Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia

Abstract

Screening for primary hyperaldosteronism (PHA) is often indicated in individuals with resistant hypertension or hypokalaemia. However, in the far larger subset of the hypertensive population who do not fit into these criteria, the evidence for screening is conflicting and dependent on the disease prevalence. The purpose of this study was to examine the prevalence of PHA in a large population with mild to moderate hypertension and without hypokalaemia using a carefully controlled study protocol including a normotensive control population. Hypertensive subjects underwent medication washout and both hypertensive and normotensive subjects placed on a high-sodium diet prior to biochemical and haemodynamic testing. Study specific cutoff values were based on results from the normotensive population studied under identical conditions. A screening test (serum aldosterone/PRA ratio [ARR]>25 with a serum aldosterone level >8 ng/dl) was followed by a confirmatory test (urine aldosterone excretion rate [AER] >17 μg/24 h) to demonstrate evidence of PHA. An elevated ARR with a concomitant elevated serum aldosterone was present in 26 (7.5%) individuals. Of these, 11 (3.2%) had an elevated AER, consistent with evidence of PHA. Individuals with PHA had higher blood pressure and lower serum potassium levels while on a high-sodium diet. Sodium restriction neutralized these differences between PHA and essential hypertensives. The prevalence of PHA in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction.

Introduction

Since Dr Conn's initial description of autonomous aldosterone secretion leading to high blood pressure and hypokalaemia,1 primary hyperaldosteronism (PHA) has been a well-known cause of secondary hypertension.2 Furthermore, although the classical description was that of surgically remedial adenomatous tumor formation it is now realized that apparent aldosterone hypersecretion more often than not is the result of ‘bilateral adrenal hyperplasia’ or even essential hypertension.3, 4 Recently, considerable controversy5, 6, 7, 8 has arisen regarding the prevalence of PHA in the mild to moderate hypertensive population who comprise 90% of hypertensives and are largely cared for by primary care providers.9 Most experts agree that relatively higher prevalence rates for PHA in high-risk populations (those with resistant hypertension or hypertension with hypokalaemia) warrant screening for PHA in this small subset of hypertensives.5, 10, 11, 12, 13 However, reported estimates of PHA in studies of the larger group of patients with normokalaemia and mild to moderate hypertension range from as low as 2% to more than 30%.11, 13, 14, 15, 16, 17, 18 The larger percentage, if correct, would justify widespread screening for this potentially curable form of hypertension.

Limitations in establishing prevalence rates for this population have been hampered by small sample sizes, sample bias, concomitant use of medications as a confounder (reported by some19 but not by others20), uncontrolled dietary sodium and potassium intake at time of testing, variations in posture at time of testing and lack of an adequate normotensive control population5, 19, 21, 22, 23 and consequent reliance on laboratory reference ranges. This variability contributes to a considerably high false-positive rate of 6–25% with general application.24, 25

Determining an accurate prevalence rate for PHA in the non-referral, mild to moderate hypertensive population might have practical significance since a low rate would influence pretest probability and selection for screening. Therefore, the aim of this study was to examine the prevalence of PHA in a diverse population of hypertensive patients without resistant hypertension or hypokalaemia – those with mild to moderate hypertension. We selected and applied practical yet established screening (serum aldosterone to renin ratio) and diagnostic (urine aldosterone excretion rate (AER) on a high-sodium diet) tests for our analysis. Assessment of the renin–angiotensin–aldosterone axis occurred under controlled dietary conditions in a General Clinical Research Center (GCRC) after withdrawal of antihypertensive medication. Comparisons were made to a large normotensive control population studied under identical conditions to derive study specific cutoff values for the screening and diagnostic tests. It should be emphasized that the main purpose of this analysis was to determine the prevalence rate of PHA in general. The cutoff values generated are specific to the strictly controlled conditions described in this study. They are not intended to represent new cutoff values for broad application. Furthermore, due to the study design we were unable to determine the underlying cause for PHA (i.e. adenoma vs hyperplasia). Hence, the prevalence of classical or ‘surgically remedial’ PHA in our population is far less than what we report in the general PHA cohort.

