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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1733
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 2 454-459
Copyright © 2006 by The Endocrine Society

Prevalence and Characteristics of the Metabolic Syndrome in Primary Aldosteronism

Francesco Fallo, Franco Veglio, Chiara Bertello, Nicoletta Sonino, Paolo Della Mea, Mario Ermani, Franco Rabbia, Giovanni Federspil and Paolo Mulatero

Departments of Medical and Surgical Sciences (F.F., P.D.M., G.F.), Statistical Sciences (N.S.), and Neurosciences, Biostatistical Section (M.E.), University of Padova, 35128 Padova, Italy; and Department of Medicine and Experimental Oncology, Hypertension Unit, University of Torino (F.V., C.B., F.R., P.M.), 10133 Torino, Italy

Address all correspondence and requests for reprints to: Dr. Francesco Fallo, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale 105, 35128 Padova, Italy. E-mail: francesco.fallo{at}unipd.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Patients with hypertension have a high prevalence of concurrent metabolic abnormalities, including obesity, dyslipidemia, and hyperglycemia. Clustering of these cardiovascular risk factors, defined as metabolic syndrome, causes a more pronounced target organ damage. Aldosterone excess has been found to be associated with glucose disorders and may contribute to cardiovascular damage.

Objective: The aim of our study was to assess the prevalence and the characteristics of the metabolic syndrome in a group of patients with hypertension due to primary aldosteronism compared with patients with essential hypertension.

Methods: The National Cholesterol Education Program Adult Treatment Panel III definition of the metabolic syndrome was used. Eighty-five patients with primary aldosteronism and 381 patients with essential hypertension were studied. Most patients were not receiving antihypertensive therapy during the investigation.

Results: Blood glucose and systolic blood pressure were higher (P < 0.05 and P < 0.01, respectively) and duration of hypertension was longer (P < 0.05) in primary aldosteronism than in essential hypertension. The prevalence of metabolic syndrome was higher in primary aldosteronism than in essential hypertension (41.1% vs. 29.6%; P < 0.05). Distribution of single components of the metabolic syndrome other than hypertension showed a higher prevalence of hyperglycemia in primary aldosteronism than in essential hypertension (27.0% vs. 15.2%; P < 0.05).

Conclusions: Our findings confirm a negative effect of aldosterone excess on glucose metabolism and suggest that the recently reported higher rates of cardiovascular events in primary aldosteronism than in essential hypertension might be due to increased prevalence of the metabolic syndrome in the former condition.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
METABOLIC ABNORMALITIES SUCH as dyslipidemia, diabetes, and obesity are more frequent in hypertensive than in normotensive subjects (1, 2, 3), and clustering of these factors in hypertension is associated with an overall high cardiovascular risk profile (4). Different terms were used by clinical investigators to define these metabolically linked cardiovascular factors, including syndrome X, insulin resistance syndrome, and metabolic syndrome (5, 6, 7, 8). Definitions were largely derived from the perspective of hyperinsulinemia and insulin resistance (9, 10) and thus were difficult to translate into clinical practice. The National Cholesterol Education Program Adult Treatment Panel III has recently proposed a definition of the metabolic syndrome based on three or more of the following five clinical variables: blood pressure, abdominal adiposity (given as waist circumference), and fasting values of high-density lipoprotein (HDL) cholesterol, triglycerides, and glucose (11).

Cross-sectional and prospective studies from Italy have shown that essential hypertensive patients with the metabolic syndrome, as defined by the Adult Treatment Panel III, have more pronounced target organ damage than those without it (12, 13, 14). A number of experimental and clinical studies recently indicated aldosterone to be a potential cardiovascular risk factor (15, 16). It seems that aldosterone excess may lead to cardiovascular damage involving mechanisms independent of its effect on blood pressure (17). A high prevalence (10–50%) of glucose intolerance and/or diabetes has been reported in primary aldosteronism, and metabolic disturbances were corrected by surgical removal of the aldosterone-producing adenoma (18, 19). This was acknowledged by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (20). A recent clinical study reported that patients with primary aldosteronism experience a higher rate of cardiovascular events than those with essential hypertension, but the importance of concurrent metabolic alterations was not addressed (21). Our study focused on the prevalence of the metabolic syndrome and its different components in a large series of patients with primary aldosteronism compared with a group of patients with essential hypertension and on the distribution and aggregation of single metabolic abnormalities in the two populations.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

