In 1957, Priest and Alexander reported a patient with peptic ulcer, diarrhea, hypokalemia, and an islet cell tumor.1 However, the first complete description of the syndrome of watery diarrhea, hypokalemia, and achlorhydria (ie, WDHA syndrome) was provided by Verner and Morrison in 1958.2 This rare condition is characterized by severe watery diarrhea caused by oversecretion of vasoactive intestinal peptide (VIP) from non–beta pancreatic islet cells. Patients usually have elevated VIP levels and require frequent hospitalizations for dehydration and/or hypokalemia. Because this condition resembles cholera, Matsumoto and colleagues (1966) suggested the alternative term pancreatic cholera.3
A small percentage of patients also have hypercalcemia, hyperglycemia, hypochlorhydria, and flushing. Multiple endocrine neoplasia type 1 (MEN-1) syndrome (ie, Werner syndrome) may be associated in a subset of patients with hypercalcemia. These tumors virtually always are intrapancreatic, although ectopic primary sites, such as the liver and jejunum, occur in about 10% of patients. In children, the VIPoma syndrome is caused by either a ganglioneuroma or ganglioneuroblastoma.
The goals of therapy include prolongation of survival, control of symptoms, and correction of electrolyte abnormalities. Surgical resection offers the only chance for cure, but the tumor has often spread to regional lymph nodes and/or to the liver at the time of diagnosis. Palliative treatment consists of surgical resection of the primary tumor with regional lymph node dissection and, if possible, resection of hepatic metastases. The use of somatostatin analogs has become the mainstay of therapy for symptom control. Other palliative measures include systemic chemotherapy, hepatic arterial embolization with or without chemotherapy, and the use of interferon alfa.
Unlike pancreatic carcinoma, aggressive intervention appears warranted in light of improved 5-year survival rates from the palliative effect of tumor debulking. Selected patients with extensive hepatic metastases have been treated with orthotopic liver transplantation with excellent results, although experience remains limited.
The pathophysiology of WDHA syndrome is best understood by reviewing the properties of VIP. VIP is a 28–amino acid regulatory peptide that is widely distributed throughout the gastrointestinal tract and brain. It has a half-life of 1-2 minutes and was first isolated by Said in 1970. The peptide is secreted, usually from non–beta islet pancreatic cells in response to food containing fat, proteins, and alcohol. It enters the portal circulation and is metabolized by the liver. VIP relaxes smooth muscles, resulting in a decrease in lower esophageal sphincter pressure, relaxation of the gastric antrum and body, and inhibition of gallbladder and intestinal circular muscle contraction.
Exogenous administration of VIP has many pharmacological actions, including positive inotropic action on the heart; vasodilatation; increase in intestinal water and electrolyte secretion; inhibition of gastrin and gastric acid secretion; and stimulation of pancreatic secretion, lipolysis, and glycolysis.
Occasionally, patients with WDHA syndrome may have elevated levels of peptide histidine methionine (PHM), a 27–amino acid peptide originally derived from porcine intestine (ie, peptide histidine isoleucine [PHI]). The distinctive features of PHI are the presence of histidine and isoleucine at the N and C terminals as opposed to most gastrointestinal peptides, which have amidated C terminal amino acids.
Although PHI/PHM acts via a different receptor on target cells, it has numerous similarities to VIP. For example, both are derived from a common precursor polypeptide and are encoded from the same mRNA. Furthermore, both peptides are co-localized in enteric neurons and VIPomas, with an identical tissue distribution and similar pharmacological activities. Although PHI infusions cause intestinal secretion and may cause WDHA syndrome, PHI is 32 times less potent than VIP. In the small percentage of patients who have secretory diarrhea with VIP levels within the reference range, other agents that have been implicated include calcitonin, gastric inhibitory peptide, pancreatic polypeptide, prostaglandins, neurotensin, and secretin.
Pancreatic endocrine tumors are uncommon, with a prevalence of less than 10 cases per million population. VIPomas are a rare subtype of pancreatic islet cell tumors, with an estimated incidence of 0.05-0.2 per million population.
Pancreatic endocrine tumors are uncommon, with a prevalence of less than 10 cases per million population. For example, data from a referral center in Ireland on the relative frequency of these tumors demonstrated an average incidence of 3.6 cases per million population per year. Insulinomas were the most common pancreatic endocrine tumor, occurring 8 times more frequently than VIPomas.
