eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

VIPomas

Author: Daniel S Tung, MD, Fellow in Endocrinology, Department of Internal Medicine, Baylor College of Medicine
Coauthor(s): Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center; Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Dec 18, 2008

Introduction

Background

The symptoms of VIPoma were described in 1958, when Verner and Morrison reported on 2 patients with a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA).1  These patients eventually succumbed to the condition as a result of dehydration and renal failure, despite attempted intravenous hydration. In 1970, Said and Mutt extracted the putative hormone causing WDHA from pig gut tissue.2 In 1973, Bloom causally linked this hormone to WDHA, in a report on 6 patients with watery diarrhea resulting from pancreatic tumors associated with raised plasma levels of this hormone. The extirpated tumors from these cases were found to contain large amounts of what is now known as vasoactive intestinal polypeptide (VIP).

Related eMedicine topics:
 Neoplasms of the Endocrine Pancreas
Pancreas, Islet Cell Tumors
VIPoma
WDHA Syndrome

Pathophysiology

Found mainly in the pancreas, VIPomas are neuroendocrine tumors that secrete vasoactive intestinal polypeptide (VIP) autonomously.

VIP has a molecular weight of 3381, consists of 28 amino acids, and belongs to the secretin-glucagon family. The VIP gene is located on chromosome 6. VIP is normally expressed in the central nervous system and in the neurons of the gastrointestinal, respiratory, and urogenital tracts, where it functions as a neurotransmitter. VIP regulates the synthesis, secretion, and action of other neuroendocrine hormones; it also regulates cytokines and chemokines. Deficiency of VIP leads to developmental and behavioral abnormalities, including impaired circadian rhythms, in animal models.3  Overexpression of VIP causes diarrhea and cancer, and overexpression of VIP receptors promotes cancerous growth. In the gastrointestinal tract, VIP is largely responsible for the relaxation of vascular and nonvascular smooth muscle and for water and electrolyte secretion. VIP is released in response to gut distension by food.

VIP is a potent stimulator of gut cyclic adenosine monophosphate (cAMP) production, which leads to massive secretion of water and electrolytes (mainly potassium). VIP resembles secretin, which stimulates the secretion of alkaline pancreatic juices. In the stomach, VIP inhibits histamine- and pentagastrin-stimulated acid secretion. Like glucagon, VIP stimulates lipolysis and glycogenolysis and has an inotropic effect on the myocardium. It also has anti-inflammatory properties and modulates the immune system. 

VIPomas arise from the pancreas in 90% of cases, but they may also be found in periganglionic tissue or at other sites, including the colon, bronchus, adrenal glands, and liver, especially in children.4  These tumors are almost always solitary, with less than 5% of cases being multicentric. VIPomas are usually greater than 3 cm at the time of diagnosis and are found primarily in the body and tail of the pancreas.

Approximately 60-80% of VIPomas are malignant and have metastasized at the time of diagnosis. Metastasis occurs most frequently in the liver, but it may also occur in the lymph nodes, lung, or kidneys.5 Approximately 5% of VIPomas are associated with multiple endocrine neoplasia type 1 (MEN 1) syndrome. Conversely, 17% of patients with MEN 1 develop VIPomas at some stage of their disease. Approximately 10% of neuroendocrine tumors of the gastrointestinal tract (except carcinoids) are VIPomas.

Related eMedicine topics:
Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 1
Wermer Syndrome (MEN Type 1)

Frequency

International

The incidence of new cases of VIPoma is 0.05-0.5 per million people per year.

Mortality/Morbidity

  • Morbidity from untreated WDHA syndrome is associated with long-standing dehydration and with electrolyte and acid-base disturbances, which may cause chronic renal failure.6
  • Death results from renal failure or cardiac arrest caused by volume depletion, hypokalemia, and severe acid-base disturbances. 

Sex

  • The male-to-female ratio for VIPoma is approximately 1:1.   

Age

  • Peak incidence occurs in the fifth decade of life, but VIPomas may occur in any age group, including in young children and elderly persons.

