Skip to main content

Advertisement

Log in

Flushing in (neuro)endocrinology

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Cutaneous flushing is a common presenting complaint in endocrine disorders. The pathophysiology of flushing involves changes in cutaneous blood flow triggered by multiple intrinsic factors that are either related to physiology or disease. Flushing can be divided into episodic or persistent causes. Episodic flushing is mediated by the release of endogenous vasoactive mediators or medications, while persistent flushing results in a fixed facial erythema with telangiectasia and cyanosis due to slow-flowing deoxygenated blood in large cutaneous blood vessels. The differential diagnosis of cutaneous flushing in neuroendocrine disorders is limited, yet encompasses a broad spectrum of benign and malignant entities, including carcinoid syndrome, pheochromocytoma, Cushing syndrome, medullary thyroid cancer, and pancreatic neuroendocrine tumors. In this review, we provide a concise and up-to-date discussion on the differential diagnosis and approach of flushing in neuroendocrinology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Image 1
Image 2

Similar content being viewed by others

References

  1. Ikizoglu G. Red face revisited: flushing. Clin Dermatol. 2014;32:800–8.

    Article  PubMed  Google Scholar 

  2. Ray D, Williams G. Pathophysiological causes and clinical significance of flushing. Br J Hosp Med. 1993;50:594–8.

    CAS  PubMed  Google Scholar 

  3. Aldrich LB, Moattari AR, Vinik AI. Distinguishing features of idiopathic flushing and carcinoid syndrome. Arch Intern Med. 1988;148:2614–8.

    Article  CAS  PubMed  Google Scholar 

  4. Stratakis CA, Mastorakos G, Mitsiades NS, Mitsiades CS, Chrousos GP. Skin manifestations of Cushing disease in children and adolescents before and after the resolution of hypercortisolemia. Pediatr Dermatol. 1998;15(4):253–8.

  5. Metcalfe DD. Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc. 2000;21:21–4.

    Article  CAS  PubMed  Google Scholar 

  6. Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis, the American Academy of Allergy, Asthma & Immunology, and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137(1):35–45.

    Article  PubMed  Google Scholar 

  7. De Filippis EA, Sabet A, Sun MR, Garber JR. Pemberton’s sign: explained nearly 70 years later. J Clin Endocrinol Metab. 2014;99(6):1949–54.

    Article  PubMed  Google Scholar 

  8. Jukic T, Kusic Z. Pemberton’s sign in patient with substernal goiter. J Clin Endocrinol Metab. 2010;95(9):4175.

    Article  CAS  PubMed  Google Scholar 

  9. Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensive review. Acta Oncol. 2003;42:672–92.

    Article  PubMed  Google Scholar 

  10. Feldman JM. Carcinoid tumors and the carcinoid syndrome. Curr Probl Surg. 1989;26(12):835–85.

    Article  CAS  PubMed  Google Scholar 

  11. Singh S, Asa SL, Dey C, Kennecke H, Laidley D, Law C, et al. Diagnosis and management of gastrointestinal neuroendocrine tumors: an evidence-based Canadian consensus. Cancer Treat Rev. 2016;47:32–45.

    Article  PubMed  Google Scholar 

  12. Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, et al.; North American Neuroendocrine Tumor Society (NANETS). The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the Jejunum, Ileum, Appendix, and Cecum. Pancreas. 2010;39(6):753–66.

  13. Liu EH, Solorzano CC, Katznelson L, Vinik AI, Wong R, Randolph G. AACE/ACE disease state clinical review: diagnosis and management of midgut carcinoids. Endocr Pract. 2015;21:534–45.

    Article  PubMed  PubMed Central  Google Scholar 

  14. O’Toole D, Kianmanesh R, Caplin M. ENETS 2016 consensus guidelines for the management of patients with digestive neuroendocrine tumors: an update. Neuroendocrinology. 2016;103(2):117–8.

    Article  PubMed  Google Scholar 

  15. Kulke MH, Shah MH, Benson 3rd AB, Bergsland E, Berlin JD, Blaszkowsky LS, et al. Neuroendocrine tumors, version 1.2015. J Natl Compr Canc Netw. 2015;13(1):78–108.

    CAS  PubMed  Google Scholar 

  16. Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendto K, Chan JA, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557–77.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Crocetti E, Paci E. Malignant carcinoids in the USA, SEER 1992–1999. An epidemiological study with 6830 cases. Eur J Cancer Prev. 2003;12:191–4.

    Article  CAS  PubMed  Google Scholar 

  18. Ganim RB, Norton JA. Recent advances in carcinoid pathogenesis, diagnosis and management. Surgical Oncol. 2000;9:173–9.

    Article  CAS  Google Scholar 

  19. Koch CA, Azumi N, Furlong MA, Jha RC, Kehoe TE, Trowbridge CH, et al. Carcinoid syndrome caused by an atypical carcinoid of the uterine cervix. J Clin Endocrinol Metab. 1999;84(11):4209–13.

