Comprehensive Physiology Wiley Online Library

Pathophysiology and Diagnosis of Disorders of the Adrenal Medulla: Focus on Pheochromocytoma

Full Article on Wiley Online Library



Abstract

The principal function of the adrenal medulla is the production and secretion of catecholamines. During stressful challenging conditions, catecholamines exert a pivotal homeostatic role. Although the main adrenomedullary catecholamine, epinephrine, has a wide array of adrenoreceptor‐mediated effects, its absence does not cause life‐threatening problems. In contrast, excess production of catecholamines due to an adrenomedullary tumor, specifically pheochromocytoma, results in significant morbidity and mortality. Despite being rare, pheochromocytoma has a notoriously bad reputation because of its potential devastating effects if undetected and untreated. The paroxysmal signs and symptoms and the risks of missing or delaying the diagnosis are well known for most physicians. Nevertheless, even today the diagnosis is still overlooked in a considerable number of patients. Prevention and complete cure are however possible by early diagnosis and appropriate treatment but these patients remain a challenge for physicians. Yet, biochemical proof of presence or absence of catecholamine excess has become more easy and straightforward due to developments in assay methodology. This also applies to radiological and functional imaging techniques for locating the tumor. The importance of genetic testing for underlying germline mutations in susceptibility genes for patients and relatives is increasingly recognized. Yet, the effectiveness of genetic testing, in terms of costs and benefits to health, has not been definitively established. Further improvement in knowledge of genotype‐phenotype relationships in pheochromocytoma will open new avenues to a more rationalized and personalized diagnostic approach of affected patients. © 2014 American Physiological Society. Compr Physiol 4:691‐713, 2014.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Diagram showing the major metabolic pathways of norepinephrine (NE), epinephrine (EPI), and dopamine (DA). The main metabolic pathway for NE is deamination by monoamine oxidase (MAO) within sympathetic nerves to dihydroxyphenylglycol (DHPG) which is the basis for the final metabolite vanillylmandelic acid (VMA). A small part of NE is converted by catechol‐O‐methyltransferase (COMT) extra‐neuronally and intra‐adrenally into normetanephrine (NMN). Epinephrine is mainly converted in the adrenal medulla to metanephrine (MN). Extra‐neuronal conversion of EPI contributes to a minor degree to MN formation. Dopamine is O‐methylated by COMT to 3‐methoxytyramine (3‐MT). Both metanephrines and 3‐MT are conjugated by gut sulphotransferase type 1A3 (Sult1A3) to sulfates (‐SO4).


Figure 1. Diagram showing the major metabolic pathways of norepinephrine (NE), epinephrine (EPI), and dopamine (DA). The main metabolic pathway for NE is deamination by monoamine oxidase (MAO) within sympathetic nerves to dihydroxyphenylglycol (DHPG) which is the basis for the final metabolite vanillylmandelic acid (VMA). A small part of NE is converted by catechol‐O‐methyltransferase (COMT) extra‐neuronally and intra‐adrenally into normetanephrine (NMN). Epinephrine is mainly converted in the adrenal medulla to metanephrine (MN). Extra‐neuronal conversion of EPI contributes to a minor degree to MN formation. Dopamine is O‐methylated by COMT to 3‐methoxytyramine (3‐MT). Both metanephrines and 3‐MT are conjugated by gut sulphotransferase type 1A3 (Sult1A3) to sulfates (‐SO4).
References
 1. Adameova A , Abdellatif Y , Dhalla NS . Role of the excessive amounts of circulating catecholamines and glucocorticoids in stress‐induced heart disease. Can J Physiol Pharmacol 87: 493‐514, 2009.
 2. Akashi YJ , Goldstein DS , Barbaro G , Ueyama T . Takotsubo cardiomyopathy: A new form of acute, reversible heart failure. Circulation 118: 2754‐2762, 2008.
 3. Amar L , Baudin E , Burnichon N , Peyrard S , Silvera S , Bertherat J , Bertagna X , Schlumberger M , Jeunemaitre X , Gimenez‐Roqueplo AP , Plouin PF . Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 92: 3822‐3828, 2007.
 4. Amar L , Bertherat J , Baudin E , Ajzenberg C , Bressac‐De Paillerets B , Chabre O , Chamontin B , Delemer B , Giraud S , Murat A , Niccoli‐Sire P , Richard S , Rohmer V , Sadoul JL , Strompf L , Schlumberger M , Bertagna X , Plouin PF , Jeunemaitre X , Gimenez‐Roqueplo AP . Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23: 8812‐8818, 2005.
 5. Amar L , Fassnacht M , Gimenez‐Roqueplo AP , Januszewicz A , Prejbisz A , Timmers H , Plouin PF . Long‐term postoperative follow‐up in patients with apparently benign pheochromocytoma and paraganglioma. Horm Metab Res 44: 385‐389, 2012.
 6. Amar L , Peyrard S , Rossignol P , Zinzindohoue F , Gimenez‐Roqueplo AP , Plouin PF . Changes in urinary total metanephrine excretion in recurrent and malignant pheochromocytomas and secreting paragangliomas. Ann N Y Acad Sci 1073: 383‐391, 2006.
 7. 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 90: 2110‐2116, 2005.
 8. Andersen KF , Altaf R , Krarup‐Hansen A , Kromann‐Andersen B , Horn T , Christensen NJ , Hendel HW . Malignant pheochromocytomas and paragangliomas ‐ the importance of a multidisciplinary approach. Cancer Treat Rev 37: 111‐119, 2011.
 9. Anderson GH, Jr. , Blakeman N , Streeten DH . The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 12: 609‐615, 1994.
 10. Ariton M , Juan CS , Avruskin TW . Pheochromocytoma: Clinical observations from a Brooklyn tertiary hospital. Endocr Pract 6: 249‐252, 2000.
 11. Astuti D , Latif F , Dallol A , Dahia PL , Douglas F , George E , Skoldberg F , Husebye ES , Eng C , Maher ER . Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69: 49‐54, 2001.
 12. Averbuch SD , Steakley CS , Young RC , Gelmann EP , Goldstein DS , Stull R , Keiser HR . Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109: 267‐273, 1988.
 13. Ayala‐Ramirez M , Feng L , Johnson MM , Ejaz S , Habra MA , Rich T , Busaidy N , Cote GJ , Perrier N , Phan A , Patel S , Waguespack S , Jimenez C . Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: Primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab 96: 717‐725, 2011.
 14. Ayala‐Ramirez M , Palmer JL , Hofmann MC , De La Cruz M , Moon BS , Waguespack SG , Habra MA , Jimenez C . Bone metastases and skeletal‐related events in patients with malignant pheochromocytoma and sympathetic paraganglioma. J Clin Endocrinol Metab 98: 1492‐1497, 2013.
 15. Baysal BE , Ferrell RE , Willett‐Brozick JE , Lawrence EC , Myssiorek D , Bosch A , Van Der Mey A , Taschner PE , Rubinstein WS , Myers EN , Richard CW, 3rd , Cornelisse CJ , Devilee P , Devlin B . Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287: 848‐851, 2000.
 16. Benn DE , Gimenez‐Roqueplo AP , Reilly JR , Bertherat J , Burgess J , Byth K , Croxson M , Dahia PL , Elston M , Gimm O , Henley D , Herman P , Murday V , Niccoli‐Sire P , Pasieka JL , Rohmer V , Tucker K , Jeunemaitre X , Marsh DJ , Plouin PF , Robinson BG . Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab 91: 827‐836, 2006.
 17. Bergland BE. Pheochromocytoma presenting as shock. Am J Emerg Med 7: 44‐48, 1989.
 18. Bevan JA , Tayo FM , Rowan RA , Bevan RD . Presynaptic alpha‐receptor control of adrenergic transmitter release in blood vessels. Fed Proc 43: 1365‐1370, 1984.
 19. Boedeker CC , Hensen EF , Neumann HP , Maier W , Van Nederveen FH , Suarez C , Kunst HP , Rodrigo JP , Takes RP , Pellitteri PK , Rinaldo A , Ferlito A . Genetics of hereditary head and neck paragangliomas. Head Neck, 2013. doi: 10.1002/hed.23436. [Epub ahead of print] PubMed PMID: 23913591.