Materials and methods

Individuals described in this report were studied by the international HyperPath (Hypertensive Pathotype) group using standardized protocols and study conditions with all assays performed in a centralized laboratory. Data were analysed from 118 normotensive and 347 hypertensive volunteers. The institutional review boards of each participating institution approved the study protocol and written informed consent was obtained from each participant.

Study participant selection

Screening history, physical and laboratory data were obtained from each participant prior to enrolment. Normotensive volunteers reported a negative personal and family history of hypertension, cardiovascular, kidney, pulmonary and liver disease. Race and ethnicity were self-defined. Measured blood pressure <130/85 mmHg, normal laboratory testing results from measures of serum electrolytes, creatinine, urinalysis, liver and thyroid function and a normal resting 12-lead EKG were required for normal volunteers to participate in the study.

Hypertensive and normotensive participants were recruited through a number of mechanisms, including mass-mailings, newspaper and posted advertisements, and referral from other study participants. In order to qualify for the study, hypertensive patients were required to have a history of hypertension with a diastolic blood pressure (DBP) 100 mmHg on no medications, DBP90 mmHg on one antihypertensive agent, or the use of two or more antihypertensive medications at the time of screening. Patients were excluded from participating in the study if they had a diastolic blood pressure >110 mmHg while on two or more medications, or the presence of hypokalaemia (serum potassium <3.5 mg/dl), and/or those with active cardiac or vascular disease. All patients on converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) or aldosterone antagonists discontinued these medications 3 months prior to the study because of their known effects on the modulation of renin–angiotensin–aldosterone system (RAAS) function in some hypertensive patients. Those on beta-blockers had their medications discontinued for 3–4 weeks. If needed, patients were placed on either a dihydropyridine calcium channel blocker or thiazide diuretic or both to control blood pressure during the washout period. All medications were discontinued 2–4 weeks prior to the study.

Responsiveness of renin and aldosterone to dietary sodium intake

Participants completed a 2-week crossover study consisting of 7 days of high dietary sodium intake (>200 mmol/day) and 7 days of low dietary sodium intake (<10 mmol/day). The duration of each diet period was chosen based on prior evidence demonstrating an average time to sodium homeostasis of approximately 5 days in hypertensive patients.26

High-sodium diet was accomplished by continuing the individual's usual diet supplemented with 2–3 packets of bullion broth at lunch and dinner (adding approximately 100–150 mmol Na/day). The Dietary Core of each center's General Clinical Research Center (GCRC) prepared all low-sodium meals, drinks and snacks after an intake interview with each participant to estimate usual caloric intake. Each diet was supplemented accordingly to contain approximately 100 mmol/day potassium to control for the independent influence of potassium on aldosterone secretion.2 Urinary sodium, potassium and AER at the end of each study week were determined from a 24-h collection obtained in a GCRC setting. Urinary creatinine excretion rates were also derived to assess completeness of collections. At the end of each diet period, subjects were admitted to the GCRC for one night and one day during which in the morning (between 0800 and 0900) haemodynamic and hormonal assessments were carried out. In order to reduce confounding from environmental stimuli or posture, all study participants remained fasting and supine for 10 h prior to study measurements including blood pressure and hormonal assessment.

Morning supine blood pressure was recorded during each study by an automatic recording device (Dinamap; Critikon, Tampa, FL, USA) at 5-min intervals and averaged for analysis.

Primary hyperaldosteronism screening and diagnostic tests

Although there are several screening tests available for PHA, the most widely used in general practice is the aldosterone/plasma renin activity ratio (ARR). The basis of the ARR as a determinant of autonomous aldosterone secretion stems from the normally direct and dependent relationship between aldosterone and endogenous angiotensin II, the latter being extrapolated from the more readily measured plasma renin activity (PRA). An elevated ratio of serum aldosterone to PRA supports the diagnosis of autonomous aldosterone secretion regardless of sodium intake.16

To increase specificity, we and others5, 7 required that an elevated ARR be accompanied by an elevated aldosterone concentration to avert falsely high ratios merely from very low PRA values. Patients with elevated ARR were then analysed for the presence of elevated urine aldosterone excretion while on the high-sodium diet to confirm biochemical evidence of PHA.13, 20, 27

Laboratory procedures

Details of laboratory procedures have been described previously.28, 29 In brief, all blood samples were collected on ice and centrifuged immediately and plasma separated and frozen until the time of assay. Urine and serum electrolytes were measured using an ion-selective electrode. PRA, serum aldosterone and urine aldosterone excretion were determined by radioimmunoassay.30, 31 The lower limit of detection for the PRA assay was 0.10 ng/ml/h.