In this prospective study, a total of 466 hypertensive patients, subdivided into 85 patients with primary aldosteronism and 381 patients with essential hypertension, were studied over the last 3 yr. All patients were referred to our two hospital-based specialized hypertension out-patient clinics. The reasons for patient referral were (22) onset of hypertension at young age, hypertension resistant to conventional antihypertensive therapy, hypertension with unexplained spontaneous or diuretic-induced hypokalemia, high plasma aldosterone, low plasma renin activity (PRA), and adrenal incidentaloma. Patients with clinical and/or laboratory evidence of associated clinical conditions, such as cerebrovascular, coronary, or peripheral artery disease; cardiac insufficiency; or renal and/or hepatic disease, and patients with a history of cardiovascular and cerebrovascular events were excluded. Renal disease was defined as the presence of serum creatinine levels greater than 133 µmol/liter in men and greater than 120 µmol/liter in women and/or albuminuria greater than 300 mg/d (23). The total number of patients who met the exclusion criteria were 11 with primary aldosteronism and 57 with essential hypertension. All blood pressure measurements were performed according to the World Health Organization International Society of Hypertension (24) as previously described (25). Most of the individuals were receiving antihypertensive treatment at presentation. For those taking medications, any agent was withdrawn at least 3 wk (up to 2 months for spironolactone) before hemodynamic, biochemical, and hormonal evaluations. In 135 patients (29%) in whom treatment could not be withdrawn for ethical reasons, a calcium channel blocker and/or an {alpha}-receptor blocker were allowed at the minimal doses required to achieve blood pressure control. These agents are known to have a neutral effect on renin and aldosterone levels (26) and not to impair glucose and lipid parameters (27, 28). In patients taking hypoglycemic or lipid-lowering drugs, treatment was withdrawn at least 1 and 3 wk before biochemical evaluation, respectively. No patient was taking glitazones. No patient was receiving insulin treatment. Patients smoking at least one cigarette daily for 1 yr in the last year were considered current smokers. Alcohol intake was assessed by multiplying the mean daily consumption for each beverage by ethanol content to give grams of alcohol per day. Patients consuming more than 40 g alcohol/d for males and more than 20 g alcohol/d for females in the last year were considered current drinkers. The duration of hypertension was obtained by careful investigation of the patient’s history and from family practitioner records.

After the first visit to our clinic, all patients were subjected to all diagnostic procedures. During this time, they consumed a normal sodium and potassium diet, i.e. 100–200 mmol/d sodium and 50–70 mmol/d potassium. The criteria used for the differential diagnosis of the different forms of primary aldosteronism and essential hypertension were previously described (29). Briefly, for diagnosis of primary aldosteronism, all patients with an upright plasma aldosterone (nanograms per deciliter)/PRA (nanograms per milliliter per hour) ratio greater than 40 in the presence of aldosterone greater than 15 ng/dl and suppressed PRA underwent saline infusion (0.9% 500 ml/h NaCl for 4 h) as a confirmatory test (30). Patients with plasma aldosterone levels that failed to fall below 5 ng/dl after the saline infusion were diagnosed as having primary aldosteronism. In these patients, a computed tomography scan with fine cuts (2.5–3 mm) of the adrenal and/or adrenal venous sampling were performed to differentiate between aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia, i.e. idiopathic hyperaldosteronism (IHA), resulting in 29 APA and 56 IHA. Adrenal vein cannulation was considered successful if the adrenal vein/inferior vena cava cortisol gradient was at least 2; lateralization was considered when the aldosterone/cortisol ratio from one adrenal was at least 4 times the ratio from the contralateral gland. Because only some of the patients (69%) underwent adrenal venous sampling, the proportions of the two subgroups of patients could be different due to underestimation of APA by the computed tomography scan (31). In all 24 subjects who underwent unilateral adrenalectomy, an adrenal adenoma was confirmed at surgery and histological examination. The presence of the inherited syndrome of glucocorticoid-remediable hyperaldosteronism was excluded by a long PCR test, as previously described (32). Among patients with primary aldosteronism who met the general exclusion criteria, four patients had APA, and seven patients had IHA. Other forms of secondary hypertension were excluded on the basis of standard biochemical, hormonal, and instrumental tests. Left ventricular hypertrophy (LVH) was diagnosed according to the Cornell voltage duration product (>2240) or the Sokolow-Lyon criteria (>38 mV) on electrocardiogram.

