Download PDF
Horm Metab Res 2017; 49(12): 957-962
DOI: 10.1055/s-0043-122238
Review
© Georg Thieme Verlag KG Stuttgart · New York

Disordered CYP11B2 Expression in Primary Aldosteronism

Celso E. Gomez-Sanchez
1   Endocrine Section, G. V. (Sonny) Montgomery VA Medical Center, Jackson, MS, USA
2   University of Mississippi Medical Center, Jackson, MS, USA
,
Maniselvan Kuppusamy
1   Endocrine Section, G. V. (Sonny) Montgomery VA Medical Center, Jackson, MS, USA
2   University of Mississippi Medical Center, Jackson, MS, USA
,
Martin Reincke
3   Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
,
Tracy Ann Williams
3   Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
4   Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Turin, Turin, Italy
› Author Affiliations
Further Information

Publication History

received 21 August 2017

accepted 24 October 2017

Publication Date:
04 December 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Primary aldosteronism is the most common type of secondary hypertension affecting 6–10% of patients with primary hypertension. PA is mainly caused by unilateral hyperaldosteronism due to an aldosterone-producing adenoma, unilateral hyperplasia with or without micronodules or bilateral zona glomerulosa hyperplasias with or without macro or micronodules. The development of antibodies against the terminal enzyme of aldosterone biosynthesis (CYP11B2) has permitted the further characterization of normal adrenals and resected adrenals from patients with primary aldosteronism. Normal adrenals exhibit two different patterns of cellular expression of CYP11B2: young individuals display a relatively uniform expression of the enzyme throughout the zona glomerulosa while the adrenals of older individuals have dispersed CYP11B2-expressing cells but have more groups of cells called aldosterone-producing cell clusters (APCC). APAs exhibit different patterns of CYP11B2 staining that vary from uniform to homogeneous. There are also a proportion of cells within the APA that co-express different enzymes that are not normally co-expressed in normal individuals. Approximately 30% of patients with unilateral hyperaldosteronism do not have an APA, but either have an increased number of CYP11B2 expressing micronodules or hyperplasia of the zona glomerulosa. In summary, the studies reported in this review are shedding new light on the pathophysiology of primary aldosteronism. The wide variation in histopathological features of the adenomas and concurrent presence of APCCs raises the possibility that most cases of unilateral production of aldosterone actually might represent bilateral asymmetric hyperplasia with nodules frequently due to the development of somatic aldosterone-driving mutations.