Clinical

History

  • The onset of VIPoma is insidious.
  • The dominant symptom is profuse diarrhea despite fasting; this symptom may persist for years before the diagnosis is established. Diarrhea may be episodic initially, but it becomes continuous as the tumor progresses. Stool volumes are typically profound, with volumes greater than 3 L per day in 70% of cases. The stool is typically odorless and tea-colored, without blood or mucus.
  • The loss of water, sodium, and chloride may lead to volume depletion, dehydration, and exhaustion among patients who are unable to replace fluid and electrolyte losses. Weight loss and even renal failure have been reported in some patients. 
  • Excretion of large amounts of potassium and bicarbonate in the stool causes hypokalemia and non–anion gap acidosis. Hypokalemia may present as muscle cramps and/or weakness.
  • Abdominal discomfort or bloating has been reported. 
  • Facial flushing involved one third of patients from a 31-case series in China.7 Other studies have also reported facial flushing, but without a reported frequency.  
  • One reported case in China involved periodic backache and a rash involving the chest, back, and upper limb. These 2 symptoms occurred before or after the diarrhea, worsened over 6 years, and resolved after surgical resection.

Physical

  • Volume depletion may lead to tachycardia, decreased skin turgor, and documented weight loss.
  • Because of marked fecal loss of potassium, patients may have muscle weakness on examination.
  • Patients may present with a mildly distended abdomen.
  • Hepatomegaly may be detected if liver metastasis has occurred. 
  • Facial flushing may be seen because of the vasodilatory effects of vasoactive intestinal polypeptide.
  • An electrocardiogram may reveal QRS widening and T-wave flattening if hypokalemia is severe.

Causes

Point mutations on chromosome 11 of the MEN1 gene have been identified in cases where VIPomas are part of MEN 1 syndrome and, to a lesser extent, in sporadic tumors.

More on VIPomas

Overview: VIPomas
Differential Diagnoses & Workup: VIPomas
Treatment & Medication: VIPomas
Follow-up: VIPomas
Multimedia: VIPomas
References
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References

  1. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. Sep 1958;25(3):374-80. [Medline].

  2. Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. Sep 18 1970;169(951):1217-8. [Medline].

  3. Aton SJ, Colwell CS, Harmar AJ, et al. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci. Apr 2005;8(4):476-83. [Medline]. [Full Text].

  4. Doherty GM. Rare endocrine tumours of the GI tract. Best Pract Res Clin Gastroenterol. Oct 2005;19(5):807-17. [Medline].

  5. Ayub A, Zafar M, Abdulkareem A, et al. Primary hepatic vipoma. Am J Gastroenterol. Jun 1993;88(6):958-61. [Medline].

  6. Grier JF. WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome: clinical features, diagnosis, and treatment. South Med J. Jan 1995;88(1):22-4. [Medline].

  7. Peng SY, Li JT, Liu YB, et al. Diagnosis and treatment of VIPoma in China: (case report and 31 cases review) diagnosis and treatment of VIPoma. Pancreas. Jan 2004;28(1):93-7. [Medline].

  8. de Herder WW. Biochemistry of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. Mar 2007;21(1):33-41. [Medline].

  9. Sofka CM, Semelka RC, Marcos HB, et al. MR imaging of metastatic pancreatic VIPoma. Magn Reson Imaging. 1997;15(10):1205-8. [Medline].

  10. Schillaci O, Corleto VD, Annibale B, et al. Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in gastro-entero pancreatic tumours. Ital J Gastroenterol Hepatol. Oct 1999;31 Suppl 2:S186-9. [Medline].

  11. Cesani F, Ernst R, Walser E, et al. Tc-99m sestamibi imaging of a pancreatic VIPoma and parathyroid adenoma in a patient with multiple type I endocrine neoplasia. Clin Nucl Med. Jun 1994;19(6):532-4. [Medline].

  12. Ruiz-Tovar J, Priego P, Martínez-Molina E, et al. Pancreatic neuroendocrine tumours. Clin Transl Oncol. Aug 2008;10(8):493-7. [Medline].

  13. Ghaferi AA, Chojnacki KA, Long WD, et al. Pancreatic VIPomas: subject review and one institutional experience. J Gastrointest Surg. Feb 2008;12(2):382-93. [Medline].

  14. Akerstrom G, Hellman P. Surgery on neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab. Mar 2007;21(1):87-109. [Medline].