Statistical analysis

Data are presented as means with s.e.m. as the measure of dispersion. In this multi-center study, homogeneity of parameters including blood pressure assessment was investigated and assured across the four centres before data were pooled and analysed. Probability was assessed by t-test with adjustments for equal and unequal variance when applicable according to Levene's test. Fisher's exact test was applied to comparison of percentages. A two-tailed P-value of <0.05 described statistical significance. Data derived from the normotensive population was used to generate study-specific cutoff values for the presence of PHA in the hypertensive population. The SPSS statistical software package was used for all analyses (SPSS version 12.0, Chicago, IL).

Results

Subject characteristics are presented in Table 1. Hypertensive patients were slightly older and had higher levels of serum aldosterone and ARR than normotensives. Serum and urine electrolytes and creatinine were similar between the two groups.

Table 1 Baseline characteristics of study population on high sodium diet

Screening for primary aldosteronism with ARR

We calculated ARR in the normotensive participants studied on a high-sodium diet. To prevent an elevated ARR from occurring merely due to smaller PRA values in the denominator, we also calculated the 95th percentile for serum aldosterone (>8 ng/dl) and required this to be present for the ARR to be considered elevated. The 95th percentile for ARR in normotensive participants was 25.

In the hypertensive patients, 68 individuals (20%) had an ARR>25 yet only 26 (7.5%) remained after requiring a serum aldosterone >8 ng/dl (Figure 1). This was considered a ‘positive ARR screen’ for PHA. All individuals with ARR>25 but serum aldosterone <8 ng/dl had PRA values 0.2 ng/ml/h, thus demonstrating the limitations of relying solely on the calculated ARR without requiring an elevated serum aldosterone level as a screening criterion. Table 2 compares characteristics of subjects with a positive and negative ARR screening test. Besides obvious differences in aldosterone and PRA, serum potassium concentrations were significantly lower (albeit in the normal range) and blood pressure was higher in the positive ARR screen group.

Figure 1
figure1

Schematic of screening analysis for hyperaldosteronism. SAC=serum aldosterone concentration, ARR=serum aldosterone/plasma renin activity ratio.

Table 2 Characteristics of hypertensive patients according to ARR screen

Determination of urine AER under high-sodium conditions

The second phase of analysis determined urine AER on a high sodium (urine sodium excretion, 224±7 mmol/24 h) and controlled potassium (urine potassium excretion, 74±2 mmol/24 h) diet. To minimize false-negative cases in this phase of the study, we used the 90th percentile value for AER in the normotensive population (17 μg/24 h) to designate cases of PHA. Of the 26 patients with an elevated ARR, 11 (3.2% of the hypertensive patients) had PHA as determined by an elevated AER. Using a more conservative 95th percentile value for AER (20 μg/24 h), the number of patients with an elevated value was eight (2.3%). In the 11 PHA patients, all had suppressed PRA levels (<0.50 ng/ml/h). Comparisons of patients with PHA and the remaining hypertensive patients revealed significantly higher blood pressure and lower serum potassium concentrations (although still in the normal range) in those with PHA (Table 3).

Table 3 Characteristics of patients according to hypertension status

Responsiveness to dietary sodium restriction

We studied the RAAS and blood pressure responsiveness to sodium restriction and upright posture in the hypertensive patients to assess the degree of volume expansion and aldosterone excess in patients with PHA. The low-sodium diet followed by 90 min upright posture produced significant responses in PRA, aldosterone and blood pressure in both PHA and hypertensive patients. Comparisons of low sodium/upright posture values between groups revealed no significant differences in aldosterone, blood pressure, or potassium (Table 4) despite baseline differences in these parameters on a high-sodium diet. Only PRA remained significantly suppressed in the PHA patients. Thus, sodium restriction and upright posture neutralized most of the differences between patients with PHA and the remaining hypertensive patients, and produced a profound drop in blood pressure in patients with PHA. Characterization of the 11 patients with PHA is provided in Table 5.

