Editorial Commentary Rapid Diagnosis of Primary Aldosteronism Oxymoron or One Small Step? Morris J. Brown See related article, pp xxx–xxx
M
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with PA who present with resistant hypertension rather than hypokalemia and an adrenal mass, are more reluctant to withdraw multiple treatments required for blood pressure control. Several drug classes can confuse initial diagnosis by altering the aldosterone–renin ratio, or blunt confirmation of unilateral hypersecretion at adrenal vein sampling, if they desuppress the secretion of aldosterone from the gland contralateral to the APA. The guideline has sought to help by lifting requirement for drug withdrawal, or for confirmatory tests, providing there are clearcut biochemical abnormalities (renin undetectable, plasma aldosterone >20 ng/dL [550 pmol/L]), and by questioning the need for adrenal vein sampling in young patients (aged 10 years since robust prospective data established that these are a potentially curable cause of at least 5% of hypertension.1 Yet, there has been little progress in bridging the gulf between potential and actual cures. The senior author of the Endocrine Society’s revised guideline, John Funder, estimates that nowhere in the world are 1% of patients with primary aldosteronism (PA) ever diagnosed, let alone treated appropriately. In response to this deficit, the Endocrine Society has concentrated their firepower on public-health measures to increase awareness and diagnosis, recommending much wider criteria for biochemical testing of plasma renin and aldosterone, and referral to specialists of suspected PA. The guideline illustrates the problem and the solution. On the one hand, PA has all the pre-requisites for modern precision medicine—rigorous, stratified diagnosis, leading to specific treatments and benefits. There is evidence that undiagnosed or uncontrolled PA is undesirable, causing increasingly resistant hypertension, and probably higher risk of cardiovascular morbidity. But the availability of a cheap medical antidote, spironolactone, and benign nature of APAs, create a hurdle to embarking on the expense and morbidity of investigations and surgery, which at best offers 30% to 60% likelihood of curing hypertension altogether.2 Because the options open to patients with PA mean that a high degree of certainty is sought for unilateral disease before committing to intervention, the seeds of a vicious circle are created in which the complexity of the steps in search of certainty raise further the bar to achieving this. To break this circle, we need to simplify or remove each of the steps in diagnosis and treatment. More widespread screening may have limited impact on the number of patients being cured of hypertension if confirmation of diagnosis, by repeating the measurements of renin and aldosterone after salt loading, is required in many patients. The Hypertension community, who are more likely than Endocrinologists to detect the patients The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the William Harvey Research Institute, Barts and the London Medical School, United Kingdom. Correspondence to Morris J. Brown, William Harvey Research Institute, Queen Mary University of London, Charterhouse Sq, London EC1M 6BQ, United Kingdom. E-mail [email protected] (Hypertension. 2017;70:00-00. DOI: 10.1161/HYPERTENSIONAHA.117.09199.) © 2017 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.117.09199
1
2 Hypertension August 2017
Figure. The Primary Aldosteronism hurdles: Ten large leaps to removing 1 small aldosterone-producing adenoma.
Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
and adapted for subsequent years for many purposes, including chemiluminescent immunoassays.9 Morimoto et al’s8 report appears to be the first application of magnetic bead technology to the measurement of renin and aldosterone; the advantage over alternative chemiluminescent ELISAs is the speed of magnetic separation of bound from unbound hormone. The authors demonstrate comparable accuracy to alternative assays and confirm the high sensitivity for renin mass estimation conferred by the double-antibody sandwich assay of large molecules. Some magnetic bead assays have been rendered portable and near-patient compatible.10 Is this the next step? Such assays are usually of value where urgent results facilitate management of emergencies. This is hardly the situation with the diagnosis of PA, which has usually been present for years or decades by the time it presents or is suspected. But if the perception of renin and aldosterone measurement as a lower hurdle than at present encourages wider screening, we can look forward to a rise >1% in the proportion of patients who are diagnosed. To gain maximum advantage from this potential rise in screening, clinicians will hope for 2 parallel developments. One is for further lifting of restriction on current drug treatment. The other is for facilitation and expansion of downstream options so that more patients screened translate into more patients cured (Figure). Because of the difficulties and dangers of withdrawing treatment in severely hypertensive patients, it is important that the physician rather than pathologist dictates treatment and interprets results in the light of current treatment. The aldosterone–renin ratio was a useful concept in gaining recognition that, as in other endocrine conditions, the operative hormone need not itself be above normal. But in hyperthyroidism or hyperparathyroidism, it is not the ratio of T4/thyroid stimulating hormone or Ca2+/parathormone that is reported, and diagnosis of PA would be helped by rational consideration of the individual hormone levels. The log-distribution of renin means that the aldosterone–renin ratio is driven more by renin than aldosterone values. Providing that patients are not receiving a β-blocker, which works by suppressing renin, the use of other drugs which usually elevate renin actually helps diagnosis. This is because a low renin despite such drugs points to Na+ retention, for which autonomous aldosterone secretion is the prime suspect, unless the plasma aldosterone is itself suppressed.
