Primary Aldosteronism: From Genetic Causes to Clinical Guidelines

  • Kazutaka Nanba
  • Hirotaka Shibata
  • William E. Rainey
Part of the Contemporary Endocrinology book series (COE)


Aldosterone is the major mineralocorticoid synthesized in the adrenal zona glomerulosa and plays a pivotal role in the regulation of intravascular volume and blood pressure. There is growing evidence that chronic inappropriate elevation in circulating aldosterone causes renal, cardiovascular, and other pathologic complications. The dysregulation of aldosterone production, also known as primary aldosteronism (PA) is the most common cause of secondary hypertension. PA is a heterogeneous group of disorders including both sporadic and familial forms. Despite significant progress in the diagnosis and management of PA, until recently the molecular mechanisms leading to inappropriate aldosterone production were largely unknown. The use of next-generation sequencing has resulted in the identification of several somatic and more rarely germline mutations underlying sporadic APA and/or familial PA, and these mutations activate intracellular calcium signaling which is the major trigger of aldosterone production. This chapter focuses on genetics and pathophysiology of PA as well as management of patients with PA.


Primary aldosteronism Aldosterone CYP11B2 Mutations Clinical guidelines 


  1. 1.
    Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3–17.PubMedGoogle Scholar
  2. 2.
    Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol. 2007;66:607–18.CrossRefGoogle Scholar
  3. 3.
    Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F, Investigators PS. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006;48:2293–300.PubMedCrossRefGoogle Scholar
  4. 4.
    Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L, Pinto M, Huete A, Oestreicher E, Foradori A, Montero J. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab. 2000;85:1863–7.PubMedGoogle Scholar
  5. 5.
    Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol. 1994;21:315–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Lim PO, Dow E, Brennan G, Jung RT, MacDonald TM. High prevalence of primary aldosteronism in the Tayside hypertension clinic population. J Hum Hypertens. 2000;14:311–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF Jr. Prevalence of primary aldosteronism among Asian hypertensive patients in Singapore. J Clin Endocrinol Metab. 2000;85:2854–9.PubMedGoogle Scholar
  8. 8.
    Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002;40:892–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky J Jr. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens. 2003;17:349–52.PubMedCrossRefGoogle Scholar
  10. 10.
    Gallay BJ, Ahmad S, Xu L, Toivola B, Davidson RC. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis. 2001;37:699–705.PubMedCrossRefGoogle Scholar
  11. 11.
    Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, 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;331:768–72.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio 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;45:440–4. 444e441-442PubMedCrossRefGoogle Scholar
  13. 13.
    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, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom 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;45:1050–4.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Azizan EAB, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AED, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GSH, 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;45:1055–60.PubMedCrossRefGoogle Scholar
  15. 15.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Hattangady NG, Olala LO, Bollag WB, Rainey WE. Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol. 2012;350:151–62.PubMedCrossRefGoogle Scholar
  17. 17.
    Capponi AM. The control by angiotensin II of cholesterol supply for aldosterone biosynthesis. Mol Cell Endocrinol. 2004;217:113–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Cherradi N, Brandenburger Y, Capponi AM. Mitochondrial regulation of mineralocorticoid biosynthesis by calcium and the StAR protein. Eur J Endocrinol. 1998;139:249–56.PubMedCrossRefGoogle Scholar
  19. 19.
    Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss JF 3rd. Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. J Biol Chem. 1997;272:32656–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Fleury A, Mathieu AP, Ducharme L, Hales DB, LeHoux JG. Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR). J Steroid Biochem Mol Biol. 2004;91:259–71.PubMedCrossRefGoogle Scholar
  21. 21.
    Manna PR, Huhtaniemi IT, Stocco DM. Mechanisms of protein kinase C signaling in the modulation of 3′,5′-cyclic adenosine monophosphate-mediated steroidogenesis in mouse gonadal cells. Endocrinology. 2009;150:3308–17.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Ogishima T, Suzuki H, Hata J, Mitani F, Ishimura Y. Zone-specific expression of aldosterone synthase cytochrome P-450 and cytochrome P-45011 beta in rat adrenal cortex: histochemical basis for the functional zonation. Endocrinology. 1992;130:2971–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Narasaka T, Suzuki T, Moriya T, Sasano H. Temporal and spatial distribution of corticosteroidogenic enzymes immunoreactivity in developing human adrenal. Mol Cell Endocrinol. 2001;174:111–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Clark AJ, Balla T, Jones MR, Catt KJ. Stimulation of early gene expression by angiotensin II in bovine adrenal glomerulosa cells: roles of calcium and protein kinase C. Mol Endocrinol. 1992;6:1889–98.PubMedGoogle Scholar
  25. 25.