Table 4 Response characteristics with dietary sodium restriction and upright posture based on hypertension status
Table 5 Characteristics of patients with primary hyperaldosteronism

Discussion

Prevalence rates play a critical role in determining the appropriate application of screening tests. Screening for a disease with a low prevalence leads to excessive false positives. With regard to PHA, there is consensus that patients with resistant hypertension or hypertension with hypokalaemia should be screened for PHA.5, 10, 11, 12, 13 Less clear, yet of possibly greater concern, is whether to screen the majority of patients who do not have these classical signs or symptoms – those with mild to moderate hypertension and normokalaemia. This group comprises 80–90% of the general hypertensive population that are cared for in the primary care settings.9 The purpose of this study was to determine the prevalence of PHA in a population of hypertensives who may not typically be considered as candidates for screening. In this analysis of a diverse yet strictly controlled group of hypertensive patients, we found the prevalence of PHA to be 3.2%. Since we were unable to determine the underlying cause for aldosterone hypersecretion (i.e. adenoma vs hyperplasia), the prevalence of classical or ‘surgically remedial’ PHA in our population is likely far less than 3.2%.

It should be emphasized that the aim of this study was not to advocate new diagnostic cutoff values or criteria. The strictly controlled study environment outlined in this report would be impractical to duplicate and as mentioned previously invariably leads to different cutoff values than those typically reported. For this reason, we provided normal control data to generate cutoff criteria.

We chose widely accepted screening and diagnostic tests to demonstrate biochemical evidence of PHA. It should be pointed out that all study participants (normotensive and hypertensive) were studied on a high-sodium diet with potassium supplementation. This resulted in laboratory values that may appear different than are reported by some reference laboratories (typically obtained during random sodium and potassium intake). However, this also allowed us to derive cutoff values from the normotensive participants studied under identical conditions. Our ARR value of 25 is similar to that of several prior reports. Our AER of 17 μg/24 h is somewhat higher than the value of 12–14 μg/24 h typically reported.32, 33, 34, 35 This is likely due to controlled potassium supplementation (total potassium intake, 100 mmol/day) in both normotensive and hypertensive populations as evidenced by higher than typical, but equivalent, urine potassium excretion rates of about 70 mmol/day (with unmeasured colonic excretion comprising the difference in intake36) and consequent potassium-mediated stimulation of aldosterone. Incidentally, an AER cutoff value of 14 μg/day (75th percentile) would raise the number of cases of PHA slightly to 15.

A comparison of individuals with PHA vs those without PHA showed significantly lower serum potassium levels and higher blood pressure at both the screening and diagnostic phases of the study. While those with PHA had significantly lower serum potassium levels, as part of the study design none had values below the lower limit of the normal range at time of entry. We found no difference in age between those with or without PHA, as has been reported by others.32, 37

We found that a low-sodium diet with upright posture led to a significant increase in PRA and serum aldosterone even in the PHA group. Interestingly, although PRA was relatively hyporesponsive in PHA patients after sodium restriction when compared to the response in those without PHA, blood pressure, serum potassium, and aldosterone (urine and serum) were not different between groups. This suggests that while PHA is uncommon in mild to moderate hypertensive patients represented by this study cohort its clinical manifestations were abrogated by dietary sodium restriction, albeit to very low levels (10 mmol/day).

Reported prevalence rates of PHA range from 2–30%, with a tendency for higher rates to be reported subsequent to more widespread use of ARR in screening.11, 13, 14, 15, 16, 17, 18 Higher prevalence rates also appear in series from hypertension referral centers, likely due to inherent selection bias (e.g. severe and/or resistant hypertension). Mulatero18 described a multi-national registry advocating widespread use of the ARR in screening for PHA. However, their analysis was performed retrospectively with different laboratory normal values, no normal control group, and was based on a hypertension referral center patient population. Fardella21 described a 10% prevalence rate for PHA among patients recruited from a hypertension referral center. Mosso37 similarly reported prevalence rates of up to 8% in a general hypertensive population. Rossi38 reported a prevalence of PHA at 6.3%, but positive results were based on comparisons to normal laboratory reference ranges and not derived from a control group studied under identical conditions.