Discussion of developments in downstream management, such as positron emission tomography computed tomography for lateralization, and ablation for treatment are for another time.11 Suffice it to say that, in the 60 years since their first discovery, the management of APAs has progressed substantially. Yet, it still resembles how medicine dealt with another 1-cm benign lesion 50 to 60 years ago—removal of a whole organ as treatment for peptic ulcer. The modern 15-minute urea breath test for helicobacter pylori may be more consequence than catalyst of the subsequent revolution in management; but, it illustrates the ability of a simple diagnostic to stratify common disease and direct specific treatments to those most likely to benefit.
Sources of Funding M.J. Brown holds a grant from the National Institute of Health Research (NIHR) to compare adrenal vein sampling with 11C-metomidate positron emission tomography computed tomography, a grant from the British Heart Foundation to evaluate endoscopic radiofrequency ablation of aldosterone-producing adenomas, and a grant from the Barts and the London Charity to develop novel imaging modalities for aldosterone producing adenomas. M.J. Brown is an NIHR Senior Investigator.
Disclosures None.
References 1. Rossi GP, Bernini G, Caliumi C, et al; PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–2300. doi: 10.1016/j. jacc.2006.07.059. 2. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:1889–1916. doi: 10.1210/jc.2015-4061. 3. Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768–772. doi: 10.1126/science.1198785. 4. Beuschlein F, Boulkroun S, Osswald A, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45:440–444, 444e1. doi: 10.1038/ ng.2550. 5. Azizan EA, Poulsen H, Tuluc P, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013;45:1055–1060. doi: 10.1038/ng.2716. 6. Åkerström T, Willenberg HS, Cupisti K, et al. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas. Endocr Relat Cancer. 2015;22:735–744. doi: 10.1530/ ERC-15-0321.
Brown Diagnosis of Primary Aldosteronism 3 7. Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, GomezSanchez CE, Williams TA, Mulatero P. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol. 2015;411:146–154. doi: 10.1016/j. mce.2015.04.022. 8. Morimoto R, Ono Y, Tezuka Y, Kudo M, Yamamoto S, Arai T, GomezSanchez CE, Sasano H, Ito S, Satoh F. Rapid screening of primary aldosteronism by a novel chemiluminescent immunoassay. Hypertension. 2017;70:xxx–xxx. doi: 10.1161/HYPERTENSIONAHA.117.09078.
9. Wognum AW, Lam V, Goudsmit R, Krystal G. A specific in vitro bioassay for measuring erythropoietin levels in human serum and plasma. Blood. 1990;76:1323–1329. 10. Sista R, Hua Z, Thwar P, Sudarsan A, Srinivasan V, Eckhardt A, Pollack M, Pamula V. Development of a digital microfluidic platform for point of care testing. Lab Chip. 2008;8:2091–2104. doi: 10.1039/b814922d. 11. Sacks BA, Sacks AC, Faintuch S. Radiofrequency ablation treatment for aldosterone-producing adenomas. Curr Opin Endocrinol Diabetes Obes. 2017;24:169–173. doi: 10.1097/MED.0000000000000329.
Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
Rapid Diagnosis of Primary Aldosteronism: Oxymoron or One Small Step? Morris J. Brown Hypertension. published online June 26, 2017; Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2017 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/early/2017/06/26/HYPERTENSIONAHA.117.09199.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/
M
Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
with PA who present with resistant hypertension rather than hypokalemia and an adrenal mass, are more reluctant to withdraw multiple treatments required for blood pressure control. Several drug classes can confuse initial diagnosis by altering the aldosterone–renin ratio, or blunt confirmation of unilateral hypersecretion at adrenal vein sampling, if they desuppress the secretion of aldosterone from the gland contralateral to the APA. The guideline has sought to help by lifting requirement for drug withdrawal, or for confirmatory tests, providing there are clearcut biochemical abnormalities (renin undetectable, plasma aldosterone >20 ng/dL [550 pmol/L]), and by questioning the need for adrenal vein sampling in young patients (aged 10 years since robust prospective data established that these are a potentially curable cause of at least 5% of hypertension.1 Yet, there has been little progress in bridging the gulf between potential and actual cures. The senior author of the Endocrine Society’s revised guideline, John Funder, estimates that nowhere in the world are 1% of patients with primary aldosteronism (PA) ever diagnosed, let alone treated appropriately. In response to this deficit, the Endocrine Society has concentrated their firepower on public-health measures to increase awareness and diagnosis, recommending much wider criteria for biochemical testing of plasma renin and aldosterone, and referral to specialists of suspected PA. The guideline illustrates the problem and the solution. On the one hand, PA has all the pre-requisites for modern precision medicine—rigorous, stratified diagnosis, leading to specific treatments and benefits. There is evidence that undiagnosed or uncontrolled PA is undesirable, causing increasingly resistant hypertension, and probably higher risk of cardiovascular morbidity. But the availability of a cheap medical antidote, spironolactone, and benign nature of APAs, create a hurdle to embarking on the expense and morbidity of investigations and surgery, which at best offers 30% to 60% likelihood of curing hypertension altogether.2 Because the options open to patients with PA mean that a high degree of certainty is sought for unilateral disease before committing to intervention, the seeds of a vicious circle are created in which the complexity of the steps in search of certainty raise further the bar to achieving this. To break this circle, we need to simplify or remove each of the steps in diagnosis and treatment. More widespread screening may have limited impact on the number of patients being cured of hypertension if confirmation of diagnosis, by repeating the measurements of renin and aldosterone after salt loading, is required in many patients. The Hypertension community, who are more likely than Endocrinologists to detect the patients The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the William Harvey Research Institute, Barts and the London Medical School, United Kingdom. Correspondence to Morris J. Brown, William Harvey Research Institute, Queen Mary University of London, Charterhouse Sq, London EC1M 6BQ, United Kingdom. E-mail [email protected] (Hypertension. 2017;70:00-00. DOI: 10.1161/HYPERTENSIONAHA.117.09199.) © 2017 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.117.09199
1
2 Hypertension August 2017
Figure. The Primary Aldosteronism hurdles: Ten large leaps to removing 1 small aldosterone-producing adenoma.
Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
and adapted for subsequent years for many purposes, including chemiluminescent immunoassays.9 Morimoto et al’s8 report appears to be the first application of magnetic bead technology to the measurement of renin and aldosterone; the advantage over alternative chemiluminescent ELISAs is the speed of magnetic separation of bound from unbound hormone. The authors demonstrate comparable accuracy to alternative assays and confirm the high sensitivity for renin mass estimation conferred by the double-antibody sandwich assay of large molecules. Some magnetic bead assays have been rendered portable and near-patient compatible.10 Is this the next step? Such assays are usually of value where urgent results facilitate management of emergencies. This is hardly the situation with the diagnosis of PA, which has usually been present for years or decades by the time it presents or is suspected. But if the perception of renin and aldosterone measurement as a lower hurdle than at present encourages wider screening, we can look forward to a rise >1% in the proportion of patients who are diagnosed. To gain maximum advantage from this potential rise in screening, clinicians will hope for 2 parallel developments. One is for further lifting of restriction on current drug treatment. The other is for facilitation and expansion of downstream options so that more patients screened translate into more patients cured (Figure). Because of the difficulties and dangers of withdrawing treatment in severely hypertensive patients, it is important that the physician rather than pathologist dictates treatment and interprets results in the light of current treatment. The aldosterone–renin ratio was a useful concept in gaining recognition that, as in other endocrine conditions, the operative hormone need not itself be above normal. But in hyperthyroidism or hyperparathyroidism, it is not the ratio of T4/thyroid stimulating hormone or Ca2+/parathormone that is reported, and diagnosis of PA would be helped by rational consideration of the individual hormone levels. The log-distribution of renin means that the aldosterone–renin ratio is driven more by renin than aldosterone values. Providing that patients are not receiving a β-blocker, which works by suppressing renin, the use of other drugs which usually elevate renin actually helps diagnosis. This is because a low renin despite such drugs points to Na+ retention, for which autonomous aldosterone secretion is the prime suspect, unless the plasma aldosterone is itself suppressed.