Each subject provided informed consent for the study, which was approved by institutional ethics committee.

Definition of metabolic syndrome

The Adult Treatment Panel III clinical definition of the metabolic syndrome requires three or more of the following findings: 1) abdominal obesity (waist circumference, >102 cm in men and >88 cm in women); 2) triglycerides 1.69 mmol/liter or greater; 3) HDL cholesterol less than 1.03 mmol/liter for men and less than 1.29 mmol/liter for women; 4) fasting glucose 6.1 mmol/liter or greater; and 5) systolic blood pressure 130 mm Hg or more and diastolic blood pressure 85 mm Hg or more. The waist circumference measurement, taken as the reference measure of abdominal obesity, was made at minimal inspiration to the nearest 0.1 cm, midway between the last rib and the iliac crest.

Laboratory methods

Blood samples for biochemical and endocrine-metabolic profiles were obtained at 0800 h after overnight fasting. For PRA and aldosterone measurements, patients were left in the recumbent position for 1 h before supine samples and for 2 h in an upright position before upright samples. PRA and aldosterone were measured as previously described (33). Briefly, PRA and aldosterone were determined by RIA with kits purchased from Sorin Biomedical Diagnostics (Saluggia, Italy). The intra- and interassay coefficients of variation for PRA were 5.4% and 9.1%, respectively; the normal range was 0.4–3.0 ng/ml·h supine and 1.5–5.2 ng/ml·h upright. The lower limit of detection for the PRA assay was 0.1 ng/ml·h. The intra- and interassay coefficients of variation for aldosterone were 7.9% and 9.6%, respectively; the normal range was 2–12 ng/dl supine and 5–30 ng/dl upright. All other biochemical variables were assayed in plasma or serum using standard methods.

Statistical analysis

All results are expressed as the mean ± SD for continuous variables and as a proportion for categorical variables. Continuous data were subjected to the Kolmogorov-Smirnov test to determine their distribution. Statistical significance between groups was assessed in normally distributed data by Student’s t test for independent samples and in nonnormally distributed data by the Mann-Whitney U test. Categorical variables were analyzed by {chi}2 analysis or Fisher’s exact test when appropriate. To test the association of factors with the presence of LVH, we entered into the univariate analysis only variables significantly different at baseline between the group with essential hypertension and the group with primary aldosteronism, i.e. aldosterone, PRA, potassium, systolic blood pressure, duration of hypertension, and all other components of the metabolic syndrome. Multiple logistic regression analysis was then used to find the independent factors associated with LVH, considering only the variables previously shown by the univariate analysis to be significantly associated with this parameter. Pearson’s correlation coefficient was calculated to test for a correlation between variables. P < 0.05 was considered statistically significant. Statistical analyses were performed using STATISTICA 6.0 (StatSoft, Tulsa, OK) for Windows.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Details of the two populations are reported in Table 1Go. As expected, plasma aldosterone, PRA, aldosterone/PRA ratio, and serum potassium were significantly different in the essential hypertension patients compared with the primary aldosteronism group. Mean blood glucose and systolic blood pressure levels were significantly higher (P < 0.05 and P < 0.01, respectively) and duration of hypertension was longer (P < 0.05) in primary aldosteronism than in essential hypertension. LVH was more frequent (P < 0.05) in primary aldosteronism than in essential hypertension. In the univariate analysis, only systolic blood pressure (P < 0.01) and duration of hypertension (P < 0.05) were associated with LVH. In the multivariate analysis, the factors independently associated with LVH remained systolic blood pressure (P < 0.01) and duration of hypertension (P < 0.05). No correlation between aldosterone (or serum potassium) and any other component of the metabolic syndrome was found in either primary aldosteronism or essential hypertension.


