Original Article
Primary aldosteronism and its various clinical scenarios Nieves Martell-Claros a, Marı´a Abad-Cardiel a, Beatriz Alvarez-Alvarez a Jose´ A. Garcı´a-Donaire a, and Cristina Ferna´ndez Pe´rez b
Background: : Primary aldosteronism is the most frequent endocrine cause of secondary hypertension. Aldosterone excess damages the cardiovascular system. Objectives: We compared biochemical; morphological, and cardiovascular risk differences among hypokalemic and normokalemic primary aldosteronism. We evaluated either both presentations correspond to two different entities or a unique disease in different evolutive stage. Material and methods: This is a retrospective study including 157 patients with primary aldosteronism divided into two groups: typical presentation (serum potassium < 3.5 mmol/l, n ¼ 87) and atypical presentation (serum potassium > 3.5 mmol/l, n ¼ 70). Results: The typical presentation group showed higher family background of ischemic heart disease (P ¼ 0.028), plasmatic aldosterone levels (P ¼ 0.001), and cardiovascular added risk (P ¼ 0.013). Although kalemia was corrected in the hypokalemic group after specific treatment, typical presentation maintained lower levels. Predictors of typical presentation were the highest tertile of aldosterone level, baseline DBP, and a longer evolution of hypertension. Aldosterone serum levels increased along time in primary aldosteronism and it can be considered as the most discriminative factor for the type of presentation. Conclusion: Primary aldosteronism presentation along with normokalemia or hypokalemia could be the same disease at different evolution stages. Adequate detection of normokalemic primary aldosteronism deserves an early and intentional diagnostic attitude. Keywords: hypertension and hypokalemia, normokalemic primary aldosteronism, primary aldosteronism, secondary hypertension
primary aldosteronism is recognized as much higher (>10%) than previously reported (25 if plasmatic renin activity is considered) and the demonstration of an abnormal adrenal glands anatomy via an image technique (hyperplasia or adenoma) and/or 2. Confirmation of an aldosterone–adrenal functional activity despite of pharmacological suppression via nor-cholesterol scintigraphy and/or 3. In the case of an adenoma, a venous adrenal sampling was performed, prior to the surgical procedure, to assess the lateralization of aldosterone overproduction. Fifteen patients were excluded because of lack of data (plasmatic renin/aldosterone levels or image technique). Primary aldosteronism hypertensive population was divided according to the lowest kalemia ever during the follow-up. We considered ‘typical presentation’ (n ¼ 87) when hypokalemia ( 84 mmHg Presentation Typical: 51% Atypical: 49%
P = 0.027
HBP evolution time > 1 year Presentation Typical: 62.5% Atypical: 37.5%
FIGURE 2 Predictive factors related to both clinical presentations. In the decision algorithm (tree-shaped structure), the differential factors for patients with typical presentation and primary aldosteronism are higher aldosterone levels, higher DBP, and longer evolution of hypertension. Typical: serum potassium less than 3.5 mEq/l; atypical: serum potassium of at least 3.5 mEq/l. HBP, high blood pressure.
Journal of Hypertension
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1229
Martell-Claros et al.
1000.0 Atypical Rsq: 0.02; P = 0.2 (K+ ≥ 3.5)
800.0
Aldosterone
Typical Rsq: 0.02; P = 0.8 (K+ < 3.5)
600.0
400.0
200.0
0.0 0
10 20 30 Time of hypertension (years)
40
FIGURE 3 Evolution of serum aldosterone levels (ng/dl). Patients with primary aldosteronism and typical presentation were more likely to have a higher and stable (light gray line) plasmatic aldosterone levels throughout the follow-up. Typical: serum Kþ less than 3.5 mEq/l; atypical serum Kþ of at least 3.5 mEq/l.
