Evolution of clinical ideas about Zollinger-Ellison syndrome

Cite item

Full Text


The paper gives the current views of the diagnosis and treatment of Zollinger-Ellison syndrome (ZES). It underlines the importance of including ZES in differential diagnosis in patient with frequently recurrent and standard-dose proton pump inhibitor therapy-resistant erosive and ulcerative lesions of the upper gastrointestinal tract. It provides the current stepwise algorithm for the diagnosis of the pathology in question. Relevant and promising treatments in patients with ZES are considered.

Full Text

Эволюция клинических представлений о синдроме Золлингера-Эллисона. - Аннотация. Представлены современные взгляды на диагностику и лечение синдрома Золлингера-Эллисона (СЗЭ). Подчеркивается важность включения СЗЭ в круг дифференциальной диагностики у пациентов с часто рецидивирующими и резистентными к терапии стандартными дозами ингибиторов протонного насоса эрозивно-язвенными поражениями верхних отделов желудочно-кишечного тракта. Представлен современный поэтапный алгоритм диагностики обсуждаемой патологии. Рассмотрены актуальные и перспективные методы лечения больных с СЗЭ.


  1. Zollinger R.M., Ellison E.H. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg 1955; 142 (4): 709-723.
  2. Gregory R.A., Tracy H.J., French J.M., Sircus W. Extraction of a gastrin-like substance from a pancreatic tumour in a case of Zollinger-Ellison syndrome. Lancet 1960; 1: 1045-1048.
  3. Гастроэнтерология: национальное руководство. Под ред. В.Т. Ивашкина, Т.Л. Лапиной. М: ГЭОТАР-Медиа 2008; 706.
  4. Jensen R.T. (orton J.A. Endocrine tumors of the pancreas and gastrointestinal tract. In: Feldman M., Friedman L.S., Brandt L.J. (eds). Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 9th ed. chap 32. Philadelphia, Pa: Saunders Elsevier 2010.
  5. Маев И.В., Кучерявый Ю.А. Болезни поджелудочной железы. В 2-х томах. М: Медицина, Шико 2008; 976.
  6. Benya R.V., Metz D.C., Venzon D.J. et al. Zollinger-Ellison syndrome can be the initial endocrine manifestation in patients with multiple endocrine neoplasia-type I. Am J Med 1994; 97 (5): 436-44.
  7. Gibril F., Schumann M., Pace A. et al. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004; 83 (1): 43-83.
  8. Shepherd J.J. The natural history of multiple endocrine neoplasia type 1. Highly uncommon or highly unrecognized? Arch Surg 1991; 126 (8): 935-952.
  9. Roy P.K., Venzon D.J., Shojamanesh H. et al. Zollinger-Ellison syndrome. Clinical presentation in 261 patients. Medicine (Baltimore). 2000; 79 (6): 379-411.
  10. Эндокринология. Национальное руководство. Краткое издание. Под ред. И.И. Дедова, Г.А. Мельниченко. М: ГЭОТАР-Медиа 2011; 752.
  11. Capurso G., Festa S., Valente R. et al. Molecular pathology and genetics of pancreatic endocrine tumours. J Mol Endocrinol 2012; 49 (1): 37-50.
  12. Rindi G., Bordi C. Endocrine tumours of the gastrointestinal tract: aetiology, molecular pathogenesis and genetics. Best Pract Res Clin Gastroenterol 2005; 19 (4): 519-534.
  13. Duerr E.M., Chung D.C. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab 2007; 21: 1-14.
  14. Corleto V.D., Delle Fave G., Jensen R.T. Molecular insights into gastrointestinal neuroendocrine tumors: Importance and recent advances. Dig Liver Dis 2002; 34: 668-680.
  15. Serrano J., Goebel S.U., Peghini P.L. et al. Alterations in the p16INK4a/CDKN2A tumor suppressor gene in gastrinomas. J Clin Endocrinol Metab 2000; 85 (11): 4146-4156.
  16. Bartsch D., Hahn S.A., Danichevski K.D. et al. Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene 1999; 18 (14): 2367-2371.
  17. Evers B.M., Rady P.L., Sandoval K. et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg 1994; 219 (6): 596-601.
  18. Goebel S.U., Iwamoto M., Raffeld M. et al. Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness. Cancer Res 2002; 62 (13): 3702-3710.
  19. Peghini P.L., Iwamoto M., Raffeld M. et al. Overexpression of epidermal growth factor and hepatocyte growth factor receptors in a proportion of gastrinomas correlates with aggressive growth and lower curability. Clin Cancer Res 2002; 8 (7): 2273-2285.
