Metabolic syndrome (MS) is frequent clinical condition in patients with hypertension. Primary aldosteronism (PA) is a common form of secondary hypertension. This study was aimed at investigating the prevalence of the MS and its components in the two major forms of PA, in unilateral aldosterone-producing adenoma (APA) and bilateral aldosterone overproduction because of idiopathic hyperaldosteronism (IHA). The diagnosis of the particular form of PA was based on adrenal venous sampling and/or successful surgery confirmed by histopathological examination. We analyzed clinical and laboratory data from 100 patients with PA (50 patients with IHA and 50 patients with APA) and from 90 patients with essential hypertension (EH). Metabolic profiles of patients with bilateral form of PA (because of IHA) were similar to EH, but differed from those in patients with unilateral form of PA (APA). The prevalence of the MS (62% in IHA, 34% in APA and 56% in EH), the body mass index value (30±4 kg m–2 in IHA, 27±5 kg m–2 in APA and 29±5 kg m–2 in EH) and triglycerides levels (1.9±0.9 mmol l–1 in IHA,1.4±0.8 mmol l–1 in APA and 2.01±1.39 mmol l–1 in EH) were all significantly (P<0.05) higher in IHA compared with APA patients. Metabolic profile of patients with bilateral form of PA (because of IHA) is similar to EH in contrast to unilateral form of PA (APA).
The metabolic syndrome (MS) is a common clinical condition that can be found in approximately one-third of patients with essential hypertension (EH). Concurrent metabolic abnormalities in MS include abdominal obesity, dyslipidemia, glucose intolerance and insulin resistance.1 Although the definition of MS varies and divergent mechanisms might be responsible for MS,2 there is evidence that the overall cardiovascular risk accompanying MS may be greater than the sum of its identifiable components.3
Primary aldosteronism (PA) caused by an autonomous aldosterone overproduction is one of the most common form of secondary hypertension. The major forms of PA include idiopathic aldosteronism (IHA) caused by bilateral adrenal hyperplasia and unilateral aldosterone-producing adenoma (APA). Other forms of PA are less common, and include unilateral hyperplasia and rare familial aldosteronism type I and II. According to multicentre PAPY study,4 the prevalence of PA in a non-selected population of hypertensive patients is 11% and even higher (19%) in a preselected population of patients with moderate-to-severe hypertension.5 Recent data show that patients with PA have a significantly higher rate of cardiovascular events than the matched patients with EH.6 The excess of aldosterone might be associated with remodeling of the left ventricle and higher albumin excretion.7, 8 Indeed, as we have shown recently, patients with PA have an increased intima-media thickness of the carotid artery and higher aortic stiffness compared with EH.9, 10
Aldosterone concentrations are elevated in obese and MS patients,11 there is an increasing body of evidence linking elevated plasma aldosterone levels to MS and its components. Clinical evidence also suggests that angiotensin II-stimulated secretion and/or stimulation of aldosterone by adipose tissue may be enhanced in obese subjects.11, 12 It was reported that prevalence of MS in patients with PA is higher compared with EH.13, 14, 15 These results were, however, questioned by recent cross-sectional study of Matrozova et al.,16 in which the investigators found no significant differences in metabolic abnormalities between patients with PA and EH.16 Moreover, in this study, fasting plasma glucose and serum lipids in PA patients were not significantly altered by successful adrenalectomy.16 However, the prevalence of MS in IHA as compared with APA patients was not analyzed in this study. The main objective of our study was therefore to compare the prevalence of MS and its major components in patients with two common forms of PA (IHA, APA) to patients with EH as a control group.
Subjects and methods
We retrospectively studied 190 hypertensive patients in three subgroups matched by age; in 50 patients with IHA, 50 patients with APA and in a control group of 90 patients with EH. Subjects were recruited from patients referred to our hypertension centre in order to exclude secondary hypertension between the years 2002 and 2009. Patients with renal failure were not included in to this study, and all the patients were on a normal sodium/potassium diet with no caloric restrictions.