Patients’ evaluation should be based on a longitudinal perspective because biological parameters are subject to frequent fluctuations, sometimes due to pharmacological effects. No differences were observed in the biochemical profile or in target organ damage, according to the type of presentation. Prevalence of metabolic syndrome did not show differences either. With respect to clinical characteristics, no statistical differences were observed between groups regarding age; however, time of evolution of hypertension was significantly different, showing a higher long term among typical presentation primary aldosteronism. This fact is pertinent because recovery after adrenalectomy is associated with a shorter time of evolution of hypertension, as published by Celen et al. [21]. Hence, an active attitude in searching for a specific diagnosis is crucial, especially in population with atypical presentation and primary aldosteronism. It must be highlighted that mean SBP and DBP are higher in patients with typical presentation (P ¼ 0.004) than atypical ones, showing a baseline systolic grade 2 hypertension [13], similarly to an already published European cohort [16]. Only high plasmatic aldosterone concentration was statistically significant in patients with typical presentation, although mean and median values are quite superior to the normal reference ones in the general population [16]. However, these data are not concordant with the previous studies that analyzed 64 patients with primary aldosteronism subdivided according to their anatomic diagnosis into different groups and concluding that a strong association with potassium levels was not found in our cohort [22]. A maintained trend to show higher aldosterone levels is observed among patients with a typical (Kþ < 3.5 mmol/l) vs. atypical presentation, irrespective of anatomical image, when analyzing the three groups: adenoma, nodular 1230
www.jhypertension.com
hyperplasia, and simple hyperplasia. Our data suggest that both presentations resemble the same clinical and very heterogeneous disease. Two rather different evolutions of data are observed in the mathematical model between groups on their association with aldosterone levels and time of evolution of hypertension. In a population with typical presentation, baseline aldosterone levels are elevated and maintained over time. Conversely aldosterone levels are low but increase during the follow-up in the atypical presentation group. Therefore, it seems that aldosterone level determines the form of presentation of primary aldosteronism, regardless of the morphology and unilateral or bilateral location of the disease. Our data show that women more frequently present with normokalemia. This might be partially explained by the aldosterone antagonism secondary to progesterone. To identify if this finding is as a result of different genetic information, a modified transcription or a modification in aldosterone physiology exceeds the clinical focus of this study. We consider quite remarkable the independence of the clinical presentations with the adrenal morphology and agree with the literature supporting that primary aldosteronism is a clinical entity with a wide phenotype, in which intermediate patients are poorly recognized [23]. Because of our results from the statistical model, the discovery of a close correlation between time of hypertension and aldosterone levels is quite important since it emphasizes the need of a more active and prompt attitude in the diagnosis of the higher risk groups for development of primary aldosteronism (resistant hypertension, hypertensive crisis, etc.). As previously commented, the most important discriminatory factor in typical presentation is very high aldosterone levels because patients allocated in the upper tertile Volume 33 Number 6 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Normokalemic and hypokalemic primary aldosteronism
have a 4.66 higher probability of being typical. The second and third discriminatory factors are DBP and the evolution time of High blood pressure (Fig. 2). The atypical presentation diagnosis of primary aldosteronism remains challenging because it is not associated with hypokalemia, has a lower level of BP, and occurs in younger patients with lesser time of evolution of their hypertension. Early and intentional diagnosis would be more cost effective in these groups. Prompt detection, diagnosis, and treatment of this particular group of primary aldosteronism may lead to decreased morbidity and mortality and improved quality of life. So, we considered that early detection of normokalemic populations with primary aldosteronism deserves an active diagnostic attitude. This study has some limitations. It is retrospective, with a large lapse of time along the follow-up. The whole sample of patients was diagnosed in our unit by the same clinical team but with different screening protocols, according to contemporary knowledge; thus, a number of hypokalemic patients with primary aldosteronism were diagnosed during the first years of follow-up. This fact can explain the higher prevalence of hypokalemic primary aldosteronism compared with most recent series [16]. In conclusion, clinical presentation of primary aldosteronism is not determined by any specific morphologic abnormality of the adrenal gland. Our results could indicate that aldosterone levels increase along time in primary aldosteronism, until their stabilization at very high values, at the same times as lowest serum potassium levels. Consequently, primary aldosteronism presentation along with normokalemia or hypokalemia seems to be the same disease at different evolution stages.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Victor RG, Kaplan NM. Systemic hypertension: mechanism and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, editors. Braundwald’s heart disease, 8th ed. Philadelphia, PA: Elsevier Saunders; 2008. pp. 1027–1048; s.l, Vol 1. 2. Chiong JR, Aronow WS, Khan IA, Nair CK, Vijayaraghavan K, Dart RA, et al. Secondary hypertension: current diagnosis and treatment. Int J Cardiol 2008; 124:6–21. 3. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol 2007; 66:607–618. 4. Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, et al. Case detection, diagnosis, and treatmentof patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:3266–3281.