    Muller J. Regulation of aldosterone biosynthesis: the end of the road? Clin Exp Pharmacol Physiol Suppl. 1998;25:S79–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol. 2004;217:67–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Pezzi V, Clyne CD, Ando S, Mathis JM, Rainey WE. Ca(2+)-regulated expression of aldosterone synthase is mediated by calmodulin and calmodulin-dependent protein kinases. Endocrinology. 1997;138:835–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Nogueira EF, Xing Y, Morris CA, Rainey WE. Role of angiotensin II-induced rapid response genes in the regulation of enzymes needed for aldosterone synthesis. J Mol Endocrinol. 2009;42:319–30.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Barrett PQ, Bollag WB, Isales CM, McCarthy RT, Rasmussen H. Role of calcium in angiotensin II-mediated aldosterone secretion. Endocr Rev. 1989;10:496–518.PubMedCrossRefGoogle Scholar
  30. 30.
    Bird IM, Hanley NA, Word RA, Mathis JM, McCarthy JL, Mason JI, Rainey WE. Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive aldosterone secretion. Endocrinology. 1993;133:1555–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Bollag WB, Barrett PQ, Isales CM, Rasmussen H. Angiotensin-II-induced changes in diacylglycerol levels and their potential role in modulating the steroidogenic response. Endocrinology. 1991;128:231–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Farese RV, Larson RE, Sabir MA, Gomez-Sanchez C. Effects of angiotensin-II and potassium on phospholipid metabolism in the adrenal zona glomerulosa. J Biol Chem. 1981;256:11093–7.PubMedGoogle Scholar
  33. 33.
    Ganguly A, Davis JS. Role of calcium and other mediators in aldosterone secretion from the adrenal glomerulosa cells. Pharmacol Rev. 1994;46:417–47.PubMedGoogle Scholar
  34. 34.
    Hunyady L, Baukal AJ, Bor M, Ely JA, Catt KJ. Regulation of 1,2-diacylglycerol production by angiotensin-II in bovine adrenal glomerulosa cells. Endocrinology. 1990;126:1001–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Kojima I, Kojima K, Kreutter D, Rasmussen H. The temporal integration of the aldosterone secretory response to angiotensin occurs via two intracellular pathways. J Biol Chem. 1984;259:14448–57.PubMedGoogle Scholar
  36. 36.
    Ganguly A, Chiou S, Fineberg NS, Davis JS. Greater importance of Ca(2+)-calmodulin in maintenance of ang II- and K(+)-mediated aldosterone secretion: lesser role of protein kinase C. Biochem Biophys Res Commun. 1992;182:254–61.PubMedCrossRefGoogle Scholar
  37. 37.
    Pezzi V, Clark BJ, Ando S, Stocco DM, Rainey WE. Role of calmodulin-dependent protein kinase II in the acute stimulation of aldosterone production. J Steroid Biochem Mol Biol. 1996;58:417–24.PubMedCrossRefGoogle Scholar
  38. 38.
    Spat A, Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004;84:489–539.PubMedCrossRefGoogle Scholar
  39. 39.
    Condon JC, Pezzi V, Drummond BM, Yin S, Rainey WE. Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase. Endocrinology. 2002;143:3651–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Nanba K, Chen A, Nishimoto K, Rainey WE. Role of Ca(2+)/calmodulin-dependent protein kinase kinase in adrenal aldosterone production. Endocrinology. 2015;156:1750–6.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Capponi AM, Lew PD, Jornot L, Vallotton MB. Correlation between cytosolic free Ca2+ and aldosterone production in bovine adrenal glomerulosa cells. Evidence for a difference in the mode of action of angiotensin II and potassium. J Biol Chem. 1984;259:8863–9.PubMedGoogle Scholar
  42. 42.
