Recently published studies from different parts of the world report significantly higher prevalence of primary hyperaldosteronism (PH) in hypertensives (ranging from 5 to 25%) than the previously accepted figures. There have been no data so far about the prevalence of PH in Central Europe. Therefore, we have undertaken this study to evaluate the prevalence of PH in patients with moderate to severe hypertension referred to a hypertension unit in the Czech Republic, together with the determination of the percentage of different subtypes of PH including familial forms. In addition to that, we have evaluated the prevalence of other types of secondary forms of hypertension.
A total of 402 consecutive patients (230 females and 172 males) with hypertension, referred to our hypertension unit, were studied. Positive aldosterone/renin ratio (ARR, (ng/100 ml)/(ng/ml/h)) 50 as a more strict marker of PH was found in 87 patients (21.6%), 30% of them were normokalaemic. The diagnosis of PH was later confirmed in 77 cases (89%); the total prevalence of PH was thus 19%. PH consisted of the following forms: idiopathic hyperaldosteronism 42%, unilateral aldosterone-producing adenoma 36%, unilateral hyperplasia 7%, nonclassifiable PH (refused operation/adrenal venous sampling) 13%, familial hyperaldosteronism type 1.2%. The prevalence of other types of secondary hypertension was as follows: pheochromocytoma 5%, renovascular 4.5%, hypercortisolism 2%, renal 0.75%.
In conclusion, we have noted that PH in the Central Europe region (Czech Republic) is the most frequent form of endocrine hypertension with a considerably high prevalence in moderate to severe hypertension. Application of more strict criteria raises the probability of correct diagnosis of PH including the early normokalaemic stages of PH.
Conn,1,2 who first described the cure of a patient with primary hyperaldosteronism (PH) in 1954, recognised that hypokalaemia was not present in all cases of PH and suggested, that normokalaemic PH may masquerade as essential hypertension and thus the prevalence could be higher. This idea was at that time rejected and forgotten for nearly 40 years and PH was considered to be rare. In the early 1980s Hiramatsu et al3 described the utility of aldosterone/renin ratio (ARR) and reported a prevalence of 2.6%. The utility of ARR has been further explored, and in the 1990s many studies were reported with prevalence ranging from 5 to 25%.4,5,6,7 The apparent differences in the described prevalences of PH in these studies may reflect different selection criteria/design and/or potential geographical differences in the occurrence of PH.
Another important finding is that normokalaemia does not exclude the diagnosis of PH. In the case of the positive screening test, the diagnosis must be confirmed by suppression tests (fludrocortisone or salt loading test) and morphological methods (CT or MRI scan). Adenomas/hyperplasias <1 cm could be possibly missed on CT scan and therefore, if suppression tests confirm the diagnosis of PH, adrenal venous sampling (AVS) is indicated.8 Furthermore, the use of ARR as the screening test has important clinical implications— more patients would be diagnosed and possibly cured when surgically treated. However, the indi-cations for the use of the ARR in all hypertensive patients still remain controversial—some authors dispute the validity of such an application.9 Another problem is that different diagnostic criteria are being used—ARR values ranging from 20 to 50.
So far there have been no data about the prevalence of PH in Central Europe (Czech Republic). Therefore, we have undertaken this study to evaluate the prevalence of primary aldosteronism in patients with moderate to severe hypertension referred to a hypertension unit in this area, together with the determination of the percentage of different subtypes of PH. We have used stricter screening criteria (ARR 50) for PH. Additionally, we have evaluated the prevalence of other types of endocrine-mediated and secondary hypertension.
Subjects and methods
We have studied 402 consecutive hypertensive subjects from all regions of the Czech Republic in 1997–2001, most of them with moderate to severe hypertension who were examined in our hypertension unit. The group consisted of 172 men and 230 women of mean age 51 years. All patients discontinued their usual antihypertensive therapy at least 14 days before admission to the hospital and were given only alpha-blockers depen-ding on the blood pressure (BP) (the medication was withdrawn and patients were followed up by the GPs). All subjects underwent diagnostic workup during short hospitalisation (3–5 days), which consisted of a variety of laboratory and morpho-logical methods to exclude potential secondary forms of hypertension.
We measured office BP (by a mercury sphygmomanometer in the sitting position according to ISH recommendations) and also performed 24-h ambulatory blood pressure monitoring (ABPM) (Spacelabs 90207, Redmont, CA, USA) in all subjects.
