Journal of Human (2003) 17, 349–352 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region

BSˇ trauch1, T Zelinka1, M Hampf2, R Bernhardt3 and J Widimsky Jr1 13rd Department of Medicine, First Faculty of Medicine, Charles University, General Faculty Hospital, Prague, Czech Republic; 2Max Delbruck Centrum fu¨r Molekula¨re Medizin, Berlin, Germany; 3Universita¨t des Saarlandes, Fachbereich Biochemie, Saarbru¨cken, Germany

Recently published studies from different parts of the confirmed in 77 cases (89%); the total prevalence of PH world report significantly higher prevalence of primary was thus 19%. PH consisted of the following forms: hyperaldosteronism (PH) in hypertensives (ranging from idiopathic hyperaldosteronism 42%, unilateral aldoster- 5 to 25%) than the previously accepted figures. There one-producing adenoma 36%, unilateral 7%, have been no data so far about the prevalence of PH in nonclassifiable PH (refused operation/adrenal venous Central Europe. Therefore, we have undertaken this sampling) 13%, familial hyperaldosteronism type 1.2%. study to evaluate the prevalence of PH in patients with The prevalence of other types of secondary hyperten- moderate to severe hypertension referred to a hyperten- sion was as follows: pheochromocytoma 5%, renovas- sion unit in the Czech Republic, together with the cular 4.5%, hypercortisolism 2%, renal 0.75%. determination of the percentage of different subtypes In conclusion, we have noted that PH in the Central of PH including familial forms. In addition to that, we Europe region (Czech Republic) is the most frequent have evaluated the prevalence of other types of form of endocrine hypertension with a considerably secondary forms of hypertension. high prevalence in moderate to severe hypertension. A total of 402 consecutive patients (230 females and Application of more strict criteria raises the probability 172 males) with hypertension, referred to our hyperten- of correct diagnosis of PH including the early normoka- sion unit, were studied. Positive / ratio laemic stages of PH. (ARR, (ng/100 ml)/(ng/ml/h)) X50 as a more strict marker Journal of Human Hypertension (2003) 17, 349–352. of PH was found in 87 patients (21.6%), 30% of them doi:10.1038/sj.jhh.1001554 were normokalaemic. The diagnosis of PH was later

Keywords: ; prevalence; aldosterone–renin ratio

Introduction prevalence ranging from 5 to 25%.4–7 The apparent

1,2 differences in the described prevalences of PH in Conn, who first described the cure of a patient these studies may reflect different selection criteria/ with primary hyperaldosteronism (PH) in 1954, design and/or potential geographical differences in recognised that hypokalaemia was not present in the occurrence of PH. all cases of PH and suggested, that normokalaemic Another important finding is that normokalaemia PH may masquerade as essential hypertension and does not exclude the diagnosis of PH. In the case thus the prevalence could be higher. This idea was of the positive screening test, the diagnosis must at that time rejected and forgotten for nearly 40 years be confirmed by suppression tests (fludrocortisone and PH was considered to be rare. In the early 1980s 3 or salt loading test) and morphological methods Hiramatsu et al described the utility of aldosterone/ (CT or MRI scan). Adenomas/ o1cm renin ratio (ARR) and reported a prevalence of 2.6%. could be possibly missed on CT scan and there- The utility of ARR has been further explored, and fore, if suppression tests confirm the diagnosis in the 1990s many studies were reported with of PH, adrenal venous sampling (AVS) is indi- cated.8 Furthermore, the use of ARR as the screen- Correspondence: Dr B Sˇ trauch, 3rd Department of Medicine, First ing test has important clinical implicationsF Faculty of Medicine, Charles University, General Faculty Hos- more patients would be diagnosed and possibly pital, U Nerocnice 1, Prague 2, 12808, Czech Republic. cured when surgically treated. However, the indi- E-mail: [email protected] Received 15 November 2002; revised 25 January 2003; accepted 3 cations for the use of the ARR in all hyper- February 2003 tensive patients still remain controversialFsome Prevalence of primary hyperaldosteronism BS˘trauch et al

