WDHA Syndrome 

Updated: Dec 01, 2016
Author: Richard K Gilroy, MBBS, FRACP; Chief Editor: Praveen K Roy, MD, AGAF 

Overview

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 and colleagues (1966) suggested the alternative term pancreatic cholera. (See Etiology, Presentation, Treatment, and Medication.)[3]

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 80%). With these pancreatic primaries, around 50% have metastasized at the time of diagnosis of the tumor. 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, phaeochromocytomas[4, 5] ). In children, the VIPoma syndrome is caused by either a ganglioneuroma or ganglioneuroblastoma.

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 and uncontrolled manner, and results appear to demonstrate a potential role, although the scarcity of the resource limits this modality’s availability.[6, 7]

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.[6, 7]

Complications

Complications of WDHA syndrome may include the following:

  • 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

  • Dehydration

  • Non–anion gap metabolic acidosis

  • Perianal skin irritation from severe diarrhea

  • Poor quality of life from severe diarrhea

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.

Etiology

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. 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 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.

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:

  • MEN1 gene

  • p16/MTS1 tumor suppressor gene

  • DPC4/Smad 4 gene - A tumor suppressor gene located on chromosome arm 18q24

  • Amplification of the HER2/neu proto-oncogene

  • Deletions in chromosome 1

  • 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.[8] (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

Occurrence in the United States

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 occurrence

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 (1998) also observed encouraging long-term outcomes in an evaluation of 241 patients with WDHA syndrome.[9] The 5-year survival rate was 94.4% in 46 patients without metastases and 59.6% in 43 patients with metastatic disease.[9]

If treatment for WDHA syndrome is unsuccessful, patients often have a poor quality of life from diarrhea and its complications.

 

Presentation

History and Physical Examination

History

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 >3L daily 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. In human studies, however, prolonged VIP infusion leads to tachyphylaxis, which may explain why only a minority of patients develop flushing.

Physical

Physical examination may reveal signs of volume depletion, malnutrition, muscle weakness, and chronic history of ill health. The muscle weakness can be associated with elevated creatine phosphokinase (CPK) and as a consequence of hypokalemic rhabdomyolysis.[10] No specific physical findings exist for WDHA syndrome, with even the flushing, which is observed in 20% of patients, occurring in many other conditions. It is believed the flushing is due to the vasodilatory properties of VIP. On occasion, the liver may be palpable and nodular, reflecting hepatic metastatic disease.

 

DDx

Diagnostic Considerations

Delay in diagnosis is not uncommon in WDHA syndrome because of the rarity of the condition and because the initial presentation may masquerade as other disease processes. The following conditions can be considered in the differential diagnosis of WDHA syndrome:

  • Surreptitious use of laxatives/medications

  • Infective diarrhea

  • Diabetic diarrhea

  • Carcinoid syndrome

  • Medullary carcinoma of the thyroid

  • Chronic idiopathic diarrhea or pseudopancreatic cholera syndrome

  • Peptide histidine isoleucine or peptide histidine methionine hypersecretion

  • Congenital secretory diarrhea

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of WDHA syndrome requires evidence of a state of hormonal excess. The definitive diagnosis requires (1) the presence of secretory diarrhea, (2) elevated serum VIP levels, and (3) the identification of a pancreatic endocrine tumor.

Patients with WDHA syndrome may initially have an indolent course, or the disease may masquerade as other, more common conditions, leading to a delay in the diagnosis. The disease can easily be missed if the diagnosis is based solely on immunocytochemistry, because pancreatic endocrine tumors frequently synthesize multiple peptides.

Imaging

Conventional imaging studies (ie, transabdominal ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI], selective angiography) can detect fewer than 60% of primary tumors and can fail to reveal metastases in more than 30% of cases.

Positron emission tomography (PET) scanning may gain greater importance in the future. This modality is more sensitive than CT scanning for tumor localization, and, when used with 18F-fluorodeoxyglucose, it may be possible to predict the presence of malignancy in poorly differentiated tumors.

Staging

Unlike insulinomas, VIPomas are generally large in size at the time of clinical presentation, and 50-90% of VIPomas are reported to be malignant. Tumor staging is assessed by a combination of conventional imaging techniques, somatostatin receptor scintigraphy (SRS), and, occasionally, endoscopic ultrasonography (EUS).