    Kojima K, Kojima I, Rasmussen H. Dihydropyridine calcium agonist and antagonist effects on aldosterone secretion. Am J Phys. 1984;247:E645–50.Google Scholar
  43. 43.
    Rossier MF, Ertel EA, Vallotton MB, Capponi AM. Inhibitory action of mibefradil on calcium signaling and aldosterone synthesis in bovine adrenal glomerulosa cells. J Pharmacol Exp Ther. 1998;287:824–31.PubMedGoogle Scholar
  44. 44.
    Oki K, Plonczynski MW, Lam ML, Gomez-Sanchez EP, Gomez-Sanchez CE. The potassium channel, Kir3.4 participates in angiotensin II-stimulated aldosterone production by a human adrenocortical cell line. Endocrinology. 2012;153:4328–35.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Hattangady NG, Karashima S, Yuan L, Ponce-Balbuena D, Jalife J, Gomez-Sanchez CE, Auchus RJ, Rainey WE, Else T. Mutated KCNJ5 activates the acute and chronic regulatory steps in aldosterone production. J Mol Endocrinol. 2016;57:1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Betancourt-Calle S, Calle RA, Isales CM, White S, Rasmussen H, Bollag WB. Differential effects of agonists of aldosterone secretion on steroidogenic acute regulatory phosphorylation. Mol Cell Endocrinol. 2001;173:87–94.PubMedCrossRefGoogle Scholar
  47. 47.
    Sculptoreanu A, Scheuer T, Catterall WA. Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase. Nature. 1993;364:240–3.PubMedCrossRefGoogle Scholar
  48. 48.
    Tremblay E, Payet MD, Gallo-Payet N. Effects of ACTH and angiotensin II on cytosolic calcium in cultured adrenal glomerulosa cells. Role of cAMP production in the ACTH effect. Cell Calcium. 1991;12:655–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Gallo-Payet N, Grazzini E, Cote M, Chouinard L, Chorvatova A, Bilodeau L, Payet MD, Guillon G. Role of Ca2+ in the action of adrenocorticotropin in cultured human adrenal glomerulosa cells. J Clin Invest. 1996;98:460–6.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kojima I, Kojima K, Rasmussen H. Role of calcium and cAMP in the action of adrenocorticotropin on aldosterone secretion. J Biol Chem. 1985;260:4248–56.PubMedGoogle Scholar
  51. 51.
    Clyne CD, Zhang Y, Slutsker L, Mathis JM, White PC, Rainey WE. Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Mol Endocrinol. 1997;11:638–49.PubMedCrossRefGoogle Scholar
  52. 52.
    Bassett MH, Zhang Y, White PC, Rainey WE. Regulation of human CYP11B2 and CYP11B1: comparing the role of the common CRE/Ad1 element. Endocr Res. 2000;26:941–51.PubMedCrossRefGoogle Scholar
  53. 53.
    Bassett MH, Suzuki T, Sasano H, White PC, Rainey WE. The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production. Mol Endocrinol. 2004;18:279–90.PubMedCrossRefGoogle Scholar
  54. 54.
    Nogueira EF, Rainey WE. Regulation of aldosterone synthase by activator transcription factor/cAMP response element-binding protein family members. Endocrinology. 2010;151:1060–70.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lu L, Suzuki T, Yoshikawa Y, Murakami O, Miki Y, Moriya T, Bassett MH, Rainey WE, Hayashi Y, Sasano H. Nur-related factor 1 and nerve growth factor-induced clone B in human adrenal cortex and its disorders. J Clin Endocrinol Metab. 2004;89:4113–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Conn JW. Plasma renin activity in primary Aldosteronism. Importance in differential diagnosis and in research of essential hypertension. JAMA. 1964;190:222–5.PubMedGoogle Scholar
  57. 57.
    Fishman LM, Kuchel O, Liddle GW, Michelakis AM, Gordon RD, Chick WT. Incidence of primary aldosteronism uncomplicated "essential" hypertension. A prospective study with elevated aldosterone secretion and suppressed plasma renin activity used as diagnostic criteria. JAMA. 1968;205:497–502.PubMedCrossRefGoogle Scholar
  58. 58.