Reviewers’ Summary Evaluations Referee 1 The major strength point of this study is that it involves patients seen in a single clinic unit during 27 years. The most interesting conclusion is that primary aldosteronism with normokalemia or hyperkalemia may represent the
Journal of Hypertension
5. Nyirenda MJ, Padfield PL. Aldosterone and refractory hypertension. Curr Opin Endocrinol Diabetes Obes 2007; 14:213–218. 6. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45:1243–1248. 7. Conn JW. Primary aldosteronism: a new clinical syndrome. J Lab Clin Med 1955; 45:3–17. 8. Mulatero P, Stowasser M, Loh K, 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. 9. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48:2293–2300. 10. Mosso L, Carvajal C, Gonza´lez A, Barraza A, Avila F, Montero J, et al. Primary aldosteronism and hypertensive disease. Hypertension 2003; 42:161–165. 11. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002; 40:892–896. 12. Boscaro M, Ronconi V, Turchi F, Giacchetti G. Diagnosis and management of primary aldosteronism. Curr Opin Endocrinol Diabetes Obes 2008; 15:332–338. 13. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 5:1105–1187. ´ lvarez B, Luque-Garcı´a L, Ferna´ndez C, 14. Abad-Cardiel M, A´lvarez-A Ferna´ndez-Cruza A, Martell-Claros N. Hypertension caused by primary hyperaldosteronism: increased heart damage and cardiovascular risk. Rev Esp Cardiol (Engl Ed) 2013; 66:47–52. 15. Chiou TT, Chiang P, Fuh M, Liu R, Lee W, Ng H, et al. Factors determining cardiovascular and renal outcomes after adrenalectomy in patients with aldosterone-producing adrenal adenoma. J Exp Med 2009; 218:17–24. 16. Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, et al. Registry, Participants of the German Conn’s. Cardiovascular and cerebrovascular comorbidities of hypokaliemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab 2009; 94:1125–1130. 17. Calhoun DA. Aldosterone and cardiovascular disease: smoke and fire. Circulation 2006; 114:2572–2574. 18. Funder JW, Reincke M. Aldosterone: a cardiovascular risk factor? Biochem Biophys Acta 2010; 1802:1188–1192. 19. Saeger W, Fassnacht M, Chita R, Prager G, Nies C, Lorenz K, et al. High diagnostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients. Hum Pathol 2003; 34:180–186. 20. Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis 2010; 52:401–409. 21. Celen O, O’Brien MJ, Melby JC, Beazley R. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg 1996; 131:646– 650. 22. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al., For the PAPY Study. Renal damage in primary aldosteronism results of the PAPY study. Hypertension 2006; 48:232–238. 23. Rossi GP, Gregianin M, Chisura-Corona M. Diagnosis and treatment of primary aldosteronism. Ann Intern Med 1995; 123:73–74.
same disease at a different stage. The major weakness is that this investigation is a retrospective study.
Referee 2 Strengths This study – demonstrates clinical presentations of aldosteronism.
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1231
Martell-Claros et al.
– determines higher aldosterone levels and more severe disease to be temporally related to disease duration. – links higher aldosterone levels to added cardiovascular risk. – provides clinical workup to differentiate between adenomas and hyperplasias causative for the aldosteronism.
1232
www.jhypertension.com
Weaknesses – Neither salt suppression studies nor salt intake at biochemical analysis are provided. – The data set is limited. – The patients are dichotomized in groups with normoand hypokalemia.