 20. Boomsma F , Alberts G , Van Eijk L , Man in ‘T Veld AJ , Schalekamp MA . Optimal collection and storage conditions for catecholamine measurements in human plasma and urine. Clin Chem 39: 2503‐2508, 1993.
 21. Bouhanick B , Fauvel J , Pont F . Biochemical misdiagnosis of pheochromocytoma in patients treated with sulfasalazine. JAMA 304: 1898‐1901, 2010.
 22. Bouloux PM , Perrett D . Interference of labetalol metabolites in the determination of plasma catecholamines by HPLC with electrochemical detection. Clin Chim Acta 150: 111‐117, 1985.
 23. Bravo E , Fouad‐Tarazi F , Rossi G , Imamura M , Lin WW , Madkour MA , Wicker P , Cressman MD , Saragoca M . A reevaluation of the hemodynamics of pheochromocytoma. Hypertension 15: I128‐131, 1990.
 24. Bravo EL. Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev 15: 356‐368, 1994.
 25. Bravo EL , Tagle R . Pheochromocytoma: State‐of‐the‐art and future prospects. Endocr Rev 24: 539‐553, 2003.
 26. Brink I , Hoegerle S , Klisch J , Bley TA . Imaging of pheochromocytoma and paraganglioma. Fam Cancer 4: 61‐68, 2005.
 27. Brouwers FM , Lenders JW , Eisenhofer G , Pacak K . Pheochromocytoma as an endocrine emergency. Rev Endocr Metab Disord 4: 121‐128, 2003.
 28. Bryant J , Farmer J , Kessler LJ , Townsend RR , Nathanson KL . Pheochromocytoma: The expanding genetic differential diagnosis. J Natl Cancer Inst 95: 1196‐1204, 2003.
 29. Buffet A , Venisse A , Nau V , Roncellin I , Boccio V , Le Pottier N , Boussion M , Travers C , Simian C , Burnichon N , Abermil N , Favier J , Jeunemaitre X , Gimenez‐Roqueplo AP . A decade (2001‐2010) of genetic testing for pheochromocytoma and paraganglioma. Horm Metab Res 44: 359‐366, 2012.
 30. Burnichon N , Briere JJ , Libe R , Vescovo L , Riviere J , Tissier F , Jouanno E , Jeunemaitre X , Benit P , Tzagoloff A , Rustin P , Bertherat J , Favier J , Gimenez‐Roqueplo AP . SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19: 3011‐3020, 2010.
 31. Burnichon N , Vescovo L , Amar L , Libe R , De Reynies A , Venisse A , Jouanno E , Laurendeau I , Parfait B , Bertherat J , Plouin PF , Jeunemaitre X , Favier J , Gimenez‐Roqueplo AP . Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 20: 3974‐3985, 2011.
 32. Carmichael S. Morphology and innervation of the adrenal medulla. In: Rosenheck K LP , editor. Stimulus‐Secretion Coupling in Chromaffin Cells. 1. Boca Raton, Florida: CRC Inc; 1987. pp. 1‐29.
 33. Carney JA. Carney triad: A syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors. J Clin Endocrinol Metab 94: 3656‐3662, 2009.
 34. Caron MG , Lefkowitz RJ . Catecholamine receptors: Structure, function, and regulation. Recent Prog Horm Res 48: 277‐290, 1993.
 35. Cascon A , Inglada‐Perez L , Comino‐Mendez I , De Cubas AA , Leton R , Mora J , Marazuela M , Galofre JC , Quesada‐Charneco M , Robledo M . Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients. Endocr Relat Cancer 20: L1‐6, 2013.
 36. Cascon A , Lopez‐Jimenez E , Landa I , Leskela S , Leandro‐Garcia LJ , Maliszewska A , Leton R , De La Vega L , Garcia‐Barcina MJ , Sanabria C , Alvarez‐Escola C , Rodriguez‐Antona C , Robledo M . Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma. Horm Metab Res 41: 672‐675, 2009.
 37. Ceccatelli S , Dagerlind A , Schalling M , Wikstrom AC , Okret S , Gustafsson JA , Goldstein M , Hokfelt T . The glucocorticoid receptor in the adrenal gland is localized in the cytoplasm of adrenaline cells. Acta Physiol Scand 137: 559‐560, 1989.
 38. Chia PL , Foo D . Tako‐tsubo cardiomyopathy precipitated by pheochromocytoma crisis. Cardiol J 18: 564‐567, 2011.
 39. Comino‐Mendez I , Gracia‐Aznarez FJ , Schiavi F , Landa I , Leandro‐Garcia LJ , Leton R , Honrado E , Ramos‐Medina R , Caronia D , Pita G , Gomez‐Grana A , De Cubas AA , Inglada‐Perez L , Maliszewska A , Taschin E , Bobisse S , Pica G , Loli P , Hernandez‐Lavado R , Diaz JA , Gomez‐Morales M , Gonzalez‐Neira A , Roncador G , Rodriguez‐Antona C , Benitez J , Mannelli M , Opocher G , Robledo M , Cascon A . Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43: 663‐667, 2011.
 40. Cook FJ , Chandler DW , Snyder DK . Effect of buspirone on urinary catecholamine assays. N Engl J Med 332: 401, 1995.
 41. Cote AM , Firoz T , Mattman A , Lam EM , Von Dadelszen P , Magee LA . The 24‐hour urine collection: Gold standard or historical practice? Am J Obstet Gynecol 199: 625 e621‐626, 2008.
 42. Crona J , Delgado Verdugo A , Maharjan R , Stalberg P , Granberg D , Hellman P , Bjorklund P . Somatic Mutations in H‐RAS in Sporadic Pheochromocytoma and Paraganglioma Identified by Exome Sequencing. J Clin Endocrinol Metab 98: E1266‐1271, 2013.
 43. Crout JR , Sjoerdsma A . Turnover and metabolism of catecholamines in patients with pheochromocytoma. J Clin Invest 43: 94‐102, 1964.
 44. Cryer PE . Adrenaline: A physiological metabolic regulatory hormone in humans? Int J Obes Relat Metab Disord 17(Suppl 3): S43‐S46; discussion S68, 1993.
 45. Dahia PL , Ross KN , Wright ME , Hayashida CY , Santagata S , Barontini M , Kung AL , Sanso G , Powers JF , Tischler AS , Hodin R , Heitritter S , Moore F , Dluhy R , Sosa JA , Ocal IT , Benn DE , Marsh DJ , Robinson BG , Schneider K , Garber J , Arum SM , Korbonits M , Grossman A , Pigny P , Toledo SP , Nose V , Li C , Stiles CD . A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 1: 72‐80, 2005.
 46. Davidson DF . Urinary catecholamine assay by HPLC: In vitro interference by some drugs. Ann Clin Biochem 25(Pt 5): 583‐584, 1988.
 47. Davidson FD. Paracetamol‐associated interference in an HPLC‐ECD assay for urinary free metadrenalines and catecholamines. Ann Clin Biochem 41: 316‐320, 2004.
 48. De Diego AM , Gandia L , Garcia AG . A physiological view of the central and peripheral mechanisms that regulate the release of catecholamines at the adrenal medulla. Acta Physiol (Oxf) 192: 287‐301, 2008.
 49. De Jong WH , Eisenhofer G , Post WJ , Muskiet FA , De Vries EG , Kema IP . Dietary influences on plasma and urinary metanephrines: Implications for diagnosis of catecholamine‐producing tumors. J Clin Endocrinol Metab 94: 2841‐2849, 2009.
 50. De Jong WH , Graham KS , Van Der Molen JC , Links TP , Morris MR , Ross HA , De Vries EG , Kema IP . Plasma free metanephrine measurement using automated online solid‐phase extraction HPLC tandem mass spectrometry. Clin Chem 53: 1684‐1693, 2007.
 51. De Lloyd AC , Munigoti S , Davies JS , Scott‐Coombes D . A rare and life‐threatening cause of pseudo‐obstruction in two surgical patients. BMJ Case Rep 2010, 2010. pii: bcr0420102882. doi: 10.1136/bcr.04.2010. 2882. PubMed PMID: 22797198; PubMed Central PMCID: PMC3027567.
