Clinical and cardiac characteristics of primary bilateral macronodular adrenal hyperplasia
Characteristics of bilateral adrenal hyperplasia
Abstract
Background: Cardiovascular disease is the leading cause of death from Cushing’s syndrome (CS). Primary bilateral macronodular adrenal hyperplasia (PBMAH), a rare cause of CS, is clinically distinct from the other common types of CS, but its cardiac characteristics have been poorly studied.
Methods: The clinical data, steroid hormones and echocardiographic variables were collected in 17 PBMAH patients. Twenty-one CS patients with cortisol-producing adenoma (CPA) were collected as controls.
Results: In the PBMAH group, the proportion of female was lower (35.30 vs 100.00%), the age was older (55.76 ± 2.42 years vs 39.57 ± 2.72 years), and the course of disease was longer [13.00 (5.00, 21.50) years vs 1.58 (1.00, 5.00) years]. The proportion of PBMAH patients with hypertension was higher than that of CPA patients (100.00% vs 61.90%). Plasma cortisol and 24h urinary free cortisol (24h UFC) were lower in PBMAH patients than that in CPA patients [morning cortisol 19.50 (15.35, 24.48) μg/dl vs 28.30 (22.88, 29.89) μg/dl, 24h UFC 106.20 (65.35, 156.58) vs 506.23 (292.53, 712.18) μg]. The PBMAH group had longer right ventricular diameter (24.06 ± 1.23 mm vs 20.48 ± 0.83 mm), left atrial diameter (39.41 ± 1.15 mm vs 32.86 ± 0.76 mm), and a higher rate of diastolic dysfunction (76.50% vs 38.10%) than the CPA group. Univariate regression analysis showed that combination of hypertension and duration of hypertension had significant effects on left atrial diameter (b=6.383, P=0.001; b = 0.276, P<0.001, respectively) and E/A ratios (b=-0.496, P< 0.001; b=0.022, P<0.001, respectively). Multivariate regression analysis showed that corticosterone level had a significant effect on systolic blood pressure (b=6.712, P=0.025).
Conclusion: Comparing to the CPA, ventricular diastolic dysfunction was common in PBMAH patients under relatively lower cortisol level. PBMAH had a high corticosterone level which may play a role in the development of hypertension and further heart changes.
References
1. Pivonello R, De Martino MC, De Leo M, Lombardi G, Colao A. Cushing's Syndrome. Endocrin Metab Clin 2008; 37(1): 135-49.
2. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet 2006; 367(9522): 1605-17.
3. Steffensen C, Bak AM, Rubeck KZ, Jorgensen JO. Epidemiology of Cushing's syndrome. Neuroendocrinology 2010; 92 Suppl 1(1-5.
4. Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing's syndrome: a systematic review and meta-analysis. Eur J Intern Med 2012; 23(3): 278-82.
5. Pikkarainen L, Sane T, Reunanen A. The survival and well-being of patients treated for Cushing's syndrome. J Intern Med 1999; 245(5): 463-8.
6. Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocr Metab 2001; 86(1): 117-23.
7. Bolland MJ, Holdaway IM, Berkeley JE, Lim S, Dransfield WJ, Conaglen JV, et al. Mortality and morbidity in Cushing's syndrome in New Zealand. Clin Endocrinol 2011; 75(4): 436-42.
8. Yaneva M, Kalinov K, Zacharieva S. Mortality in Cushing's syndrome: data from 386 patients from a single tertiary referral center. Eur J Endocrinol 2013; 169(5): 621-7.
9. Ntali G, Asimakopoulou A, Siamatras T, Komninos J, Vassiliadi D, Tzanela M, et al. Mortality in Cushing's syndrome: systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol 2013; 169(5): 715-23.
10. Dekkers OM, Horvath-Puho E, Jorgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, et al. Multisystem morbidity and mortality in Cushing's syndrome: a cohort study. J Clin Endocr Metab 2013; 98(6): 2277-84.
11. Pereira AM, Delgado V, Romijn JA, Smit JW, Bax JJ, Feelders RA. Cardiac dysfunction is reversed upon successful treatment of Cushing's syndrome. Eur J Endocrinol 2010; 162(2): 331-40.
12. Muiesan ML, Lupia M, Salvetti M, Grigoletto C, Sonino N, Boscaro M, et al. Left ventricular structural and functional characteristics in Cushing's syndrome. J Am Coll Cardiol 2003; 41(12): 2275-9.
13. Kamenicky P, Redheuil A, Roux C, Salenave S, Kachenoura N, Raissouni Z, et al. Cardiac structure and function in Cushing's syndrome: a cardiac magnetic resonance imaging study. J Clin Endocr Metab 2014; 99(11): E2144-53.
14. Stratakis CA. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotropin- independent Cushing syndrome). Endocr Dev 2008; 13(117-32.
15. Hannah-Shmouni F, Berthon A, Faucz FR, Briceno JM, Maria AG, Demidowich A, et al. Mass spectrometry-based steroid profiling in primary bilateral macronodular adrenocortical hyperplasia. Endocr-Relat Cancer 2020; 27(7): 403-13.
16. Zhou J, Zhang M, Bai X, Cui S, Pang C, Lu L, et al. Demographic Characteristics, Etiology, and Comorbidities of Patients with Cushing's Syndrome: A 10-Year Retrospective Study at a Large General Hospital in China. Int J Endocrinol 2019; 2019(7159696.
