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原发性双侧肾上腺大结节性增生导致的库欣综合征

Author
André Lacroix, MD
Section Editor
Lynnette K Nieman, MD
Deputy Editor
Kathryn A Martin, MD
Translators
叶山东, 主任医师，教授

引言

库欣综合征的病因中，有3种发病罕见、常为双侧分布的肾上腺皮质结节病：

●促肾上腺皮质激素(ACTH)依赖性双侧大结节性增生，继发于库欣病或异位ACTH综合征患者的长期肾上腺刺激。

●ACTH非依赖性肾上腺小结节性增生及其最常见的变异型[原发性色素结节性肾上腺皮质疾病(primary pigmented nodular adrenocortical disease, PPNAD)]，可为散发性也可为家族性(作为Carney综合征的一部分)。

●原发性双侧肾上腺大结节性增生(bilateral macronodular adrenal hyperplasia, BMAH)，之前被称为ACTH非依赖性双侧肾上腺大结节性增生(ACTH-independent bilateral macronodular adrenal hyperplasia, AIMAH)。

本文将总结BMAH。其他导致库欣综合征的其他病因及PPNAD将单独讨论。 (参见“库欣综合征的病因和病理生理学”和“原发性色素结节性肾上腺皮质病所致库欣综合征”)

                           

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Literature review current through: 2017-06 . | This topic last updated: 2017-04-21.
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References
Top
  1. Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009; 23:245.
  2. Lacroix A, Ndiaye N, Tremblay J, Hamet P. Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr Rev 2001; 22:75.
  3. Lacroix A, Baldacchino V, Bourdeau I, et al. Cushing's syndrome variants secondary to aberrant hormone receptors. Trends Endocrinol Metab 2004; 15:375.
  4. Libé R, Coste J, Guignat L, et al. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome. Eur J Endocrinol 2010; 163:129.
  5. Hsiao HP, Kirschner LS, Bourdeau I, et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab 2009; 94:2930.
  6. Mircescu H, Jilwan J, N'Diaye N, et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing's syndrome? J Clin Endocrinol Metab 2000; 85:3531.
  7. Hofland J, Hofland LJ, van Koetsveld PM, et al. ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase. Orphanet J Rare Dis 2013; 8:142.
  8. Lacroix A, Bolté E, Tremblay J, et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing's syndrome. N Engl J Med 1992; 327:974.
  9. Reznik Y, Allali-Zerah V, Chayvialle JA, et al. Food-dependent Cushing's syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 1992; 327:981.
  10. de Herder WW, Hofland LJ, Usdin TB, et al. Food-dependent Cushing's syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab 1996; 81:3168.
  11. Groussin L, Perlemoine K, Contesse V, et al. The ectopic expression of the gastric inhibitory polypeptide receptor is frequent in adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia, but rare in unilateral tumors. J Clin Endocrinol Metab 2002; 87:1980.
  12. N'Diaye N, Tremblay J, Hamet P, et al. Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing's syndrome. J Clin Endocrinol Metab 1998; 83:2781.
  13. N'Diaye N, Hamet P, Tremblay J, et al. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent cushing's syndrome. J Clin Endocrinol Metab 1999; 84:2616.
  14. Preumont V, Mermejo LM, Damoiseaux P, et al. Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing's syndrome. Horm Metab Res 2011; 43:287.
  15. Lampron A, Bourdeau I, Oble S, et al. Regulation of aldosterone secretion by several aberrant receptors including for glucose-dependent insulinotropic peptide in a patient with an aldosteronoma. J Clin Endocrinol Metab 2009; 94:750.
  16. Lampron A, Bourdeau I, Hamet P, et al. Whole genome expression profiling of glucose-dependent insulinotropic peptide (GIP)- and adrenocorticotropin-dependent adrenal hyperplasias reveals novel targets for the study of GIP-dependent Cushing's syndrome. J Clin Endocrinol Metab 2006; 91:3611.
  17. Bertherat J, Contesse V, Louiset E, et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab 2005; 90:1302.
  18. Albiger NM, Occhi G, Mariniello B, et al. Food-dependent Cushing's syndrome: from molecular characterization to therapeutical results. Eur J Endocrinol 2007; 157:771.