Laboratory Studies

Lab studies used in the diagnosis and evaluation of WDHA syndrome include the following:

  • Electrolytes - Hypokalemia is present in 90-100% of patients and is secondary to the heavy losses of potassium in the diarrheal fluid; patients often have coexisting hypomagnesemia and non–anion gap metabolic acidosis, reflecting the severity of the diarrhea

  • Serum glucose - Hyperglycemia occurs in 25-50% of VIPomas secondary to the glycogenolytic effect of VIP in the liver

  • Serum chromogranin A - Studies demonstrate that serum chromogranin A levels may be useful for assessing tumor progression, relapse, and tumor burden

  • Serum gastrin and gastric acid - Serum gastrin measurement and tests of gastric acid secretion are no longer performed routinely; Verner and Morrison proposed the term watery diarrhea, hypokalemia, and hypochlorhydria (WDHH) because as many as 76% of patients have hypochlorhydria and not achlorhydria[2]

  • Stool electrolytes - The diarrhea in WDHA syndrome is secretory; the stool osmotic gap typically is less than 50 mEq/L

  • Urine - The urine should be tested to detect surreptitious laxative abuse (eg, phenolphthalein)

Serum calcium

Hypercalcemia occurs in 25-76% of patients with WDHA syndrome. Nearly 6% of these patients have associated MEN-1 syndrome with resultant hypercalcemia secondary to hyperparathyroidism.

A retrospective study reported that pancreatic endocrine tumors causing hypercalcemia were almost always malignant.

Although VIP has osteolytic activity, neither this mechanism nor elevated parathyroid hormone–binding protein levels in these patients have been established conclusively as the cause of hypercalcemia.

Fasting VIP levels

A VIP assay should be performed using a reliable radioimmunoassay at the time when the patient is symptomatic because, occasionally, the VIP levels may be within the reference range between episodes of diarrhea. The reference range for fasting levels in most laboratories is 0-190 pg/mL.

One study reported that provocative testing with pentagastrin produced an increase in VIP plasma levels of 81% over the basal values.

Stool volume

Virtually all patients have stool volumes greater than 700 mL daily, and nearly 80% have stool volumes greater than 3 L daily; volumes as high as 20 L/d have been reported in the literature. The diagnosis of WDHA is doubtful if the daily stool volume is less than 700mL. Note that the diarrhea persists despite fasting.

Scintigraphy

Somatostatin receptor scintigraphy with single-photon emission CT scanning

Somatostatin receptor scintigraphy (SRS) using (indium-diethylene triamine pentaacetic acid-phenylalanine [In-DTPA-DPhe]) octreotide is the most sensitive modality for identifying the primary tumor or metastatic disease.

SRS can be used to localize more than 90% of hepatic metastases. This technique also has the advantage of surveying the entire body and is more sensitive than a bone scan for detecting bone metastases.

Additional imaging with MRI and selective angiography is helpful for better defining the location of liver metastases and detecting small lesions that are not identified using SRS.

The results of SRS imaging should be interpreted in the clinical context of each patient because as many as 12% of SRS localizations can be falsely positive due to the presence of somatostatin receptors in normal tissues (eg, lymphocytes, thyroid tissue), as well as benign and malignant processes.

Studies on specificity are important, but, when interpreted within the correct clinical context, changes in treatment occurred in only 2.7% of patients who underwent SRS imaging.

Other

Iodine-123 (123 I) VIP scintigraphy has been used occasionally to identify tumors in patients with negative conventional imaging results and a negative finding on SRS scan. Northern blotting analysis reveals that VIP tumors possess somatostatin receptor subtype 3, which binds to somatostatin-14 and VIP with higher affinity than octreotide.[11]

According to Virgolini et al, gallium-68 (68 Ga)-labeled DOTA-Tyr(3)-octreotide has shown promising results in patients with pancreatic islet-cell tumors, based on high-affinity binding to the somatostatin receptor subtype 2.[11] When combined with PET scanning technology, a change in patient management was reported in up to 30% of patients.[12]

When labeled with yttrium-90 (90 Y) or lutetium-177 (177 Lu), some somatostatin analogues have been applied to patients in advanced stages of the disease. However, despite positive response data in 50% of patients, long-term results and survival rates are lacking.

Procedures

Endoscopic ultrasonography

Endoscopic ultrasonography (EUS) and SRS should be viewed as complementary studies when evaluating patients with WDHA syndrome.

If the results of SRS are negative and the patient is a surgical candidate, EUS is the next diagnostic procedure of choice for tumor localization because it is a sensitive method for detecting intrapancreatic tumors greater than 0.5cm. (VIPomas are almost entirely intrapancreatic.) Considerable expertise is required to acquire proficiency in this technique.