Blood samples were taken for electrolytes as well as for hormonal tests including PRA and aldosterone in both recumbent and upright positions. All hormonal parameters were calculated by the usual commercial methods. Aldosterone and renin concentrations were measured using commercial RIA methods (Immunotech, France). Our laboratory's aldosterone normal reference values were 20–150 ng/l and PRA 0.7–2.6 ng/ml/h. (The conversion between units used for aldosterone levels is as follows: to get aldosterone in pmol/l, multiply aldosterone in ng/100 ml by 27.7.) We have calculated the ARR (ng/100 ml)/(ng/ml/h) in all 402 patients both in recumbent and upright positions. The criterion for provisional diagnosis of PH was the ARR 50 (PRA and aldosterone levels measured after 2 h upright position). The confirmation of the diagnosis of PH was based on (1) elevated ARR (50 ng/l), (2) suppressed PRA (0.7 ng/ml/h) and elevated plasma aldosterone (150 ng/l) levels, and (3) the absence of or mild suppression of plasma aldosterone after saline infusion (plasma aldo-sterone 85 ng/l) as previously described.10 The suppression test was performed in the morning after at least 8 h of recumbent position. In patients who were treated by adrenalectomy, the diagnosis was also confirmed by histology. The adrenal CT scan was performed in all the patients screened positive for PH. In all, 20 patients also underwent adrenal venous sampling in order to further differentiate the subtypes of PH.
Genetic screening for the exclusion of dexamethasone-suppressible hyperaldosteronism was also performed in patients with PH. The molecular genetic test can be performed with a single PCR according to our previously published procedure.11,12
Other potential secondary causes of hypertension were confirmed by means of the usual morphological and laboratory methods. In case no secondary cause was elucidated, the patient was considered to have ‘essential’ hypertension.
ARR50 was found in 87 patients (21.6%). In all, 30% of them were normokalaemic. The diagnosis of PH was confirmed by the criteria described earlier in this text in 77 cases of the 87 (89%); the total prevalence is hence 19%. The prevalence of PH and other types of secondary hypertension is shown in Figure 1 (PH 19%, pheochromocytoma 5%, renal artery stenosis (renovascular) 4%, hypercortisolism 2%, renal hypertension 1%). Basic characteristics of the patients with PH are shown in Table 1.
Basic characteristics of all the hypertensive patients and hypertensive patients without PA are shown in Table 2.
The presence of the different forms of PH is shown in Figure 2 (idiopathic hyperaldosteronism 42%, aldosterone-producing adenoma 36%, unilateral hyperplasia 7%, nonclassifiable PA (refused operation, adrenal venous sampling) 13%, familial hyperaldosteronism type I 2%).
We have demonstrated a relatively high prevalence of PH in patients with moderate to severe hypertension in our study. Our study is, to our knowledge, the first one related to the Central Europe region. In concordance with the results of earlier prevalence studies,3,4,5,6,7 we have confirmed that PH is not as rare as was previously thought and appears to be the most frequent form of endocrine-mediated hypertension. It thus appears that there are no major geographical differences in the occurrence of PH. As of the percentage of the subtypes of PH, the majority of our patients had idiopathic hyperaldosteronism with bilateral overproduction. One-third of our patients had an aldosterone-producing adenoma later confirmed by histology. In 7% of patients with PH after diagnosing unilateral overproduction by AVS, unilateral adrenalectomy was indicated with the histologic finding of hyperplasia.
Unfortunately, a smaller percentage of our patients rejected further examination (adrenal venous sampling) after having normal CT scan and therefore spironolactone therapy was started.
Familial hyperaldosteronism type I (glucocorticoid-remediable aldosteronism, GRA) was relatively rare. In addition to our previously described family with GRA,12 we have found only one other case.
The ARR is a very useful tool as a screening test for diagnosing PA in patients with moderate to severe hypertension even in the absence of hypokalaemia. According to previous data, the use of stricter ARR criteria (ARR50 (ng/100 ml)/(ng/ml/h) increases the probability of diagnosis of PA.4 We confirmed this observation since in our study in 89% of patients with ARR equal to or higher than 50 the diagnosis was confirmed. This stricter screening marker thus appears to be clinically more reliable than frequently used ARR 20–30.13,14 There is an ongoing debate about the use of ARR as a screening test in all hypertensive subjects.9 Our policy to use the ARR in all patients with moderate to severe hypertension and also in those with suggestive laboratory/morphological findings was substantiated by the results of this study. The proportion of normokalaemic patients in our study was 30% less than previously published—the higher prevalence of hypokalaemia might be because of some degree of preselection.
The results of our study also have limitations—the patients referred to our unit might have been in some way preselected, and it would be difficult to predict the prevalence in the general hypertensive population. However, the nonselective hypertensive population is difficult to define.15 On the other hand, all our patients were consecutively referred and no patient was rejected. Our data may thus apply to patients with moderate to severe hypertension.
In conclusion, we have noted that PA is the most frequent form of endocrine hypertension with a considerably high prevalence in moderate to severe hypertension in the Czech Republic. Idiopathic hyperaldosteronism may represent the common form of PH, while familial hyperaldosteronism ap-pears to be rare. The use of more strict screening cri-teria raises the probability of correct diagnosis of PA including the early normokalaemic stages of PA.
This study was supported by Project No J 13198: 11110000-2 of the Ministry of Education, Youth and Sports of the Czech Republic
About this article
Journal of Human Hypertension (2014)