 52. De Souza F , Altenburg Odebrecht Curi Gismondi R, Henriques Cunha Neto S, De Mattos MA. Tako‐tsubo‐like cardiomyopathy and extra‐adrenal pheochromocytoma: Case report and literature review. Clin Res Cardiol 97: 397‐401, 2008.
 53. Delellis R , Lloyd R , Heitz P , Eng C . Pathology and Genetics of Tumours of Endocrine Organs. Lyon, France: IARC Press 2004.
 54. Dimski T , Heinen‐Lauten J , Krep H . Basal tako‐tsubo cardiomyopathy. Induction of a pheochromocytoma after general anesthesia. Anaesthesist 57: 143‐146, 2008.
 55. Edstrom Elder E , Hjelm Skog AL , Hoog A , Hamberger B . The management of benign and malignant pheochromocytoma and abdominal paraganglioma. Eur J Surg Oncol 29: 278‐283, 2003.
 56. Ehrhart‐Bornstein M , Hinson JP , Bornstein SR , Scherbaum WA , Vinson GP . Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 19: 101‐143, 1998.
 57. Eisenhofer G. The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol Ther 91: 35‐62, 2001.
 58. Eisenhofer G , Bornstein SR , Brouwers FM , Cheung NK , Dahia PL , De Krijger RR , Giordano TJ , Greene LA , Goldstein DS , Lehnert H , Manger WM , Maris JM , Neumann HP , Pacak K , Shulkin BL , Smith DI , Tischler AS , Young WF, Jr . Malignant pheochromocytoma: Current status and initiatives for future progress. Endocr Relat Cancer 11: 423‐436, 2004.
 59. Eisenhofer G , Brown S , Peitzsch M , Pelzel D , Lattke P , Glockner S , Stell A , Prejbisz A , Fassnacht M , Beuschlein F , Januszewicz A , Siegert G , Reichmann H . Levodopa therapy in Parkinson's disease: Influence on liquid chromatographic tandem mass spectrometric‐based measurements of plasma and urinary normetanephrine, metanephrine and methoxytyramine. Ann Clin Biochem 51: 38‐46, 2014.
 60. Eisenhofer G , Ehrhart‐Bornstein M , Bornstein S . The adrenal medulla. Physiology and Pathophysiology. In: Bolis CL LJ , Govoni S , editor. Handbook of the Autonomic Nervous System in Health and Disease. New York, Basel: Marcel Dekker Inc; 2003. pp. 185‐224.
 61. Eisenhofer G , Friberg P , Pacak K , Goldstein DS , Murphy DL , Tsigos C , Quyyumi AA , Brunner HG , Lenders JW . Plasma metadrenalines: Do they provide useful information about sympatho‐adrenal function and catecholamine metabolism? Clin Sci (Lond) 88: 533‐542, 1995.
 62. Eisenhofer G , Goldstein DS , Sullivan P , Csako G , Brouwers FM , Lai EW , Adams KT , Pacak K . Biochemical and clinical manifestations of dopamine‐producing paragangliomas: Utility of plasma methoxytyramine. J Clin Endocrinol Metab 90: 2068‐2075, 2005.
 63. Eisenhofer G , Goldstein DS , Walther MM , Friberg P , Lenders JW , Keiser HR , Pacak K . Biochemical diagnosis of pheochromocytoma: How to distinguish true‐ from false‐positive test results. J Clin Endocrinol Metab 88: 2656‐2666, 2003.
 64. Eisenhofer G , Huynh TT , Hiroi M , Pacak K . Understanding catecholamine metabolism as a guide to the biochemical diagnosis of pheochromocytoma. Rev Endocr Metab Disord 2: 297‐311, 2001.
 65. Eisenhofer G , Huynh TT , Pacak K , Brouwers FM , Walther MM , Linehan WM , Munson PJ , Mannelli M , Goldstein DS , Elkahloun AG . Distinct gene expression profiles in norepinephrine‐ and epinephrine‐producing hereditary and sporadic pheochromocytomas: Activation of hypoxia‐driven angiogenic pathways in von Hippel‐Lindau syndrome. Endocr Relat Cancer 11: 897‐911, 2004.
 66. Eisenhofer G , Huysmans F , Pacak K , Walther MM , Sweep FC , Lenders JW . Plasma metanephrines in renal failure. Kidney Int 67: 668‐677, 2005.
 67. Eisenhofer G , Keiser H , Friberg P , Mezey E , Huynh TT , Hiremagalur B , Ellingson T , Duddempudi S , Eijsbouts A , Lenders JW . Plasma metanephrines are markers of pheochromocytoma produced by catechol‐O‐methyltransferase within tumors. J Clin Endocrinol Metab 83: 2175‐2185, 1998.
 68. Eisenhofer G , Kopin IJ , Goldstein DS . Catecholamine metabolism: A contemporary view with implications for physiology and medicine. Pharmacol Rev 56: 331‐349, 2004.
 69. Eisenhofer G , Lattke P , Herberg M , Siegert G , Qin N , Darr R , Hoyer J , Villringer A , Prejbisz A , Januszewicz A , Remaley A , Martucci V , Pacak K , Ross HA , Sweep FC , Lenders JW . Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma. Ann Clin Biochem 50: 62‐69, 2013.
 70. Eisenhofer G , Lenders JW , Goldstein DS , Mannelli M , Csako G , Walther MM , Brouwers FM , Pacak K . Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem 51: 735‐744, 2005.
 71. Eisenhofer G , Lenders JW , Linehan WM , Walther MM , Goldstein DS , Keiser HR . Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel‐Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 340: 1872‐1879, 1999.
 72. Eisenhofer G , Lenders JW , Siegert G , Bornstein SR , Friberg P , Milosevic D , Mannelli M , Linehan WM , Adams K , Timmers HJ , Pacak K . Plasma methoxytyramine: A novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer 48: 1739‐1749, 2012.
 73. Eisenhofer G , Lenders JW , Timmers H , Mannelli M , Grebe SK , Hofbauer LC , Bornstein SR , Tiebel O , Adams K , Bratslavsky G , Linehan WM , Pacak K . Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem 57: 411‐420, 2011.
 74. Eisenhofer G , Pacak K , Huynh TT , Qin N , Bratslavsky G , Linehan WM , Mannelli M , Friberg P , Grebe SK , Timmers HJ , Bornstein SR , Lenders JW . Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer 18: 97‐111, 2011.
 75. Eisenhofer G , Rivers G , Rosas AL , Quezado Z , Manger WM , Pacak K . Adverse drug reactions in patients with phaeochromocytoma: Incidence, prevention and management. Drug Saf 30: 1031‐1062, 2007.
 76. Eisenhofer G , Rundquist B , Aneman A , Friberg P , Dakak N , Kopin IJ , Jacobs MC , Lenders JW . Regional release and removal of catecholamines and extraneuronal metabolism to metanephrines. J Clin Endocrinol Metab 80: 3009‐3017, 1995.
 77. Eisenhofer G , Walther MM , Huynh TT , Li ST , Bornstein SR , Vortmeyer A , Mannelli M , Goldstein DS , Linehan WM , Lenders JW , Pacak K . Pheochromocytomas in von Hippel‐Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86: 1999‐2008, 2001.
 78. Eisenhofer G , Whitley R , Rosano T . Catecholamines and serotonin. In: Burtis C , Ashwood E , Bruns D , editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. USA: Elsevier Saunders; 2012. pp. 851‐894.
 79. Erickson D , Kudva YC , Ebersold MJ , Thompson GB , Grant CS , Van Heerden JA , Young WF, Jr . Benign paragangliomas: Clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 86: 5210‐5216, 2001.
 80. Erlic Z , Rybicki L , Peczkowska M , Golcher H , Kann PH , Brauckhoff M , Mussig K , Muresan M , Schaffler A , Reisch N , Schott M , Fassnacht M , Opocher G , Klose S , Fottner C , Forrer F , Plockinger U , Petersenn S , Zabolotny D , Kollukch O , Yaremchuk S , Januszewicz A , Walz MK , Eng C , Neumann HP , European‐American Pheochromocytoma Study G. Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res 15: 6378‐6385, 2009.