The strengths of our findings include a strictly controlled study protocol, a large group of similarly studied normal individuals, and broad multinational and cultural heterogeneity. We also employed a lengthy wash-out period for medications known to influence RAAS activity27, 39, 40, 41 whether or not they are felt to influence the interpretation of screening or diagnostic tests.19, 20

Limitations of this study include shortcomings inherent to a secondary analysis of a data set. Also, we did not have the ability to comment on specific adrenal pathology (e.g. aldosterone producing adenomas or hyperplasia) although it should be realized that these procedures are conducted to determine the etiology of inappropriate aldosterone secretion only after first establishing biochemical evidence of autonomous aldosterone secretion such as demonstrated in this study. Some have advocated qualifying an elevated ARR to include either an elevated aldosterone concentration and/or a fixed, minimum PRA level in order to avoid false positives generated solely from low PRA values.5 In this study, we imposed an elevated serum aldosterone concentration based on results from the normotensive subjects before considering results from the diagnostic test. Had we also applied an absolute PRA cutoff value (0.4 ng/ml/h) the prevalence rate for PHA would have been reduced to 2.5%.

The higher sodium content (approximately 220 mmol/day) and longer duration of dietary sodium intake (7 days) described in this study diet could have led to greater suppression of RAAS activity and thereby influenced our analyses. While the sodium content of most Western diets is in the 140–180 mmol/day range,42 this intake lies on the upper, flat portion of the dose–response curve for RAAS activity.43 The 7-day diet period was chosen based on prior evidence demonstrating an average time to sodium homeostasis of approximately 5 days in hypertensive patients.26 Thus, the longer duration and higher sodium intake would actually reduce the frequency of false positives due to delayed suppression of urine aldosterone excretion, which might have appeared with a shorter period and/or lesser sodium intake.

The findings of sodium responsiveness were under conditions of extreme sodium restriction and therefore not clinically practical to advocate. However, defining a dose–response relationship between sodium intake and haemodynamic and hormonal factor might warrant investigation to determine the potency of sodium restriction in the treatment of PHA.

In summary (Table 6), we found that the prevalence of PHA in a population with mild to moderate hypertension without hypokalaemia was at most 3.2%. Among those with PHA, most of the clinical manifestations were neutralized by dietary sodium restriction. A low prevalence rate might influence screening behaviours in this population.

Table 6 Summary of current literature and contributions from this study

References

  1. 1

    Conn JW . Primary aldosteronism. J Lab Clin Med 1955; 45: 661–664.

    CAS  PubMed  Google Scholar 

  2. 2

    Williams JS, Williams GH . 50th anniversary of aldosterone. J Clin Endocrinol Metab 2003; 88: 2364–2372.

    CAS  Article  Google Scholar 

  3. 3

    McAreavey D, Murray GD, Lever AF, Robertson JI . Similarity of idiopathic aldosteronism and essential hypertension. A statistical comparison. Hypertension 1983; 5: 116–121.

    CAS  Article  Google Scholar 

  4. 4

    Fraser R, Lever AF, Brown JJ, Robertson JI . Cautions over idiopathic aldosteronism. Lancet 2001; 358: 332.

    CAS  Article  Google Scholar 

  5. 5

    Kaplan NM . Cautions over the current epidemic of primary aldosteronism. Lancet 2001; 357: 953–954.

    CAS  Article  Google Scholar 

  6. 6

    Connell JM . Is there an epidemic of primary aldosteronism? J Hum Hypertens 2002; 16: 151–152.

    CAS  Article  Google Scholar 

  7. 7

    Padfield PL . Primary aldosteronism, a common entity? the myth persists. J Hum Hypertens 2002; 16: 159–162.

    CAS  Article  Google Scholar 

  8. 8

    Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004; 351: 33–41.

