WDHA Syndrome Workup

  • Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD   more...
 
Updated: May 11, 2012
 

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).

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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.

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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.[5]

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.[5] When combined with PET scanning technology, a change in patient management was reported in up to 30% of patients.[64]

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.

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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.

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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.[49] They are collectively called amine precursor uptake and decarboxylation (APUD) tumors, or APUDomas.

Histologic classification cannot be used to predict whether a tumor is benign or malignant. Malignancy can be confirmed only when evidence of local invasion or metastatic spread is present.

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 frequently are multihormonal, with more than 50% of tumors containing more than 1 hormone. Massive amyloid deposition has been reported in one case in which islet-associated polypeptide and calcitonin were believed to be candidates for the amyloidogenic peptide.

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Contributor Information and Disclosures
Author

Sandeep Mukherjee, MB, BCh, MPH, FRCPC  Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Coauthor(s)

Randall E Brand, MD  Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center

Randall E Brand, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Richard K Gilroy, MBBS, FRACP  Associate Professor, Medical Director of Liver Transplantation and Hepatology, Department of Internal Medicine, Kansas University Medical Center

Disclosure: genetech, gilead, NPS pharmaceuticals Salary Speaking and teaching

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Additional Contributors

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Manoop S Bhutani, MD Professor, Co-Director, Center for Endoscopic Research, Training and Innovation (CERTAIN), Director, Center for Endoscopic Ultrasound, Department of Medicine, Division of Gastroenterology, University of Texas Medical Branch; Director, Endoscopic Research and Development, The University of Texas MD Anderson Cancer Center

Manoop S Bhutani, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Institute of Ultrasound in Medicine, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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