Additional imaging studies (eg, CT scanning, MRI) should be performed to exclude metastatic disease because EUS cannot be used to evaluate the liver or the upper abdomen adequately.

Intraoperative ultrasonography

This technique is recommended during surgical exploration because it may help to identify additional tumors that were not detected by other methods.

Selective angiography with hepatic venous sampling

This functional localization study is performed when SRS and EUS findings are negative. Hepatic venous samples should be obtained to determine hormonal gradients for tumor localization.

Histologic Findings

Pancreatic islet tumors that cause the WDHA syndrome are believed to originate from cells that are part of the neuroendocrine cell system. These tumors share cytochemical properties with carcinoid tumors, medullary carcinomas of the thyroid, melanomas, and pheochromocytomas.[13] They are collectively called amine precursor uptake and decarboxylation (APUD) tumors, or APUDomas.

With VIP-producing tumors, the histologic classification cannot be used to predict whether a tumor is benign or malignant. Malignancy is confirmed by identifying evidence of local invasion or metastatic spread.

These tumors are composed of sheets of small, round cells with uniform nuclei and cytoplasm. Mitotic figures are rare. Electron-dense granules are present that contain various products, including the following, that are characteristic of neuroendocrine differentiation:

  • Various amines

  • Neuron-specific enolase

  • Synaptophysins

  • Alpha and beta subunits of human chorionic gonadotrophin

  • Chromogranins A, B, and C

Immunocytochemistry reveals that these tumors not uncommonly stain positive for more than one hormone (approximately 50%).

 

Treatment

Approach Considerations

A multispecialty team composed of gastroenterologists, surgeons, radiologists, and oncologists should evaluate patients with WDHA syndrome.

Because of the rarity of VIPomas, most treatment recommendations are based on experience with pancreatic endocrine tumors. Most experts agree, however, that chemotherapy and interferon are indicated for patients with extensive metastatic disease. Even so, no agreement exists as to when such treatment should be started.

Management of WDHA syndrome is initially directed at treating symptoms related to hormone excess and, subsequently, at the tumor itself.

Resuscitation

Rehydration and correction of electrolyte and acid-base abnormalities are the most urgent steps in patient care. These can be lifesaving measures because the most common cause of death in these patients is acute renal failure associated with hypokalemia.

Octreotide

This is a long-acting, synthetic analog of somatostatin, which inhibits the release of VIP. Octreotide controls diarrhea in as many as 87% of patients; however, it reduces tumor size in a minority of patients who receive this treatment. Slow-release lanreotide and Sandostatin LAR are 2 longer-acting preparations that have been developed. Lanreotide is not available in the United States.

Antidiarrheals

Antidiarrheal medications, such as loperamide (Imodium), may be used in addition to octreotide in patients with breakthrough diarrhea.

Surgery

Surgical resection currently remains the cornerstone of successful treatment and provides the only hope for cure, because 50-60% of VIPomas are malignant. Therefore, all patients should be considered for exploratory laparotomy, with the exception of those with unresectable metastatic disease or with coexisting medical illnesses that preclude surgery.[14]

No surgical discussion is complete without reference to the role of liver transplantation in metastatic WDHA syndrome. Although this was first described in 1990, caution should be exercised when considering this modality of therapy as 5-year survival rates are only 50% and likely below that necessary for allocation of this scarce resource to being a standard of care.

Referrals

Patients should be advised to seek treatment at a major referral center that has expertise in this field. This is true particularly for the subset of patients with nonresectable disease who may be candidates for innovative, potentially lifesaving treatment protocols.

Chemotherapy

Streptozotocin and doxorubicin have emerged as the agents of choice. This is based primarily on a 1992 Eastern Cooperative Oncology Group (ECOG) study in which the combined use of these agents was associated with a 69% response rate, which was significantly higher than the 45% rate for the streptozotocin and 5-fluorouracil (5-FU) combination or the 30% response rate with chlorozotocin alone.

A review of 322 patients with metastatic disease treated with interferon alfa suggested that interferon has minimal tumoricidal activity, although it may stabilize tumor growth in 20-30% of patients.

A case report from France demonstrated major clinical improvement and regression in tumor size in a patient with jejunal VIPoma metastatic to the liver and peritoneum who was treated with a combination of interferon alfa and 5-FU.

