eMedicine Specialties > Gastroenterology > Systemic Disease
WDHA Syndrome: Treatment & Medication
Updated: Jun 4, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
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 life-saving 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. It controls diarrhea in as many as 87% of patients and may reduce the tumor size in a minority of patients. Slow-release lanreotide and Sandostatin LAR are 2 longer-acting preparations that have been developed, but 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.
- Chemotherapy
- Several chemotherapeutic agents have been used to treat patients with metastatic disease. Streptozotocin and doxorubicin have emerged as the agents of choice 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 30% 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 treated with a combination of interferon alfa and 5-FU.
- Because of the scarcity of this condition and the incomplete understanding of its natural history, interpreting the effectiveness of these therapeutic interventions is difficult.
- Interventional radiology
- Because most metastatic tumors in the liver are highly vascular and receive their blood supply by 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, which improved 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 that had not responded to surgical debulking, antidiarrheals, octreotide, and targeted radioisotope injections.6
Surgical Care
Surgical resection 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.
- 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. An intraoperative ultrasound 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 by 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 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 diarrheogenic syndrome, one reasonable alternative when faced with this clinical conundrum is to close the abdomen and to perform further localizing studies.
- Cytoreductive/debulking surgery
- Cytoreductive/debulking surgery may prolong life expectancy in certain patients. However, the natural history of metastatic WDHA syndrome is not well understood because of its rarity, and, as a result, no studies have evaluated cytoreductive surgery in a controlled prospective manner to determine if survival is improved.
- As expected, 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.
- 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.
- 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 evaluating patients with extrahepatic pancreatic endocrine tumors, particularly noncarcinoid tumors.
Consultations
A multispecialty team comprised of gastroenterologists, surgeons, radiologists, and oncologists should evaluate patients with WDHA syndrome. Because of the rarity of VIPomas, most treatment recommendations are based on the experience of pancreatic endocrine tumors. Octreotide is recommended for symptom control and may have minor antineoplastic effects. Most experts agree that chemotherapy and interferon are indicated for patients with extensive metastatic disease; however, no agreement exists as to when such treatment should be started. New treatment modalities undoubtedly will be devised for chemotherapy, hormonal modulation, and receptor modulation; however, surgical resection currently remains the cornerstone of successful treatment.
- Oncologist
- Interventional radiologist
Diet
No dietary modifications are required.
Activity
Activity is unrestricted.
Medication
Medications used to treat WDHA syndrome are divided into 2 categories, antisecretory agents (eg, somatostatin and its synthetic derivatives) and chemotherapeutic agents. Conventional antidiarrheals are useful adjuncts to somatostatin analogs.
Antisecretory agents
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 the diarrhea of WDHA syndrome.
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. Radioactive-labeled somatostatin derivatives currently are being investigated in the treatment of these tumors.
Octreotide (Sandostatin, Sandostatin LAR)
A synthetic analog of somatostatin with a half-life of approximately 100 min.
A potent physiological inhibitor of numerous GI functions, including (1) release of GI peptides (eg, CCK, gastrin, secretin), (2) gastric acid secretion, (3) intestinal blood flow, (4) gall bladder and intestinal motility, (5) pancreatic enzyme secretion, and (6) small intestinal mucosal secretion. These inhibitory effects, either alone or in combination, contribute to the antidiarrheal effect. These 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 or 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.
Adult
Sandostatin: 50-150 mcg SC q4-8h; doses as high as 500-1000 mcg/d have been used
Sandostatin LAR: 30 mg IM q3-4wk
Pediatric
2-20 mcg/kg SC qd; experience is limited because of the rarity of this condition in children
May reduce effects of cyclosporine; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dose adjustment
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse effects are common but rarely severe enough to discontinue treatment; discomfort at injection site is common; postprandial hyperglycemia is reported occasionally; the most common adverse effects are GI and include nausea, abdominal cramps, and alterations in bowel habit that usually improve with time; long-term use results in development of gallstones and/or sludge in as many as 52% patients; however, the percentage of patients developing symptomatic gallstone disease is low
Lanreotide (Somatuline LA)
Somatostatin analog with a considerably longer half-life than octreotide.
Currently not available in the United States.
Adult
30 mg IM q10-14d
Pediatric
Not established
May increase absorption of bromocriptine
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Transient abdominal pain, pain at injection site, and hypoglycemia were reported in 3 of 16 patients in a European study
Antineoplastic agents
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)
Naturally occurring nitrosourea originally discovered as antibiotic obtained from Streptomyces achromogenes. Capable of inhibiting DNA synthesis during all stages of mammalian cycle through liberation of alkylating and carbamoylating moieties. Streptozotocin has a methylnitrosourea (MNU) moiety attached to 2 carbon of glucose and has special affinity for islet of Langerhans cells. Has half-life of approximately 15 min, and only 10-20% of dose recovered in urine.
Adult
500 mg/m2/d IV for 5 d; repeat q6wk for combination regimens
Pediatric
Not established
Aminoglycosides, loop diuretics, and doxorubicin may increase nephrotoxicity; phenytoin may decrease effects
Documented hypersensitivity; jaundice; renal failure; leucopenia; thrombocytopenia
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Severe nausea and vomiting are common; liver dysfunction can occur; renal toxicity is dose-related and cumulative; requires close monitoring of renal, hepatic, and hematologic functions; hyperglycemia is a frequent adverse effect because the drug destroys pancreatic islet cells
Chlorozotocin (DCNU, Dome, NSC 178248)
Not available in the United States. Antineoplastic nitrosourea in which the 2 carbon of glucose is substituted by the chloronitrosourea group (CNU).