Key words

aldosteronism - aldosterone synthase - promary aldosteronism - immunochemistry
 

  • References

  • 1 Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young Jr. WF. The management of primary aldosteronism: Case detection, diagnosis, and treatment: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2016; 101: 1889-1916
    CrossrefPubMedGoogle Scholar
  • 2 Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: A controlled cross-sectional study. Hypertension 2013; 62: 331-336
    CrossrefPubMedGoogle Scholar
  • 3 Reincke M, Fischer E, Gerum S, Merkle K, Schulz S, Pallauf A, Quinkler M, Hanslik G, Lang K, Hahner S, Allolio B, Meisinger C, Holle R, Beuschlein F, Bidlingmaier M, Endres S. Observational study mortality in treated primary aldosteronism: The German Conn's registry. Hypertension 2012; 60: 618-624
    CrossrefPubMedGoogle Scholar
  • 4 Korah HE, Scholl UI. An update on familial hyperaldosteronism. Horm Metab Res 2015; 47: 941-946
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel J-M. A chimaeric 11b-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355: 262-265
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 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: 768-772
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32: 81-151
    CrossrefPubMedGoogle Scholar
  • 10 Hattangady NG, Olala LO, Bollag WB, Rainey WE. Acute and chronic regulation of aldosterone production. Molecular and cellular endocrinology 2012; 350: 151-162
    CrossrefPubMedGoogle Scholar
  • 11 Bulow HE, Bernhardt R. Analyses of the CYP11B gene family in the guinea pig suggest the existence of a primordial CYP11B gene with aldosterone synthase activity. Eur J Biochem 2002; 269: 3838-3846
    CrossrefPubMedGoogle Scholar
  • 12 Okamoto M, Nonaka Y, Takemori H, Doi J. Molecular identity and gene expression of aldosterone synthase cytochrome P450. Biochem Biophys Res Commun 2005; 338: 325-330
    CrossrefPubMedGoogle Scholar
  • 13 Chavarri MR, Yamakita N, Chiou S, Gomez-Sanchez CE. Calf adrenocortical fasciculata cells secrete aldosterone when placed in primary culture. J Steroid Biochem Mol b Biol 1993; 45: 493-500
    PubMedGoogle Scholar
  • 14 Nishimoto K, Koga M, Seki T, Oki K, Gomez-Sanchez EP, Gomez-Sanchez CE, Naruse M, Sakaguchi T, Morita S, Kosaka T, Oya M, Ogishima T, Yasuda M, Suematsu M, Kabe Y, Omura M, Nishikawa T, Mukai K. Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism. Mol Cell Endocrinol 2017; 441: 124133
    PubMedGoogle Scholar
  • 15 Nishimoto K, Nakagawa K, Li D, Kosaka T, Oya M, Mikami S, Shibata H, Itoh H, Mitani F, Yamazaki T, Ogishima T, Suematsu M, Mukai K. Adrenocortical zonation in humans under normal and pathological conditions. J Clin Endocrinol Metab 2010; 95: 2296-2305
    CrossrefPubMedGoogle Scholar
  • 16 Gomez-Sanchez CE, Qi X, Velarde-Miranda C, Plonczynski MW, Parker CR, Rainey W, Satoh F, Maekawa T, Nakamura Y, Sasano H, Gomez-Sanchez EP. Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol 2014; 383: 111-117
    CrossrefPubMedGoogle Scholar
  • 17 Yamazaki Y, Nakamura Y, Omata K, Ise K, Tezuka Y, Ono Y, Morimoto R, Nozawa Y, Gomez-Sanchez CE, Tomlins SA, Rainey WE, Ito S, Satoh F, Sasano H. Histopathological classification of cross-sectional image-negative hyperaldosteronism. J Clin Endocrinol Metab 2017; 102: 1182-1192
    PubMedGoogle Scholar
  • 18 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 U S A 2015; 112: E4591-E4599
    CrossrefPubMedGoogle Scholar
  • 19 Nakamura Y, Maekawa T, Felizola SJ, Satoh F, Qi X, Velarde-Miranda C, Plonczynski MW, Ise K, Kikuchi K, Rainey WE, Gomez-Sanchez EP, Gomez-Sanchez CE, Sasano H. Adrenal CYP11B1/2 expression in primary aldosteronism: Immunohistochemical analysis using novel monoclonal antibodies. Mol Cell Endocrinol 2014; 392: 73-79
    CrossrefPubMedGoogle Scholar
  • 20 Teo AE, Garg S, Johnson TI, Zhao W, Zhou J, Gomez-Sanchez CE, Gurnell M, Brown MJ. Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin). Hypertension 2017; 69: 1207-1216
    CrossrefPubMedGoogle Scholar
  • 21 Mitani F. Functional zonation of the rat adrenal cortex: the development and maintenance. Proc Jpn Acad Ser B Phys Biol Sci 2014; 90: 163-183
    CrossrefPubMedGoogle Scholar
  • 22 Romero DG, Yanes LL, de Rodriguez AF, Plonczynski MW, Welsh BL, Reckelhoff JF, Gomez-Sanchez EP, Gomez-Sanchez CE. Disabled-2 is expressed in adrenal zona glomerulosa and is involved in aldosterone secretion. Endocrinology 2007; 148: 2644-2652
    CrossrefPubMedGoogle Scholar
  • 23 Nishimoto K, Seki T, Hayashi Y, Mikami S, Al-Eyd G, Nakagawa K, Morita S, Kosaka T, Oya M, Mitani F, Suematsu M, Kabe Y, Mukai K. Human adrenocortical remodeling leading to aldosterone-producing cell cluster generation. Int J Endocrinol 2016; 7834356
    PubMedGoogle Scholar
  • 24 Boulkroun S, Samson-Couterie B, Dzib JF, Lefebvre H, Louiset E, Amar L, Plouin PF, Lalli E, Jeunemaitre X, Benecke A, Meatchi T, Zennaro MC. Adrenal cortex remodeling and functional zona glomerulosa hyperplasia in primary aldosteronism. Hypertension 2010; 56: 885-892
    CrossrefPubMedGoogle Scholar
  • 25 Nanba K, Vaidya A, Williams GH, Zheng I, Else T, Rainey WE. Age-Related Autonomous Aldosteronism. Circulation 2017; 136: 347-355
    CrossrefPubMedGoogle Scholar