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  		TABLE 1. Baseline characteristics of patients with primary aldosteronism and essential hypertension, with and without the metabolic syndrome (MS)

 
Patients with primary aldosteronism (either APA or IHA subtype) had a significantly higher prevalence of the metabolic syndrome than essential hypertensive patients (35 of 85, i.e. 41.1%, vs. 113 of 381 patients, i.e. 29.6%, respectively; P < 0.05). In particular, the different combinations of metabolic syndrome components among all patients with the metabolic syndrome in the two populations are shown in Table 2Go.


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  		TABLE 2. Different combinations of metabolic syndrome (MS) components among all patients with MS in the two populations

 
The distribution of single metabolic syndrome components other than hypertension is shown in Table 3Go. In primary aldosteronism, a high waist circumference occurred most frequently, followed by hypertriglyceridemia, whereas high fasting plasma glucose was third, and low HDL cholesterol was last. In essential hypertension, a high waist circumference occurred most frequently, followed by hypertriglyceridemia, low HDL cholesterol, and high fasting glucose. The overall prevalence of hyperglycemia was higher in primary aldosteronism than in essential hypertension (23 of 85 patients in primary aldosteronism, i.e. 27.0%, vs. 58 of 381 patients in essential hypertension, i.e. 15.2%; P < 0.05). If the distribution of the components was considered only in patients with the metabolic syndrome from each group, the prevalence of hyperglycemia remained higher in primary aldosteronism than in essential hypertensive patients despite the much smaller number of patients included in the statistical analysis (19 of 35 in primary aldosteronism, i.e. 54.2%, vs. 39 of 113 in essential hypertension, i.e. 34.5%; P < 0.05). The proportion of patients found to have diabetes mellitus, i.e. those with fasting plasma glucose levels above 7.0 mmol/liter on two separate occasions (20), was higher in primary aldosteronism than in essential hypertension patients (seven of 85, i.e. 8.2%, vs. 13 of 381 patients, i.e. 3.4%; P < 0.05). Also, the proportion of patients with primary aldosteronism taking hypoglycemic agents before the study was higher than in patients with essential hypertension (six of 85, i.e. 7.0%, vs. nine of 381 patients, i.e. 2.3%; P < 0.05). At variance, the proportion of patients with primary aldosteronism taking lipid-lowering drugs before the study was not different from that of patients with essential hypertension (four of 85, i.e. 4.7%, vs. 19 of 381 patients, i.e. 4.9%; not significant).


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  		TABLE 3. Prevalence (percentage) of the individual components of metabolic syndrome (MS) in the two populations

 
The two subgroups of APA and IHA were similar in age, sex, body mass index, creatinine, and all components of the metabolic syndrome (including blood pressure, duration of hypertension, proportions of smokers and alcohol drinkers, and proportion of patients with LVH; data not shown). However, APA patients had a lower serum potassium level (3.27 ± 0.7 vs. 3.89 ± 0.6 mmol/liter; P < 0.01), a higher plasma aldosterone level (54.2 ± 30.6 vs. 26.6 ± 8.3 ng/dl; P < 0.001), and a higher aldosterone/PRA ratio (352 ± 243 vs. 185 ± 103; P < 0.001) than IHA patients.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study indicates that patients with primary aldosteronism (APA or IHA subtype) have a significantly higher prevalence of metabolic syndrome, as defined by Adult Treatment Panel III criteria, than essential hypertensive patients (41.1% vs. 29.6%; P < 0.05). The prevalence of the metabolic syndrome in our essential hypertensive patients was higher, as expected, than that reported in a general population (23.1%) with similar demographic characteristics recruited in the same geographical area of Italy (33) and was similar to that reported in recent studies of essential hypertensive cohorts in Italy (12, 13, 14).