  15. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer. Sep 1 2008;113(5):921-9. [Medline].

  16. Bramley PN, Lodge JP, Losowsky MS, et al. Treatment of metastatic Vipoma by liver transplantation. Clin Transplant. Oct 1990;4(5 part 1):276-8; discussion 279. [Medline].

  17. Soga J, Yakuwa Y. Vipoma/diarrheogenic syndrome: a statistical evaluation of 241 reported cases. J Exp Clin Cancer Res. Dec 1998;17(4):389-400. [Medline].

  18. Cellier C, Yaghi C, Cuillerier E, et al. Metastatic jejunal VIPoma: beneficial effect of combination therapy with interferon-alpha and 5-fluorouracil. Am J Gastroenterol. Jan 2000;95(1):289-93. [Medline].

  19. Jensen RT. Pancreatic endocrine tumors: recent advances. Ann Oncol. 1999;10 Suppl 4:170-6. [Medline].

  20. Mansour JC, Chen H. Pancreatic endocrine tumors. J Surg Res. Jul 2004;120(1):139-61. [Medline].

  21. Marks IN, Bank S, Louw JH. Islet cell tumor of the pancreas with reversible watery diarrhea and achlorhydria. Gastroenterology. Apr 1967;52(4):695-708. [Medline].

  22. Remme CA, de Groot GH, Schrijver G. Diagnosis and treatment of VIPoma in a female patient. Eur J Gastroenterol Hepatol. Jan 2006;18(1):93-9. [Medline].

  23. Robichon A, Marie JC. Selective photolabeling of high and low affinity binding sites for vasoactive intestinal peptide (VIP): evidence for two classes of covalent VIP-receptor complexes in intestinal cell membranes. Endocrinology. Mar 1987;120(3):978-85. [Medline].

  24. Shan L, Nakamura Y, Nakamura M, et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Lab Invest. Apr 1998;78(4):471-5. [Medline].

  25. Swift PG, Bloom SR, Harris F. Watery diarrhoea and ganglioneuroma with secretion of vasoactive intestinal peptide. Arch Dis Child. Nov 1975;50(11):896-9. [Medline]. [Full Text].

  26. Tennvall J, Ljungberg O, Ahren B, et al. Radiotherapy for unresectable endocrine pancreatic carcinomas. Eur J Surg Oncol. Feb 1992;18(1):73-6. [Medline].

  27. Verner JV, Morrison AB. Endocrine pancreatic islet disease with diarrhea. Report of a case due to diffuse hyperplasia of nonbeta islet tissue with a review of 54 additional cases. Arch Intern Med. Mar 1974;133(3):492-9. [Medline].

  28. Virgolini I, Kurtaran A, Leimer M, et al. Location of a VIPoma by iodine-123-vasoactive intestinal peptide scintigraphy. J Nucl Med. Sep 1998;39(9):1575-9. [Medline]. [Full Text].

  29. Warner RR. Enteroendocrine tumors other than carcinoid: a review of clinically significant advances. Gastroenterology. May 2005;128(6):1668-84. [Medline].

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Further Reading

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Keywords

VIPoma, pancreatic cancer, cancer pancreas, pancreatic cancer symptoms, neuroendocrine tumor, neuroendocrine carcinoma, pancreatic tumor, pancreas tumor, multiple endocrine neoplasia, pancreas tumors, pancreatic tumors, Verner-Morrison syndrome, pancreatic cholera, watery diarrhea-hypokalemia-achlorhydria syndrome, WDHA syndrome, vasoactive intestinal polypeptide, VIP, pancreatic endocrine tumor, multiple endocrine neoplasia type 1 syndrome, MEN 1

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Contributor Information and Disclosures

Author

Daniel S Tung, MD, Fellow in Endocrinology, Department of Internal Medicine, Baylor College of Medicine
Daniel S Tung, MD is a member of the following medical societies: American Association of Clinical Endocrinologists and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Frederick H Ziel, MD, Chief of Endocrinology, Kaiser Permanente Woodland Hills, Associate Professor, Department of Internal Medicine, Division of Diabetes and Endocrinology, University of California at Los Angeles
Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC
Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Nutrition, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Informatics Association, American Society for Bone and Mineral Research, American Society of Law Medicine and Ethics, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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