  19. Bourdeau I, D'Amour P, Hamet P, et al. Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome. J Clin Endocrinol Metab 2001; 86:5534.
  20. Horiba N, Suda T, Aiba M, et al. Lysine vasopressin stimulation of cortisol secretion in patients with adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1995; 80:2336.
  21. Lacroix A, Tremblay J, Touyz RM, et al. Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing's syndrome, and orthostatic hypotension. J Clin Endocrinol Metab 1997; 82:2414.
  22. Mune T, Murase H, Yamakita N, et al. Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002; 87:5706.
  23. Miyamura N, Taguchi T, Murata Y, et al. Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines: detection of the aberrant hormone receptors on adrenal gland. Endocrine 2002; 19:319.
  24. Lee S, Hwang R, Lee J, et al. Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia. Clin Endocrinol (Oxf) 2005; 63:625.
  25. Vezzosi D, Cartier D, Régnier C, et al. Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors. Eur J Endocrinol 2007; 156:21.
  26. Lacroix A, Tremblay J, Rousseau G, et al. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing's syndrome. N Engl J Med 1997; 337:1429.
  27. Miyamura N, Tsutsumi A, Senokuchi H, et al. A case of ACTH-independent macronodular adrenal hyperplasia: simultaneous expression of several aberrant hormone receptors in the adrenal gland. Endocr J 2003; 50:333.
  28. Mazzuco TL, Thomas M, Martinie M, et al. Cellular and molecular abnormalities of a macronodular adrenal hyperplasia causing beta-blocker-sensitive Cushing's syndrome. Arq Bras Endocrinol Metabol 2007; 51:1452.
  29. Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing's syndrome. N Engl J Med 1999; 341:1577.
  30. Goodarzi MO, Dawson DW, Li X, et al. Virilization in bilateral macronodular adrenal hyperplasia controlled by luteinizing hormone. J Clin Endocrinol Metab 2003; 88:73.
  31. Feelders RA, Lamberts SW, Hofland LJ, et al. Luteinizing hormone (LH)-responsive Cushing's syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro. J Clin Endocrinol Metab 2003; 88:230.
  32. Cartier D, Lihrmann I, Parmentier F, et al. Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing's syndrome. J Clin Endocrinol Metab 2003; 88:248.
  33. Mannelli M, Ferruzzi P, Luciani P, et al. Cushing's syndrome in a patient with bilateral macronodular adrenal hyperplasia responding to cisapride: an in vivo and in vitro study. J Clin Endocrinol Metab 2003; 88:4616.
  34. Louiset E, Contesse V, Groussin L, et al. Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome. J Clin Endocrinol Metab 2006; 91:4578.
  35. Shenker A, Weinstein LS, Moran A, et al. Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS. J Pediatr 1993; 123:509.
  36. Burgess JR, Harle RA, Tucker P, et al. Adrenal lesions in a large kindred with multiple endocrine neoplasia type 1. Arch Surg 1996; 131:699.
  37. Swords FM, Baig A, Malchoff DM, et al. Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol Endocrinol 2002; 16:2746.
  38. Louiset E, Isvi K, Gasc JM, et al. Ectopic expression of serotonin7 receptors in an adrenocortical carcinoma co-secreting renin and cortisol. Endocr Relat Cancer 2008; 15:1025.
  39. Nakamura Y, Son Y, Kohno Y, et al. Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II. Endocrine 2001; 15:57.
  40. Assie G, Louiset E, Sturm N, et al. Systematic analysis of G protein-coupled receptor gene expression in adrenocorticotropin-independent macronodular adrenocortical hyperplasia identifies novel targets for pharmacological control of adrenal Cushing's syndrome. J Clin Endocrinol Metab 2010; 95:E253.
  41. Lacroix A. Heredity and cortisol regulation in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013; 369:2147.