Previous anti-hypertensive therapy was withdrawn in all patients at least 2 weeks (in case of spironolactone at least 4 weeks) before the investigation in our centre. To standardize the treatment and to eliminate the interference of anti-hypertensive drugs with the renin–angiotensin–aldosterone system, the anti-hypertension therapy for all patients was switched to an α-blocker (doxazosin) and slow-releasing calcium channel blocker (verapamil).17 Patients with hypokalaemia have continued with oral potassium supplementation. The suspicion of PA was based by the findings of aldosterone–renin ratio >40 (ng per 100 ml)/(ng ml–1 h–1), plasma renin activity <0.7 ng ml–1 h–1 and plasma aldosterone >15 ng per 100 ml when measured after 2-h upright position. The diagnosis of PA was confirmed by the lack of aldosterone suppression (<7 ng per 100 ml) after an intravenous saline load (2 l of 0.9% saline infused over 4 h).17 Differential diagnosis of PA forms (IHA and APA) was supported by a computed tomography scan and by a selective adrenal vein sampling (AVS). In addition, the diagnosis of APA was confirmed when successful laparoscopic adrenalectomy was associated with normalization of plasma renin activity and plasma aldosterone levels, and by histological verification. The diagnosis of IHA was based on bilateral aldosterone overproduction assessed by AVS procedure. We used AVS criteria according to a previously published guidelines.17 Success was defined as adrenal vein/inferior vena cava cortisol gradient >2 and the lateralization was considered to be present when the aldosterone/cortisol ratio at one side was four times greater than that in contralateral vein.
All hormonal tests were performed by radioimmunoanalysis using commercially available kits (Immunotech, Beckman Coulter Company, Prague, Czech Republic). All other biochemical parameters were analyzed using multianalyzers (Hitachi 717, Boehringer Mannheim, Germany) in the Institutional Central Laboratory. Adrenal venous sampling was performed without ACTH stimulation as recommended elsewhere.17
Blood pressure measurement
Clinical blood pressure (BP) values were obtained using a validated oscillometric sphygmomanometer (Dinamap, Critikon, Tampa, FL, USA). Three measurements of BP were obtained in the sitting position after a 5-min rest period. Final office BP was calculated as average from the second and third BP readings. The 24-h ambulatory BP monitoring was performed during hospitalization using an oscillometric device (SpaceLabs 90207; SpaceLabs Medical, Redmond, WA, USA).
Definition of MS
We used the International Diabetes Federation 2006 definition of the MS18 and the new common definition for clinical diagnosis of the MS published in 2009.19 Criteria for the International Diabetes Federation 2006 definition of the MS are as follows: presence of central obesity defined as waist circumference with ethnicity-specific values or body mass index (BMI) ⩾30 kg m–2, plus any two of the following factors: (a) triglycerides ⩾1.7 mmol l–1, or specific treatment for this lipid abnormality; (b) high-density lipoprotein (HDL)-cholesterol <1.03 mmol l–1 in males and <1.29 mmol l–1 in females, or specific treatment for this lipid abnormality, (c) systolic BP ⩾130 mm Hg or diastolic BP ⩾85 mm Hg or treatment of previously diagnosed hypertension, (d) fasting plasma glucose ⩾5.6 mmol l–1 or previously diagnosed type 2 diabetes mellitus.18 According to new criteria published in 2009 diagnosis of the MS is based on the presence of any three of the following five risk factors: (1) elevated waist circumference (population- and country-specific definitions), (2) triglycerides ⩾1.7 mmol l–1, or drug treatment for elevated triglycerides, (3) HDL-cholesterol <1.0 mmol l–1 in males and <1.3 mmol l–1 in females, or drug treatment for reduced HDL-cholesterol, (4) systolic BP ⩾130 mm Hg and/or diastolic BP ⩾85 mm Hg, or anti-hypertensive drug treatment in a patient with a history of hypertension and (5) fasting glucose ⩾5.6 mmol l–1, or drug treatment of elevated glucose.19
The differences in clinical and laboratory parameters were studied between individual subgroups of patients as well as between pool of all PA patients (regardless of PA form) and EH patients. The statistical analysis was performed by STATISTICA software version 8 (Statsoft Inc., Tulsa, OK, USA). Data are expressed as means±s.d. and as proportions for continuous and categorical variables, respectively. One-way analysis of variance followed by Newman–Keuls post hoc test was used to compare normally distributed variables between groups. Non-parametric variables were tested with Kruskal–Wallis analysis of variance test. Multivariate regression analysis was used to adjust for differences in baseline clinical variables. P-value <0.05 was considered significant.
