Reviews in Endocrine and Metabolic Disorders

, Volume 8, Issue 4, pp 309–320 | Cite as

Adrenal causes of hypertension: Pheochromocytoma and primary aldosteronism



The clinical presentations of the patient with pheochromocytoma—a rare endocrine neoplasm—include adrenal incidentaloma, hypertensive paroxysms, sustained apparent polygenic hypertension, hypertension in pregnancy, and hypertensive crisis induced by anesthesia. Although when undiagnosed a pheochromocytoma can be lethal, it can usually be cured with surgery. Biochemical documentation with measurements of fractionated metanephrines and catecholamines should precede imaging studies. Abdomen and pelvis computed imaging is usually the first imaging test. Careful preoperative pharmacologic preparation is important for a successful surgical outcome. Adrenal pheochromocytomas can usually be removed laparoscopically, whereas, catecholamine-secreting paragangliomas typically require an open approach. All first degree relatives of pheochromocytoma patients should have biochemical testing. In addition, molecular genetic testing for germline mutations should be considered in most patients with adrenal pheochromocytoma and in all patients with paraganglioma. Primary aldosteronism is a relatively common form of secondary hypertension—affecting 5 to 10% of all patients with hypertension. A plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio should be obtained in patients with hypertension and hypokalemia, resistant hypertension, adrenal incidentaloma and hypertension, onset of hypertension at a young age (e.g., < 20 years of age), severe hypertension (e.g., ≥160 mm Hg systolic or ≥100 mm Hg diastolic), or whenever the clinician is considering other forms of secondary hypertension. The PAC/PRA ratio is a case finding test and a positive result should be confirmed with aldosterone suppression testing with either oral or intravenous sodium loading. The treatment goals for patients with primary aldosteronism are to prevent the morbidity and mortality associated with hypertension, hypokalemia, and cardiovascular damage. Both the subtype of primary aldosteronism and patient preference should dictate the treatment approach.