    Kaplan NM. Hypokalemia in the hypertensive patient, with observations on the incidence of primary aldosteronism. Ann Intern Med. 1967;66:1079–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Sinclair AM, Isles CG, Brown I, Cameron H, Murray GD, Robertson JW. Secondary hypertension in a blood pressure clinic. Arch Intern Med. 1987;147:1289–93.PubMedCrossRefGoogle Scholar
  60. 60.
    Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara M, Nagata H, Izumiyama T. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients. Arch Intern Med. 1981;141:1589–93.PubMedCrossRefGoogle Scholar
  61. 61.
    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF Jr. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045–50.PubMedCrossRefGoogle Scholar
  62. 62.
    Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F, Montero J, Huete A, Gederlini A, Fardella CE. Primary aldosteronism and hypertensive disease. Hypertension. 2003;42:161–5.PubMedCrossRefGoogle Scholar
  63. 63.
    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;101:1889–916.PubMedCrossRefGoogle Scholar
  64. 64.
    Fallo F, Veglio F, Bertello C, Sonino N, Della Mea P, Ermani M, Rabbia F, Federspil G, Mulatero P. Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab. 2006;91:454–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Reincke M, Meisinger C, Holle R, Quinkler M, Hahner S, Beuschlein F, Bidlingmaier M, Seissler J, Endres S. Participants of the German Conn's R is primary aldosteronism associated with diabetes mellitus? Results of the German Conn's registry. Horm Metab Res. 2010;42:435–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Monticone S, Viola A, Tizzani D, Crudo V, Burrello J, Galmozzi M, Veglio F, Mulatero P. Primary aldosteronism: who should be screened? Horm Metab Res. 2012;44:163–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Mulatero P, Rabbia F, Milan A, Paglieri C, Morello F, Chiandussi L, Veglio F. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension. 2002;40:897–902.PubMedCrossRefGoogle Scholar
  68. 68.
    Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, Tanabe A. Task force committee on primary Aldosteronism TJES guidelines for the diagnosis and treatment of primary aldosteronism--the Japan Endocrine Society 2009. Endocr J. 2011;58:711–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Douillard C, Houillier P, Nussberger J, Girerd X. SFE/SFHTA/AFCE consensus on primary Aldosteronism, part 2: first diagnostic steps. Ann Endocrinol (Paris). 2016;77:192–201.CrossRefGoogle Scholar
  70. 70.
    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;99:2745–53.PubMedCrossRefGoogle Scholar
  71. 71.
    Kempers MJ, Lenders JW, van Outheusden L, van der Wilt GJ, Schultze Kool LJ, Hermus AR, Deinum J. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med. 2009;151:329–37.PubMedCrossRefGoogle Scholar
  72. 72.
    Rossi GP, Barisa M, Allolio B, Auchus RJ, Amar L, Cohen D, Degenhart C, Deinum J, Fischer E, Gordon R, Kickuth R, Kline G, Lacroix A, Magill S, Miotto D, Naruse M, Nishikawa T, Omura M, Pimenta E, Plouin PF, Quinkler M, Reincke M, Rossi E, Rump LC, Satoh F, Schultze Kool L, Seccia TM, Stowasser M, Tanabe A, Trerotola S, Vonend O, Widimsky J Jr, Wu KD, Wu VC, Pessina AC. The Adrenal Vein Sampling International Study (AVIS) for identifying the major subtypes of primary aldosteronism. J Clin Endocrinol Metab. 2012;97:1606–14.PubMedCrossRefGoogle Scholar
  73. 73.
    Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg. 2005;29:155–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Harris DA, Au-Yong I, Basnyat PS, Sadler GP, Wheeler MH. Review of surgical management of aldosterone secreting tumours of the adrenal cortex. Eur J Surg Oncol. 2003;29:467–74.PubMedCrossRefGoogle Scholar
  75. 75.
    Celen O, O'Brien MJ, Melby JC, Beazley RM. Factors influencing outcome of surgery for primary aldosteronism. Arch Surg. 1996;131:646–50.PubMedCrossRefGoogle Scholar
  76. 76.
