation for aldosterone-producing adenoma. Urinary kallikrein excretion (UKal), determined by the esterase method, was measured in 10 normotensive volunteers, 10 patients with essential hypertension and in 7 patients with primary aldosteronism before and after operative removal of the adenoma. UKal values were low in 5 of the patients with essential hypertension. Preoperative UKal values in the patients with aldosteronism did not differ significantly from those of the normal subjects, but decreased in all after operation in parallel with changes in urinary excretion of tetrahydroaldosterone and plasma aldosterone concentration. The study supports the assumption of an association between the renal kallikrein-kinin system and the mineralo-corticoid state in man.     

原发性醛固酮增多症功能诊断试验可靠性分析

原发性醛固酮增多症是最常见的导致继发性高血压的病因之一，在高血压人群中发病率高达10％-18％。在原发性醛固酮增多症的诊断中，功能诊断非常重要。目前临床常用的功能试验有血醛固酮／肾素比值的测定、静脉盐水滴注抑制试验、24h尿醛固酮及其代谢物的测定以及开博通试验等。本文将对此类功能试验的诊断可靠性作一综述。