The basic characteristics of the studied groups are shown in Table 1. We reported no differences in the duration of hypertension at the time of our investigation among the studied groups. Proportion of patients with MS (according to both definitions, the IDF definition from 2006 and the new common definition from 2009), was significantly higher in IHA compared with APA patients. When we calculated potential differences between men and women in IHA group, because of gender imbalance, only height, body weight and HDL-cholesterol levels were significantly different. All other measured parameters including BMI, cholesterol, triglycerides levels and the prevalence of MS were almost identical in IHA group regardless of the gender (data not shown). According to multivariate model, the differences in the prevalence of the MS remained significant even after adjustment for gender imbalance in both groups (P=0.009 and P=0.003 for MS-IDF and MS-2009, respectively).
There were no differences in the prevalence of diabetes mellitus, impaired glucose tolerance and use of antidiabetic drugs among the three groups. Proportion of patients with hyperlipidemia was higher in the IHA group but we found no significant intergroup differences in the use of antidyslipidemic treatment.
Patients with EH had lower 24-h BP levels compared with PA group, but no significant differences in office BP were noted.
Plasma aldosterone levels, aldosterone–renin ratio and serum potassium levels were, as expected, significantly different between studied groups. Serum sodium concentrations were higher in both forms of PA compared with EH, while serum potassium concentrations were significantly lower in PA. There was no correlation between serum potassium levels and glucose levels (for all tested variables R2<0.03). Serum creatinine concentrations were higher in EH compared with APA. Total cholesterol and HDL-cholesterol levels were higher in EH compared with other two groups. Patients with IHA had compared with APA higher triglycerides concentrations and lower levels of HDL-cholesterol. No differences in glucose levels and microalbuminuria among studied groups were noted.
As a result of the significant differences in the prevalence of the MS (both definition) between IHA and APA patients, we also tested if there are differences in the components of the MS between EH and PA taken altogether as a one group. We found significantly higher plasma cholesterol, low-density lipoprotein-cholesterol and triglycerides levels in EH compared with PA. In spite of these results, 38% of patients in the EH group used lipid-lowering drugs versus 20% in the PA group. PA patients had higher systolic and diastolic BP levels in comparison with EH (data not shown).
We have found metabolic differences between two main forms of PA, for example, IHA and APA. Patients with IHA had significantly higher levels of BMI, triglycerides and markedly lower values of plasma HDL levels compared with APA patients. In concordance with these findings, the prevalence of MS based on two definitions, was also significantly higher in IHA compared with APA. Higher prevalence of MS and metabolic differences was independent of between-group gender imbalance. Metabolic phenotype of IHA patients in our study was similar to EH patients, which is in concordance with the Medical Research Council investigators belief that IHA patients are close to low renin EH.20
The precise mechanisms responsible for higher prevalence of MS in IHA patients compared with APA are not clear and may involve several potential factors such as age or duration of hypertension, dyslipidemia or diabetes mellitus. No significant intergroup differences in age and duration of hypertension, diabetes mellitus or dyslipidemia were, however, noted in our study. Gender imbalance may also have a role, but differences in the prevalence of MS between IHA and APA remained statistically significant even after the adjustment for this factor.
Higher prevalence of MS in IHA patients compared with APA could be due to higher BMI and more frequent abnormalities in lipid profile in IHA patients. Indeed, we noted that more patients were using hypolipidemic drugs in the IHA group as compared with the APA group. Surprisingly, we have, however, did not find any correlation between lipid concentrations and plasma aldosterone values in neither of the two groups (for all tested variables R2<0.06).
Recent cross-sectional studies showed the association between aldosterone concentrations and MS and its components.21, 22 Plasma aldosterone levels are increased in obese hypertensive patients. In the large Italian PAPY study,23 a positive correlation between BMI and plasma aldosterone independently of age, BP, gender and sodium intake was, however, found only in EH and not in PA patients. Our study support this observation—in agreement with the PAPY study23 we also did not find significant correlation between BMI and plasma aldosterone levels. Actually, in our study, plasma levels of aldosterone were higher in patients with APA as compared with patients with IHA.