 81. Esler M. Sympathetic nervous activation in essential hypertension: Commonly neglected as a therapeutic target, usually ignored as a drug side effect. Hypertension 55: 1090‐1091, 2010.
 82. Esler M , Jennings G , Korner P , Willett I , Dudley F , Hasking G , Anderson W , Lambert G . Assessment of human sympathetic nervous system activity from measurements of norepinephrine turnover. Hypertension 11: 3‐20, 1988.
 83. Favier J , Briere JJ , Burnichon N , Riviere J , Vescovo L , Benit P , Giscos‐Douriez I , De Reynies A , Bertherat J , Badoual C , Tissier F , Amar L , Libe R , Plouin PF , Jeunemaitre X , Rustin P , Gimenez‐Roqueplo AP . The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One 4: e7094, 2009.
 84. Favier J , Buffet A , Gimenez‐Roqueplo AP . HIF2A mutations in paraganglioma with polycythemia. N Engl J Med 367: 2161; author reply 2161‐2162, 2012.
 85. Feuerstein G , Gutman Y . Preferential secretion of adrenaline or noradrenaline by the cat adrenal in vivo in response to different stimuli. Br J Pharmacol 43: 764‐775, 1971.
 86. Fliedner SM , Lehnert H , Pacak K . Metastatic paraganglioma. Semin Oncol 37: 627‐637, 2010.
 87. Furuta N , Kiyota H , Yoshigoe F , Hasegawa N , Ohishi Y . Diagnosis of pheochromocytoma using [123I]‐compared with [131I]‐metaiodobenzylguanidine scintigraphy. Int J Urol 6: 119‐124, 1999.
 88. Gill AJ , Benn DE , Chou A , Clarkson A , Muljono A , Meyer‐Rochow GY , Richardson AL , Sidhu SB , Robinson BG , Clifton‐Bligh RJ . Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma‐pheochromocytoma syndromes. Hum Pathol 41: 805‐814, 2010.
 89. Gimenez‐Roqueplo AP , Caumont‐Prim A , Houzard C , Hignette C , Hernigou A , Halimi P , Niccoli P , Leboulleux S , Amar L , Borson‐Chazot F , Cardot‐Bauters C , Delemer B , Chabolle F , Coupier I , Libe R , Peitzsch M , Peyrard S , Tenenbaum F , Plouin PF , Chatellier G , Rohmer V . Imaging work‐up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: A multicenter prospective study from the PGL.EVA Investigators. J Clin Endocrinol Metab 98: E162‐173, 2013.
 90. Gimenez‐Roqueplo AP , Dahia PL , Robledo M . An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res 44: 328‐333, 2012.
 91. Gimenez‐Roqueplo AP , Favier J , Rustin P , Rieubland C , Kerlan V , Plouin PF , Rotig A , Jeunemaitre X . Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma. J Clin Endocrinol Metab 87: 4771‐4774, 2002.
 92. Giovanella L , Squin N , Ghelfo A , Ceriani L . Chromogranin A immunoradiometric assay in diagnosis of pheochromocytoma: Comparison with plasma metanephrines and 123I‐MIBG scan. Q J Nucl Med Mol Imaging 50: 344‐347, 2006.
 93. Goldstein DS. Stress, Catecholamines, and Cardiovascular Disease. New York‐Oxford: Oxford University Press 1995.
 94. Goldstein RE , O'neill JA, Jr ., Holcomb GW, III , Morgan WM, III , Neblett WW, III , Oates JA , Brown N , Nadeau J , Smith B , Page DL , Abumrad NN , Scott HW, Jr . Clinical experience over 48 years with pheochromocytoma. Ann Surg 229: 755‐764; discussion 764‐756, 1999.
 95. Grassi G , Cattaneo BM , Seravalle G , Lanfranchi A , Mancia G . Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension 31: 68‐72, 1998.
 96. Grouzmann E , Drouard‐Troalen L , Baudin E , Plouin PF , Muller B , Grand D , Buclin T . Diagnostic accuracy of free and total metanephrines in plasma and fractionated metanephrines in urine of patients with pheochromocytoma. Eur J Endocrinol 162: 951‐960, 2010.
 97. Guimaraes S , Moura D . Vascular adrenoceptors: An update. Pharmacol Rev 53: 319‐356, 2001.
 98. Hammond PJ , Murphy D , Carachi R , Davidson DF , Mcintosh D . Childhood phaeochromocytoma and paraganglioma: 100% incidence of genetic mutations and 100% survival. J Pediatr Surg 45: 383‐386, 2010.
 99. Hao HX , Khalimonchuk O , Schraders M , Dephoure N , Bayley JP , Kunst H , Devilee P , Cremers CW , Schiffman JD , Bentz BG , Gygi SP , Winge DR , Kremer H , Rutter J . SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325: 1139‐1142, 2009.
 100. Henry JP , Sagne C , Bedet C , Gasnier B . The vesicular monoamine transporter: From chromaffin granule to brain. Neurochem Int 32: 227‐246, 1998.
 101. Hescot S , Leboulleux S , Amar L , Vezzosi D , Borget I , Bournaud‐Salinas C , De La Fouchardiere C , Libe R , Do Cao C , Niccoli P , Tabarin A , Raingeard I , Chougnet C , Giraud S , Gimenez‐Roqueplo AP , Young J , Borson‐Chazot F , Bertherat J , Wemeau JL , Bertagna X , Plouin PF , Schlumberger M , Baudin E , For the French Group Of E, Adrenal t. One‐year progression‐free survival of therapy‐naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 98: 4006‐4012, 2013.
 102. Hickman PE , Leong M , Chang J , Wilson SR , Mcwhinney B . Plasma free metanephrines are superior to urine and plasma catecholamines and urine catecholamine metabolites for the investigation of phaeochromocytoma. Pathology 41: 173‐177, 2009.
 103. Hoegerle S , Nitzsche E , Altehoefer C , Ghanem N , Manz T , Brink I , Reincke M , Moser E , Neumann HP . Pheochromocytomas: Detection with 18F DOPA whole body PET–initial results. Radiology 222: 507‐512, 2002.
 104. Houston MC . Clonidine hydrochloride: Review of pharmacologic and clinical aspects. Prog Cardiovasc Dis 23: 337‐350, 1981.
 105. Huang H , Abraham J , Hung E , Averbuch S , Merino M , Steinberg SM , Pacak K , Fojo T . Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: Recommendation from a 22‐year follow‐up of 18 patients. Cancer 113: 2020‐2028, 2008.
 106. Huber K , Kalcheim C , Unsicker K . The development of the chromaffin cell lineage from the neural crest. Auton Neurosci 151: 10‐16, 2009.
 107. Ilias I , Sahdev A , Reznek RH , Grossman AB , Pacak K . The optimal imaging of adrenal tumours: A comparison of different methods. Endocr Relat Cancer 14: 587‐599, 2007.
 108. Ito Y , Fujimoto Y , Obara T . The role of epinephrine, norepinephrine, and dopamine in blood pressure disturbances in patients with pheochromocytoma. World J Surg 16: 759‐763; discussion 763‐754, 1992.
 109. Jacques AE , Sahdev A , Sandrasagara M , Goldstein R , Berney D , Rockall AG , Chew S , Reznek RH . Adrenal phaeochromocytoma: Correlation of MRI appearances with histology and function. Eur Radiol 18: 2885‐2892, 2008.
 110. Jalil ND , Pattou FN , Combemale F , Chapuis Y , Henry JF , Peix JL , Proye CA . 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 164: 23‐28, 1998.
 111. Jimenez C , Rohren E , Habra MA , Rich T , Jimenez P , Ayala‐Ramirez M , Baudin E . Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep 15: 356‐371, 2013.
 112. Kebebew E , Duh QY . Benign and malignant pheochromocytoma: Diagnosis, treatment, and follow‐Up. Surg Oncol Clin N Am 7: 765‐789, 1998.
 113. Kimura N , Miura Y , Nagatsu I , Nagura H . Catecholamine synthesizing enzymes in 70 cases of functioning and non‐functioning phaeochromocytoma and extra‐adrenal paraganglioma. Virchows Arch A Pathol Anat Histopathol 421: 25‐32, 1992.