  20. Furukawa M., Raffeld M., Mateo C. et al. Increased expression of insulin-like growth factor I and/or its receptor in gastrinomas is associated with low curability, increased growth, and development of metastases. Clin Cancer Res 2005; 11 (9): 3233-3242.
  21. Larsson C., Skogseid B., Oberg K. et al. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature 1988; 332: 85-87.
  22. Lemos M.C., Thakker R.V. Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene. Hum Mutat 2008; 29 (1): 22-32.
  23. Yang Y., Hua X. In search of tumor suppressing functions of menin. Mol Cell Endocrinol 2007; 265-266: 34-41.
  24. Hashimoto M., Kyo S., Hua X. et al. Role of menin in the regulation of telomerase activity in normal and cancer cells. Int J Oncol 2008; 33 (2): 333-340.
  25. Karnik S.K., Hughes C.M., Gu X. et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci USA 2005; 102: 14659-14664.
  26. Гуревич Л.Е. Диагностика нейроэндокринных опухолей желудочно-кишечного тракта. Практ онкол 2005; 4: 193-201.
  27. Jensen R.T., Niederle B., Mitry E. et al. Gastrinoma (duodenal and pancreatic). Neuroendocrinology 2006; 84: 173-182.
  28. Gurevich L., Kazantseva I., Isakov V. et al. The analysis of immunophenotype of gastrin-producing tumors of pancreas and gastrointestinal tract. Cancer 2003; 98 (9): 1967-1976.
  29. Ellison E.C., Johnson J.A. The Zollinger-Ellison syndrome: a comprehensive review of historical, scientific, and clinical considerations. Curr Probl Surg 2009; 46: 13-16.
  30. Ito T., Cadiot G., Jensen R.T. Diagnosis of Zollinger-Ellison syndrome: increasingly difficult. World J Gastroenterol 2012; 18 (39): 5495-5503.
  31. Ellison E.H., Wilson S.D. The Zollinger-Ellison syndrome: Re-appraisal and evaluation of 260 registered cases. Ann Surg 1964; 160: 512-530.
  32. Stabile B.E., Morrow D.J., Passaro J.E. The gastrinoma triangle: operative implications. Am J Surg 1984; 147: 25-31.
  33. Norton J.A., Fraker D.L., Alexander H.R. et al. Surgery increases survival in patients with gastrinoma. Ann Surg 2006; 244: 410-419.
  34. Weber H.C., Venzon D.J., Lin J.T. et al. Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: A prospective long-term study. Gastroenterology 1995; 108: 1637-1649.
  35. Yu F., Venzon D.J., Serrano J. et al. Prospective study of the clinical course, prognostic factors and survival in patients with longstanding Zollinger-Ellison syndrome. J Clin Oncol 1999; 17: 615-630.
  36. Weber H.C., Venzon D.J., Jensen R.T., Metz D.C. Studies on the interrelation between Zollinger-Ellison syndrome, Helicobacter pylori and proton pump inhibitor therapy. Gastroenterology 1997; 112: 84-91.
  37. Miller L.S., Vinayek R., Frucht H. et al. Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology 1990; 98: 341-346.
  38. Hoffmann K.M., Furukawa M., Jensen R.T. Duodenal neuroendocrine tumors: Classification, functional syndromes, diagnosis and medical treatment. Best Pract Res Clin Gastroenterol 2005; 19: 675-697.
  39. Tomassetti P., Campana D., Piscitelli L. et al. Treatment of Zollinger-Ellison syndrome. World J Gastroenterol 2005; 11 (35): 5423-5432.
  40. Jensen R.T., Berna M.J., Bingham M.D. Norton J.A. Inherited pancreatic endocrine tumor syndromes: Advances in molecular pathogenesis, diagnosis, management and controversies. Cancer 2008; 113 (Suppl): 1087-1043.
  41. Jensen R.T. Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med 1998; 243: 477-488.
  42. Arnold R. Diagnosis and differential diagnosis of hypergastrinemia. Wien Klin Wochenschr 2007; 119: 564-569.
  43. Banasch M., Schmitz F. Diagnosis and treatment of gastrinoma in the era of proton pump inhibitors. Wien Klin Wochenschr 2007; 119: 573-578.
  44. Berna M.J., Hoffmann K.M., Serrano J. et al. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore) 2006; 85: 295-330.
  45. Osefo N., Ito T., Jensen R.T. Gastric acid hypersecretory states: recent insights and advances. Curr Gastroenterol Rep 2009; 11 (6): 433-441.
  46. Berna M.J., Hoffmann K.M., Long S.H. et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore) 2006; 85 (6): 331-364.