17. Espiard S, Drougat L, Libe R, Assie G, Perlemoine K, Guignat L, et al. ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences. J Clin Endocr Metab 2015; 100(6): E926-35.
18. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing's Disease. Endocr Rev 2015; 36(4): 385-486.
19. Albiger NM, Regazzo D, Rubin B, Ferrara AM, Rizzati S, Taschin E, et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype. Endocrine 2017; 55(3): 959-68.
20. Ohashi A, Yamada Y, Sakaguchi K, Inoue T, Kubo M, Fushimi H. A natural history of adrenocorticotropin-independent bilateral adrenal macronodular hyperplasia (AIMAH) from preclinical to clinically overt Cushing's syndrome. Endocr J 2001; 48(6): 677-83.
21. Walker BR, Williams BC. Corticosteroids and vascular tone: mapping the messenger maze. Clin Sci 1992; 82(6): 597-605.
22. Hadoke PW, Macdonald L, Logie JJ, Small GR, Dover AR, Walker BR. Intra-vascular glucocorticoid metabolism as a modulator of vascular structure and function. Cell Mol Life Sci 2006; 63(5): 565-78.
23. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004; 117(3): 399-412.
24. Mulatero P, Glorioso N, Fallo F, Soro A, Morra DCS, Carra R, et al. Absence of D147E mutation of CYP11B2 gene in hypertensive patients with increased corticosterone and aldosterone production. Eur J Endocrinol 2001; 144(4): 397-400.
25. Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser R. Evidence of coexisting changes in 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activity in subjects with untreated essential hypertension. Hypertension 1995; 25(1): 67-70.
26. Yan X, Jin J, Su X, Yin X, Gao J, Wang X, et al. Intestinal Flora Modulates Blood Pressure by Regulating the Synthesis of Intestinal-Derived Corticosterone in High Salt-Induced Hypertension. Circ Res 2020; 126(7): 839-53.
27. Ivy JR, Oosthuyzen W, Peltz TS, Howarth AR, Hunter RW, Dhaun N, et al. Glucocorticoids Induce Nondipping Blood Pressure by Activating the Thiazide-Sensitive Cotransporter. Hypertension 2016; 67(5): 1029-37.
28. Lou YK, Wen C, Li M, Adams DJ, Wang MX, Yang F, et al. Decreased renal expression of nitric oxide synthase isoforms in adrenocorticotropin-induced and corticosterone-induced hypertension. Hypertension 2001; 37(4): 1164-70.
29. Nicolov N, Todorova M, Ilieva T, Velkov Z, Lolov R, Petkova M, et al. Effect of calcium blocking agent verapamil on blood pressure, ventricular contractility, parathyroid hormone, calcium and phosphorus in plasma, catecholamines, corticosterone and plasma renin activity in spontaneously hypertensive rats. Clin Exp Hypertens A 1988; 10(2): 273-88.
30. Cima I, Corazza N, Dick B, Fuhrer A, Herren S, Jakob S, et al. Intestinal epithelial cells synthesize glucocorticoids and regulate T cell activation. J Exp Med 2004; 200(12): 1635-46.
31. Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 2013; 153(4): 812-27.
32. Nakamura T, Kurihara I, Kobayashi S, Yokota K, Murai-Takeda A, Mitsuishi Y, et al. Intestinal Mineralocorticoid Receptor Contributes to Epithelial Sodium Channel-Mediated Intestinal Sodium Absorption and Blood Pressure Regulation. J Am Heart Assoc 2018; 7(13):
33. Mullins LJ, Kenyon CJ, Bailey MA, Conway BR, Diaz ME, Mullins JJ. Mineralocorticoid Excess or Glucocorticoid Insufficiency: Renal and Metabolic Phenotypes in a Rat Hsd11b2 Knockout Model. Hypertension 2015; 66(3): 667-73.
34. Hattori T, Murase T, Iwase E, Takahashi K, Ohtake M, Tsuboi K, et al. Glucocorticoid-induced hypertension and cardiac injury: effects of mineralocorticoid and glucocorticoid receptor antagonism. Nagoya J Med Sci 2013; 75(1-2): 81-92.
35. Liu HB, Zhang J, Sun YY, Li XY, Jiang S, Liu MY, et al. Dietary salt regulates epithelial sodium channels in rat endothelial cells: adaptation of vasculature to salt. Brit J Pharmacol 2015; 172(23): 5634-46.
36. Zafir A, Banu N. Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress 2009; 12(2): 167-77.
37. Ohtani T, Mano T, Hikoso S, Sakata Y, Nishio M, Takeda Y, et al. Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the progression to heart failure. J Hypertens 2009; 27(5): 1074-83.
Copyright (c) 2023 Sisi Miao, Lin Lu, Shengyong Si, Dandan Peng, Ya Zhong, Zhijing Li, Zhenqiu Yu
This work is licensed under a Creative Commons Attribution 4.0 International License.
The published articles will be distributed under the Creative Commons Attribution 4.0 International License (CC BY). It is allowed to copy and redistribute the material in any medium or format, and remix, transform, and build upon it for any purpose, even commercially, as long as appropriate credit is given to the original author(s), a link to the license is provided and it is indicated if changes were made. Users are required to provide full bibliographic description of the original publication (authors, article title, journal title, volume, issue, pages), as well as its DOI code. In electronic publishing, users are also required to link the content with both the original article published in Journal of Medical Biochemistry and the licence used.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.