Discussion of developments in downstream management, such as positron emission tomography computed tomography for lateralization, and ablation for treatment are for another time.11 Suffice it to say that, in the 60 years since their first discovery, the management of APAs has progressed substantially. Yet, it still resembles how medicine dealt with another 1-cm benign lesion 50 to 60 years ago—removal of a whole organ as treatment for peptic ulcer. The modern 15-minute urea breath test for helicobacter pylori may be more consequence than catalyst of the subsequent revolution in management; but, it illustrates the ability of a simple diagnostic to stratify common disease and direct specific treatments to those most likely to benefit.
Sources of Funding M.J. Brown holds a grant from the National Institute of Health Research (NIHR) to compare adrenal vein sampling with 11C-metomidate positron emission tomography computed tomography, a grant from the British Heart Foundation to evaluate endoscopic radiofrequency ablation of aldosterone-producing adenomas, and a grant from the Barts and the London Charity to develop novel imaging modalities for aldosterone producing adenomas. M.J. Brown is an NIHR Senior Investigator.
Disclosures None.
References 1. Rossi GP, Bernini G, Caliumi C, et al; PAPY Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–2300. doi: 10.1016/j. jacc.2006.07.059. 2. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:1889–1916. doi: 10.1210/jc.2015-4061. 3. Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768–772. doi: 10.1126/science.1198785. 4. Beuschlein F, Boulkroun S, Osswald A, et al. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet. 2013;45:440–444, 444e1. doi: 10.1038/ ng.2550. 5. Azizan EA, Poulsen H, Tuluc P, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet. 2013;45:1055–1060. doi: 10.1038/ng.2716. 6. Åkerström T, Willenberg HS, Cupisti K, et al. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas. Endocr Relat Cancer. 2015;22:735–744. doi: 10.1530/ ERC-15-0321.
Brown Diagnosis of Primary Aldosteronism 3 7. Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, GomezSanchez CE, Williams TA, Mulatero P. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol. 2015;411:146–154. doi: 10.1016/j. mce.2015.04.022. 8. Morimoto R, Ono Y, Tezuka Y, Kudo M, Yamamoto S, Arai T, GomezSanchez CE, Sasano H, Ito S, Satoh F. Rapid screening of primary aldosteronism by a novel chemiluminescent immunoassay. Hypertension. 2017;70:xxx–xxx. doi: 10.1161/HYPERTENSIONAHA.117.09078.
9. Wognum AW, Lam V, Goudsmit R, Krystal G. A specific in vitro bioassay for measuring erythropoietin levels in human serum and plasma. Blood. 1990;76:1323–1329. 10. Sista R, Hua Z, Thwar P, Sudarsan A, Srinivasan V, Eckhardt A, Pollack M, Pamula V. Development of a digital microfluidic platform for point of care testing. Lab Chip. 2008;8:2091–2104. doi: 10.1039/b814922d. 11. Sacks BA, Sacks AC, Faintuch S. Radiofrequency ablation treatment for aldosterone-producing adenomas. Curr Opin Endocrinol Diabetes Obes. 2017;24:169–173. doi: 10.1097/MED.0000000000000329.
Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
Rapid Diagnosis of Primary Aldosteronism: Oxymoron or One Small Step? Morris J. Brown Hypertension. published online June 26, 2017; Downloaded from http://hyper.ahajournals.org/ by guest on June 28, 2017
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2017 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/early/2017/06/26/HYPERTENSIONAHA.117.09199.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/