    Article  CAS  PubMed  Google Scholar 

  20. Vinik AI, Gonin J, England BG, Jackson T, McLeod MK, Cho K. Plasma substance-P in neuroendocrine tumors and idiopathic flushing: the value of pentagastrin stimulation tests and the effects of somatostatin analog. J Clin Endocrinol Metab. 1990;70(6):1702–9.

    Article  CAS  PubMed  Google Scholar 

  21. Balks HJ, Conlon JM, Creutzfeldt W, Stockmann F. Circulating bradykinin-like immunoreactivity and the pentagastrin-induced carcinoid flush. Clin Endocrinol. 1988;29(2):141–51.

    Article  CAS  Google Scholar 

  22. Parson HK, Harati H, Cooper D, Vinik AI. Role of prostaglandin D2 and the autonomous nervous system in niacin-induced flushing. J Diabetes. 2013;5(1):59–67.

    Article  CAS  PubMed  Google Scholar 

  23. Belch JJ, Small M, McKenzie F, Hill PA, Lowe GD, McIntyre DE, et al. DDAVP stimulates prostacyclin production. Thromb Haemost. 1982;47(2):122–3.

    CAS  PubMed  Google Scholar 

  24. Feldman JM, O’Dorisio TM. Role of neuropeptides and serotonin in the diagnosis of carcinoid tumors. Am J Med. 1986;81:41–8.

    Article  CAS  PubMed  Google Scholar 

  25. Eriksson B, Oberg K, Stridsberg M. Tumor markers in neuroendocrine tumors. Digestion. 2000;62 Suppl 1:33–8.

    Article  CAS  PubMed  Google Scholar 

  26. Nehar D, Lombard-Bohas C, Olivieri S, et al. Interest of chromogranin A for diagnosis and follow-up of endocrine tumours. Clin Endocrinol. 2004;60:644–52.

    Article  CAS  Google Scholar 

  27. Ruszniewski P, Ish-Shalom S, Wymenga M, O’Toole D, Arnold R, Tomassetti P, et al. Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28-day prolonged-release formulation of lanreotide. Neuroendocrinology. 2004;80:244–51.

    Article  CAS  PubMed  Google Scholar 

  28. Pokuri VK, Fong MK, Iyer R. Octreotide and lanreotide in gastroenteropancreatic neuroendocrine tumors. Curr Oncol Rep. 2016;18(1):7.

    Article  PubMed  Google Scholar 

  29. Woltering EA, Wright AE, Stevens MA, Wang YZ, Boudreaux JP, Mamikunian G, et al. Development of effective prophylaxis against intraoperative carcinoid crisis. J Clin Anesth. 2016;32:189–93.

    Article  CAS  PubMed  Google Scholar 

  30. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–42.

    Article  CAS  PubMed  Google Scholar 

  31. Chen H, Sippel RS, O’Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39:775–83.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kopetschke R, Slisko M, Kilisli A, Tuschy U, Wallaschofski H, Fassnacht M, et al. Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol. 2009;161(2):355–61.

    Article  CAS  PubMed  Google Scholar 

  33. 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. Nouv Presse Med. 1981;10(11):869–72.

    CAS  PubMed  Google Scholar 

  34. Metz SA, Halter JB, Porte Jr D, Robertson RP. Suppression of plasma catecholamines and flushing by clonidine in man. J Clin Endocrinol Metab. 1978;46:83–90.

    Article  CAS  PubMed  Google Scholar 

  35. McGuinness ME, Talbert RL. Pharmacologic stress testing: experience with dipyridamole, adenosine, and dobutamine. Am J Hosp Pharm. 1994;51:328–46. quiz 404–5.

    CAS  PubMed  Google Scholar 

  36. Mouri T, Takahashi K, Sone M, et al. Calcitonin gene-related peptide-like immunoreactivities in pheochromocytomas. Peptides. 1989;10:201–4.

    Article  CAS  PubMed  Google Scholar 

  37. Herrera MF, Stone E, Deitel M, Asa SL. Pheochromocytoma producing multiple vasoactive peptides. Arch Surg. 1992;127:105–8.

    Article  CAS  PubMed  Google Scholar 

  38. Smith SL, Slappy AL, Fox TP, Scolapio JS. Pheochromocytoma producing vasoactive intestinal peptide. Mayo Clin Proc. 2002;77:97–100.

    Article  PubMed  Google Scholar 

  39. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Matsuo H, Eto T. Isolation and characterization of peptides which act on rat platelets, from a pheochromocytoma. Biochem Biophys Res Commun. 1992;185:134–41.

    Article  CAS  PubMed  Google Scholar 

  40. Letizia C, Rossi G, Cerci S. Adrenomedullin and endocrine disorders. Panminerva Med. 2003;45:241–51.

    CAS  PubMed  Google Scholar 

  41. Nicholls MG, Lainchbury JG, Lewis LK, et al. Bioactivity of adrenomedullin and proadrenomedullin N-terminal 20 peptide in man. Peptides. 2001;22:1745–52.

    Article  CAS  PubMed  Google Scholar 

  42. Gläsker S, Neumann HPH, Koch CA, Vortmeyer AO. Von Hippel-Lindau Disease. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, Koch C, McLachlan R, New M, Rebar R, Singer F, Vinik A, Weickert MO, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. 2015 Jul 11.