Volume 33 Number 6 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Primary aldosteronism and its various clinical scenarios Nieves Martell-Claros a, Marı´a Abad-Cardiel a, Beatriz Alvarez-Alvarez a Jose´ A. Garcı´a-Donaire a, and Cristina Ferna´ndez Pe´rez b
Background: : Primary aldosteronism is the most frequent endocrine cause of secondary hypertension. Aldosterone excess damages the cardiovascular system. Objectives: We compared biochemical; morphological, and cardiovascular risk differences among hypokalemic and normokalemic primary aldosteronism. We evaluated either both presentations correspond to two different entities or a unique disease in different evolutive stage. Material and methods: This is a retrospective study including 157 patients with primary aldosteronism divided into two groups: typical presentation (serum potassium < 3.5 mmol/l, n ¼ 87) and atypical presentation (serum potassium > 3.5 mmol/l, n ¼ 70). Results: The typical presentation group showed higher family background of ischemic heart disease (P ¼ 0.028), plasmatic aldosterone levels (P ¼ 0.001), and cardiovascular added risk (P ¼ 0.013). Although kalemia was corrected in the hypokalemic group after specific treatment, typical presentation maintained lower levels. Predictors of typical presentation were the highest tertile of aldosterone level, baseline DBP, and a longer evolution of hypertension. Aldosterone serum levels increased along time in primary aldosteronism and it can be considered as the most discriminative factor for the type of presentation. Conclusion: Primary aldosteronism presentation along with normokalemia or hypokalemia could be the same disease at different evolution stages. Adequate detection of normokalemic primary aldosteronism deserves an early and intentional diagnostic attitude. Keywords: hypertension and hypokalemia, normokalemic primary aldosteronism, primary aldosteronism, secondary hypertension
primary aldosteronism is recognized as much higher (>10%) than previously reported (25 if plasmatic renin activity is considered) and the demonstration of an abnormal adrenal glands anatomy via an image technique (hyperplasia or adenoma) and/or 2. Confirmation of an aldosterone–adrenal functional activity despite of pharmacological suppression via nor-cholesterol scintigraphy and/or 3. In the case of an adenoma, a venous adrenal sampling was performed, prior to the surgical procedure, to assess the lateralization of aldosterone overproduction. Fifteen patients were excluded because of lack of data (plasmatic renin/aldosterone levels or image technique). Primary aldosteronism hypertensive population was divided according to the lowest kalemia ever during the follow-up. We considered ‘typical presentation’ (n ¼ 87) when hypokalemia ( 84 mmHg Presentation Typical: 51% Atypical: 49%
P = 0.027
HBP evolution time > 1 year Presentation Typical: 62.5% Atypical: 37.5%
FIGURE 2 Predictive factors related to both clinical presentations. In the decision algorithm (tree-shaped structure), the differential factors for patients with typical presentation and primary aldosteronism are higher aldosterone levels, higher DBP, and longer evolution of hypertension. Typical: serum potassium less than 3.5 mEq/l; atypical: serum potassium of at least 3.5 mEq/l. HBP, high blood pressure.
Journal of Hypertension
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1229
Martell-Claros et al.
1000.0 Atypical Rsq: 0.02; P = 0.2 (K+ ≥ 3.5)
800.0
Aldosterone
Typical Rsq: 0.02; P = 0.8 (K+ < 3.5)
600.0
400.0
200.0
0.0 0
10 20 30 Time of hypertension (years)
40
FIGURE 3 Evolution of serum aldosterone levels (ng/dl). Patients with primary aldosteronism and typical presentation were more likely to have a higher and stable (light gray line) plasmatic aldosterone levels throughout the follow-up. Typical: serum Kþ less than 3.5 mEq/l; atypical serum Kþ of at least 3.5 mEq/l.
