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Horm Metab Res 2015; 47(13): 935-940
DOI: 10.1055/s-0035-1565182
Review

Primary Aldosteronism: New Answers, New Questions

J. W. Funder
1   Hudson Institute of Medical Research and Monash University, Clayton, Australia
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Abstract

There have been 2, and possibly 3, major questions for primary aldosteronism (PA) answered at least in principle over the past 5 years. The first is that of somatic mutations underlying the majority of aldosterone producing adenomas. The second is the extension of our knowledge of the genetics of familial hypertension, and the third the role of renal intercalated cells in sodium homeostasis. New questions for the next 5 years include a single accepted confirmatory/exclusion test; standardisation of assays and cut-offs; alternatives to universal adrenal venous sampling; reclassification of ‘low renin hypertension’; recognition of the extent of ‘occult’ PA; inclusion of low-dose mineralocorticoid receptor antagonist in first-line therapy for hypertension; and finally, possible resolution of the aldosterone/inappropriate sodium status enigma at the heart of the cardiovascular damage in PA.

Key words

aldosterone - familial hyperaldosteronism type II and III - lateralisation - APA - ACTH - endogenous ouabain - mineralocorticoid receptor antagonist


Publication History

Received: 18 August 2015

Accepted: 19 October 2015

Article published online:
20 November 2015

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young Jr WF, Montori VM. 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
    CrossrefPubMedSearch in Google Scholar
  • 2 Nishikawa T, Omura M., Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A. Task Force Committee on Primary Aldosteronism, The Japan Endocrine Society. Guidelines for the diagnosis and treatment of primary aldosteronism – the Japan Endocrine Society 2009. Endocr J 2011; 58: 711-721
    CrossrefPubMedSearch in Google Scholar
  • 3 Choi M, Scholl UI, Yue P, Bjorklund P, Zhao BX, Nelson-Williams C, Ji WZ, Cho YS, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331: 768-772
    CrossrefPubMedSearch in Google Scholar
  • 4 Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L, Mulatero P, Samson-Couterie B, Hahner S, Quinkler M, Fallo F, Letizia C, Allolio B, Ceolotto G, Cicala MV, Lang K, Lefebvre H, Lenzini L, Maniero C, Monticone S, Perrocheau M, Pilon C, Plouin PF, Rayes N, Seccia TM, Veglio F, Williams TA, Zinnamosca L, Mantero F, Benecke A, Jeunemaitre X, Reincke M, Zennaro MC. Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension 2012; 59: 592-598
    CrossrefPubMedSearch in Google Scholar
  • 5 Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar I, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allollo B, Samson-Couterie B, Benecke A, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 2013; 45: 440-444
    CrossrefPubMedSearch in Google Scholar
  • 6 Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 2013; 45: 1055-1060
    CrossrefPubMedSearch in Google Scholar
  • 7 Scholl UI, Goh G, Stolting G, Campos de Oliveira R, Choi M, Overton JD, Fonseca AL, Korah R, Starker LP, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrōm G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-1054
    CrossrefPubMedSearch in Google Scholar
  • 8 Scholl UI, Healy JM, Thiel A, Fonseca KL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kűcűkkölű S, Riemer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T. Novel somatic mutations in primary aldosteronism are related to the clinical, radiological and pathological phenotype. Clin Endocrinol (Oxf). 2015 Aug 7 10.1111.cen.12873
    PubMedSearch in Google Scholar
  • 9 Charmandari E, Sertedaki A, Kino T, Merakou C, Hoffman DA, Hatch MM, Hurt DE, Lin L, Xekouki P, Stratakis CA, Chrousos GP. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. J Clin Endocrinol Metab 2012; 97: E1532-E1539
    CrossrefPubMedSearch in Google Scholar
  • 10 Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, Fischer E, Tizzani D, Pallauf A, Viola A, Amar L, Williams TA, Strom TM, Graf E, Bandulik S, Penton D, Plouin PF, Warth R, Allolio B, Jeunemaitre X, Veglio F, Reincke M. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension 2012; 59: 235-240
    CrossrefPubMedSearch in Google Scholar
  • 11 Akerstrom T, Crona J, Delgado Verdugo A, Starker LF, Cupisti K, Willenberg HS, Knoefel WT, Saeger W, Feller A, Ip J, Soon P, Anlauf M, Alesina PF, Schmid KW, Decaussin M, Levillain P, Wangberg B, Peix JL, Robinson B, Zedenius J, Backdahl M, Caramuta S, Iwen KA, Botling I, Stalberg P, Kraimps JL, Dralle H, Hellman P, Sidhu S, Westin G, Lehnert H, Walz MK, Akerstrom G, Carling T, Choi M, Lifton RP, Bjorklund P. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One 2012; 7: e41926