The known duration of hypertension was longer, and systolic blood pressure was significantly higher in primary aldosteronism than in essential hypertension. This is not surprising, based on previous observations of refractoriness to therapy (34) and greater severity of hypertension (35) in primary aldosteronism compared with essential hypertension. Because both the duration of hypertension and systolic blood pressure levels were not different in patients with and without the metabolic syndrome, a causal relationship of these variables with the development of the metabolic syndrome seems unlikely. The distribution of single components of the metabolic syndrome other than hypertension showed that only hyperglycemia was significantly more prevalent in primary aldosteronism than in essential hypertension (27.0% vs. 15.2%; P < 0.05). Moreover, the proportion of patients taking glucose-lowering agents before the study or with diabetes was significantly higher in primary aldosteronism than in essential hypertension. Analyzing the order of prevalence of each component of the metabolic syndrome, high waist circumference was the most frequent in both essential hypertension and primary aldosteronism. Therefore, in our patients the higher prevalence of the metabolic syndrome in primary aldosteronism than in essential hypertension was mainly due to the association of hypertension, hyperglycemia, and high waist circumference. Within patients with the metabolic syndrome, the prevalence of hyperglycemia was confirmed to be significantly higher in primary aldosteronism than in essential hypertension. In contrast, low HDL cholesterol was the most potent discriminant between the presence and absence of the metabolic syndrome in either primary aldosteronism (45.7% vs. 4.0%) or essential hypertension (48.6% vs. 6.3%). Thus, low HDL cholesterol seems to be strongly associated with this condition. Waist circumference was the least discriminant variable.

The main finding of our study was indeed the higher frequency of altered glucose metabolism, alone or as a component of the metabolic syndrome, in patients with primary aldosteronism than in those with essential hypertension. Aldosterone overproduction could have induced a blood glucose elevation, increasing the probability for the occurrence of the metabolic syndrome compared with patients with essential hypertension and normal aldosterone levels. Previous studies in a small clinical series of patients reported glucose intolerance (36) and reduced insulin sensitivity in primary aldosteronism, probably due to a direct effect of aldosterone on insulin receptor function (18, 37). Insulin resistance was initially ascribed to the effect of hypokalemia per se on insulin receptors (38), whereas subsequent observations have shown its persistence in patients with primary aldosteronism during potassium infusion given to maintain normal serum potassium levels and eliminate hypokalemia as a confounding factor (39). However, whether potassium repletion improves glucose tolerance in primary aldosteronism is unclear. Also, in experimental studies, extracellular potassium has been found to stimulate insulin release by ß-cells (40); thus, serum potassium changes may be potentially involved in the regulation of insulin secretion (41). The pathogenetic contributions of aldosterone excess and/or hypokalemia to the glucose disturbances in primary aldosteronism remain to be elucidated.

A higher prevalence of the metabolic syndrome, in particular of a more frequent alteration of glucose metabolism in primary aldosteronism, may contribute to the increased cardiovascular risk in this hypertensive state. The metabolic syndrome has, in fact, been shown in epidemiological studies to be associated with the risk of both type 2 diabetes mellitus (42) and cardiovascular disease (43). In our study the presence of LVH as a potent "bioassay" of cardiovascular disease (44) in the two patient populations was assessed. In agreement with a number of reports using echocardiography, a greater prevalence of LVH was found in primary aldosteronism than in essential hypertension (45, 46), with no difference in LVH between patients with the metabolic syndrome and those without it. These results in essential hypertensive patients are in accordance with some previous studies (12, 47) and at variance with others (13, 14). Multiple regression analysis showed that only systolic blood pressure and duration of hypertension, but neither all other components of the metabolic syndrome nor aldosterone levels, were independently associated with LVH in our patients, as observed in a general population (48). Systolic hypertension as the component of the metabolic syndrome most strongly associated with LVH in primary aldosteronism does not exclude that aldosterone may act as a cardiovascular risk factor through mechanisms independent from cardiac cell hypertrophy and hyperplasia (49). In this regard, insulin is a known determinant of vascular function, and insulin resistance is associated with impaired vascular nitric oxide synthase activity and reduced nitric oxide production (50, 51). Our findings confirm a negative effect of aldosterone excess on glucose metabolism and suggest that the recently reported higher rates of cardiovascular events in primary aldosteronism than in essential hypertension (21) might be due to increased prevalence of the metabolic syndrome in the former condition.


   Footnotes
 
First Published Online November 15, 2005

Abbreviations: APA, Aldosterone-producing adenoma; HDL, high-density lipoprotein; IHA, idiopathic hyperaldosteronism; LVH, left ventricular hypertrophy; PRA, plasma renin activity.

Received August 2, 2005.

Accepted November 4, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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