Most patients with WDHA syndrome have hepatic metastases at the time of diagnosis, but these tumors usually grow slowly. Therefore, despite advanced disease, patients can have extended survival. A report from Florida on 18 patients noted a mean survival of 3.5 years, with the longest disease-free survival being 15 years and the longest overall survival being 15 years. If treatment is unsuccessful, patients often have a poor quality of life from diarrhea and its complications.
A slight female preponderance appears to exist.
The age at diagnosis has a bimodal distribution, ranging from 10 months to 9 years in children and 32-81 years in adults.
Diarrhea is the most common symptom and occurs in at least 89% of patients. Although typically described as painless, the diarrhea may initially be episodic and can be associated with abdominal cramps. Diarrhea eventually becomes voluminous (ie, stool output >3 L/d in 80% of patients). It is secretory in nature and persists with fasting. It is often described as having the appearance of weak tea.
Weight loss has been reported in 72% of patients.
Abdominal pain is a common symptom, occurring in 50% of patients.
Flushing is observed in 20% of patients and has been attributed to the vasodilatory effects of VIP. However, in human studies, prolonged VIP infusion leads to tachyphylaxis, which may explain why only a minority of patients develop flushing.
Physical examination may reveal signs of volume depletion and chronic ill health. No specific physical findings exist except for flushing, which is observed in 20% patients and is believed to be due to the vasodilatory properties of VIP.
WDHA syndrome occurs in 6% of patients with MEN-1 syndrome. Significant advances have been made in elucidating the molecular pathogenesis of WDHA syndrome and other pancreatic endocrine tumors. Studies provide evidence for the importance of several genes, such as the (1) MEN1 gene; (2) p16/MTS1 tumor suppressor gene; (3) DPC4/Smad 4 gene, a tumor suppressor gene located on chromosome arm 18q24; (4) amplification of the HER2/neu proto-oncogene; (5) deletions in chromosome 1; and (6) a possible tumor suppressor gene on chromosome arm 3p.
Alterations in the MEN1 gene and the p16/MTS1 1 tumor suppressor gene are particularly important in tumor pathogenesis.
The inherited MEN-1 syndrome is caused by mutations in a 10-exon gene that is located on chromosome arm 11q13, which encodes for a protein that interacts with AP1 transcription factor Jun D.
The loss of heterozygosity at the MEN1 locus occurs in nearly 93% of sporadic pancreatic endocrine tumors, with mutations in the MEN1 gene locus reported in 27-39% of sporadic tumors.
Unlike mutations in the multiple endocrine neoplasia type 2 (MEN-2) gene (ie, MEN2), MEN1 gene mutations in sporadic tumors appear to be distributed throughout the 9 coding exons and are believed to be an early event in tumorigenesis.
The frequency and allelic mutations of the MEN1 gene in pancreatic endocrine tumors associated with MEN-1 were analyzed in a study. Allelic deletions of the MEN1 locus were described in 43% of these tumors, and mutations of the MEN1 gene were noted in 13% of these tumors. In most tumor groups, the frequency of allelic deletions at band 11q13 was 2-3 times higher than the frequency of gene mutations. Other factors, such as tumor suppressor genes on band 11q13, may be involved in tumorigenesis of these neoplasms.
Studies provide evidence that p16/MTS1 tumor suppressor gene alterations located on chromosome arm 9p21 occur in a significant percentage of pancreatic endocrine tumors. These inactivating mutations result in loss of cell cycle inhibition and reportedly occur in nearly 92% of these tumors.
A significant proportion of VIPomas develop malignant degeneration; however, currently, predicting which tumors will follow such a course is not possible. Hopefully, in the future, the molecular aberrations in this subset of patients may be identified, allowing earlier and more aggressive treatment.
A report by Tannapfel et al studied the frequency of the BRAF and k-ras-2 mutations in primary neuroendocrine gastroenteropancreatic tumors.4 (The BRAF gene, one of the human isoforms of RAF, is activated by ras, leading to cooperative effects in cells responsive to growth factor signals). Although their results suggested BRAF mutations do not have a role in tumorigenesis of neuroendocrine tumors, the authors hypothesized that activation of the RAF/mitogen-activated protein kinase pathway might have a causative role in the development of neuroendocrine tumors, independent of BRAF or k-ras-2 mutation.