    Article  Google Scholar 

  9. 9

    Yakovlevitch M, Black HR . Resistant hypertension in a tertiary care clinic. Arch Intern Med 1991; 151: 1786–1792.

    CAS  Article  Google Scholar 

  10. 10

    Litchfield WR, Dluhy RG . Primary aldosteronism. Endocrinol Metab Clin North Am 1995; 24: 593–612.

    CAS  Article  Google Scholar 

  11. 11

    Ganguly A . Prevalence of primary aldosteronism in unselected hypertensive populations: screening and definitive diagnosis. J Clin Endocrinol Metab 2001; 86: 4002–4004.

    CAS  Article  Google Scholar 

  12. 12

    Stowasser M, Gordon RD . Primary aldosteronism – careful investigation is essential and rewarding. Mol Cell Endocrinol 2004; 217: 33–39.

    CAS  Article  Google Scholar 

  13. 13

    Young Jr WF . Minireview: primary aldosteronism – changing concepts in diagnosis and treatment. Endocrinology 2003; 144: 2208–2213.

    CAS  Article  Google Scholar 

  14. 14

    Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC . High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol 1994; 21: 315–318.

    CAS  Article  Google Scholar 

  15. 15

    Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, Klemm SA . Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol 1993; 20: 296–298.

    CAS  Article  Google Scholar 

  16. 16

    Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara M et al. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients. Arch Intern Med 1981; 141: 1589–1593.

    CAS  Article  Google Scholar 

  17. 17

    Streeten DH, Tomycz N, Anderson GH . Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 1979; 67: 403–413.

    CAS  Article  Google Scholar 

  18. 18

    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004; 89: 1045–1050.

    CAS  Article  Google Scholar 

  19. 19

    Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L et al. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension 2002; 40: 897–902.

    CAS  Article  Google Scholar 

  20. 20

    Schwartz GL, Turner ST . Screening for primary aldosteronism in essential hypertension: diagnostic accuracy of the ratio of plasma aldosterone concentration to plasma renin activity. Clin Chem 2005; 51: 386–394.

    CAS  Article  Google Scholar 

  21. 21

    Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 2000; 85: 1863–1867.

    CAS  PubMed  Google Scholar 

  22. 22

    Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young Jr WF . Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab 2000; 85: 2854–2859.

    CAS  PubMed  Google Scholar 

  23. 23

    Stowasser M . Primary aldosteronism: revival of a syndrome. J Hypertens 2001; 19: 363–366.

    CAS  Article  Google Scholar 

  24. 24

    Hambling C, Jung RT, Browning MC, Gunn A, Anderson JM . Primary hyperaldosteronism – evaluation of procedures for diagnosis and localization. Q J Med 1993; 86: 383–392.

    CAS  PubMed  Google Scholar 

  25. 25

    Naomi S, Iwaska T, Umeda T, Inoue J, Hamasaki S, Miura F et al. Clinical evaluation of the captopril screening test for primary aldosteronism. Jpn Heart J 1985; 26: 549–556.

    CAS  Article  Google Scholar 

  26. 26

    Hollenberg NK, Moore T, Shoback D, Redgrave J, Rabinowe S, Williams GH . Abnormal renal sodium handling in essential hypertension. Relation to failure of renal and adrenal modulation of responses to angiotensin II. Am J Med 1986; 81: 412–418.

    CAS  Article  Google Scholar 

  27. 27

    Gordon RD . Primary aldosteronism. J Endocrinol Invest 1995; 18: 495–511.

    CAS  Article  Google Scholar 

  28. 28

    Raji A, Williams GH, Jeunemaitre X, Hopkins PN, Hunt SC, Hollenberg NK et al. Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake. J Hypertens 2001; 19: 99–105.

    CAS  Article  Google Scholar 

  29. 29

    Hopkins PN, Lifton RP, Hollenberg NK, Jeunemaitre X, Hallouin MC, Skuppin J et al. Blunted renal vascular response to angiotensin II is associated with a common variant of the angiotensinogen gene and obesity. J Hypertens 1996; 14: 199–207.