350 authors dispute the validity of such an application.9 (3) the absence of or mild suppression of plasma Another problem is that different diagnostic aldosterone after saline infusion (plasma aldo- criteria are being usedFARR values ranging from sterone p85 ng/l) as previously described.10 The 20 to 50. suppression test was performed in the morning after So far there have been no data about the at least 8 h of recumbent position. In patients who prevalence of PH in Central Europe (Czech Repub- were treated by adrenalectomy, the diagnosis was lic). Therefore, we have undertaken this study to also confirmed by histology. The adrenal CT scan evaluate the prevalence of primary aldostero- was performed in all the patients screened positive nism in patients with moderate to severe hyper- for PH. In all, 20 patients also underwent adrenal tension referred to a hypertension unit in this area, venous sampling in order to further differentiate the together with the determination of the percentage subtypes of PH. of different subtypes of PH. We have used stric- Genetic screening for the exclusion of dexametha- ter screening criteria (ARR X50) for PH. Addition- sone-suppressible hyperaldosteronism was also per- ally, we have evaluated the prevalence of other formed in patients with PH. The molecular genetic types of endocrine-mediated and secondary test can be performed with a single PCR according to hypertension. our previously published procedure.11,12 Other potential secondary causes of hypertension were confirmed by means of the usual morphologi- Subjects and methods cal and laboratory methods. In case no secondary cause was elucidated, the patient was considered to We have studied 402 consecutive hypertensive have ‘essential’ hypertension. subjects from all regions of the Czech Republic in 1997–2001, most of them with moderate to severe hypertension who were examined in our Results hypertension unit. The group consisted of 172 men and 230 women of mean age 51 years. All ARRX50 was found in 87 patients (21.6%). In all, patients discontinued their usual antihypertensive 30% of them were normokalaemic. The diagnosis of therapy at least 14 days before admission to the PH was confirmed by the criteria described earlier in hospital and were given only alpha-blockers depen- this text in 77 cases of the 87 (89%); the total ding on the pressure (BP) (the medication prevalence is hence 19%. The prevalence of PH and was withdrawn and patients were followed up by other types of is shown in the GPs). All subjects underwent diagnostic workup Figure 1 (PH 19%, pheochromocytoma 5%, renal during short hospitalisation (3–5 days), which artery stenosis (renovascular) 4%, hypercortisolism consisted of a variety of laboratory and morpho- 2%, renal hypertension 1%). Basic characteristics of logical methods to exclude potential secondary the patients with PH are shown in Table 1. forms of hypertension. Basic characteristics of all the hypertensive We measured office BP (by a mercury sphygmo- patients and hypertensive patients without PA are manometer in the sitting position according to ISH shown in Table 2. recommendations) and also performed 24-h ambu- The presence of the different forms of PH is shown latory monitoring (ABPM) (Space- in Figure 2 (idiopathic hyperaldosteronism 42%, labs 90207, Redmont, CA, USA) in all subjects. aldosterone-producing adenoma 36%, unilateral Blood samples were taken for electrolytes as well hyperplasia 7%, nonclassifiable PA (refused opera- as for hormonal tests including PRA and aldosterone tion, adrenal venous sampling) 13%, familial hyper- in both recumbent and upright positions. All aldosteronism type I 2%). hormonal parameters were calculated by the usual commercial methods. Aldosterone and renin con- centrations 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 calcu- lated 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 X50 (PRA and aldosterone levels measured after 2 h upright position). The confirmation of the diagnosis of PH was based on (1) elevated ARR (X50 ng/l), (2) suppressed PRA (p0.7 ng/ml/h) and Figure 1 Prevalence of different forms of secondary hypertension elevated plasma aldosterone (X150 ng/l) levels, and in 402 patients with moderate to severe hypertension.

Journal of Human Hypertension Prevalence of primary hyperaldosteronism BS˘trauch et al