 114. King KS , Chen CC , Alexopoulos DK , Whatley MA , Reynolds JC , Patronas N , Ling A , Adams KT , Xekouki P , Lando H , Stratakis CA , Pacak K . Functional imaging of SDHx‐related head and neck paragangliomas: Comparison of 18F‐fluorodihydroxyphenylalanine, 18F‐fluorodopamine, 18F‐fluoro‐2‐deoxy‐D‐glucose PET, 123I‐metaiodobenzylguanidine scintigraphy, and 111In‐pentetreotide scintigraphy. J Clin Endocrinol Metab 96: 2779‐2785, 2011.
 115. King KS , Prodanov T , Kantorovich V , Fojo T , Hewitt JK , Zacharin M , Wesley R , Lodish M , Raygada M , Gimenez‐Roqueplo AP , Mccormack S , Eisenhofer G , Milosevic D , Kebebew E , Stratakis CA , Pacak K . Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: Significant link to SDHB mutations. J Clin Oncol 29: 4137‐4142, 2011.
 116. Kobal SL , Paran E , Jamali A , Mizrahi S , Siegel RJ , Leor J . Pheochromocytoma: Cyclic attacks of hypertension alternating with hypotension. Nat Clin Pract Cardiovasc Med 5: 53‐57, 2008.
 117. La Batide‐Alanore A , Chatellier G , Plouin PF . Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens 21: 1703‐1707, 2003.
 118. Lagerstedt SA , O'kane DJ , Singh RJ . Measurement of plasma free metanephrine and normetanephrine by liquid chromatography‐tandem mass spectrometry for diagnosis of pheochromocytoma. Clin Chem 50: 603‐611, 2004.
 119. Lassnig E , Weber T , Auer J , Nomeyer R , Eber B . Pheochromocytoma crisis presenting with shock and tako‐tsubo‐like cardiomyopathy. Int J Cardiol 134: e138‐140, 2009.
 120. Latif F , Tory K , Gnarra J , Yao M , Duh FM , Orcutt ML , Stackhouse T , Kuzmin I , Modi W , Geil L , Et Al. Identification of the von Hippel‐Lindau disease tumor suppressor gene. Science 260: 1317‐1320, 1993.
 121. Lee S , Nakamura E , Yang H , Wei W , Linggi MS , Sajan MP , Farese RV , Freeman RS , Carter BD , Kaelin WG, Jr. , Schlisio S . Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: Developmental culling and cancer. Cancer Cell 8: 155‐167, 2005.
 122. Lenders JW , Eisenhofer G , Armando I , Keiser HR , Goldstein DS , Kopin IJ . Determination of metanephrines in plasma by liquid chromatography with electrochemical detection. Clin Chem 39: 97‐103, 1993.
 123. Lenders JW , Eisenhofer G , Mannelli M , Pacak K . Phaeochromocytoma. Lancet 366: 665‐675, 2005.
 124. Lenders JW , Keiser HR , Goldstein DS , Willemsen JJ , Friberg P , Jacobs MC , Kloppenborg PW , Thien T , Eisenhofer G . Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 123: 101‐109, 1995.
 125. Lenders JW , Pacak K , Walther MM , Linehan WM , Mannelli M , Friberg P , Keiser HR , Goldstein DS , Eisenhofer G . Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA 287: 1427‐1434, 2002.
 126. Lenders JW , Willemsen JJ , Eisenhofer G , Ross HA , Pacak K , Timmers HJ , Sweep CG . Is supine rest necessary before blood sampling for plasma metanephrines? Clin Chem 53: 352‐354, 2007.
 127. Leung K , Stamm M , Raja A , Low G . Pheochromocytoma: The range of appearances on ultrasound, CT, MRI, and functional imaging. AJR Am J Roentgenol 200: 370‐378, 2013.
 128. Levenson JA , Safar ME , London GM , Simon AC . Haemodynamics in patients with phaeochromocytoma. Clin Sci (Lond) 58: 349‐356, 1980.
 129. Liao WB , Liu CF , Chiang CW , Kung CT , Lee CW . Cardiovascular manifestations of pheochromocytoma. Am J Emerg Med 18: 622‐625, 2000.
 130. Littler WA , Honour AJ . Direct arterial pressure, heart rate, and electrocardiogram in unrestricted patients before and after removal of a phaeochromocyoma. Q J Med 43: 441‐449, 1974.
 131. Livett BG. Adrenal medullary chromaffin cells in vitro. Physiol Rev 64: 1103‐1161, 1984.
 132. Lo CY , Lam KY , Wat MS , Lam KS . Adrenal pheochromocytoma remains a frequently overlooked diagnosis. Am J Surg 179: 212‐215, 2000.
 133. Lopez‐Jimenez E , Gomez‐Lopez G , Leandro‐Garcia LJ , Munoz I , Schiavi F , Montero‐Conde C , De Cubas AA , Ramires R , Landa I , Leskela S , Maliszewska A , Inglada‐Perez L , De La Vega L , Rodriguez‐Antona C , Leton R , Bernal C , De Campos JM , Diez‐Tascon C , Fraga MF , Boullosa C , Pisano DG , Opocher G , Robledo M , Cascon A . Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL‐related pheochromocytomas. Mol Endocrinol 24: 2382‐2391, 2010.
 134. Lorenzo FR , Yang C , Ng Tang Fui M , Vankayalapati H , Zhuang Z , Huynh T , Grossmann M , Pacak K , Prchal JT . A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. J Mol Med (Berl) 91: 507‐512, 2013.
 135. Lyon AR , Rees PS , Prasad S , Poole‐Wilson PA , Harding SE . Stress (Takotsubo) cardiomyopathy–a novel pathophysiological hypothesis to explain catecholamine‐induced acute myocardial stunning. Nat Clin Pract Cardiovasc Med 5: 22‐29, 2008.
 136. Majewski H , Mcculloch MW , Rand MJ , Story DF . Adrenaline activation of prejunctional beta‐adrenoceptors in guinea‐pig atria. Br J Pharmacol 71: 435‐444, 1980.
 137. Manger W , Gifford R . Clinical and Experimental Pheochromocytoma. Cambridge, MA: Blackwell Science 1996.
 138. Manger WM. The protean manifestations of pheochromocytoma. Horm Metab Res 41: 658‐663, 2009.
 139. Mannelli M , Ianni L , Cilotti A , Conti A . Pheochromocytoma in Italy: A multicentric retrospective study. Eur J Endocrinol 141: 619‐624, 1999.
 140. Mansmann G , Lau J , Balk E , Rothberg M , Miyachi Y , Bornstein SR . The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev 25: 309‐340, 2004.
 141. Mantero F , Terzolo M , Arnaldi G , Osella G , Masini AM , Ali A , Giovagnetti M , Opocher G , Angeli A . A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 85: 637‐644, 2000.
 142. Maurice JB , Troke R , Win Z , Ramachandran R , Al‐Nahhas A , Naji M , Dhillo W , Meeran K , Goldstone AP , Martin NM , Todd JF , Palazzo F , Tan T . A comparison of the performance of (6)(8)Ga‐DOTATATE PET/CT and (1)(2)(3)I‐MIBG SPECT in the diagnosis and follow‐up of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 39: 1266‐1270, 2012.
 143. 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 30: 648‐652, 2000.
 144. Merke DP , Chrousos GP , Eisenhofer G , Weise M , Keil MF , Rogol AD , Van Wyk JJ , Bornstein SR . Adrenomedullary dysplasia and hypofunction in patients with classic 21‐hydroxylase deficiency. N Engl J Med 343: 1362‐1368, 2000.
 145. Milardovic R , Corssmit EP , Stokkel M . Value of 123I‐MIBG Scintigraphy in Paraganglioma. Neuroendocrinology 91: 94‐100, 2010.
 146. Motulsky HJ , Insel PA . Adrenergic receptors in man: Direct identification, physiologic regulation, and clinical alterations. N Engl J Med 307: 18‐29, 1982.
 147. Mozley PD , Kim CK , Mohsin J , Jatlow A , Gosfield E, III , Alavi A . The efficacy of iodine‐123‐MIBG as a screening test for pheochromocytoma. J Nucl Med 35: 1138‐1144, 1994.