    CrossrefPubMedSearch in Google Scholar
  • 12 Murthy M, Azizan EA, Brown MJ, O’Shaughnessy KM. Characterization of a novel somatic KCNJ5 mutation dell157 in an aldosterone-producing adenoma. J Hypertens 2012; 30: 1827-1833
    CrossrefPubMedSearch in Google Scholar
  • 13 Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, Sterner G, Warth R, Mulatero P, Rainey WE. A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J Clin Endocrinol Metab 2013; 98: E1861-E1865
    CrossrefPubMedSearch in Google Scholar
  • 14 Kuppusamy M, Caroccia B, Stindl J, Bandulik S, Lenzini L, Giocco F, Fishman V, Zanotti G, Gomez-Sanchez C, Bader M, Warth R, Rossi GP. A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium. J Clin Endocrinol Metab 2014; 99: E1765-E1773
    CrossrefPubMedSearch in Google Scholar
  • 15 Cheng CJ, Sung CC, Wu ST, Lin YC, Sytwu H-K, Huang CL, Lin SH. Novel KCNJ5 mutations in sporadic aldosterone-producing adenoma reduce Kir3.4 membrane abundance. J Clin Endocrinol Metab 2015; 100: E155-E163
    CrossrefPubMedSearch in Google Scholar
  • 16 Markou A, Sertedak A, Kaltsas G, Androulakis I, Marakaki C, Pappa T, Gouli A, Papanastasiou L, Fountoulakis S, Zacharoulis A, Karavidas A, Ragkou D, Charmandari E, Chrousos GP, Piaditis GP. Stress-induced aldosterone hypersecretion in a substantial subset of patients with essential hypertension. J Clin Endocrinol Metab 2015; 100: 2857-2864
    CrossrefPubMedSearch in Google Scholar
  • 17 Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GP. A meta-analysis of somatic KCNJ5 K+ channel mutations in 1636 patients with an aldosterone-producing adenoma. J Clin Endocrinol Metab 2015; 100: E1089-E1095
    CrossrefPubMedSearch in Google Scholar
  • 18 Azizan EA, Murthy M, Stowasser M, Gordon R, Kowalski B, Xu S, Brown MJ, O’Shaughnessy KM. Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. Hypertension 2012; 59: 587-591
    CrossrefPubMedSearch in Google Scholar
  • 19 Mulatero P, Monticone S, Rainey WE, Veglio F, Williams TA. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol 2013; 9: 104-112
    CrossrefPubMedSearch in Google Scholar
  • 20 Taguchi R, Yamada M, Nakajima Y, Satoh T, Hashimoto K, Shibusawa N, Ozawa A, Okada S, Rokutanda N, Takata D, Koibuchi Y, Horiguchi J, Oyama T, Takeyoshi I, Mori M. Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. J Clin Endocrinol Metab 2012; 97: 1311-1319
    CrossrefPubMedSearch in Google Scholar
  • 21 Kitamoto T, Suematsu S, Matsuzawa Y, Suematsu S, Matsuzawa Y, Saito J, Omura M, Nishikawa T. Comparison of cardiovascular complications in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenomas. J Atheroscler Thromb 2015; 22: 191-200
    CrossrefPubMedSearch in Google Scholar
  • 22 Zeng FF, Zhu LM, Nie AF, Li XY, Lin JR, Zhang K, Chen J, Zhou WL, Shen ZJ, Zhu YC, Wang JG, Zhu DL, Gao PJ. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension 2015; 65: 622-628
    CrossrefPubMedSearch in Google Scholar
  • 23 Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 1966; 95: 1109-1119
    PubMedSearch in Google Scholar
  • 24 Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355: 262-265
    CrossrefPubMedSearch in Google Scholar
  • 25 Torpy DJ, Gordon RD, Lin JP, Huggard PR, Taymans SE, Stowasser M, Chrousos GP, Stratakis CA. Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene. J Clin Endocrinol Metab 1998; 83: 3214-3218
    PubMedSearch in Google Scholar
  • 26 Carss KJ, Stowasser M, Gordon RD, O’Shaughnessy KM. Further study of chromosome 7p22 to identify the molecular basis of familial hyperaldosteronism type II. J Hum Hypertens 2011; 25: 560-564
    CrossrefPubMedSearch in Google Scholar
  • 27 Mulatero P, Tizzani D, Viola A, Bertello C, Monticone S, Mengozzi G, Schiavone D, Williams TA, Einaudi S, La Grotta A, Rabbia F, Veglio F. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in Torino-GENetic forms). Hypertension 2011; 58: 797-803
    CrossrefPubMedSearch in Google Scholar
  • 28 Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 2008; 93: 3117-3123
    CrossrefPubMedSearch in Google Scholar
  • 29 Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, Couch R, Hammer LK, Harley FL, Farhi A, Wang WH, Lifton RP. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci USA 2012; 109: 2533-2538
    CrossrefPubMedSearch in Google Scholar