Two important independent studies were published on the treatment of pancreatic neuroendocrine tumors. The investigational chemotherapies used were sunitinib and everolimus.[15, 16] Interestingly, although the overall response rates were 9.8% and 4.8%, respectively, the progression free survivals did alter significantly in favor of use of these agents (sunitinib = 11.4 mo vs 5.5 mo, p< 0.0001; everolimus 11 mo vs 4.6 mo, p< 0.001). For sunitinib, the most common grade 3 side effects were neutropenia and hypertension; with everolimus, the most common were stomatitis and fatigue. When specifically looking at the WDHA subgroup of pancreatic neoplasms, isolated case reports have suggested benefit.

Because of the rarity of WDHA syndrome and the incomplete understanding of its natural history, interpreting the effectiveness of chemotherapeutic interventions is difficult. In most clinical studies no clear survival benefit has been demonstrated.

Hepatic Artery Occlusion

Because most metastatic tumors in the liver are highly vascular and receive their blood supply through the hepatic artery, hepatic artery occlusion, with or without chemotherapy, may be used for palliative treatment in patients with a patent portal vein.

In one large study involving 111 patients with metastatic pancreatic endocrine tumors or carcinoid tumors, hepatic artery occlusion was associated with an objective beneficial response in 60% of patients. This rate increased to 80% of patients with the use of chemotherapy (ie, doxorubicin, dacarbazine, streptozotocin, 5-FU). In this study, chemoembolization was also associated with longer remission time (ie, 4 mo vs 18 mo).

Another study reported that chemoembolization with doxorubicin in iodized acid combined with gelatin or sponge particles resulted in improved symptoms in 68-100% of patients and a decrease in tumor size and/or hormone levels in 57-100% of patients.

A report by Case et al reported dramatic improvement in diarrhea following hepatic artery embolization in a patient with VIPoma and liver metastases who had not responded to surgical debulking, antidiarrheals, octreotide, and targeted radioisotope injections.[17]

Surgical Exploration

During exploration, the liver should be examined carefully for metastatic disease and an attempt should be made to resect isolated hepatic metastasis.

A careful examination of the entire pancreas requires an extended Kocher maneuver, with incision of the retroperitoneum on the superior and inferior aspects of the pancreatic body. Mobilization of the spleen may be required in order to examine the pancreatic tail, and the small bowel should be explored for extrapancreatic tumors.

Although VIPomas are usually intrapancreatic, nearly 10% tumors may have an ectopic location, occurring frequently along the ganglia of the autonomic nervous system. Intraoperative ultrasonography is recommended for identifying tumors that were not detected preoperatively and for establishing the presence of local invasion.

Pancreatectomy

Isolated tumors in the pancreatic body or tail should be removed by distal pancreatectomy, with or without splenectomy. Laparoscopic resection has been performed successfully in 2 patients, but experience remains limited.

More proximal tumors in the pancreatic head or body may be treated with enucleation rather than a Whipple procedure because these more radical techniques have not always been associated with better outcomes.

However, a review of 125 patients with neuroendocrine tumors by the Johns Hopkins Group revealed that the most common operation performed was pancreaticoduodenectomy (in 40% of patients). The most favorable outcome in this retrospective series was observed in patients with benign functional tumors and in those with completely resected malignant tumors.

Blind distal pancreatectomy

Blind distal pancreatectomy is a controversial procedure that is occasionally performed in symptomatic patients in whom no tumor is found, because of the 20% rate of islet cell hyperplasia in symptomatic patients.

Because other hormones may cause the diarrheagenic syndrome, one reasonable alternative when faced with this clinical conundrum is to close the abdomen and to perform further localizing studies.

Vaccination

Pneumococcal vaccination should be administered to all patients who undergo distal pancreatectomy and splenectomy.

Cytoreductive/Debulking Surgery

Although only a minority of patients with metastatic WDHA syndrome have resectable disease, whether patients whose illness is well controlled with medical therapy experience any long-term benefit from debulking surgery is unclear.

Indeed, while cytoreductive/debulking surgery may prolong life expectancy in certain patients, the natural history of metastatic WDHA syndrome is not well understood because of its rarity. As a result, no studies have evaluated cytoreductive surgery in a controlled, prospective manner to determine if survival is improved.

 

Medication

Medication Summary

Medications used to treat WDHA syndrome are divided into 2 categories: (1) antisecretory agents (eg, somatostatin and its synthetic derivatives) to treat secretory diarrhea and (2) chemotherapeutic agents. Conventional antidiarrheals are useful adjuncts to somatostatin analogs.

Preliminary data suggest that octreotide administered postoperatively is associated with a lower rate of complications, such as the development of pancreatic fistula. As a result, many surgical units routinely administer octreotide until the abdominal drains have been removed and the patient is eating normally.

Histamine 2 (H2)–receptor antagonists or proton pump inhibitors should be administered postoperatively to prevent hyperacidity, because rebound hyperchlorhydria is common in the postoperative period.

Surgery, however, is the only curative therapy. Neither somatostatin nor interferon alfa has significant tumoricidal properties, although they may have a tumorostatic effect.

Somatostatin Analogs

Class Summary

Antisecretory agents are used to treat the profuse secretory diarrhea of WDHA syndrome after patients have been resuscitated adequately. Although conventional antidiarrheals may play an adjunctive role, somatostatin derivatives are the most effective and cost-saving drugs for treating diarrhea in this disease.

Because VIPomas possess somatostatin receptors, somatostatin and its synthetic derivatives are used not only for tumor imaging but also to inhibit hormonal secretion of functional tumors. Radioactively labeled somatostatin derivatives currently are being investigated in the treatment of these tumors.

Octreotide (Sandostatin, Sandostatin LAR)

Octreotide is a synthetic analog of somatostatin with a half-life of approximately 100 minutes.

It is a potent physiologic inhibitor of numerous gastrointestinal (GI) functions, including the following:

These inhibitory effects, either alone or in combination, contribute to the antidiarrheal effect. Antisecretory agents improve diarrhea in as many as 86% of patients with WDHA syndrome and have been reported to decrease tumor size in up to 16% patients.

Octreotide may stabilize tumor growth in some patients but has only minimal tumoricidal activity. Some patients with troublesome diarrhea experience reduced responsiveness to octreotide with time, and, although the VIP levels decline, they do not return to baseline values. Two possible reasons for such tachyphylaxis are accelerated octreotide degradation and down-regulation of somatostatin receptors. Regardless of the mechanism, rebound diarrhea can be difficult to treat.

Sandostatin LAR is a long-acting somatostatin analog that is currently not available in the United States.

Lanreotide (Somatuline LA)

Lanreotide is a somatostatin octapeptide analog with a considerably longer half-life than octreotide. It inhibits multiple endocrine, exocrine, and neuroendocrine mechanisms. Lanreotide reduces insulinlike growth factor-1 and growth hormone secretion.

Antineoplastics, Other

Class Summary

Chemotherapeutic agents are used to treat metastatic WDHA syndrome when surgical resection is not possible. The combination of streptozotocin and doxorubicin is superior to streptozotocin and 5-FU in the treatment of advanced islet cell carcinoma. Chlorozotocin alone is similar in efficacy to streptozotocin plus 5-FU but has fewer adverse effects than streptozotocin-containing regimens.

Streptozotocin (Zanosar)

Streptozotocin is a naturally occurring nitrosourea that was originally discovered as an antibiotic obtained from Streptomyces achromogenes. It is capable of inhibiting deoxyribonucleic acid (DNA) synthesis during all stages of the mammalian cycle through liberation of alkylating and carbamoylating moieties.

Streptozotocin has a methylnitrosourea (MNU) moiety attached to 2 carbon of glucose and has a special affinity for islet of Langerhans cells. It has a half-life of approximately 15 minutes; only 10-20% of the dose is recovered in urine.

Chlorozotocin (DCNU, Dome, NSC 178248)

Chlorozotocin is not available in the United States. It is an antineoplastic nitrosourea in which the 2 carbon of glucose is substituted with the chloronitrosourea group (CNU).

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline antibiotic derived from the fungus S peucetius var caesius. It intercalates with DNA and disrupts many functions, including DNA and RNA synthesis. Its maximum toxicity occurs during S phase of the cell cycle.

Doxorubicin has a multiphasic disappearance curve, with half-lives ranging up to 30 hours. It does not cross the blood-brain barrier but is taken up rapidly by the heart, lungs, liver, kidneys, and spleen.

Fluorouracil (Adrucil)

Fluorouracil is a pyrimidine analog of uracil, which inhibits RNA function and thymidylate synthesis. Fluorouracil requires enzymatic conversion to a nucleotide to exert cytotoxic activity. Interruption of thymidylate synthesis results in inhibition of DNA synthesis while RNA and protein production continues. This causes an imbalance in growth that is not compatible with cell survival.

Fluorouracil is administered parenterally and is metabolized primarily in the liver. It is inactivated by reduction of the pyrimidine ring by dihydrouracil dehydrogenase. Because this enzyme is widely distributed in body, dose modification of fluorouracil is not required in the presence of liver disease. Fluorouracil readily enters the cerebrospinal fluid (CSF), with values that slowly subside over 9 hours. Urinary excretion of a single intravenous (IV) dose is only 11% in 24 hours.

Immunomodulators

Class Summary

Interferons are glycoproteins with a variety of biologic actions. They are important cytokines that have immunomodulating, antiviral, and antiproliferative properties. Interferons alfa and beta are produced by most cells in response to viral infections, while interferon gamma is produced only by T lymphocytes.

Interferon alfa-2b (Intron A)

Interferon alfa is a highly purified protein containing 165 amino acid residues. Interferons must be administered subcutaneously or intramuscularly. Interferon alfa is rapidly inactivated in body fluids and various tissues, with an initial half-life of 40 minutes and a terminal half-life of 5 hours. Negligible amounts are excreted renally. Interferon has been used as monotherapy and in combination with octreotide.

Antidiarrheals

Class Summary

These agents are often used with somatostatin analogs. Although a wide variety of these medications has been tried, the most commonly used antidiarrheal is loperamide (Imodium).

Loperamide (Imodium, Diamode)

Loperamide is a synthetic piperidine derivative that slows intestinal transit by direct effect on nerve endings and intestinal wall ganglia. It interferes with cholinergic and noncholinergic mechanisms involved in peristalsis, resulting in reduced activity of the intestinal wall muscles. Like diphenoxylate and morphine, it may enhance contractions of intestinal circular muscles, thus increasing segmentation and retarding intestinal forward motion.

Loperamide is more specific, longer-acting, and 3 times more potent than diphenoxylate on a weight basis. Neither tolerance to the antidiarrheal effect of loperamide nor physical dependence on the drug has been reported.

The apparent elimination half-life of loperamide in healthy adults is 9-14 hours. Less than 2% of the drug is excreted in urine; 30% is excreted as an intact molecule in feces. Enterohepatic circulation has been described in animals. Whether loperamide crosses the placenta or is distributed in milk is unknown.

Histamine H2 Antagonists

Class Summary

H2 blockers are reversible competitive blockers of histamine at H2 receptors, particularly those in the gastric parietal cells (where they inhibit acid secretion). The H2 antagonists are highly selective, they do not affect the H1 receptors, and they are not anticholinergic agents.

Histamine 2 (H2)–receptor antagonists or proton pump inhibitors should be administered postoperatively to prevent hyperacidity, because rebound hyperchlorhydria is common in the postoperative period.

Ranitidine (Zantac)

This agent inhibits histamine stimulation of H2 receptors in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Famotidine (Pepcid)

Famotidine competitively inhibits histamine at the H2 receptors in gastric parietal cells, reducing gastric acid secretion, gastric volume, and hydrogen concentrations.

Nizatidine (Axid, Axid AR)

This agent competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Cimetidine (Tagamet HB 200)

This agent inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.

Proton Pump Inhibitors

Class Summary

PPIs inhibit gastric acid secretion by inhibition of the H+/K+/ATPase enzyme system in the gastric parietal cells. IV therapy may be a useful adjunct via stabilization of the clot by increasing intragastric pH.

H2-receptor antagonists or proton pump inhibitors should be administered postoperatively to prevent hyperacidity, because rebound hyperchlorhydria is common in the postoperative period.

Lansoprazole (Prevacid)

Lansoprazole is a substituted benzimidazole that covalently and irreversibly binds the hydrogen potassium/ATPase, thereby inhibiting acid secretion. This agent is available as an IV formulation, oral (PO) capsule, or SoluTab. Strawberry-flavored SoluTabs can be dissolved in water for easy administration to children. Dissolve the 15-mg SoluTab in 4 mL of water and the 30-mg SoluTab in 10 mL of water.

Omeprazole (Prilosec)

Omeprazole is a substituted benzimidazole that suppresses acid secretion by specific inhibition of hydrogen potassium/ATPase at the secretory surface of the parietal cell.

Pantoprazole (Protonix)

Pantoprazole is a substituted benzimidazole that suppresses acid secretion by specific inhibition of hydrogen potassium/ATPase at the secretory surface of the parietal cell.

Esomeprazole magnesium (Nexium)

This agent suppresses gastric acid secretion by specifically inhibiting the H+/K+/ATPase enzyme system at the secretory surface of gastric parietal cells.