 148. Mulligan LM , Kwok JB , Healey CS , Elsdon MJ , Eng C , Gardner E , Love DR , Mole SE , Moore JK , Papi L , Et Al . Germ‐line mutations of the RET proto‐oncogene in multiple endocrine neoplasia type 2A. Nature 363: 458‐460, 1993.
 149. Munion GL , Seaton JF , Harrison TS . HPLC for urinary catecholamines and metanephrines with alpha‐methyldopa. J Surg Res 35: 507‐514, 1983.
 150. Nagatsu T , Mizutani K , Sudo Y , Nagatsu I . Tyrosine hydroxylase in human adrenal glands and human pheochromocytoma. Clin Chim Acta 39: 417‐424, 1972.
 151. Nagatsu T. Tyrosine hydroxylase: Human isoforms, structure and regulation in physiology and pathology. Essays Biochem 30: 15‐35, 1995.
 152. Nakada T , Furuta H , Katayama T . Catecholamine metabolism in pheochromocytoma and normal adrenal medullae. J Urol 140: 1348‐1351, 1988.
 153. Neary NM , King KS , Pacak K . Drugs and pheochromocytoma–don't be fooled by every elevated metanephrine. N Engl J Med 364: 2268‐2270, 2011.
 154. Neumann HP , Bausch B , Mcwhinney SR , Bender BU , Gimm O , Franke G , Schipper J , Klisch J , Altehoefer C , Zerres K , Januszewicz A , Eng C , Smith WM , Munk R , Manz T , Glaesker S , Apel TW , Treier M , Reineke M , Walz MK , Hoang‐Vu C , Brauckhoff M , Klein‐Franke A , Klose P , Schmidt H , Maier‐Woelfle M , Peczkowska M , Szmigielski C , Eng C , Freiburg‐Warsaw‐Columbus Pheochromocytoma Study G. Germ‐line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346: 1459‐1466, 2002.
 155. Neumann HP , Pawlu C , Peczkowska M , Bausch B , Mcwhinney SR , Muresan M , Buchta M , Franke G , Klisch J , Bley TA , Hoegerle S , Boedeker CC , Opocher G , Schipper J , Januszewicz A , Eng C , European‐American Paraganglioma Study G. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA 292: 943‐951, 2004.
 156. Niemann S , Muller U . Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26: 268‐270, 2000.
 157. Olson SW , Deal LE , Piesman M . Epinephrine‐secreting pheochromocytoma presenting with cardiogenic shock and profound hypocalcemia. Ann Intern Med 140: 849‐851, 2004.
 158. 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 27: 193‐202, 2004.
 159. Osinga TE , Van Den Eijnden MH , Kema IP , Kerstens MN , Dullaart RP , De Jong WH , Sluiter WJ , Links TP , Van Der Horst‐Schrivers AN . Unilateral and bilateral adrenalectomy for pheochromocytoma requires adjustment of urinary and plasma metanephrine reference ranges. J Clin Endocrinol Metab 98: 1076‐1083, 2013.
 160. Pacak K . Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 92: 4069‐4079, 2007.
 161. Pacak K , Eisenhofer G , Ahlman H , Bornstein SR , Gimenez‐Roqueplo AP , Grossman AB , Kimura N , Mannelli M , Mcnicol AM , Tischler AS , International Symposium On P. Pheochromocytoma: Recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3: 92‐102, 2007.
 162. Pacak K , Jochmanova I , Prodanov T , Yang C , Merino MJ , Fojo T , Prchal JT , Tischler AS , Lechan RM , Zhuang Z . New syndrome of paraganglioma and somatostatinoma associated with polycythemia. J Clin Oncol 31: 1690‐1698, 2013.
 163. Pacak K , Lenders J , Eisenhofer G . Pheochromocytoma: Diagnosis, Localization and Treatment. Oxford: Wiley‐Blackwell 2007.
 164. Padfield PL , Stewart MJ . Ambulatory blood pressure monitoring in secondary hypertension. J Hypertens Suppl 9: S69‐71, 1991.
 165. Page LB , Raker JW , Berberich FR . Pheochromocytoma with predominant epinephrine secretion. Am J Med 47: 648‐652, 1969.
 166. Pamporaki C , Darr R , Bursztyn M , Glockner S , Bornstein SR , Lenders JW , Pacak K , Krinner A , Eisenhofer G . Plasma‐free vs deconjugated metanephrines for diagnosis of phaeochromocytoma. Clin Endocrinol (Oxf) 79: 476‐483, 2013.
 167. Parati G , Esler M . The human sympathetic nervous system: Its relevance in hypertension and heart failure. Eur Heart J 33: 1058‐1066, 2012.
 168. Park BK , Kim CK , Kwon GY , Kim JH . Re‐evaluation of pheochromocytomas on delayed contrast‐enhanced CT: Washout enhancement and other imaging features. Eur Radiol 17: 2804‐2809, 2007.
 169. Pasini B , Stratakis CA . SDH mutations in tumorigenesis and inherited endocrine tumours: Lesson from the phaeochromocytoma‐paraganglioma syndromes. J Intern Med 266: 19‐42, 2009.
 170. Peaston RT , Graham KS , Chambers E , Van Der Molen JC , Ball S . Performance of plasma free metanephrines measured by liquid chromatography‐tandem mass spectrometry in the diagnosis of pheochromocytoma. Clin Chim Acta 411: 546‐552, 2010.
 171. Peitzsch M , Pelzel D , Glockner S , Prejbisz A , Fassnacht M , Beuschlein F , Januszewicz A , Siegert G , Eisenhofer G . Simultaneous liquid chromatography tandem mass spectrometric determination of urinary free metanephrines and catecholamines, with comparisons of free and deconjugated metabolites. Clin Chim Acta 418: 50‐58, 2013.
 172. Perry CG , Sawka AM , Singh R , Thabane L , Bajnarek J , Young WF, Jr . The diagnostic efficacy of urinary fractionated metanephrines measured by tandem mass spectrometry in detection of pheochromocytoma. Clin Endocrinol (Oxf) 66: 703‐708, 2007.
 173. Petteys BJ , Graham KS , Parnas ML , Holt C , Frank EL . Performance characteristics of an LC‐MS/MS method for the determination of plasma metanephrines. Clin Chim Acta 413: 1459‐1465, 2012.
 174. Pillai D , Ross HA , Kratzsch J , Pedrosa W , Kema I , Hoad K , Rouaix N , Fathi M , Nader H , Mathian B , Grouzmann E . Proficiency test of plasma free and total metanephrines: Report from a study group. Clin Chem Lab Med 47: 786‐790, 2009.
 175. Platts JK , Drew PJ , Harvey JN . Death from phaeochromocytoma: Lessons from a post‐mortem survey. J R Coll Physicians Lond 29: 299‐306, 1995.
 176. Plouin PF , Degoulet P , Tugaye A , Ducrocq MB , Menard J . Screening for phaeochromocytoma : in which hypertensive patients? A semiological study of 2585 patients, including 11 with phaeochromocytoma (author's transl). Nouv Presse Med 10: 869‐872, 1981.
 177. 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 86: 1480‐1486, 2001.
 178. Plouin PF , Fitzgerald P , Rich T , Ayala‐Ramirez M , Perrier ND , Baudin E , Jimenez C . Metastatic pheochromocytoma and paraganglioma: Focus on therapeutics. Horm Metab Res 44: 390‐399, 2012.
 179. Prejbisz A , Lenders JW , Eisenhofer G , Januszewicz A . Cardiovascular manifestations of phaeochromocytoma. J Hypertens 29: 2049‐2060, 2011.
 180. Prejbisz A , Lenders JW , Eisenhofer G , Januszewicz A . Mortality associated with phaeochromocytoma. Horm Metab Res 45: 154‐158, 2013.
 181. Pritchard J , Barnes J , Germond S , Hartman O , De Kraker J , Lewis I , Lockwood L , Wallendszus K . Stage and urinary catecholamine metabolite excretion in neuroblastoma. European Neuroblastoma Study Group. Lancet 2: 514‐515, 1989.