Hypokalemia is thought of as potentially influencing glucose levels and/or tolerance independently of aldosterone concentrations.24, 25 Potassium can regulate insulin receptor function and glucose-stimulated insulin secretion by β-cells.26 A positive correlation between adiponectine with insulin-sensitizing properties and potassium was recently noted in PA and low renin hypertensive patients.27 Prolonged hypokalemia in PA could thus contribute to low adiponectin levels and insulin resistance. In our study, however, significantly higher plasma potassium concentrations were observed in IHA compared with APA patients. Aldosterone and/or mineralocorticoid receptor activation with its complex metabolic effects might have a more profound effect on insulin sensitivity than does hypokalemia, which is in agreement with our previous clamp study in PA.28 Indeed, in our study, lower potassium levels in APA were not transmitted into intergroup differences in the prevalence of glucose disorders and/or glucose levels between APA and IHA.
Previous observations suggested that mineralocorticoid excess may induce abnormalities in insulin secretion and action11 and, consequently, higher prevalence of hyperglycaemia or diabetes mellitus in patients with PA.11, 12, 13 However, in a recent cross-sectional study no differences in fasting plasma glucose levels were noted in patients with PA and EH.16 This is in agreement with our present study in which we also did not find any significant differences in the fasting plasma glucose levels and prevalence of diabetes mellitus between all groups including EH. Our results are compatible with our earlier findings that in patients with PA there are no differences in the prevalence of diabetes mellitus before and after adrenalectomy.29
Aldosterone can also affect insulin receptor function11, 30 with adverse metabolic consequences. Potential proadipogenic role of aldosterone with subsequent negative effect on insulin sensitivity through production of cytokines (adipocytokines)/fatty acids was reported.11, 30 Differences between the production of various cytokines/fatty acids between two main forms of aldosterone overproduction may thus also have a role. It has been shown that metabolic parameters in PA and EH are related to adiponectin gene variants.15 We cannot therefore exclude the possibility that differences in adiponectin gene polymorphism between IHA and APA do not contribute to different metabolic phenotypes observed in our study.
Another possibility is that the mineralocorticoid receptor, expressed in adipose tissue, or its activation, may have an important role in the development of MS,25 and variations in mineralocorticoid receptor and/or activation of mineralocorticoid receptor may also contribute to observed metabolic differences between two major forms of PA.
In the study from Fallo et al.13 a higher prevalence of the MS in patients with PA compared with EH was reported, but this difference was due to higher plasma glucose levels in patients with PA, which could be related to a higher prevalence of diabetes mellitus.31 In our study, there were no significant differences in the prevalence of diabetes mellitus, higher plasma glucose levels or use of antidiabetic drugs among all studied groups.
Our data differs from those of previous cross-sectional study of Matrozova et al.,16 in which no significant differences in metabolic abnormalities in the different subtypes of PA and EH patients were noted. The classification of various forms of PA in the study of Matrozova (lateralized, nonlateralized, undetermined PA) does not, however, enable to clearly define the forms of PA according the guidelines17 because AVS was not performed in all patients and no histopathological data were given in operated patients. Regardless of these findings, it is evident that MS in patients with EH and PA (IHA) is frequent and may contribute to high cardiovascular risk.6, 32
Our study may be limited by its retrospective design because of relatively lower number of new patients with PA analyzed by AVS every year. This is caused by the fact, that approximately 30% of new PA patients in our centre refuse potential surgical approach and therefore AVS is not performed.
In conclusion, our data indicate that PA with bilateral overproduction (IHA) has a higher occurrence of metabolic abnormalities, including MS, in comparison with APA. IHA is a common form of PA, which seems to be metabolically similar to EH. Higher prevalence of MS in IHA may thus result also in higher cardiometabolic risk.
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This work was supported by Research projects from Czech Ministry of Education, Youth and Sports No: 21620807 and 21620817.
The authors declare no conflict of interest.
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Šomlóová, Z., Widimský, J., Rosa, J. et al. The prevalence of metabolic syndrome and its components in two main types of primary aldosteronism. J Hum Hypertens 24, 625–630 (2010). https://doi.org/10.1038/jhh.2010.65
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