351 Table 1 Basic characteristics of patients with confirmed primary studies,3–7 we have confirmed that PH is not as rare aldosteronism (values are means 7 s.d.) as was previously thought and appears to be the most frequent form of endocrine-mediated hyper- Total 77 Mean age (years) 50 7 11 tension. It thus appears that there are no major Sex M/W 37/40 geographical differences in the occurrence of PH. As Casual BP (SBP/DBP) (mmHg) 167 7 22/103 7 11 of the percentage of the subtypes of PH, the majority Plasma levels (mmol/l) 3.51 7 0.55 of our patients had idiopathic hyperaldosteronism Plasma aldosterone levels (ng/l) 422 7 369 PRA (ng/ml/h) 0.22 7 0.19 with bilateral overproduction. One-third of our ARR (ng/100 ml)/(ng/ml/h) 459 7 733 patients had an aldosterone-producing adenoma BMI (kg/m2) 29.2 7 5.4 later confirmed by histology. In 7% of patients with PH after diagnosing unilateral overproduction by BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood AVS, unilateral adrenalectomy was indicated with pressure; PRA, plasma renin activity; ARR, aldosterone/renin ratio. the histologic finding of hyperplasia. Unfortunately, a smaller percentage of our Table 2 Basic characteristics of all 402 patients and 325 patients patients rejected further examination (adrenal ve- without PH with moderate to severe hypertension referred to our 7 nous sampling) after having normal CT scan and hypertension unit (values are means s.d.) therefore therapy was started. All patients Patients Familial hyperaldosteronism type I (glucocorti- without PH coid-remediable aldosteronism, GRA) was relatively rare. In addition to our previously described family Total 402 325 with GRA,12 we have found only one other case. Mean age (years) 51 7 12 51 7 13 The ARR is a very useful tool as a screening test Sex M/W 172/230 135/190 for diagnosing PA in patients with moderate to Casual BP (SBP/DBP) 166 7 24/101 7 14 165 7 24/100 7 14 (mmHg) severe hypertension even in the absence of hypoka- Plasma potassium 4 7 0.45 4.2 7 0.46 laemia. According to previous data, the use of levels (mmol/l) stricter ARR criteria (ARRX50 (ng/100 ml)/(ng/ml/ Plasma aldosterone 188 7 229 125 7 113 h) increases the probability of diagnosis of PA.4 We levels (ng/l) PRA (ng/ml/h) 1.7 7 2.8 2.2 7 3 confirmed this observation since in our study in ARR (ng/100 ml)/ 113 7 378 22 7 41 89% of patients with ARR equal to or higher than 50 (ng/ml/h) the diagnosis was confirmed. This stricter screening BMI (kg/m2) 29.3 7 5.6 29.4 7 5.7 marker thus appears to be clinically more reliable than frequently used ARR 20–30.13,14 There is an See Table 1. 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 substan- tiated by the results of this study. The proportion of normokalaemic patients in our study was 30% less than previously publishedFthe higher preva- lence of hypokalaemia might be because of some degree of preselection. The results of our study also have limita- tionsFthe 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 Figure 2 Presence of different forms of primary aldosteronism in referred and no patient was rejected. Our data may 77 patients (FH I ¼ familial hyperaldosteronism type I). 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 Discussion considerably high prevalence in moderate to severe hypertension in the Czech Republic. Idiopathic We have demonstrated a relatively high prevalence hyperaldosteronism may represent the common of PH in patients with moderate to severe hyperten- form of PH, while familial hyperaldosteronism ap- sion in our study. Our study is, to our knowledge, pears to be rare. The use of more strict screening cri- the first one related to the Central Europe region. In teria raises the probability of correct diagnosis of concordance with the results of earlier prevalence PA including the early normokalaemic stages of PA.

Journal of Human Hypertension Prevalence of primary hyperaldosteronism BS˘trauch et al

352 Acknowledgement 8 Gordon RD, Stowasser M. Primary aldosteronism: are we diagnosing and operating on too few patients? This study was supported by Project No J 13198: World J Surg 2001; 25: 941–947. 11110000-2 of the Ministry of Education, Youth and 9 Kaplan NM. Cautious over the current epidemic of Sports of the Czech Republic primary aldosteronism. Lancet. London 2001; 357: 953–954. 10 Ganguly A. Primary aldosteronism. N Engl J Med 1998; 339: 1828–1834. References 11 Peters J et al. Molekular-biologie. Klinik und Therapie steroidbedingter Hypertonien. In: Ganten D, Ruckpaul 1 Conn JW. Primary aldosteronism, a new clinical K (eds). Handbuch der Molekularen Medizin. Springer- syndrome. J Lab Clin Med 1955; 45: 16–17. Verlag: Berlin, 1998, pp 413–452. 2 Conn JW. The evolution of primary aldosteronism 12 Seeman T, Widimsky J, Hampf M, Bernhardt R. 1954–1967. Harvey Lect 1968; 62: 257–291. Abolished nocturnal blood pressure fall in a boy with 3 Hiramatsu et al. A screening test to identify aldoster- glucocorticoid-remediable aldosteronism. J Hum one-producing adenoma by measuring plasma Hypertens. 1999; 13: 823–828. renin activity. Arch Intern Med 1981; 141: 13 Magill SB et al. Comparison of adrenal venous 1589–1593. sampling and computed tomography in the differentia- 4 Fardella C et al. Primary hyperaldosteronism in tion of primary aldosteronism. J Clin Endocrinol essential hypertensives: prevalence, biochemical pro- Metab. 2001; 86: 1067–1071. file and molecular biology. J Clin Endocrinol Metab 14 Gordon RD, Stowasser M, Klemm SA, Tunny TJ. 2000; 85: 1863–1867. Primary aldosteronism and other forms of mineralo- 5 Loh K et al. Prevalence of primary aldosteronism corticoid hypertension. In: Swales JD (ed). Textbook among Asian hypertensive patients in Singapore. J Clin of Hypertension. Blackwell Scientific Publications: Endocrinol Metab 2000; 85: 2854–2859. London, 1994, pp 865–892. 6 Lim PO et al. High prevalence of primary aldosteron- 15 Gordon RD et al. Evidence that primary aldosteronism ism in the Tayside hypertension clinic population. may not be uncommon: 12% incidence among anti- J Hum Hypertens 2000; 14: 311–315. hypertensive drug trail volunteers. Clin Exp Pharma- 7 Stowasser M. Primary aldosteronism: rare bird or col Physiol 1993; 20: 296–298. common cause of secondary hypertension? Curr Hypertens Rep 2001; 3: 230–239.

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