    CAS  Article  Google Scholar 

  30. 30

    Emanuel RL, Cain JP, Williams GH . Double antibody radioimmunoassay of renin activity and angiotensin II in human peripheral plasma. J Lab Clin Med 1973; 81: 632–640.

    CAS  PubMed  Google Scholar 

  31. 31

    Underwood RH, Williams GH . The simultaneous measurement of aldosterone, cortisol, and corticosterone in human peripheral plasma by displacement analysis. J Lab Clin Med 1972; 79: 848–862.

    CAS  PubMed  Google Scholar 

  32. 32

    Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P . Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002; 40: 892–896.

    CAS  Article  Google Scholar 

  33. 33

    Magill SB, Raff H, Shaker JL, Brickner RC, Knechtges TE, Kehoe ME et al. Comparison of adrenal vein sampling and computed tomography in the differentiation of primary aldosteronism. J Clin Endocrinol Metab 2001; 86: 1066–1071.

    CAS  PubMed  Google Scholar 

  34. 34

    Ganguly A . Primary aldosteronism. N Engl J Med 1998; 339: 1828–1834.

    CAS  Article  Google Scholar 

  35. 35

    Bravo EL, Tarazi RC, Dustan HP, Fouad FM, Textor SC, Gifford RW et al. The changing clinical spectrum of primary aldosteronism. Am J Med 1983; 74: 641–651.

    CAS  Article  Google Scholar 

  36. 36

    Kunzelmann K, Mall M . Electrolyte transport in the mammalian colon: mechanisms and implications for disease. Physiol Rev 2002; 82: 245–289.

    CAS  Article  Google Scholar 

  37. 37

    Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F, Montero J et al. Primary aldosteronism and hypertensive disease. Hypertension 2003; 42: 161–165.

    CAS  Article  Google Scholar 

  38. 38

    Rossi E, Regolisti G, Negro A, Sani C, Davoli S, Perazzoli F . High prevalence of primary aldosteronism using postcaptopril plasma aldosterone to renin ratio as a screening test among Italian hypertensives. Am J Hypertens 2002; 15: 896–902.

    CAS  Article  Google Scholar 

  39. 39

    Gordon MS, Williams GH, Hollenberg NK . Renal and adrenal responsiveness to angiotensin II: influence of beta adrenergic blockade. Endocr Res 1992; 18: 115–131.

    CAS  Article  Google Scholar 

  40. 40

    Manhem P, Hokfelt B . Prolonged clonidine treatment: catecholamines, renin activity and aldosterone following exercise in hypertensives. Acta Med Scand 1981; 209: 253–260.

    CAS  Article  Google Scholar 

  41. 41

    Brown MJ, Hopper RV . Calcium-channel blockade can mask the diagnosis of Conn's syndrome. Postgrad Med J 1999; 75: 235–236.

    CAS  Article  Google Scholar 

  42. 42

    Zhou BF, Stamler J, Dennis B, Moag-Stahlberg A, Okuda N, Robertson C et al. Nutrient intakes of middle-aged men and women in China, Japan, United Kingdom, and United States in the late 1990s: the INTERMAP study. J Hum Hypertens 2003; 17: 623–630.

    CAS  Article  Google Scholar 

  43. 43

    Adler GK, Moore TJ, Hollenberg NK, Williams GH . Changes in adrenal responsiveness and potassium balance with shifts in sodium intake. Endocr Res 1987; 13: 419–445.

    CAS  Article  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health grants HL47651, HL59424, HL77234, DK63214, Specialized Center of Research in Hypertension (HL55000), National Center for Research Resources (General Clinical Research Centers) in Boston (M01 RR 02635) and Salt Lake City (M01 RR 00064) and the Department of Veterans Affairs- Health Services Research and Development (TEL-02-100). Dr J Williams was in part supported by a Brigham and Women's Hospital Research Council Dual-mentorship grant. We gratefully acknowledge the assistance of the dietary, nursing, administrative and laboratory staffs of the clinical research centers.

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Williams, J., Williams, G., Raji, A. et al. Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia. J Hum Hypertens 20, 129–136 (2006). https://doi.org/10.1038/sj.jhh.1001948

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Keywords

  • hyperaldosteronism
  • dietary sodium
  • essential hypertension

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