COMMENTARY
Screening for Primary Aldosteronism: Whom and How? Michael Doumas, MD, PhD;1,2 Vasilios Athyros, MD, PhD;1 Vasilios Papademetriou, MD, PhD3 From the 2nd Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece;1 George Washington University, Washington, DC;2 and Veteran Affairs Medical Center and Georgetown University, Washington, DC3
Arterial hypertension is a major public health problem that affects more than 1 billion patients worldwide, a number that is expected to rise to 1.5 billion1 because of aging of the population and the wide adoption of an unhealthy lifestyle. Arterial hypertension is of unknown origin (“essential”) in the majority of cases and is considered secondary in a small fraction of hypertensive patients. However, given the large number of hypertensive individuals, the question of “whom and how to screen?” for secondary causes is of utmost importance based on the limited financial and staff resources worldwide. Secondary hypertension is a multifactorial clinical entity, with more than 40 diseases that cause blood pressure elevation. However, many causes are either rare (renin-producing tumor) or easily identified (chronic kidney disease, Cushing syndrome, hyperthyroidism and hypothyroidism). Therefore, special attention needs to be given to common secondary causes that are not easily recognized, including primary aldosteronism.2 The prevalence of primary aldosteronism ranges between 5% and 50%, mainly because of selection bias since highly specialized centers report very high prevalence rates.3 A large study in general practice from Italy, the PA Prevalence in Hypertensives (PAPY) study, reported a prevalence of 11.2%,4 while we have recently reported a similar prevalence in patients with resistant hypertension, a population with presumed much higher prevalence rates.5 Therefore, a prevalence rate of 5% to 10% among the general hypertensive population seems a rational estimation based on available data. In this issue of the Journal, a Canadian group from Calgary attempts to provide an answer to the burning question “whom and how to screen?” for primary aldosteronism.6 Rye and colleagues6 retrospectively analyzed the data of two patient groups. Patients in the first group (n=58) had confirmed primary aldosteronism with surgically removed adrenal adenoma, while patients in the second group (n=59) were either highly likely to have primary aldosteronism or declined surgery for proved adrenal adenomas. The authors measured plasma renin activity without adjusting current antihypertensive medication, apart from mineralocorticoid antagonists that were stopped for 6 weeks. It was found that the 95th percentile of plasma renin activity
Address for correspondence: Michael Doumas, 2nd Propedeutic Department of Internal Medicine, Aristotle University, 49, Konstantinoupoleos Street, 54643 Thessaloniki, Greece E-mail: [email protected] DOI: 10.1111/jch.12521
distribution was 1.0 mg/mL/h. In other words, when the plasma renin activity levels were higher than the cutoff limit of 1.0 mg/mL/h (while antihypertensive therapy was unaltered except for mineralocorticoid antagonists), the patient was highly unlikely (95%) to have primary aldosteronism. Of equal importance, the diagnosis was difficult to miss in the 5% of the remaining cases because of a strong suspicion for primary aldosteronism in these patients. The study comes from a very experienced center with a long-time interest in the diagnosis of primary aldosteronism7,8 and proposes an attractive screening test (plasma renin activity) for primary aldosteronism. The proposed screening test seems valid even when performed without adjustments in current antihypertensive therapy, avoiding the inconvenience and risks of drug adjustment. Some aspects, however, limit the generalization of study findings. First, this is a retrospective, single-center study with a moderate number of patients. Therefore, the inherent limitations of the retrospective nature of the study and the limited number of study participants need to be taken into account. In addition, the diagnostic algorithm that was used in this center partly deviates from the one which is currently recommended by experts in this field and followed by the majority of expert centers worldwide.9 The possibility of overdiagnosis in the second group of patients (“high probability for primary aldosteronism”) cannot be definitely excluded, even if it seems likely that the majority (if not all) of included patients indeed had primary aldosteronism. However, even in the case of overdiagnosis, the main message of the study remains unaltered, since the proposed cutoff level is used for diagnosis exclusion and not for diagnosis confirmation. What really blurs the essence of the study is the lack of an appropriate control group composed of patients with high blood pressure, with and without suspicion for primary aldosteronism. This control group will help identify the rate of hypertensive patients with low renin levels while taking antihypertensive medications and will thus provide valuable information for the validity and the cost-effectiveness of the proposed test in the general hypertensive population and/or specific subgroups of patients. This type of study is of paramount importance for answering the question “whom and how to screen” for primary aldosteronism. It has to be realized that the diagnosis of primary aldosteronism in real life is time-consuming and tricky.10,11 Patients have to stop the use of antihypertensive medication and begin a-blockers and calcium antagonists in order to be screened with the aldosterone/ renin ratio (ARR). In patients with a high ARR and high The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