    Streeten DH, Anderson GH Jr, Wagner S. Effect of age on response of secondary hypertension to specific treatment. Am J Hypertens. 1990;3:360–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Sawka AM, Young WF, Thompson GB, Grant CS, Farley DR, Leibson C, van Heerden JA. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med. 2001;135:258–61.PubMedCrossRefGoogle Scholar
  78. 78.
    de Gasparo M, Joss U, Ramjoue HP, Whitebread SE, Haenni H, Schenkel L, Kraehenbuehl C, Biollaz M, Grob J, Schmidlin J, et al. Three new epoxy-spirolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther. 1987;240:650–6.PubMedGoogle Scholar
  79. 79.
    Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature. 1995;374:135–41.PubMedCrossRefGoogle Scholar
  80. 80.
    Monticone S, Hattangady NG, Nishimoto K, Mantero F, Rubin B, Cicala MV, Pezzani R, Auchus RJ, Ghayee HK, Shibata H, Kurihara I, Williams TA, Giri JG, Bollag RJ, Edwards MA, Isales CM, Rainey WE. Effect of KCNJ5 mutations on gene expression in aldosterone-producing adenomas and adrenocortical cells. J Clin Endocrinol Metab. 2012;97:E1567–72.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, Sterner C, Warth R, Mulatero P, Rainey WE. A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2013;98:E1861–5.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Mulatero P, Monticone S, Rainey WE, Veglio F, Williams TA. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol. 2013;9:104–12.PubMedCrossRefGoogle Scholar
  83. 83.
    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 U S A. 2012;109:2533–8.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Funder JW. Genetic disorders in primary aldosteronism-familial and somatic. J Steroid Biochem Mol Biol. 2016;Google Scholar
  85. 85.
    Williams TA, Monticone S, Mulatero P. KCNJ5 mutations are the most frequent genetic alteration in primary aldosteronism. Hypertension. 2015;65:507–9.PubMedCrossRefGoogle Scholar
  86. 86.
    Lenzini L, Rossitto G, Maiolino G, Letizia C, Funder JW, Rossi GPA. Meta-analysis of somatic KCNJ5 K(+) channel mutations in 1636 patients with an aldosterone-producing adenoma. J Clin Endocrinol Metab. 2015;100:E1089–95.PubMedCrossRefGoogle Scholar
  87. 87.
    Williams TA, Monticone S, Schack VR, Stindl J, Burrello J, Buffolo F, Annaratone L, Castellano I, Beuschlein F, Reincke M, Lucatello B, Ronconi V, Fallo F, Bernini G, Maccario M, Giacchetti G, Veglio F, Warth R, Vilsen B, Mulatero P. Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas. Hypertension. 2014;63:188–95.PubMedCrossRefGoogle Scholar
  88. 88.
    Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kucukkoylu S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T. Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype. Clin Endocrinol. 2015;83:779–89.CrossRefGoogle Scholar
  89. 89.
    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 J, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Wang B, Li X, Zhang X, Ma X, Chen L, Zhang Y, Lyu X, Tang Y, Huang Q, Gao Y, Fan Y, Ouyang J. Prevalence and characterization of somatic mutations in Chinese aldosterone-producing adenoma patients. Medicine (Baltimore). 2015;94:e708.CrossRefGoogle Scholar
  91. 91.
    Zheng 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;65:622–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Kuppusamy M, Caroccia B, Stindl J, Bandulik S, Lenzini L, Gioco 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:E1765–73.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Nanba K, Omata K, Tomlins SA, Giordano TJ, Hammer GD, Rainey WE, Else T. Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations. Eur J Endocrinol. 2016;175:K1–6.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    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;59:235–40.PubMedCrossRefGoogle Scholar
  95. 95.
    Gomez-Sanchez CE, Montgomery M, Ganguly A, Holland OB, Gomez-Sanchez EP, Grim CE, Weinberger MH. Elevated urinary excretion of 18-oxocortisol in glucocorticoid-suppressible aldosteronism. J Clin Endocrinol Metab. 1984;59:1022–4.PubMedCrossRefGoogle Scholar
  96. 96.
    Gordon RD, Hamlet SM, Tunny TJ, Gomez-Sanchez CE, Jayasinghe LS. Distinguishing aldosterone-producing adenoma from other forms of hyperaldosteronism and lateralizing the tumour pre-operatively. Clin Exp Pharmacol Physiol. 1986;13:325–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Stowasser M, Bachmann AW, Tunny TJ, Gordon RD. Production of 18-oxo-cortisol in subtypes of primary aldosteronism. Clin Exp Pharmacol Physiol. 1996;23:591–3.PubMedCrossRefGoogle Scholar
  98. 98.