 182. Proye C , Fossati P , Fontaine P , Lefebvre J , Decoulx M , Wemeau JL , Dewailly D , Rwamasirabo E , Cecat P . Dopamine‐secreting pheochromocytoma: An unrecognized entity? Classification of pheochromocytomas according to their type of secretion. Surgery 100: 1154‐1162, 1986.
 183. Qin Y , Yao L , King EE , Buddavarapu K , Lenci RE , Chocron ES , Lechleiter JD , Sass M , Aronin N , Schiavi F , Boaretto F , Opocher G , Toledo RA , Toledo SP , Stiles C , Aguiar RC , Dahia PL . Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 42: 229‐233, 2010.
 184. Raber W , Raffesberg W , Bischof M , Scheuba C , Niederle B , Gasic S , Waldhausl W , Roden M . Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Arch Intern Med 160: 2957‐2963, 2000.
 185. Ram CV , Fierro‐Carrion GA . Pheochromocytoma. Semin Nephrol 15: 126‐137, 1995.
 186. Rand MJ , Majewski H , Medgett IC , Mcculloch MW , Story DF . Prejunctional receptors modulating autonomic neuroeffector transmission. Circ Res 46: I70‐76, 1980.
 187. Rosano TG , Swift TA , Hayes LW . Advances in catecholamine and metabolite measurements for diagnosis of pheochromocytoma. Clin Chem 37: 1854‐1867, 1991.
 188. Rosas AL , Kasperlik‐Zaluska AA , Papierska L , Bass BL , Pacak K , Eisenhofer G . Pheochromocytoma crisis induced by glucocorticoids: A report of four cases and review of the literature. Eur J Endocrinol 158: 423‐429, 2008.
 189. Rufini V , Treglia G , Castaldi P , Perotti G , Giordano A . Comparison of metaiodobenzylguanidine scintigraphy with positron emission tomography in the diagnostic work‐up of pheochromocytoma and paraganglioma: A systematic review. Q J Nucl Med Mol Imaging 57: 122‐133, 2013.
 190. Sahdev A , Sohaib A , Monson JP , Grossman AB , Chew SL , Reznek RH . CT and MR imaging of unusual locations of extra‐adrenal paragangliomas (pheochromocytomas). Eur Radiol 15: 85‐92, 2005.
 191. Santoro F , Ieva R , Spennati G , De Gennaro L , Correale M , Di Biase M , Brunetti ND . Tako‐Tsubo cardiomyopathy in a teen girl with pheochromocytoma. Int J Cardiol 160: e48‐49, 2012.
 192. 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 88: 553‐558, 2003.
 193. Schuldiner S , Shirvan A , Linial M . Vesicular neurotransmitter transporters: From bacteria to humans. Physiol Rev 75: 369‐392, 1995.
 194. Schurmeyer TH , Engeroff B , Dralle H , Von Zur Muhlen A. Cardiological effects of catecholamine‐secreting tumours. Eur J Clin Invest 27: 189‐195, 1997.
 195. Sheaves R , Chew SL , Grossman AB . The dangers of unopposed beta‐adrenergic blockade in phaeochromocytoma. Postgrad Med J 71: 58‐59, 1995.
 196. Sheps SG , Jiang NS , Klee GG . Diagnostic evaluation of pheochromocytoma. Endocrinol Metab Clin North Am 17: 397‐414, 1988.
 197. Shtukmaster S , Schier MC , Huber K , Krispin S , Kalcheim C , Unsicker K . Sympathetic neurons and chromaffin cells share a common progenitor in the neural crest in vivo. Neural Dev 8: 12, 2013.
 198. Sibal L , Jovanovic A , Agarwal SC , Peaston RT , James RA , Lennard TW , Bliss R , Batchelor A , Perros P . Phaeochromocytomas presenting as acute crises after beta blockade therapy. Clin Endocrinol (Oxf) 65: 186‐190, 2006.
 199. Sinclair AM , Isles CG , Brown I , Cameron H , Murray GD , Robertson JW . Secondary hypertension in a blood pressure clinic. Arch Intern Med 147: 1289‐1293, 1987.
 200. Singh RJ , Eisenhofer G . High‐throughput, automated, and accurate biochemical screening for pheochromocytoma: Are we there yet? Clin Chem 53: 1565‐1567, 2007.
 201. Sinning C , Keller T , Abegunewardene N , Kreitner KF , Munzel T , Blankenberg S . Tako‐Tsubo syndrome: Dying of a broken heart? Clin Res Cardiol 99: 771‐780, 2010.
 202. Sjoerdsma A. Catecholamine metabolism in patients with pheochromocytoma. Pharmacol Rev 11: 374‐378, 1959.
 203. Sjoerdsma A , King WM , Leeper L , Udenfriend S . Demonstration of the 3‐methoxy analog of norepinephrine in man. Science 127: 876, 1957.
 204. Sloand EM , Thompson BT . Propranolol‐induced pulmonary edema and shock in a patient with pheochromocytoma. Arch Intern Med 144: 173‐174, 1984.
 205. Smithwick RH , Greer WE , Et Al . Pheochromocytoma; a discussion of symptoms, signs and procedures of diagnostic value. N Engl J Med 242: 252‐257, 1950.
 206. Solanki KK , Bomanji J , Moyes J , Mather SJ , Trainer PJ , Britton KE . A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta‐iodobenzylguanidine (MIBG). Nucl Med Commun 13: 513‐521, 1992.
 207. Spes C , Knape A , Mudra H . Recurrent tako‐tsubo‐like left ventricular dysfunction (apical ballooning) in a patient with pheochromocytoma ‐ a case report. Clin Res Cardiol 95: 307‐311, 2006.
 208. Stolk RF , Bakx C , Mulder J , Timmers HJ , Lenders JW . Is the excess cardiovascular morbidity in pheochromocytoma related to blood pressure or to catecholamines? J Clin Endocrinol Metab 98: 1100‐1106, 2013.
 209. Stratakis CA , Carney JA . The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney‐Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 266: 43‐52, 2009.
 210. Streeten DH , Anderson GH, Jr . Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. Am J Hypertens 9: 760‐769, 1996.
 211. Taieb D , Neumann H , Rubello D , Al‐Nahhas A , Guillet B , Hindie E . Modern nuclear imaging for paragangliomas: Beyond SPECT. J Nucl Med 53: 264‐274, 2012.
 212. Taieb D , Timmers HJ , Hindie E , Guillet BA , Neumann HP , Walz MK , Opocher G , De Herder WW , Boedeker CC , De Krijger RR , Chiti A , Al‐Nahhas A , Pacak K , Rubello D , European Association of Nuclear M. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 39: 1977‐1995, 2012.
 213. Timmers HJ , Chen CC , Carrasquillo JA , Whatley M , Ling A , Eisenhofer G , King KS , Rao JU , Wesley RA , Adams KT , Pacak K . Staging and functional characterization of pheochromocytoma and paraganglioma by 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography. J Natl Cancer Inst 104: 700‐708, 2012.
 214. Timmers HJ , Chen CC , Carrasquillo JA , Whatley M , Ling A , Havekes B , Eisenhofer G , Martiniova L , Adams KT , Pacak K . Comparison of 18F‐fluoro‐L‐DOPA, 18F‐fluoro‐deoxyglucose, and 18F‐fluorodopamine PET and 123I‐MIBG scintigraphy in the localization of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 94: 4757‐4767, 2009.
 215. Timmers HJ , Eisenhofer G , Carrasquillo JA , Chen CC , Whatley M , Ling A , Adams KT , Pacak K . Use of 6‐[18F]‐fluorodopamine positron emission tomography (PET) as first‐line investigation for the diagnosis and localization of non‐metastatic and metastatic phaeochromocytoma (PHEO). Clin Endocrinol (Oxf) 71: 11‐17, 2009.
 216. Timmers HJ , Pacak K , Huynh TT , Abu‐Asab M , Tsokos M , Merino MJ , Baysal BE , Adams KT , Eisenhofer G . Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. J Clin Endocrinol Metab 93: 4826‐4832, 2008.
 217. Timmers HJ , Taieb D , Pacak K . Current and future anatomical and functional imaging approaches to pheochromocytoma and paraganglioma. Horm Metab Res 44: 367‐372, 2012.