547
Commentary
aldosterone levels, confirmatory testing needs to be performed (sodium loading with saline or fludrocortisone). Confirmatory tests are essential since only about half of patients with a high ARR will be diagnosed with primary aldosteronism.5 Then, the type of primary aldosteronism has to be identified––adrenal adenoma or hyperplasia. Imaging techniques such as noninterventional (computed tomography, magnetic resonance imaging, or scintigraphy with iodocholesterol) or interventional (adrenal venous sampling) are used for this purpose. It can be easily observed that this algorithm is time-consuming. More important, however, the interpretation of the findings of these tests might be tricky. Aldosterone suppression might be controversial when both confirmatory tests are used. Computed tomography and magnetic resonance imaging might be misleading (an adrenal nodule might be an adenoma or the prevailing nodule of bilateral hyperplasia and vice versa an adenoma at initial stages might be small enough to be detected), and noninterventional findings do not always match the findings of adrenal venous sampling. Therefore, clinical judgment based on adequate experience is required to evaluate controversial results and appropriately manage these patients by avoiding unnecessary surgery.12 The million-dollar question arises: “Do we have the money, the manpower, and the experts to search 1.5 billion hypertensive patients worldwide for primary aldosteronism?” We believe that the answer is obviously negative. However, is this feasible in the United States and Western European countries that are wealthy and adequately staffed with medical doctors? We believe that the answer is negative once again. From the financial point of view, 70 million Americans should be screened with ARR and confirmatory tests should be performed in about 20% (assuming a 10% prevalence rate of primary aldosteronism and a 50% rate of false-positive results). Following the confirmatory tests in 14 million US patients, about 7 million should be further tested with imaging techniques and adrenal venous sampling in order to identify and surgically remove an adenoma in about 3 million patients. Are the central administration and insurance companies ready and willing to accept these costs? Do we have enough experienced centers specialized in primary aldosteronism and enough interventional radiologists highly experienced in adrenal venous sampling scattered in each corner of the United States? The answer in both questions seems negative.
548
The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
The authors of this study propose an attractive option: the unadjusted plasma renin activity measurement as an exclusion screening test for primary aldosteronism. In the case that the findings of this study hold true and will be confirmed by further larger studies, the two initial steps (medication switch and ARR) might be replaced by a single measurement of plasma renin activity and further investigation will be limited in patients with renin levels below 1.0 mg/mL/h. It has to be highlighted, however, that the study findings have to be replicated and confirmed by further studies, which will be prospective, in larger numbers, performed in less-selected populations and in experienced centers using appropriate diagnostic algorithms. In the case, however, that the findings prove true, it will be a significant step toward the simplification of the diagnostic algorithm for primary aldosteronism, reinforcing its wider application in hypertensive patients. References 1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217– 223. 2. Faselis C, Doumas M, Papademetriou V. Common secondary causes of resistant hypertension and rational for treatment. Int J Hypertens. 2011;2011:236239. 3. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens. 2004;22:863–869. 4. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–2300. 5. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008;371:1921–1926. 6. Rye P, So B, Harvey A, et al. Unadjusted plasma renin activity as a ‘first look’ test to decide upon further investigations for primary aldosteronism. J Clin Hypertens (Greenwich). 2015;17:541–546. 7. Kline GA, Pasieka JL, Harvey A, et al. High-probability features of primary aldosteronism may obviate the need for confirmatory testing without increasing false-positive diagnoses. J Clin Hypertens (Greenwich). 2014;16:488–496. 8. Kline GA, So B, Dias VC, et al. Catheterization during adrenal vein sampling for primary aldosteronism: failure to use (1-24) ACTH may increase apparent failure rate. J Clin Hypertens (Greenwich). 2013;15:480–484. 9. Funder JW, Carey RM, Fardella C, et al. Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:3266–3281. 10. Karagiannis A, Tziomalos K, Kakafika A, et al. Medical treatment as an alternative to adrenalectomy in patients with aldosterone-producing adenomas. Endocr Relat Cancer. 2008;15:693–700. 11. Karagiannis A. Treatment of primary aldosteronism: where are we now? Rev Endocr Metab Disord. 2011;12:15–20. 12. Douma S, Petidis K, Kamparoudis A, et al. Surgical management of primary aldosteronism: not everything that shines is gold. Clin Exp Hypertens. 2012;34:53–56.