Pheochromocytoma Hyperaldosteronism 


  1. 1.
    Lloyd RV, Tischler AS, Kimura N, McNicol AM, Young WF Jr. Adrenal tumors: Introduction. In: DeLellis RA, Lloyd RV, Heitz PU, Eng C, editors. World health organization classification of tumours: pathology and genetics of tumours of endocrine organs. Lyon, France: IARC; 2004. p. 136–8.Google Scholar
  2. 2.
    Stenstrom G, Svardsudd K. Phaeochromocytoma in Sweden, 1958–81. An analysis of the National Cancer Registry Data. Acta Med Scand 1986;220:225–32.PubMedCrossRefGoogle Scholar
  3. 3.
    Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50-year autopsy series. Mayo Clin Proc 1981;56:354–60.PubMedGoogle Scholar
  4. 4.
    Lo C-Y, Lam K-Y, Wat M-S, Lam KS. Adrenal pheochromocytoma remains a frequently overlooked diagnosis. Am J Surg 2000;179:212–5.PubMedCrossRefGoogle Scholar
  5. 5.
    McNeil AR, Blok BH, Koelmeyer TD, Burke MP, Hilton JM. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust N Z J Med 2000;30:648–52.PubMedGoogle Scholar
  6. 6.
    Ariton M, Juan CS, AvRuskin TW. Pheochromocytoma: clinical observations from a Brooklyn tertiary hospital. Endocr Pract 2000;6:249–52.PubMedGoogle Scholar
  7. 7.
    Anderson GH, Blakeman N, Streeten DH. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994;12:609–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Omura M, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 2004;27:193–202.PubMedCrossRefGoogle Scholar
  9. 9.
    Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. Am J Roentgenol 2005;185:684–88.Google Scholar
  10. 10.
    Young WF. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 2007;356:601–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Young WF, Maddox DE. Spells: in search of a cause. Mayo Clin Proc 1995;70:757–65.PubMedCrossRefGoogle Scholar
  12. 12.
    Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H, Opocher G, Maher ER, et al. European Network for the Study of Adrenal Tumours (ENS@T) Pheochromocytoma Working Group: Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 2006;65:699–705.CrossRefGoogle Scholar
  13. 13.
    Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 1999;74:543–52.PubMedCrossRefGoogle Scholar
  14. 14.
    Erickson D, Kudva YC, Ebersold MJ, Thompson GB, Grant CS, vanHeerden JA, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 2001;86:5210–16.PubMedCrossRefGoogle Scholar
  15. 15.
    Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, et al. Freiburg-Warsaw-Columbus Pheochromocytoma Study Group: germ-line mutations in nonsyndromeic pheochromocytoma. N Engl J Med 2002;346:1459–66.PubMedCrossRefGoogle Scholar
  16. 16.
    Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, et al. European–American Paraganglioma Study Group: distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 2004;292:943–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 2006;91:827–36.PubMedCrossRefGoogle Scholar
  18. 18.
    Young AL, Baysal BE, Deb A, Young WF. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab 2002;87:4101–05.PubMedCrossRefGoogle Scholar
  19. 19.
    Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab (in press).Google Scholar
  20. 20.
    Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, et al. COMETE Network: Mutations in SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 2003;63:5615–21.PubMedGoogle Scholar
  21. 21.
    Young WF Jr. Pheochromocytoma: 1926–1993. Trends Endocrinol Metab 1993;4:122.CrossRefPubMedGoogle Scholar
  22. 22.
    Taylor RL, Singh RJ. Validation of liquid chromatography-tandem mass spectrometry method for analysis of urinary conjugated metanephrine and normetanephrine for screening of pheochromocytoma. Clin Chem 2002;48:533–9.PubMedGoogle Scholar
  23. 23.
    Kudva YC, Sawka AM, Young WF Jr. Clinical review 164: The laboratory diagnosis of adrenal pheochromocytoma: the Mayo Clinic experience. J Clin Endocrinol Metab 2003;88:4533–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Sawka AM, Jaeschke R, Singh RJ, Young WF Jr. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 2003;88:553–8.PubMedCrossRefGoogle Scholar
  25. 25.
    d’Herbomez M, Forzy G, Bauters C, Tierny C, Pigny P, Carnaille B, et al. An analysis of the biochemical diagnosis of 66 pheochromocytomas. Eur J Endocrinol 2007;156:569–75.PubMedCrossRefGoogle Scholar
  26. 26.
    Perry CG, Sawka AM, Singh R, Thabane L, Bajnarek J, Young WF. The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf) 2007;66:703–8.CrossRefGoogle Scholar
  27. 27.
    Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Vaclavik J, Stejskal D, Lacnak B, Lazarova M, Jedelsky L, Kadalova L, et al. Free plasma metanephrines as a screening test for pheochromocytoma in low-risk patients. J Hypertens 2007;25:1427–31.PubMedCrossRefGoogle Scholar
  29. 29.
    Sawka AM, Prebtani AP, Thabane L, Gafni A, Levine M, Young WF. A systematic review of the literature examining the diagnostic efficacy of measurement of fractionate plasma free metanephrines in the biochemical diagnosis of pheochromocytoma. BMC Endocr Disord 2004;294:2.CrossRefGoogle Scholar
  30. 30.
    Sawka AM, Gafni A, Thabane L, Young WF Jr. The economic implications of three biochemical screening algorithms for pheochromocytoma. J Clin Endocrinol Metab 2004;89:2859–66.PubMedCrossRefGoogle Scholar
  31. 31.
    Jalil ND, Pattou FN, Combemale F, Chapuis Y, Henry JF, Peix JL, et al. Effectiveness and limits of preoperative imaging studies for the localisation of pheochromocytomas and paragangliomas: a review of 282 cases. French Association of Surgery (AFC), and The French Association of Endocrine Surgeons (AFCE). Eur J Surg 1998;164:23–8.PubMedCrossRefGoogle Scholar
  32. 32.
    Bravo EL. Pheochromocytoma: an approach to antihypertensive management. Ann N Y Acad Sci 2002;970:1–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Combemale F, Carnaille B, Tavernier B, Hautier MB, Thevenot A, Scherpereel P, et al. Exclusive use of calcium channel blockers and cardioselective beta-blockers in the pre- and peri-operative management of pheochromocytomas. 70 cases. Ann Chir 1998;52:341–5.PubMedGoogle Scholar
  34. 34.
    Lebuffe G, Dosseh ED, Tek G, Tytgat H, Moreno S, Tavernier B, et al. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia 2005;60:439–44.PubMedCrossRefGoogle Scholar
  35. 35.
    Memtsoudis SG, Swamidoss C, Psoma M. Anesthesia for adrenal surgery. In: Linos D van Heerden JA, editors. Adrenal glands: diagnostic aspects and surgical therapy. New York: Springer; 2005. p. 287–97.Google Scholar