    Nakamura Y, Satoh F, Morimoto R, Kudo M, Takase K, Gomez-Sanchez CE, Honma S, Okuyama M, Yamashita K, Rainey WE, Sasano H, Ito S. 18-oxocortisol measurement in adrenal vein sampling as a biomarker for subclassifying primary aldosteronism. J Clin Endocrinol Metab. 2011;96:E1272–8.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Mulatero P, di Cella SM, Monticone S, Schiavone D, Manzo M, Mengozzi G, Rabbia F, Terzolo M, Gomez-Sanchez EP, Gomez-Sanchez CE, Veglio F. 18-hydroxycorticosterone, 18-hydroxycortisol, and 18-oxocortisol in the diagnosis of primary aldosteronism and its subtypes. J Clin Endocrinol Metab. 2012;97:881–9.PubMedCrossRefGoogle Scholar
  100. 100.
    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;65:1096–102.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Eisenhofer G, Dekkers T, Peitzsch M, Dietz AS, Bidlingmaier M, Treitl M, Williams TA, Bornstein SR, Haase M, Rump LC, Willenberg HS, Beuschlein F, Deinum J, Lenders JW, Reincke M. Mass spectrometry-based adrenal and peripheral venous steroid profiling for subtyping primary Aldosteronism. Clin Chem. 2016;62:514–24.PubMedCrossRefGoogle Scholar
  102. 102.
    Williams TA, Peitzsch M, Dietz AS, Dekkers T, Bidlingmaier M, Riester A, Treitl M, Rhayem Y, Beuschlein F, Lenders JW, Deinum J, Eisenhofer G, Reincke M. Genotype-specific steroid profiles associated with aldosterone-producing adenomas. Hypertension. 2016;67:139–45.PubMedCrossRefGoogle Scholar
  103. 103.
    Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE. Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. Endocrinology. 2012;153:1774–82.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Azizan EA, Lam BY, Newhouse SJ, Zhou J, Kuc RE, Clarke J, Happerfield L, Marker A, Hoffman GJ, Brown MJ. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. J Clin Endocrinol Metab. 2012;97:E819–29.PubMedCrossRefGoogle Scholar
  105. 105.
    Monticone S, Castellano I, Versace K, Lucatello B, Veglio F, Gomez-Sanchez CE, Williams TA, Mulatero P. Immunohistochemical, genetic and clinical characterization of sporadic aldosterone-producing adenomas. Mol Cell Endocrinol. 2015;411:146–54.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Nanba K, Chen AX, Omata K, Vinco M, Giordano TJ, Else T, Hammer GD, Tomlins SA, Rainey WE. Molecular heterogeneity in aldosterone-producing adenomas. J Clin Endocrinol Metab. 2016;101:999–1007.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension. 2014;64:354–61.PubMedCrossRefGoogle Scholar
  108. 108.
    Stindl J, Tauber P, Sterner C, Tegtmeier I, Warth R, Bandulik S. Pathogenesis of adrenal aldosterone-producing adenomas carrying mutations of the Na(+)/K(+)-ATPase. Endocrinology. 2015;156:4582–91.PubMedCrossRefGoogle Scholar
  109. 109.
    Tauber P, Aichinger B, Christ C, Stindl J, Rhayem Y, Beuschlein F, Warth R, Bandulik S. Cellular pathophysiology of an adrenal adenoma-associated mutant of the plasma membrane Ca(2+)-ATPase ATP2B3. Endocrinology. 2016;157:2489–99.PubMedCrossRefGoogle Scholar
  110. 110.
    Reimer EN, Walenda G, Seidel E, Scholl UI. CACNA1H(M1549V) mutant calcium channel causes autonomous aldosterone production in HAC15 cells and is inhibited by Mibefradil. Endocrinology. 2016;157:3016–22.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Kazutaka Nanba
    • 1
  • Hirotaka Shibata
    • 2
  • William E. Rainey
    • 1
  1. 1.Departments of Molecular and Integrative Physiology and Internal MedicineUniversity of MichiganAnn ArborUSA
  2. 2.Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of MedicineOita UniversityYufuJapan

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