  43. Wells Jr SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Koch CA. Molecular pathogenesis of MEN2-associated tumors. Fam Cancer. 2005;4(1):3–7.

    Article  PubMed  Google Scholar 

  45. Brauer VF, Scholz GH, Neumann S, Lohmann T, Paschke R, Koch CA. RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed? Endocr Pract. 2004;10(1):5–9.

    Article  PubMed  Google Scholar 

  46. Lepage C, Bouvier AM, Phelip JM, Hatem C, Vernet C, Faivre J. Incidence and management of malignant digestive endocrine tumours in a well defined French population. Gut. 2004;53:549–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19:1727–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kimura W, Kuroda A, Morioka Y. Clinical pathology of endocrine tumors of the pancreas. Analysis of autopsy cases. Dig Dis Sci. 1991;36:933–42.

    Article  CAS  PubMed  Google Scholar 

  49. Miehle K, Tannapfel A, Lamesch P, Borte G, Schenker E, Kluge R, et al. Pancreatic neuroendocrine tumor with ectopic adrenocorticotropin production upon second recurrence. J Clin Endocrinol Metab. 2004;89(8):3731–6.

    Article  CAS  PubMed  Google Scholar 

  50. Nilubol N, Freedman EM, Quezado MM, Patel D, Kebebew E. Pancreatic neuroendocrine tumor secreting vasoactive intestinal peptide and dopamine with pulmonary emboli: a case report. J Clin Endocrinol Metab. 2016;101(10):3564–7.

    Article  PubMed  Google Scholar 

  51. Baur AD, Pavel M, Prasad V, Denecke T. Diagnostic imaging of pancreatic neuroendocrine neoplasms (pNEN): tumor detection, staging, prognosis, and response to treatment. Acta Radiol. 2016;57(3):260–70.

    Article  PubMed  Google Scholar 

  52. Stratakis CA. Diagnosis and clinical genetics of Cushing syndrome in pediatrics. Endocrinol Clin N Am. 2016;45:311–28.

    Article  Google Scholar 

  53. Robyn JA, Koch CA, Montalto J, Yong A, Warne GL, Batch JA. Cushing’s syndrome in childhood and adolescence. J Paediatr Child Health. 1997;33(6):522–7.

    Article  CAS  PubMed  Google Scholar 

  54. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86:117–23.

    CAS  PubMed  Google Scholar 

  55. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol. 1994;40:479–84.

    Article  CAS  Google Scholar 

  56. Afshari A, Ardeshirpour Y, Lodish MB, et al. Facial plethora: modern technology for quantifying an ancient clinical sign and its use in Cushing syndrome. J Clin Endocrinol Metab. 2015;100:3928–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. McReynolds SM, Freidberg SR, Guay AT, Lee AK, Pazianos AG, Hussain SF. Hot flushes in men with pituitary adenoma. Surg Neurol. 1995;44:14–7. discussion 7–8.

    Article  CAS  PubMed  Google Scholar 

  58. Myers BM, Miralles GD, Taylor CA, Gastineau DA, Pisani RJ, Talley NJ. POEMS syndrome with idiopathic flushing mimicking carcinoid syndrome. Am J Med. 1991;90:646–8.

    Article  CAS  PubMed  Google Scholar 

  59. Niepomniszcze H, Amad RH. Skin disorders and thyroid diseases. J Endocrinol Invest. 2001;24:628–38.

    Article  CAS  PubMed  Google Scholar 

  60. Zouboulis CC, Liakou AI. Images in clinical medicine. Flashing, pulsating angioma. N Engl J Med. 2012;366(24):e36.

    Article  PubMed  Google Scholar 

  61. Seo I, Bargo PR, Kollias N. Simultaneous assessment of pulsating and total blood in inflammatory skin lesions using functional diffuse reflectance spectroscopy in the visible range. J Biomed Opt. 2010;15(6):060507.

    Article  PubMed  Google Scholar 

  62. Sassarini J, Lumsden MA. Vascular function and cardiovascular risk factors in women with severe flushing. Maturitas. 2015;80:379–83.

    Article  PubMed  Google Scholar 

  63. Crandall CJ, Manson JE, Hohensee CM, Horvath S, Wactawski-Wende J, LeBlanc, E, et al. Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women’s Health Initiative Study. Menopause. Published ahead of print.

  64. Krause MS, Nakaijma ST. Hormonal and nonhormonal treatment of vasomotor symptoms. Obstet Gyncecol Clin N Am. 2015;42:163–79.

    Article  Google Scholar 

  65. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, et al. Treatment of symptoms of the menopause: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(11):3975–4011.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Fady Hannah-Shmouni or Christian A. Koch.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hannah-Shmouni, F., Stratakis, C.A. & Koch, C.A. Flushing in (neuro)endocrinology. Rev Endocr Metab Disord 17, 373–380 (2016). https://doi.org/10.1007/s11154-016-9394-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-016-9394-8

Keywords

Navigation