  42. Louiset E, Duparc C, Young J, et al. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. N Engl J Med 2013; 369:2115.
  43. KIRSCHNER MA, POWELL RD Jr, LIPSETT MB. CUSHING'S SYNDROME: NODULAR CORTICAL HYPERPLASIA OF ADRENAL GLANDS WITH CLINICAL AND PATHOLOGICAL FEATURES SUGGESTING ADRENOCORTICAL TUMOR. J Clin Endocrinol Metab 1964; 24:947.
  44. Cheitlin RA, Westphal M, Cabrera CM, et al. Cushing's syndrome due to bilateral adrenal macronodular hyperplasia with undetectable ACTH: cell culture of adenoma cells on extracellular matrix. Horm Res 1988; 29:162.
  45. Malchoff CD, Rosa J, DeBold CR, et al. Adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia: an unusual cause of Cushing's syndrome. J Clin Endocrinol Metab 1989; 68:855.
  46. Swain JM, Grant CS, Schlinkert RT, et al. Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation. Arch Surg 1998; 133:541.
  47. Findlay JC, Sheeler LR, Engeland WC, Aron DC. Familial adrenocorticotropin-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 1993; 76:189.
  48. Minami S, Sugihara H, Sato J, et al. ACTH independent Cushing's syndrome occurring in siblings. Clin Endocrinol (Oxf) 1996; 44:483.
  49. Nies C, Bartsch DK, Ehlenz K, et al. Familial ACTH-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia clinically affecting only female family members. Exp Clin Endocrinol Diabetes 2002; 110:277.
  50. Imöhl M, Köditz R, Stachon A, et al. [Catecholamine-dependent hereditary Cushing's syndrome - follow-up after unilateral adrenalectomy]. Med Klin (Munich) 2002; 97:747.
  51. Someya T, Koyano H, Osawa Y. ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) in two brothers and a sister. Folia Endocrinologica 1996; 72:762.
  52. Watson TD, Patel SJ, Nardi PM. Case 121: familial adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing syndrome. Radiology 2007; 244:923.
  53. Assié G, Libé R, Espiard S, et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome. N Engl J Med 2013; 369:2105.
  54. Faucz FR, Zilbermint M, Lodish MB, et al. Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation. J Clin Endocrinol Metab 2014; 99:E1113.
  55. Alencar GA, Lerario AM, Nishi MY, et al. ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia. J Clin Endocrinol Metab 2014; 99:E1501.
  56. Gagliardi L, Schreiber AW, Hahn CN, et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2014; 99:E1784.
  57. Elbelt U, Trovato A, Kloth M, et al. Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma. J Clin Endocrinol Metab 2015; 100:E119.
  58. Cao Y, He M, Gao Z, et al. Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome. Science 2014; 344:913.
  59. Ringel MD, Schwindinger WF, Levine MA. Clinical implications of genetic defects in G proteins. The molecular basis of McCune-Albright syndrome and Albright hereditary osteodystrophy. Medicine (Baltimore) 1996; 75:171.
  60. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325:1688.
  61. Boston BA, Mandel S, LaFranchi S, Bliziotes M. Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing's syndrome and nodular adrenal hyperplasia. J Clin Endocrinol Metab 1994; 79:890.
  62. Fragoso MC, Domenice S, Latronico AC, et al. Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J Clin Endocrinol Metab 2003; 88:2147.
  63. Beuschlein F, Fassnacht M, Assié G, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med 2014; 370:1019.
  64. Swords FM, Noon LA, King PJ, Clark AJ. Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene. Mol Cell Endocrinol 2004; 213:149.
  65. Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database. Eur J Endocrinol 2012; 166:269.
  66. Yoshida M, Hiroi M, Imai T, et al. A case of ACTH-independent macronodular adrenal hyperplasia associated with multiple endocrine neoplasia type 1. Endocr J 2011; 58:269.