  • 26 Nishimoto K, Seki T, Kurihara I, Yokota K, Omura M, Nishikawa T, Shibata H, Kosaka T, Oya M, Suematsu M, Mukai K. Case Report: Nodule development from subcapsular aldosterone-producing cell clusters causes hyperaldosteronism. J Clin Endocrinol Metab 2016; 101: 6-9
    CrossrefPubMedGoogle Scholar
  • 27 Williams TA, Monticone S, Mulatero P. KCNJ5 mutations are the most frequent genetic alteration in primary aldosteronism. Hypertension 2015; 65: 507-509
    CrossrefPubMedGoogle Scholar
  • 28 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: 354-361
    CrossrefPubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 Williams TA, Lenders JW, Burrello J, Beuschlein F, Reincke M. KCNJ5 Mutations: Sex, Salt and Selection. Horm Metab Res 2015; 47: 953-958
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 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: 440-444
    CrossrefPubMedGoogle Scholar
  • 32 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
    CrossrefPubMedGoogle Scholar
  • 33 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: 1050-1054
    CrossrefPubMedGoogle Scholar
  • 34 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
    CrossrefPubMedGoogle Scholar
  • 35 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-K6
    CrossrefPubMedGoogle 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, Kusters B. Adrenal nodularity and somatic mutations in primary aldosteronism: One node is the culprit?. J Clin Endocrinol Metab 2014; 99: E1341-E1351
    CrossrefPubMedGoogle Scholar
  • 37 Fernandes-Rosa FL, Giscos-Douriez I, Amar L, Gomez-Sanchez CE, Meatchi T, Boulkroun S, Zennaro MC. Different somatic mutations in multinodular adrenals with aldosterone-producing adenoma. Hypertension 2015; 66: 1014-1022
    CrossrefPubMedGoogle Scholar
  • 38 Nanba K, Tsuiki M, Sawai K, Mukai K, Nishimoto K, Usui T, Tagami T, Okuno H, Yamamoto T, Shimatsu A, Katabami T, Okumura A, Kawa G, Tanabe A, Naruse M. Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry. J Clin Endocrinol Metab 2013; 98: 1567-1574
    CrossrefPubMedGoogle Scholar
  • 39 Nanba AT, Nanba K, Byrd JB, Shields JJ, Giordano TJ, Miller BS, Rainey WE, Auchus RJ, Turcu AF. Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism. Clin Endocrinol (Oxf) 2017; DOI: 10.1111/cen.13442. [EPub ahead of print]
    CrossrefPubMedGoogle Scholar
  • 40 Young Jr. WF, Stanson AW, Thompson GB, Grant CS, Farley DR, Van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004; 136: 1227-1235
    CrossrefPubMedGoogle Scholar
  • 41 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-E829
    CrossrefPubMedGoogle Scholar
  • 42 Ono Y, Nakamura Y, Maekawa T, Felizola SJ, Morimoto R, Iwakura Y, Kudo M, Seiji K, Takase K, Arai Y, Gomez-Sanchez CE, Ito S, Sasano H, Satoh F. Different expression of 11beta-hydroxylase and aldosterone synthase between aldosterone-producing microadenomas and macroadenomas. Hypertension 2014; 64: 438-444
    CrossrefPubMedGoogle Scholar
  • 43 Nakamura Y, Kitada M, Satoh F, Maekawa T, Morimoto R, Yamazaki Y, Ise K, Gomez-Sanchez CE, Ito S, Arai Y, Dezawa M, Sasano H. Intratumoral heterogeneity of steroidogenesis in aldosterone-producing adenoma revealed by intensive double- and triple-immunostaining for CYP11B2/B1 and CYP17. Mol Cell Endocrinol 2016; 422: 57-63
    CrossrefPubMedGoogle Scholar
  • 44 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: 881-889
    CrossrefPubMedGoogle Scholar
  • 45 Omura M, Sasano H, Fujiwara T, Yamaguchi K, Nishikawa T. Unique cases of unilateral hyperaldosteronemia due to multiple adrenocortical micronodules, which can only be detected by selective adrenal venous sampling. Metabolism 2002; 51: 350-355
    CrossrefPubMedGoogle Scholar
  • 46 Omura M, Sasano H, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T. Clinical characteristics of aldosterone-producing microadenoma, macroadenoma, and idiopathic hyperaldosteronism in 93 patients with primary aldosteronism. Hypertens Res 2006; 29: 883-889
    CrossrefPubMedGoogle Scholar
  • 47 Williams TA, JWM Lenders, Mulatero P, Burrello J, Rottenkolber M, Adolf C, Satoh F, Amar L, Quinkler M, Deinum J, Beuschlein F, Kitamoto KK, Pham U, Morimoto R, Umakoshi H, Prejbisz A, Kocjan T, Naruse M, Stowasser M, Nishikawa T, Young Jr. WF, Gomez-Sanchez CE, Funder JW, Reincke M. Outcomes after adrenalectomy for unilateral primary aldosteronism: An international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol 2017; 5: 689-699
    CrossrefPubMedGoogle Scholar
  • 48 Gomez-Sanchez CE, Rossi GP, Fallo F, Mannelli M. Progress in primary aldosteronism: Present challenges and perspectives. Horm Metab Res 2010; 42: 374-381
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Fernandes-Rosa FL, Boulkroun S, Zennaro MC. Somatic and inherited mutations in primary aldosteronism. J Mol Endocrinol 2017; 59: R47-R63
    CrossrefPubMedGoogle Scholar
  • 50 Prada ETA, Burrello J, Reincke M, Williams TA. Old and New Concepts in the Molecular Pathogenesis of Primary Aldosteronism. Hypertension 2017; 70: 875-881
    PubMedGoogle Scholar
  • 51 Gomez-Sanchez CE, Qi X, Gomez-Sanchez EP, Sasano H, Bohlen MO, Wisgerhof M. Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3. Molecular and cellular endocrinology 2017; 439: 74-80
    CrossrefPubMedGoogle Scholar
  • 52 Monticone S, Hattangady NG, Penton D, Isales C, 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: 1861-1865
    CrossrefPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar