Background
The syndrome of watery diarrhea, hypokalemia, and achlorhydria (ie, WDHA syndrome) is a rare condition characterized by severe, watery diarrhea resulting from the oversecretion of vasoactive intestinal peptide (VIP) from non–beta pancreatic islet cells. [1, 2] Patients usually have elevated VIP levels and have a history of frequent hospitalizations for dehydration and/or hypokalemia. Because this condition resembles cholera, Matsumoto et al suggested the alternative term pancreatic cholera. [3] (See Etiology, Presentation, Treatment, and Medication.)
A small percentage of patients with WDHA syndrome also have hypercalcemia, hyperglycemia, hypochlorhydria, and flushing. Multiple endocrine neoplasia type 1 (MEN-1) syndrome (ie, Wermer syndrome) is present in a very small subset of patients with hypercalcemia and WDHA syndrome. (See Etiology.)
VIP-secreting tumors are rare, affecting 0.05-0.2 per million adults, and these tumors most often originate in the pancreas (approximately 95%). With these pancreatic primaries, around 50% have metastasized at the time of diagnosis of the tumor. [4] Other ectopic primary sites of VIP production include the liver and jejunum in about 10% of patients with WDHA syndrome, and, on occasion, other tumors can deteriorate into VIP-producing tumors (eg, pheochromocytomas [5, 6] ). In children, the VIPoma syndrome is usually associated with a ganglioneuroma or ganglioneuroblastoma; cases related to pheochromocytoma and mastocytoma have also been reported in children. [7]
The goals of therapy are prolongation of life, control of symptoms, and correction of the electrolyte abnormalities. Surgical resection offers the only chance for cure, but the tumor not uncommonly has 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. Liver transplantation has been performed in an uncontrolled manner, and results appear to demonstrate a potential role, although the scarcity of the resource limits this modality’s availability. [8, 9]
When managed medically, 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. (See Treatment and Medication.)
In contrast to pancreatic carcinoma treatment, an aggressive surgical approach in WDHA syndrome appears warranted in light of improved 5-year survival rates with palliative debulking of tumors. Selected patients with extensive hepatic metastases have been treated with orthotopic liver transplantation with excellent results, although experience remains limited. [8, 9]
Patient education
Patients should be advised to seek treatment at a center with expertise in this field. Patients need to be aware that dehydration and acute renal failure are significant complications and that they must seek hospitalization if they are not doing well at home. [10]
Pathophysiology
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. [4] The peptide is secreted, usually from non–beta islet pancreatic cells in response to food containing fat, proteins, and alcohol; it has a half-life of 1-2 minutes. 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 the gallbladder and intestinal circular muscle contraction.
Exogenous administration of VIP has many pharmacologic 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 the 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, in contrast 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 messenger ribonucleic acid (mRNA). Furthermore, both peptides are co-localized in enteric neurons and VIPomas, with an identical tissue distribution and similar pharmacologic 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 with secretory diarrhea who have VIP levels within the reference range, other agents that have been implicated as the diarrhea’s cause include calcitonin, gastric inhibitory peptide, pancreatic polypeptide, prostaglandins, neurotensin, and secretin.
Etiology
Genetics
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, including the following:
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MEN1 gene
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p16/MTS1 tumor suppressor gene
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DPC4/Smad 4 gene: A tumor suppressor gene located on chromosome arm 18q21 [11]
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Amplification of the HER2/neu proto-oncogene
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Deletions in chromosome 1
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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.
Mutations in MEN1
Unlike mutations in the 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.
Mutations in p16/MTS1
Studies provide evidence that p16/MTS1 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.
RAF/mitogen-activated protein kinase pathway
A report by Tannapfel et al studied the frequency of the BRAF and k-ras-2 mutations in primary neuroendocrine gastroenteropancreatic tumors. [12] (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 may have a causative role in the development of neuroendocrine tumors, independent of BRAF or k-ras-2 mutation.
Malignant degeneration
A significant proportion of VIPomas develop malignant degeneration, although predicting which tumors will follow such a course is currently not possible. The hope is that in the future, the molecular aberrations in this subset of patients may be identified, allowing earlier and more aggressive treatment.
Epidemiology
United States data
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.
International data
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.
Sex- and age-related demographics
A slight female preponderance in WDHA syndrome appears to exist. The age at diagnosis for individuals with the syndrome has a bimodal distribution, ranging from 10 months to 9 years in children and 32-81 years in adults.
Prognosis
There are no prognostic models for WDHA syndrome. In general, the extent of disease, presence of metastases, and whether the disease is able to be resected are the more powerful prognostic factors. A proper assessment of the prognosis for WDHA syndrome is limited because of the rarity of the condition. Patients with resectable disease have a 5-year survival rate as high as 79%, while patients with incompletely resected or unresectable disease have a 5-year survival rate of only 28%. Note that these patients represent only a very small proportion (5-9%) of patients with metastatic disease.
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.
A paper from the Mayo Clinic, Jacksonville, reported 5- and 10-year survival rates for malignant tumors of 88% and 25%, respectively.
Soga and Yakuwa also observed encouraging long-term outcomes in an evaluation of 241 patients with WDHA syndrome. [13] The 5-year survival rate was 94.4% in 46 patients without metastases and 59.6% in 43 patients with metastatic disease. [13]
If treatment for WDHA syndrome is unsuccessful, patients often have a poor quality of life from diarrhea and its complications.
Complications
Complications of WDHA syndrome may include the following:
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Acute renal failure associated with hypokalemia: This is the most common cause of death in WDHA syndrome; the typical renal lesion observed in these patients is a vacuolar tubular nephropathy
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Dehydration
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Non–anion gap metabolic acidosis
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Perianal skin irritation from severe diarrhea
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Poor quality of life from severe diarrhea