  36. 36.
    Plouin PF, Duclos JM, Soppelsa F, Boublil G, Chatellier G. Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab 2001;86:1480–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Hack HA. The perioperative management of children with phaeochromocytoma. Paediatr Anaesth 2000;10:463–76.PubMedCrossRefGoogle Scholar
  38. 38.
    Reddy VS, O’Neill JA, Holcomb GW, Neblett WW, Pietsch JB, Morgan WM, et al. Twenty-five-year surgical experience with pheochromocytoma in children. Am Surg 2000;66:1085–91.PubMedGoogle Scholar
  39. 39.
    Grant C. Pheochromocytoma. In: Clark O, Duh Q-Y, Kebebew E, editors. Textbook of endocrine surgery. Philadelphia: Elsevier Saunders; 2005. p. 621–33.CrossRefGoogle Scholar
  40. 40.
    Cheah WK, Clark OH, Horn JK, Siperstein AE, Duh QY. Laparoscopic adrenalectomy for pheochromocytoma. World J Surg 2002;26:1048–51.PubMedCrossRefGoogle Scholar
  41. 41.
    Kercher KW, Novitsky YW, Park A, Matthews BD, Litwin DE, Heniford BT. Laparoscopic curative resection of pheochromocytomas. Ann Surg 2005;241:919–26.PubMedCrossRefGoogle Scholar
  42. 42.
    Shen WT, Sturgeon C, Clark OH, Duh QY, Kebebew E. Should pheochromocytoma size influence surgical approach? A comparison of 90 malignant and 60 benign pheochromocytomas. Surgery 2004;136:1129–37.PubMedCrossRefGoogle Scholar
  43. 43.
    Diner EK, Franks ME, Behari A, Linehan WM, Walther MM. Partial adrenalectomy: the National Cancer Institute experience. Urology 2005;66:19–23.PubMedCrossRefGoogle Scholar
  44. 44.
    Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005;90:2110–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Pawlu C, Bausch B, Reisch N, Neumann HP. Genetic testing for pheochromocytoma-associated syndromes. Ann Endocrinol (Paris) 2005;66:178–88.Google Scholar
  46. 46.
    Eisenhofer G, Bornstein SR, Brouwers FM, Cheung NK, Dahia PL, de Krijger RR, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer 2004;11:423–36.PubMedCrossRefGoogle Scholar
  47. 47.
    Scholz T, Eisenhofer G, Pacak K, Dralle H, Lehnert H. Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 2007;92:1217–25.PubMedCrossRefGoogle Scholar
  48. 48.
    Sisson JC. Radiopharmaceutical treatment of pheochromocytomas. Ann N Y Acad Sci 2002;970:54–60.PubMedCrossRefGoogle Scholar
  49. 49.
    Safford SD, Coleman RE, Gockerman JP, Moore J, Feldman JM, Leight GS, et al. Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery 2003;134:956–62.PubMedCrossRefGoogle Scholar
  50. 50.
    Rose B, Matthay KK, Price D, Huberty J, Klencke B, Norton JA, et al. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer 2003;98:239–48.PubMedCrossRefGoogle Scholar
  51. 51.
    Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC. The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Investig 1997;20:648–58.Google Scholar
  52. 52.
    Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, et al. Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988;109:267–73.PubMedGoogle Scholar
  53. 53.
    Harper MA, Murnaghan GA, Kennedy L, Hadden DR, Atkinson AB. Phaeochromocytoma in pregnancy. Five cases and a review of the literature. Br J Obstet Gynaecol 1989;96:594–606.PubMedGoogle Scholar
  54. 54.
    Conn JW. Presidential address. I. Painting background. II. Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45:3–17.PubMedGoogle Scholar
  55. 55.
    Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf) 2007;66:607–18.CrossRefGoogle Scholar
  56. 56.
    Berglund G, Andersson O, Wilhelmsen L. Prevalence of primary and secondary hypertension: studies in a random population sample. Br Med J 1976;2:554–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Streeten DHP, Tomycz N, Anderson GH Jr. Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 1979;67:403–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89:1045–50.PubMedCrossRefGoogle Scholar
  59. 59.
    Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism: a systematic review of the literature. Endocrinol Metab Clin N Am 2002;31:619–32.PubMedCrossRefGoogle Scholar
  60. 60.
    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
  61. 61.
    Young WF Jr, Hogan, MJ. Renin-independent hypermineralocorticoidism. Trends Endocrinol Metab 1994;5:97–106.CrossRefPubMedGoogle Scholar
  62. 62.
    Young WF Jr, Klee GG. Primary aldosteronism: diagnostic evaluation. Endocrinol Metab Clin N Am 1988;17:367–95.PubMedGoogle Scholar
  63. 63.
    Sawka AM, Young WF, Thompson GB, Grant CS, Farley DR, Leibson C, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001;135:258–61.PubMedGoogle Scholar
  64. 64.
    Young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA. Role for adrenal venous sampling in primary aldosteronism. Surgery 2004;136:1227–35.PubMedCrossRefGoogle Scholar
  65. 65.
    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;45:1243–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Stowasser M, Sharman J, Leano R, Gordon RD, Ward G, Cowley D, et al. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab 2005;90:5070–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Gockel I, Heintz A, Polta M, Junginger T. Long-term results of endoscopic adrenalectomy for Conn’s syndrome. Am Surg 2007;73:174–80.PubMedGoogle Scholar
  68. 68.
    Lumachi F, Ermani M, Basso SM, Armanini D, Iacobone M, Favia G. Long-term results of adrenalectomy in patients with aldosterone-producing adenomas: multivariate analysis of factors affecting unresolved hypertension and review of the literature. Am Surg 2005;71:864–9.PubMedGoogle Scholar
  69. 69.
    Sywak M, Pasieka JL. Long-term follow-up and cost benefit of adrenalectomy in patients with primary hyperaldosteronism. Br J Surg 2002;89:1587–93.PubMedCrossRefGoogle Scholar
  70. 70.
    Lim PO, Young WF, MacDonald TM. A review of the medical treatment of primary aldosteronism. J Hypertens 2001;19:353–61.PubMedCrossRefGoogle Scholar
  71. 71.
    Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, Plouin PF, et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol 1987;60:820–5.PubMedCrossRefGoogle Scholar
  72. 72.
    Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998;31:445–50.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Mayo Medical SchoolMayo ClinicRochesterUSA
  2. 2.Divisions of Endocrinology, Metabolism, Nutrition and Internal Medicine, and Internal MedicineMayo Clinic and Mayo FoundationRochesterUSA

Personalised recommendations