 218. Tischler AS. Pheochromocytoma and extra‐adrenal paraganglioma: Updates. Arch Pathol Lab Med 132: 1272‐1284, 2008.
 219. Tischler AS . Paraganglia. In: Mills SE , editor. Histology for Pathologists. 4th ed: Lippincott, Williams & Wilkins, Philadelphia; 2012. pp. 1277‐1299.
 220. Tischler AS , Kimura N , Mcnicol AM . Pathology of pheochromocytoma and extra‐adrenal paraganglioma. Ann N Y Acad Sci 1073: 557‐570, 2006.
 221. Tolis G , Kuchel O . The multiple faces of the pheochromocytoma. Can Med Assoc J 116: 337‐338, 1977.
 222. Tsujimoto G , Manger WM , Hoffman BB . Desensitization of beta‐adrenergic receptors by pheochromocytoma. Endocrinology 114: 1272‐1278, 1984.
 223. Tulen JH , Boomsma F , Man In't Veld AJ . Cardiovascular control and plasma catecholamines during rest and mental stress: Effects of posture. Clin Sci (Lond) 96: 567‐576, 1999.
 224. Unsicker K , Huber K , Schober A , Kalcheim C . Resolved and open issues in chromaffin cell development. Mech Dev 130: 324‐329, 2013.
 225. Unsicker K , Huber K , Schutz G , Kalcheim C . The chromaffin cell and its development. Neurochem Res 30: 921‐925, 2005.
 226. Vaclavik J , Stejskal D , Lacnak B , Lazarova M , Jedelsky L , Kadalova L , Janosova M , Frysak Z , Vlcek P . Free plasma metanephrines as a screening test for pheochromocytoma in low‐risk patients. J Hypertens 25: 1427‐1431, 2007.
 227. Van Eps RG , Van den Meiracker AH , Boomsma F , Man In't Veld AJ , Schalekamp MA . Diurnal variation of blood pressure in patients with catecholamine‐producing tumors. Am J Hypertens 7: 492‐497, 1994.
 228. Van Nederveen FH , Gaal J , Favier J , Korpershoek E , Oldenburg RA , De Bruyn EM , Sleddens HF , Derkx P , Riviere J , Dannenberg H , Petri BJ , Komminoth P , Pacak K , Hop WC , Pollard PJ , Mannelli M , Bayley JP , Perren A , Niemann S , Verhofstad AA , De Bruine AP , Maher ER , Tissier F , Meatchi T , Badoual C , Bertherat J , Amar L , Alataki D , Van Marck E , Ferrau F , Francois J , De Herder WW , Peeters MP , Van Linge A , Lenders JW , Gimenez‐Roqueplo AP , De Krijger RR , Dinjens WN . An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: A retrospective and prospective analysis. Lancet Oncol 10: 764‐771, 2009.
 229. Van Vliet PD , Burchell HB , Titus JL . Focal myocarditis associated with pheochromocytoma. N Engl J Med 274: 1102‐1108, 1966.
 230. Vander Heiden MG , Cantley LC , Thompson CB . Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324: 1029‐1033, 2009.
 231. Viskochil D , Buchberg AM , Xu G , Cawthon RM , Stevens J , Wolff RK , Culver M , Carey JC , Copeland NG , Jenkins NA , Et Al . Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62: 187‐192, 1990.
 232. Vollmer RR. Selective neural regulation of epinephrine and norepinephrine cells in the adrenal medulla – cardiovascular implications. Clin Exp Hypertens 18: 731‐751, 1996.
 233. Vollmer RR , Baruchin A , Kolibal‐Pegher SS , Corey SP , Stricker EM , Kaplan BB . Selective activation of norepinephrine‐ and epinephrine‐secreting chromaffin cells in rat adrenal medulla. Am J Physiol 263: R716‐721, 1992.
 234. Waguespack SG , Rich T , Grubbs E , Ying AK , Perrier ND , Ayala‐Ramirez M , Jimenez C . A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 95: 2023‐2037, 2010.
 235. Waldmeier PC , Antonin KH , Feldtrauer JJ , Grunenwald C , Paul E , Lauber J , Bieck P . Urinary excretion of O‐methylated catecholamines, tyramine and phenyl‐ethylamine by volunteers treated with tranylcypromine and CGP 11305 A. Eur J Clin Pharmacol 25: 361‐368, 1983.
 236. Werbel SS , Ober KP . Pheochromocytoma. Update on diagnosis, localization, and management. Med Clin North Am 79: 131‐153, 1995.
 237. Willemsen JJ , Ross HA , Lenders JW , Sweep FC . Stability of urinary fractionated metanephrines and catecholamines during collection, shipment, and storage of samples. Clin Chem 53: 268‐272, 2007.
 238. Willemsen JJ , Ross HA , Wolthers BG , Sweep CG , Kema IP . Evaluation of specific high‐performance liquid‐chromatographic determinations of urinary metanephrine and normetanephrine by comparison with isotope dilution mass spectrometry. Ann Clin Biochem 38: 722‐730, 2001.
 239. Willemsen JJ , Sweep CG , Lenders JW , Ross HA . Stability of plasma free metanephrines during collection and storage as assessed by an optimized HPLC method with electrochemical detection. Clin Chem 49: 1951‐1953, 2003.
 240. Wong DL , Lesage A , Siddall B , Funder JW . Glucocorticoid regulation of phenylethanolamine N‐methyltransferase in vivo. FASEB J 6: 3310‐3315, 1992.
 241. Wong DL , Siddall BJ , Ebert SN , Bell RA , Her S . Phenylethanolamine N‐methyltransferase gene expression: Synergistic activation by Egr‐1, AP‐2 and the glucocorticoid receptor. Brain Res Mol Brain Res 61: 154‐161, 1998.
 242. Yamaguchi S , Shibata H , Miyashita K , Kurihara I , Murai‐Takeda A , Mitsuishi Y , Motosugi Y , Saito Y , Hayashi K , Itoh H . Gastrointestinal pseudo‐obstruction after debulking surgery of malignant pheochromocytoma, improved by intravenous administration of alpha‐adrenergic receptor blocker, phentolamine. Hypertens Res 33: 753‐754, 2010.
 243. Zelinka T , Petrak O , Turkova H , Holaj R , Strauch B , Krsek M , Vrankova AB , Musil Z , Duskova J , Kubinyi J , Michalsky D , Novak K , Widimsky J . High incidence of cardiovascular complications in pheochromocytoma. Horm Metab Res 44: 379‐384, 2012.
 244. Zelinka T , Strauch B , Pecen L , Widimsky J, Jr . Diurnal blood pressure variation in pheochromocytoma, primary aldosteronism and Cushing's syndrome. J Hum Hypertens 18: 107‐111, 2004.
 245. Zelinka T , Strauch B , Petrak O , Holaj R , Vrankova A , Weisserova H , Pacak K , Widimsky J, Jr . Increased blood pressure variability in pheochromocytoma compared to essential hypertension patients. J Hypertens 23: 2033‐2039, 2005.
 246. Zhuang Z , Yang C , Lorenzo F , Merino M , Fojo T , Kebebew E , Popovic V , Stratakis CA , Prchal JT , Pacak K . Somatic HIF2A gain‐of‐function mutations in paraganglioma with polycythemia. N Engl J Med 367: 922‐930, 2012.
 247. Zuckerman‐Levin N , Tiosano D , Eisenhofer G , Bornstein S , Hochberg Z . The importance of adrenocortical glucocorticoids for adrenomedullary and physiological response to stress: A study in isolated glucocorticoid deficiency. J Clin Endocrinol Metab 86: 5920‐5924, 2001.

Related Articles:

Adrenergic Regulation of Vascular Smooth Muscle
Catecholamines in the Brain and Responses to Environmental Challenges
Endocrine Hypertension
Synthesis, Storage, and Secretion of Adrenal Medullary Hormones: Physiology and Pathophysiology

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Jacques W. M. Lenders, Graeme Eisenhofer. Pathophysiology and Diagnosis of Disorders of the Adrenal Medulla: Focus on Pheochromocytoma. Compr Physiol 2014, 4: 691-713. doi: 10.1002/cphy.c130034