Screening for Primary Aldosteronism: Whom and How? Michael Doumas, MD, PhD;1,2 Vasilios Athyros, MD, PhD;1 Vasilios Papademetriou, MD, PhD3 From the 2nd Propedeutic Department of Internal Medicine, Aristotle University, Thessaloniki, Greece;1 George Washington University, Washington, DC;2 and Veteran Affairs Medical Center and Georgetown University, Washington, DC3
Arterial hypertension is a major public health problem that affects more than 1 billion patients worldwide, a number that is expected to rise to 1.5 billion1 because of aging of the population and the wide adoption of an unhealthy lifestyle. Arterial hypertension is of unknown origin (“essential”) in the majority of cases and is considered secondary in a small fraction of hypertensive patients. However, given the large number of hypertensive individuals, the question of “whom and how to screen?” for secondary causes is of utmost importance based on the limited financial and staff resources worldwide. Secondary hypertension is a multifactorial clinical entity, with more than 40 diseases that cause blood pressure elevation. However, many causes are either rare (renin-producing tumor) or easily identified (chronic kidney disease, Cushing syndrome, hyperthyroidism and hypothyroidism). Therefore, special attention needs to be given to common secondary causes that are not easily recognized, including primary aldosteronism.2 The prevalence of primary aldosteronism ranges between 5% and 50%, mainly because of selection bias since highly specialized centers report very high prevalence rates.3 A large study in general practice from Italy, the PA Prevalence in Hypertensives (PAPY) study, reported a prevalence of 11.2%,4 while we have recently reported a similar prevalence in patients with resistant hypertension, a population with presumed much higher prevalence rates.5 Therefore, a prevalence rate of 5% to 10% among the general hypertensive population seems a rational estimation based on available data. In this issue of the Journal, a Canadian group from Calgary attempts to provide an answer to the burning question “whom and how to screen?” for primary aldosteronism.6 Rye and colleagues6 retrospectively analyzed the data of two patient groups. Patients in the first group (n=58) had confirmed primary aldosteronism with surgically removed adrenal adenoma, while patients in the second group (n=59) were either highly likely to have primary aldosteronism or declined surgery for proved adrenal adenomas. The authors measured plasma renin activity without adjusting current antihypertensive medication, apart from mineralocorticoid antagonists that were stopped for 6 weeks. It was found that the 95th percentile of plasma renin activity
Address for correspondence: Michael Doumas, 2nd Propedeutic Department of Internal Medicine, Aristotle University, 49, Konstantinoupoleos Street, 54643 Thessaloniki, Greece E-mail: [email protected] DOI: 10.1111/jch.12521
distribution was 1.0 mg/mL/h. In other words, when the plasma renin activity levels were higher than the cutoff limit of 1.0 mg/mL/h (while antihypertensive therapy was unaltered except for mineralocorticoid antagonists), the patient was highly unlikely (95%) to have primary aldosteronism. Of equal importance, the diagnosis was difficult to miss in the 5% of the remaining cases because of a strong suspicion for primary aldosteronism in these patients. The study comes from a very experienced center with a long-time interest in the diagnosis of primary aldosteronism7,8 and proposes an attractive screening test (plasma renin activity) for primary aldosteronism. The proposed screening test seems valid even when performed without adjustments in current antihypertensive therapy, avoiding the inconvenience and risks of drug adjustment. Some aspects, however, limit the generalization of study findings. First, this is a retrospective, single-center study with a moderate number of patients. Therefore, the inherent limitations of the retrospective nature of the study and the limited number of study participants need to be taken into account. In addition, the diagnostic algorithm that was used in this center partly deviates from the one which is currently recommended by experts in this field and followed by the majority of expert centers worldwide.9 The possibility of overdiagnosis in the second group of patients (“high probability for primary aldosteronism”) cannot be definitely excluded, even if it seems likely that the majority (if not all) of included patients indeed had primary aldosteronism. However, even in the case of overdiagnosis, the main message of the study remains unaltered, since the proposed cutoff level is used for diagnosis exclusion and not for diagnosis confirmation. What really blurs the essence of the study is the lack of an appropriate control group composed of patients with high blood pressure, with and without suspicion for primary aldosteronism. This control group will help identify the rate of hypertensive patients with low renin levels while taking antihypertensive medications and will thus provide valuable information for the validity and the cost-effectiveness of the proposed test in the general hypertensive population and/or specific subgroups of patients. This type of study is of paramount importance for answering the question “whom and how to screen” for primary aldosteronism. It has to be realized that the diagnosis of primary aldosteronism in real life is time-consuming and tricky.10,11 Patients have to stop the use of antihypertensive medication and begin a-blockers and calcium antagonists in order to be screened with the aldosterone/ renin ratio (ARR). In patients with a high ARR and high The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