Adult
150 mg/m2 q7wk
Pediatric
Not established
None reported
Documented hypersensitivity; jaundice; renal failure; leucopenia; thrombocytopenia
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Myelosuppression, nausea, and vomiting of short duration may occur
Doxorubicin (Adriamycin, Rubex)
Anthracycline antibiotic derived from fungus Streptomyces peucetius var caesius. Intercalates with DNA and disrupts many functions, including DNA and RNA synthesis. Maximum toxicity occurs during S phase of cell cycle.
Doxorubicin has multiphasic disappearance curve, with half-lives ranging up to 30 h. Does not cross blood-brain barrier but taken up rapidly by heart, lungs, liver, kidney, and spleen.
Adult
5 mg/m2 IV; repeat after 21 d of each 6-wk treatment cycle when administered with streptozotocin
Pediatric
Not established
May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease its plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; preexisting myelosuppression
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Myelosuppression is major dose-limiting complication, with leucopenia reaching its lowest level in the second week of therapy; stomatitis, GI disturbances, and alopecia are frequent complications; cardiotoxicity is a unique characteristic of anthracycline antibiotics manifested by CHF unresponsive to digoxin; extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function
Fluorouracil (Adrucil)
Pyrimidine analog of uracil, which inhibits RNA function and thymidylate synthesis. Requires enzymatic conversion to nucleotide to exert cytotoxic activity. Interruption of thymidylate synthesis results in inhibition of DNA synthesis while RNA and protein production continues. Results in an imbalance in growth that is not compatible with cell survival.
Administered parenterally and metabolized primarily in liver. Inactivated by reduction of pyrimidine ring by dihydrouracil dehydrogenase. Because enzyme widely distributed in body, dose modification not required in presence of liver disease. Readily enters CSF, with values that slowly subside over 9 h. Urinary excretion of a single IV dose is only 11% in 24 h.
Adult
400 mg/m2 IV qd for 5 d concurrently with streptozotocin
Pediatric
Not established
Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, and thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents
Documented hypersensitivity; bone marrow suppression; serious infection
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Nausea, oral and GI ulcers, depression of immune system, and failure of hemopoiesis may occur; adjust dosage in renal impairment.
Interferons
Interferons are glycoproteins with a variety of biological 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 only produced by T lymphocytes.
Interferon alfa (Roferon-A, Intron A)
Highly purified protein, containing 165 amino acid residues. Interferons must be administered SC or IM. Rapidly inactivated in body fluids and various tissues, with initial half-life of 40 min and a terminal half-life of 5 h. Negligible amounts excreted renally. Interferon has been used as monotherapy and combined with octreotide.
Adult
5 million U SC 3 times/wk
Pediatric
Not established
Theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Documented hypersensitivity; myelosuppression; severe depression
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Early adverse effects include a flulike illness with fever, chills, nausea, and headache occurring about 6 h after injection; fatigue, myalgia, and malaise occur a few weeks later; bone marrow suppression and alopecia are observed in 1-5% of patients, although predicting which adverse effects will occur is not possible; it may precipitate or worsen underlying autoimmune diseases, the most common of which is thyroiditis
Antidiarrheals
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)
Synthetic piperidine derivative that slows intestinal transit by direct effect on nerve endings and intestinal wall ganglia. 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. It 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 reported.
Apparent elimination half-life in healthy adults is 9-14 h. Less than 2% of the drug is excreted in urine, and 30% is excreted as an intact molecule in feces. Enterohepatic circulation described in animals. Whether loperamide crosses placenta or distributed in milk is unknown.
Adult
4 mg PO initially, then 2 mg after each loose stool; not to exceed 16 mg/d
Pediatric
Not established; 0.08-0.24 mg/kg PO divided bid/tid is suggested
Phenothiazines, tricyclic antidepressants, and CNS depressants may increase its toxicity
Documented hypersensitivity; diarrhea resulting from infections; pseudomembranous colitis
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Discontinue use if no clinical improvement is observed in 48 h; because loperamide is primarily metabolized in liver, CNS toxicity should be monitored in patients with hepatic insufficiency; should not be used if high fever or blood in stool is noted; perform resuscitation of dehydrated patients before administering antidiarrheals; caution in children <2 y; no well-controlled studies of loperamide in pregnant women exist, it should only be used in pregnancy when clearly needed; use caution in breastfeeding women because whether the drug is distributed in milk is not clear
More on WDHA Syndrome |
| Overview: WDHA Syndrome |
| Differential Diagnoses & Workup: WDHA Syndrome |
 Treatment & Medication: WDHA Syndrome |
| Follow-up: WDHA Syndrome |
| References |
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Further Reading
Keywords
pancreatic cholera; Verner-Morrison syndrome; VIPoma syndrome; watery diarrhea, hypokalemia, and achlorhydria syndrome; vasoactive intestinal peptide; VIP; non–beta pancreatic islet cells; dehydration; hypokalemia; ganglioneuroma; ganglioneuroblastoma; hypercalcemia; hyperglycemia; hypochlorhydria; flushing; multiple endocrine neoplasia type 1 syndrome; MEN-1 syndrome; Werner syndrome; watery diarrhea, hypokalemia, and hypochlorhydria syndrome; WDHH syndrome; amine precursor uptake and decarboxylation tumors; APUD tumors; APUDomas