  • 30 Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Beady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahike C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-1054
    CrossrefPubMedSearch in Google Scholar
  • 31 Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T, Juhlin CC, Quack I, Rump LC, Thiel A, Lande M, Frazier BG, Rasoulpour M, Bowlin DL, Sethna CB, Trachtman H, Fahlke C, Lifton RP. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 2015; 4: e06315
    CrossrefPubMedSearch in Google Scholar
  • 32 Shibata S, Rinehart J, Zhang J, Moeckel G, Castaneda-Bueno M, Stiegler AL, Boggon TJ, Gamba G, Lifton RP. Cell Metab 2013; 18: 660-671
    CrossrefPubMedSearch in Google Scholar
  • 33 Funder JW. Angiotensin retains sodium by dephosphorylating mineralocorticoid receptors in renal intercalated cells. Cell Metab 2013; 18: 609-610
    CrossrefPubMedSearch in Google Scholar
  • 34 Okubo S, Niimura F, Nishimura H, Takemoto F, Fogo A, Matsusaka T, Ichikawa I. Angiotensin-independent Mechanism for Aldosterone Synthesis during Chronic Extracellular Fluid Volume Depletion. J Clin Invest 1997; 99: 855-860
    CrossrefPubMedSearch in Google Scholar
  • 35 Gioco F, Seccia TM, Gomez-Sanchez EP, Rossi GP, Gomez-Sanchez CE. Hypertension 2015; 66: 724-730
    CrossrefPubMedSearch in Google Scholar
  • 36 Dekkers T, ter Meer M, Lenders JW, Hermus AR, Schultze Kool L, Langenhuijsen JF, Nishimoto K, Ogishima T, Mukai K, Azizan EA, Tops B, Deinum J, Küsters B. Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit?. J Clin Endocrinol Metab 2014; 99: E1341-E1351
    CrossrefPubMedSearch in Google Scholar
  • 37 Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, Liu CJ, Sanjanwala AR, Edwards MA, Gomez-Sanchez CE, Nanba K, Rainey WE. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA 2015; 112: E4591-E4599
    CrossrefPubMedSearch in Google Scholar
  • 38 Ahmed AH, Cowley D, Wolley M, Gordon RD, Xu S, Taylor PJ, Stowasser M. Seated saline suppression testing for the diagnosis of primary aldosteronism: a preliminary study. J Clin Endocrinol Metab 2014; 99: 2745-2753
    CrossrefPubMedSearch in Google Scholar
  • 39 Mulatero P, di Cella SM, Monticone S, Schiavone D, Manzo M, Menguzzi G, Rabbia F, Terzolo M, Gomez-Sanchez EP, Gomez-Sanchez CE, Vegllo F. 18-hydroxycorticosterone, 18 hydroxy cortisol and 18-oxocortisol in the diagnosis of primary aldosteronism and its subtypes. J Clin Endocrinol Metab 2012; 97: 881-889
    CrossrefPubMedSearch in Google Scholar
  • 40 Satoh F, Morimoto R, Ono Y, Iwakura Y, Omata K, Kudo M, Takase K, Seiji K, Sasamoto H, Honma S, Okuyama M, Yamashita K, Gomez-Sanchez CE, Rainey WE, Arai Y, Sasano H, Nakamura Y, Ito S. Measurement of peripheral plasma 18-oxocortisol can discriminate unilateral adenoma from bilateral diseases in patients with primary aldosteronism. Hypertension 2015; 65: 1096-1102
    CrossrefPubMedSearch in Google Scholar
  • 41 Helber A, Wambach G, Hummerich W, Bonner G, Meurer KA, Kaufmann W. Evidence for a subgroup of essential hypertensives with non-suppressible excretion of aldosterone during sodium loading. Klin Wochenschr 1980; 58: 439-447
    CrossrefPubMedSearch in Google Scholar
  • 42 Levy DG, Rocha R, Funder JW. Distinguishing the antihypertensive and electrolyte effects of eplerenone. J Clin Endocrinol Metab 2004; 89: 2736-2740
    CrossrefPubMedSearch in Google Scholar
  • 43 Mihailidou AS, Le TYL, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 2009; 54: 1306-1312
    Search in Google Scholar
  • 44 Ori Y, Chagnac A, Korzets A, Zingerman B, Herman-Edelstein M, Bergman M, Gafter U, Salman H. Regression of left ventricular hypertrophy in patients with primary aldosteronism/low-renin hypertension on low-dose spironolactone. Nephrol Dial Transplant 2013; 28: 1787-1793
    CrossrefPubMedSearch in Google Scholar
  • 45 Gouli A, Kaltsas G, Tzonou A, Markou A, Androulakis II, Ragkou D, Vamvakidis K, Zografos G, Kontogeorgos G, Chrousos GP, Piaditis G. High prevalence of autonomous aldosterone secretion among patients with essential hypertension. Eur J Clin Invest 2011; 41: 1227-1236
    CrossrefPubMedSearch in Google Scholar
  • 46 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
    CrossrefPubMedSearch in Google Scholar
  • 47 Funder JW. Primary aldosteronism: are we missing the wood for the trees?. Horm Metab Res 2012; 44: 251-253
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Eide IK, Torjesen PA, Drolsum A, Babovic A, Lilledahl NP. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens 2004; 22: 2217-2226
    CrossrefPubMedSearch in Google Scholar
  • 49 Funder JW. Primary aldosteronism and salt. Pflugers Arch 2015; 467: 587-594
    CrossrefPubMedSearch in Google Scholar