547
Commentary
aldosterone levels, confirmatory testing needs to be performed (sodium loading with saline or fludrocortisone). Confirmatory tests are essential since only about half of patients with a high ARR will be diagnosed with primary aldosteronism.5 Then, the type of primary aldosteronism has to be identified––adrenal adenoma or hyperplasia. Imaging techniques such as noninterventional (computed tomography, magnetic resonance imaging, or scintigraphy with iodocholesterol) or interventional (adrenal venous sampling) are used for this purpose. It can be easily observed that this algorithm is time-consuming. More important, however, the interpretation of the findings of these tests might be tricky. Aldosterone suppression might be controversial when both confirmatory tests are used. Computed tomography and magnetic resonance imaging might be misleading (an adrenal nodule might be an adenoma or the prevailing nodule of bilateral hyperplasia and vice versa an adenoma at initial stages might be small enough to be detected), and noninterventional findings do not always match the findings of adrenal venous sampling. Therefore, clinical judgment based on adequate experience is required to evaluate controversial results and appropriately manage these patients by avoiding unnecessary surgery.12 The million-dollar question arises: “Do we have the money, the manpower, and the experts to search 1.5 billion hypertensive patients worldwide for primary aldosteronism?” We believe that the answer is obviously negative. However, is this feasible in the United States and Western European countries that are wealthy and adequately staffed with medical doctors? We believe that the answer is negative once again. From the financial point of view, 70 million Americans should be screened with ARR and confirmatory tests should be performed in about 20% (assuming a 10% prevalence rate of primary aldosteronism and a 50% rate of false-positive results). Following the confirmatory tests in 14 million US patients, about 7 million should be further tested with imaging techniques and adrenal venous sampling in order to identify and surgically remove an adenoma in about 3 million patients. Are the central administration and insurance companies ready and willing to accept these costs? Do we have enough experienced centers specialized in primary aldosteronism and enough interventional radiologists highly experienced in adrenal venous sampling scattered in each corner of the United States? The answer in both questions seems negative.
548
The Journal of Clinical Hypertension
Vol 17 | No 7 | July 2015
The authors of this study propose an attractive option: the unadjusted plasma renin activity measurement as an exclusion screening test for primary aldosteronism. In the case that the findings of this study hold true and will be confirmed by further larger studies, the two initial steps (medication switch and ARR) might be replaced by a single measurement of plasma renin activity and further investigation will be limited in patients with renin levels below 1.0 mg/mL/h. It has to be highlighted, however, that the study findings have to be replicated and confirmed by further studies, which will be prospective, in larger numbers, performed in less-selected populations and in experienced centers using appropriate diagnostic algorithms. In the case, however, that the findings prove true, it will be a significant step toward the simplification of the diagnostic algorithm for primary aldosteronism, reinforcing its wider application in hypertensive patients. References 1. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217– 223. 2. Faselis C, Doumas M, Papademetriou V. Common secondary causes of resistant hypertension and rational for treatment. Int J Hypertens. 2011;2011:236239. 3. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens. 2004;22:863–869. 4. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–2300. 5. Douma S, Petidis K, Doumas M, et al. Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study. Lancet. 2008;371:1921–1926. 6. Rye P, So B, Harvey A, et al. Unadjusted plasma renin activity as a ‘first look’ test to decide upon further investigations for primary aldosteronism. J Clin Hypertens (Greenwich). 2015;17:541–546. 7. Kline GA, Pasieka JL, Harvey A, et al. High-probability features of primary aldosteronism may obviate the need for confirmatory testing without increasing false-positive diagnoses. J Clin Hypertens (Greenwich). 2014;16:488–496. 8. Kline GA, So B, Dias VC, et al. Catheterization during adrenal vein sampling for primary aldosteronism: failure to use (1-24) ACTH may increase apparent failure rate. J Clin Hypertens (Greenwich). 2013;15:480–484. 9. Funder JW, Carey RM, Fardella C, et al. Endocrine Society. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:3266–3281. 10. Karagiannis A, Tziomalos K, Kakafika A, et al. Medical treatment as an alternative to adrenalectomy in patients with aldosterone-producing adenomas. Endocr Relat Cancer. 2008;15:693–700. 11. Karagiannis A. Treatment of primary aldosteronism: where are we now? Rev Endocr Metab Disord. 2011;12:15–20. 12. Douma S, Petidis K, Kamparoudis A, et al. Surgical management of primary aldosteronism: not everything that shines is gold. Clin Exp Hypertens. 2012;34:53–56.