Patients’ evaluation should be based on a longitudinal perspective because biological parameters are subject to frequent fluctuations, sometimes due to pharmacological effects. No differences were observed in the biochemical profile or in target organ damage, according to the type of presentation. Prevalence of metabolic syndrome did not show differences either. With respect to clinical characteristics, no statistical differences were observed between groups regarding age; however, time of evolution of hypertension was significantly different, showing a higher long term among typical presentation primary aldosteronism. This fact is pertinent because recovery after adrenalectomy is associated with a shorter time of evolution of hypertension, as published by Celen et al. [21]. Hence, an active attitude in searching for a specific diagnosis is crucial, especially in population with atypical presentation and primary aldosteronism. It must be highlighted that mean SBP and DBP are higher in patients with typical presentation (P ¼ 0.004) than atypical ones, showing a baseline systolic grade 2 hypertension [13], similarly to an already published European cohort [16]. Only high plasmatic aldosterone concentration was statistically significant in patients with typical presentation, although mean and median values are quite superior to the normal reference ones in the general population [16]. However, these data are not concordant with the previous studies that analyzed 64 patients with primary aldosteronism subdivided according to their anatomic diagnosis into different groups and concluding that a strong association with potassium levels was not found in our cohort [22]. A maintained trend to show higher aldosterone levels is observed among patients with a typical (Kþ < 3.5 mmol/l) vs. atypical presentation, irrespective of anatomical image, when analyzing the three groups: adenoma, nodular 1230
www.jhypertension.com
hyperplasia, and simple hyperplasia. Our data suggest that both presentations resemble the same clinical and very heterogeneous disease. Two rather different evolutions of data are observed in the mathematical model between groups on their association with aldosterone levels and time of evolution of hypertension. In a population with typical presentation, baseline aldosterone levels are elevated and maintained over time. Conversely aldosterone levels are low but increase during the follow-up in the atypical presentation group. Therefore, it seems that aldosterone level determines the form of presentation of primary aldosteronism, regardless of the morphology and unilateral or bilateral location of the disease. Our data show that women more frequently present with normokalemia. This might be partially explained by the aldosterone antagonism secondary to progesterone. To identify if this finding is as a result of different genetic information, a modified transcription or a modification in aldosterone physiology exceeds the clinical focus of this study. We consider quite remarkable the independence of the clinical presentations with the adrenal morphology and agree with the literature supporting that primary aldosteronism is a clinical entity with a wide phenotype, in which intermediate patients are poorly recognized [23]. Because of our results from the statistical model, the discovery of a close correlation between time of hypertension and aldosterone levels is quite important since it emphasizes the need of a more active and prompt attitude in the diagnosis of the higher risk groups for development of primary aldosteronism (resistant hypertension, hypertensive crisis, etc.). As previously commented, the most important discriminatory factor in typical presentation is very high aldosterone levels because patients allocated in the upper tertile Volume 33 Number 6 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Normokalemic and hypokalemic primary aldosteronism
have a 4.66 higher probability of being typical. The second and third discriminatory factors are DBP and the evolution time of High blood pressure (Fig. 2). The atypical presentation diagnosis of primary aldosteronism remains challenging because it is not associated with hypokalemia, has a lower level of BP, and occurs in younger patients with lesser time of evolution of their hypertension. Early and intentional diagnosis would be more cost effective in these groups. Prompt detection, diagnosis, and treatment of this particular group of primary aldosteronism may lead to decreased morbidity and mortality and improved quality of life. So, we considered that early detection of normokalemic populations with primary aldosteronism deserves an active diagnostic attitude. This study has some limitations. It is retrospective, with a large lapse of time along the follow-up. The whole sample of patients was diagnosed in our unit by the same clinical team but with different screening protocols, according to contemporary knowledge; thus, a number of hypokalemic patients with primary aldosteronism were diagnosed during the first years of follow-up. This fact can explain the higher prevalence of hypokalemic primary aldosteronism compared with most recent series [16]. In conclusion, clinical presentation of primary aldosteronism is not determined by any specific morphologic abnormality of the adrenal gland. Our results could indicate that aldosterone levels increase along time in primary aldosteronism, until their stabilization at very high values, at the same times as lowest serum potassium levels. Consequently, primary aldosteronism presentation along with normokalemia or hypokalemia seems to be the same disease at different evolution stages.
ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.
REFERENCES 1. Victor RG, Kaplan NM. Systemic hypertension: mechanism and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P, editors. Braundwald’s heart disease, 8th ed. Philadelphia, PA: Elsevier Saunders; 2008. pp. 1027–1048; s.l, Vol 1. 2. Chiong JR, Aronow WS, Khan IA, Nair CK, Vijayaraghavan K, Dart RA, et al. Secondary hypertension: current diagnosis and treatment. Int J Cardiol 2008; 124:6–21. 3. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol 2007; 66:607–618. 4. Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, et al. Case detection, diagnosis, and treatmentof patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93:3266–3281.
Reviewers’ Summary Evaluations Referee 1 The major strength point of this study is that it involves patients seen in a single clinic unit during 27 years. The most interesting conclusion is that primary aldosteronism with normokalemia or hyperkalemia may represent the
Journal of Hypertension
5. Nyirenda MJ, Padfield PL. Aldosterone and refractory hypertension. Curr Opin Endocrinol Diabetes Obes 2007; 14:213–218. 6. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005; 45:1243–1248. 7. Conn JW. Primary aldosteronism: a new clinical syndrome. J Lab Clin Med 1955; 45:3–17. 8. Mulatero P, Stowasser M, Loh K, 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. 9. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48:2293–2300. 10. Mosso L, Carvajal C, Gonza´lez A, Barraza A, Avila F, Montero J, et al. Primary aldosteronism and hypertensive disease. Hypertension 2003; 42:161–165. 11. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 2002; 40:892–896. 12. Boscaro M, Ronconi V, Turchi F, Giacchetti G. Diagnosis and management of primary aldosteronism. Curr Opin Endocrinol Diabetes Obes 2008; 15:332–338. 13. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 5:1105–1187. ´ lvarez B, Luque-Garcı´a L, Ferna´ndez C, 14. Abad-Cardiel M, A´lvarez-A Ferna´ndez-Cruza A, Martell-Claros N. Hypertension caused by primary hyperaldosteronism: increased heart damage and cardiovascular risk. Rev Esp Cardiol (Engl Ed) 2013; 66:47–52. 15. Chiou TT, Chiang P, Fuh M, Liu R, Lee W, Ng H, et al. Factors determining cardiovascular and renal outcomes after adrenalectomy in patients with aldosterone-producing adrenal adenoma. J Exp Med 2009; 218:17–24. 16. Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, et al. Registry, Participants of the German Conn’s. Cardiovascular and cerebrovascular comorbidities of hypokaliemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab 2009; 94:1125–1130. 17. Calhoun DA. Aldosterone and cardiovascular disease: smoke and fire. Circulation 2006; 114:2572–2574. 18. Funder JW, Reincke M. Aldosterone: a cardiovascular risk factor? Biochem Biophys Acta 2010; 1802:1188–1192. 19. Saeger W, Fassnacht M, Chita R, Prager G, Nies C, Lorenz K, et al. High diagnostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients. Hum Pathol 2003; 34:180–186. 20. Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog Cardiovasc Dis 2010; 52:401–409. 21. Celen O, O’Brien MJ, Melby JC, Beazley R. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg 1996; 131:646– 650. 22. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al., For the PAPY Study. Renal damage in primary aldosteronism results of the PAPY study. Hypertension 2006; 48:232–238. 23. Rossi GP, Gregianin M, Chisura-Corona M. Diagnosis and treatment of primary aldosteronism. Ann Intern Med 1995; 123:73–74.
same disease at a different stage. The major weakness is that this investigation is a retrospective study.
Referee 2 Strengths This study – demonstrates clinical presentations of aldosteronism.
www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1231
Martell-Claros et al.
– determines higher aldosterone levels and more severe disease to be temporally related to disease duration. – links higher aldosterone levels to added cardiovascular risk. – provides clinical workup to differentiate between adenomas and hyperplasias causative for the aldosteronism.
1232
www.jhypertension.com
Weaknesses – Neither salt suppression studies nor salt intake at biochemical analysis are provided. – The data set is limited. – The patients are dichotomized in groups with normoand hypokalemia.
Volume 33 Number 6 June 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