  67. Lee KT, Arnott RD, McLean CA, et al. Corticotropin-independent macronodular adrenal hyperplasia associated with insulinoma. Endocr Pract 2011; 17:e43.
  68. Sato M, Soma M, Nakayama T, et al. A case of adrenocorticotropin-independent bilateral adrenal macronodular hyperplasia (AIMAH) with primary hyperparathyroidism (PHPT). Endocr J 2006; 53:111.
  69. Kartheuser A, Walon C, West S, et al. Familial adenomatous polyposis associated with multiple adrenal adenomas in a patient with a rare 3' APC mutation. J Med Genet 1999; 36:65.
  70. Matyakhina L, Freedman RJ, Bourdeau I, et al. Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab 2005; 90:3773.
  71. Libé R, Fratticci A, Coste J, et al. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res 2008; 14:4016.
  72. Bimpaki EI, Iliopoulos D, Moraitis A, Stratakis CA. MicroRNA signature in massive macronodular adrenocortical disease and implications for adrenocortical tumourigenesis. Clin Endocrinol (Oxf) 2010; 72:744.
  73. Skogseid B, Larsson C, Lindgren PG, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 1992; 75:76.
  74. Oheda T, Noguchi Y, Morio H, et al. Study on steroidogenic activity of ACTH-independent macronodular adrenocortical hyperplasia which occurred in brothers in a cancer family. Folia Endocrinologica 1995; 71:416.
  75. Wada S, Kitahama S, Togashi A, et al. Preclinical Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia with excessive secretion of 18-hydroxydeoxycorticosterone and corticosterone. Intern Med 2002; 41:304.
  76. Ghayee HK, Rege J, Watumull LM, et al. Clinical, biochemical, and molecular characterization of macronodular adrenocortical hyperplasia of the zona reticularis: a new syndrome. J Clin Endocrinol Metab 2011; 96:E243.
  77. Doppman JL, Chrousos GP, Papanicolaou DA, et al. Adrenocorticotropin-independent macronodular adrenal hyperplasia: an uncommon cause of primary adrenal hypercortisolism. Radiology 2000; 216:797.
  78. Alencar GA, Fragoso MC, Yamaga LY, et al. (18)F-FDG-PET/CT imaging of ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) demonstrating increased (18)F-FDG uptake. J Clin Endocrinol Metab 2011; 96:3300.
  79. Aron DC, Findling JW, Fitzgerald PA, et al. Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome. Report of two cases and review of the literature. Am J Med 1981; 71:302.
  80. Smals AG, Pieters GF, van Haelst UJ, Kloppenborg PW. Macronodular adrenocortical hyperplasia in long-standing Cushing's disease. J Clin Endocrinol Metab 1984; 58:25.
  81. Vassiliadi DA, Ntali G, Stratigou T, et al. Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas. Endocrine 2011; 40:437.
  82. Malchoff CD, MacGillvray D, Malchoff DM. Adrenocortical hormone-independent adrenal hyperplasia. Endocrinologist 1996; 6:79.
  83. Boronat M, Lucas T, Barceló B, et al. Cushing's syndrome due to autonomous macronodular adrenal hyperplasia: long-term follow-up after unilateral adrenalectomy. Postgrad Med J 1996; 72:614.
  84. Lamas C, Alfaro JJ, Lucas T, et al. Is unilateral adrenalectomy an alternative treatment for ACTH-independent macronodular adrenal hyperplasia?: Long-term follow-up of four cases. Eur J Endocrinol 2002; 146:237.
  85. Iacobone M, Albiger N, Scaroni C, et al. The role of unilateral adrenalectomy in ACTH-independent macronodular adrenal hyperplasia (AIMAH). World J Surg 2008; 32:882.
  86. Xu Y, Rui W, Qi Y, et al. The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias. World J Surg 2013; 37:1626.
  87. Young WF Jr, du Plessis H, Thompson GB, et al. The clinical conundrum of corticotropin-independent autonomous cortisol secretion in patients with bilateral adrenal masses. World J Surg 2008; 32:856.
  88. Almeida MQ, Harran M, Bimpaki EI, et al. Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions. J Clin Endocrinol Metab 2011; 96:E728.