  47. Roy P.K., Venzon D.J., Feigenbaum K.M. et al. Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis - a prospective NIH study of 235 patients and a review of 984 cases in the literature. Medicine (Baltimore) 2001; 80 (3): 189-222.
  48. Ardill J.E., Erikkson B. The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut. Endocr Relat Cancer 2003; 10 (4): 459-462.
  49. Sahani D.V., Bonaffini P.A., Fernández-Del Castillo C. et al. Gastroenteropancreatic neuroendocrine tumors: role of imaging in diagnosis and management. Radiology 2013; 266 (1): 38-61.
  50. Tan E.H., Tan C.H. Imaging of gastroenteropancreatic neuroendocrine tumors. World J Clin Oncol 2011; 2 (1): 28-43.
  51. Sundin A., Garske U., Orlefors H. Nuclear imaging of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 2007; 21: 69-85.
  52. McLean A.M., Fairclough P.D. Endoscopic ultrasound in the localisation of pancreatic islet cell tumours. Best Pract Res Clin Endocrinol Metab 2005; 19: 177-193.
  53. Assalia A., Gagner M. Laparoscopic pancreatic surgery for islet cell tumors of the pancreas. World J Surg 2004; 28: 1239-1247.
  54. Lorenz K., Dralle H. Surgical treatment of sporadic gastrinoma. Wien Klin Wochenschr 2007; 119: 597-601.
  55. Norton J.A., Alexander H.R., Fraker D.L. et al. Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases or survival in patients with Zollinger-Ellison syndrome (ZES)? Ann Surg 2004; 239: 617-626.
  56. Triponez F., Goudet P., Dosseh D. et al. Is surgery beneficial for MEN1 patients with small ≤2 cm) (onfunctioning pancreaticoduodenal endocrine tumor? An analysis of 65 patients from the GTE. World J Surg 2006; 30: 654-662.
  57. Nieto J.M., Pisegna J.R. The role of proton pump inhibitors in the treatment of Zollinger-Ellison syndrome. Expert Opin Pharmacother 2006; 7 (2): 169-175.
  58. Shojamanesh H., Gibril F., Louie A. et al. Prospective study of the antitumor efficacy of long-term octreotide treatment in patients with progressive metastatic gastrinoma. Cancer 2002; 94: 331-343.
  59. Faiss S., Pape U.F., Bohmig M. et al. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors - the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol- 2003; 21: 2689-2696.
  60. Plockinger U., Wiedenmann B. Management of metastatic endocrine tumours. Best Pract Res Clin Gastroenterol 2005; 19: 553-576.
  61. O'Toole D., Hentic O., Corcos O., Ruszniewski P. Chemotherapy for gastro-enteropancreatic endocrine tumours. Neuroendocrinology 2004; 80 (Suppl 1): 79-84.
  62. Touzios J.G., Kiely J.M., Pitt S.C. et al. Neuroendocrine hepatic metastases: Does aggressive management improve survival? Ann Surg 2005; 241: 776-783.
  63. Elvin A., Skogseid B., Hellman P. Radiofrequency ablation of neuroendocrine liver metastases. Abdom Imag 2005; 30: 427-434.
  64. Paganelli G., Zoboli S., Cremonesi M. et al. Receptor-mediated radiotherapy with 90Y-DOTAD-Phe1-Tyr3-octreotide. Eur J Nucl Med 2001; 28: 426-434.
  65. Kwekkeboom D.J., de Herder W.W., Kam B.L. et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26 (13): 2124-2130.
  66. Kulke M.H., Lenz H.J., Meropol N.J. et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008; 26: 3403-3410.
  67. Wiedmann M.W., Mössner J. Safety and efficacy of sunitinib in patients with unresectable pancreatic neuroendocrine tumors. Clin Med Insights Oncol 2012; 6: 381-393.
  68. Peng L., Schwarz R.E. Pancreatic neuroendocrine tumors: signal pathways and targeted therapies. Curr Mol Med 2013; 13 (3): 333-339.
  69. Ito T., Igarashi H., Uehara H. et al. Pharmacotherapy of Zollinger-Ellison syndrome. Expert Opin Pharmacother 2013; 14 (3): 307-321.

Copyright (c) 2014 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Address of the Editorial Office:

  • Novij Zykovskij proezd, 3, 40, Moscow, 125167

Correspondence address:

  • Alabyan Street, 13/1, Moscow, 127055, Russian Federation

Managing Editor:

  • Tel.: +7 (926) 905-41-26
  • E-mail: e.gorbacheva@ter-arkhiv.ru


© 2018-2021 "Consilium Medicum" Publishing house

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies