Pediatric Zollinger-Ellison Syndrome 

Updated: Oct 06, 2017
Author: Tiffany J Patton, MD; Chief Editor: Carmen Cuffari, MD 

Overview

Background

Zollinger-Ellison syndrome (ZES) is a rare condition characterized by peptic ulcers that are refractory to conventional medical therapy. Gastrin-producing tumors or gastrinomas cause excessive gastric acid secretion, leading to these ulcers of the upper gastrointestinal (GI) tract, as well as diarrhea and severe abdominal pain (see the following image).[1]

Somatostatin receptor scintigraphy in a young pati Somatostatin receptor scintigraphy in a young patient with Zollinger-Ellison syndrome. Besides physiologic uptake in the kidneys and the spleen, 2 pathologic hot spots are present, one in the area of the duodenum and another next to the pancreas.

Childhood gastrinomas account for about 2% of all Zollinger-Ellison syndrome cases in the United States. The overall incidence of gastrinomas occurring sporadically or in association with multiple endocrine neoplasia type 1 (MEN-1) is 0.1-3 per million; the prevalence of MEN-1 is 0.2-2 cases per 100,000 population. MEN-1 is diagnosed in 30-38% of patients with gastrinomas, whereas 20-61% of patients diagnosed with MEN-1 are found to have gastrinomas associated with Zollinger-Ellison syndrome.

Until 1992, 60 cases of Zollinger-Ellison syndrome in children had been reported worldwide.

In 2004, Gibril et al published a large, prospective study of 107 patients with Zollinger-Ellison syndrome associated with MEN-1 and reported that 78% of patients were white, 10% were black, and 9% were Hispanic.[2] The incidence of this disease in male children is 4 times greater than that of female children, which is in contrast to Zollinger-Ellison syndrome in adults, in which a slight male predominance is noted.[3]

The youngest patient reported with Zollinger-Ellison syndrome was a boy aged 7 years. Gastrinomas have been found in patients aged 90 years and younger, with the most common age at diagnosis being 30-50 years.

This syndrome was originally described by Zollinger and Ellison in 1955.[4] In 1960, Cawkwell described the first childhood case of Zollinger-Ellison syndrome in The New Zealand Medical Journal.

See also Pediatric Multiple Endocrine Neoplasia, Pediatric VIPoma, Gastrinoma, Zollinger-Ellison Syndrome, Wermer Syndrome (MEN Type 1), and Peptic Ulcer Disease.

Etiology and Pathophysiology

Gastrinomas may be sporadic or may be associated with multiple endocrine neoplasia type 1 (MEN-1). Data suggest that the gene for MEN-1, called MENIN, is also involved in the pathogenesis of at least one third of sporadic neuroendocrine tumors (NETs), including gastrinomas. Therefore, all patients who are under evaluation for Zollinger-Ellison syndrome (ZES) should undergo genetic testing for MEN-1.

MEN-1 is known to cause multiple tumors within the pancreas, pituitary, parathyroid, and adrenal glands through an autosomal dominant pattern of inheritance. Patients with MEN-1 may also have an increased risk of skin lesions and carcinoid and smooth muscle tumors. MEN-1 is due to mutations in the tumor suppressor gene MEN1, located on chromosome 11q13. MEN1 encodes a transcriptional regulator protein, menin. Patients with MEN-1 have one germline mutation and one somatic mutation that lead to inactivation of menin.

Gastrinomas are neuroendocrine tumors that are usually found in the duodenum wall (approximately 50%) or in the pancreas. Approximately 85% of gastrinomas are located in the gastrinoma triangle, which is superiorly bound by the confluence of the cystic and common bile duct, inferiorly bound by the second and third portions of the duodenum, and medially bound by the head and body of the pancreas.[5] When gastrinomas are found in the pancreas, they are non–beta islet cell tumors. However, in addition to locations in the duodenum and pancreas, gastrinomas have been described in the lymph nodes, liver/biliary tree, gastric antrum, and jejunum. Rare reports have described extra-gastrointestinal (GI) gastrinomas occurring in the heart, ovaries, lung, splenic hilum, and renal capsule.[6]

Gastrinomas are the second most common neuroendocrine tumors in the overall population, after insulinomas and before vasoactive intestinal polypeptide tumors (VIPomas) and glucagonomas. Gastrinomas may secrete not only high levels of gastrin, causing peptic ulcer disease (PUD) but also may secrete other hormones such as adrenocorticotropic hormone (ACTH), vasoactive intestinal polypeptide (VIP), and glucagon. Gastrinomas may also produce various peptides such as insulin, pancreatic polypeptide, glucagon, chromogranin A, neuron-specific enolase, and the alpha and beta subunits of human chorionic gonadotropin (HCG).

Carcinoid tumors are GI neuroendocrine tumors that are mostly indolent; however, they may secrete various hormones and biogenic amines that cause carcinoid syndrome.[7] Gastric carcinoids (type 2 carcinoids) occur almost exclusively in patients with MEN-1 who have Zollinger-Ellison syndrome (21–30% of patients with MEN-1) and can be malignant in 10–30% of cases.[8]

Prognosis

Before the introduction of acid-suppressing drugs, including histamine H2-receptor antagonists and, more recently, proton pump inhibitors (PPIs), Zollinger-Ellison syndrome (ZES) carried high mortality rates. Because safe control of gastric acid hypersecretion can be achieved with PPIs in virtually all patients, mortality and morbidity are now attributed to advanced disease with metastases to liver and bones.[9] Due to small numbers, it is not clear whether gastrinoma tumor growth in children is less aggressive than in adults, as previously thought.

In a study from the National Institutes of Health (NIH) involving 151 patients with Zollinger-Ellison syndrome, the 10-year survival rate was 94% in the overall Zollinger-Ellison syndrome population.[10] The survival rate at 10 years was slightly lower (89%) when Zollinger-Ellison syndrome was associated with multiple endocrine neoplasia type 1 (MEN-1). In the latter condition, a high prevalence of gastric carcinoids has been described; these carcinoids can be malignant in 10–30% of cases; thus, they require active surveillance to prevent increased mortality.

Gastrinomas may be malignant or benign, but they are typically slow growing. Early studies reported malignancy rates as high as 65% in adults. More recent studies report a malignancy rate of closer to 30%. Lymph nodes, liver, and bone metastases are the most common, although occurrence rates in children are unknown. One case report described a renal gastrinoma in a 12-year-old child.[11]

Approximately 60% of gastrinomas are benign at the time of diagnosis, without metastases. Because of the small size of gastrinomas, cure (disease free for at least 5 y) is achieved in only 20-40% of cases.

The development of liver metastases, especially a rapidly enlarging metastatic lesion, is considered an unfavorable sign; however, depending on the tumor biology, patients with liver metastases have survived 10 years and longer. Patients with gastrinomas releasing adrenocorticotropic hormone (ACTH), which causes Cushing syndrome, or who have bone metastasis also have a poor prognosis and should receive antitumor treatment.[3]

Complications

With the introduction of PPIs that are effective in almost all patients, acid-related complications are now reduced to a minimum. Complications of peptic ulcer disease (PUD) before the diagnosis include perforation, bleeding, and esophagitis. A stricture of the gastroesophageal junction may develop.

 

Presentation

History and Physical Examination

The typical presentation of Zollinger-Ellison syndrome (ZES) is severe abdominal pain, with or without diarrhea. Most children present with complications of peptic ulcer disease (PUD), such as bleeding from an ulcer or duodenal perforation.

Abdominal pain

The abdominal pain is due to peptic ulcers, which can be found in the upper gastrointestinal (GI) tract in 90-95% of patients. These ulcers are often multiple (see the following image) or in unusual locations. In 70% of patients, single or multiple ulcers are found in the first part of the duodenum. However, ulcers in the second or third part of the duodenum or in the jejunum are highly suggestive of Zollinger-Ellison syndrome. Other characteristics of Zollinger-Ellison syndrome ulcers include a size larger than 2 cm and a refractory behavior to conventional therapy.

Diarrhea

The second most common symptom of Zollinger-Ellison syndrome ulcers is diarrhea, which is seen in 50-65% of patients. Diarrhea may be the only symptom; however, it can also precede or follow the ulcer formation. The diarrhea is due to mucosal damage by activated pepsinogens that result from excessive acid secretion. Other mechanisms of diarrhea in Zollinger-Ellison syndrome include inhibition of sodium and water absorption, bile acid insolubility, and inactivation of pancreatic enzymes, leading to both malabsorptive (steatorrhea) and secretory states.[12]

Other symptoms

Zollinger-Ellison syndrome may also manifest as symptoms of gastroesophageal reflux and, in severe cases, has been associated with esophageal stenosis or Barrett mucosa in adults.

Because Zollinger-Ellison may present with many vague, common GI symptoms, the correct diagnosis is often delayed by 4-6 years.[13, 14]

Physical findings

The physical examination findings in affected patients are often normal. These children may have abdominal tenderness and, in the case of perforation, they may have peritoneal signs. Patients who experience anemia due to bleeding ulcers may appear pale and may have tachycardia and/or fatigue.

Staging

Staging Zollinger-Ellison syndrome (ZES) is based on tumor size (>2-3 cm) and metastases to the lymph nodes, liver, or both. Metastases to the liver are associated with poor prognosis and have been reported to occur in roughly 60% of patients with pancreatic gastrinoma versus less than 10% in patients with duodenal gastrinoma.[15]

Tumor size does not relate to serum gastrin levels or the severity of symptoms.

Ectopic Cushing syndrome, tumor flow cytometry features, and overexpression of certain growth factors such as human epidermal growth factor receptor 2 (HER2/neu) are associated with aggressive gastrinomas and poor prognosis.

 

DDx

Diagnostic Considerations

As noted earlier, owing to the generally nonspecific GI symptoms and signs of Zollinger-Ellison syndrome (ZES), particularly in children, the correct diagnosis may be delayed. When evaluating patients with suspected Zollinger-Ellison syndrome, also consider reflux disease, Barrett esophagitis, esophageal stenosis, and the following conditions:

  • Hypochlorhydria due to chronic atrophic gastritis

  • Prolonged proton pump inhibitor (PPI) use

  • GI bleeding

  • Gastric outlet obstruction

Differential Diagnoses

 

Workup

Approach Considerations

Laboratory studies to confirm the diagnosis of Zollinger-Ellison syndrome (ZES) measurements of the fasting serum and gastrin levels, secretin and calcium stimulation tests, and measurements of the basal acid output.[16]

If the patient has multiple endocrine neoplasia type 1 (MEN-1), other laboratory abnormalities may be suggestive of Zollinger-Ellison syndrome, such as the following:

  • High plasma calcium levels

  • High parathyroid hormone (PTH) levels

  • High prolactin (PL) levels

Conventional radiologic studies (computed tomography [CT] scanning, transabdominal ultrasonography, and magnetic resonance imaging [MRI]) may not be helpful owing to the small size of most gastrinomas (< 2 cm). Nuclear imaging with somatostatin receptor scintigraphy (SRS) (octreotide scanning), however, may be useful in identifying these tumors.

Operative techniques such as palpation, duodenal transillumination, and intraoperative ultrasonography can be used during laparotomy for the 20% of gastrinomas that somatostatin receptor scintigraphy (SRS) and other imaging studies fail to visualize.

Because patients with MEN-1 and Zollinger-Ellison syndrome are at risk for developing enterochromaffin-like (ECL) cell tumors, they require regular gastroscopy with multiple biopsies of all parts of the stomach and systematic biopsies of all mucosal lesions to detect these carcinoids.

Fasting Gastrin Levels and Secretin/Calcium Stimulation Tests

Serum gastrin levels higher than 100 pg/mL are highly suggestive of Zollinger-Ellison syndrome (ZES). If the gastric pH level is less than 2, a gastrin level greater than 1000 pg/mL is diagnostic of this disease.[17, 18]

However, if the patient is not receiving acid-suppressing medication, and the gastric pH levels are higher than 2, Zollinger-Ellison syndrome can be ruled out.

If the gastrin level is in the range of 100-1000 pg/mL, and the pH level is less than 2, a secretin stimulation test must be performed.

Secretin stimulation test

After obtaining blood to measure the basal gastrin level, intravenously (IV) administer 2 IU/kg of secretin. Then, obtain blood at 2.5, 5, 10, 15, and 30 minutes. The increase of the serum gastrin levels greater than 200 pg/mL is diagnostic of Zollinger-Ellison syndrome.

The physiologic mechanism of the secretin test remains unclear; however, it is the most important diagnostic test to exclude other conditions with increased acid secretion, hypergastrinemia, or both.

Clinical conditions in which patients present with hypergastrinemia, such as gastric outlet obstruction, pernicious anemia, renal failure, and achlorhydria due to atrophic gastritis, must be excluded with secretin provocative testing.

Calcium stimulation test

If Zollinger-Ellison syndrome is strongly suspected and the secretin test result is negative, the test can either be repeated or a calcium stimulation test can be performed. Although this test is less commonly used, less sensitive, and has a greater side effect profile with IV calcium infusion, the calcium stimulation test is considered highly specific for gastrinomas.[8]

Basal Acid Output Levels

Before measurement of the basal acid output (BAO), acid-inhibitory agents must be discontinued, as follows: 2 days for H2-receptor antagonists and 7 days for proton pump inhibitors (PPIs).

In the 24 hours before the test, the patient receives antacids.

A nasogastric tube (NGT) is placed into the antrum, and the stomach is emptied.

Four consecutive samples of gastric fluid are collected; a quadruplicate of each sample is titrated to pH 7 with 0.2 N sodium hydroxide, whereas the basal acid output is determined with a radiometer titrator.

In an unoperated stomach, a basal acid output of more than 15 mEq/h is diagnostic of Zollinger-Ellison syndrome (ZES). If the patient underwent gastric resection for acid reduction, a basal acid output of more than 10 mEq/h is diagnostic for this condition.

Nuclear Imaging

Because most gastrinomas are smaller than 2 cm, visualizing them with conventional imaging techniques, such as computed tomography (CT) scanning, transabdominal ultrasonography, and magnetic resonance imaging (MRI), is difficult.

Somatostatin receptor scintigraphy (SRS), or octreotide scanning, can reveal 57-78% of gastrinomas and has a sensitivity of 84-94%.[19] This technique is currently the single most effective imaging modality for gastrinomas, but it is highly dependent on the tumor size. SRS may not accurately reveal tumor size or location and is best used in conjunction with CT scanning with intravenous (IV) contrast. SRS is also useful, because it allows for whole-body scanning and measurement of whole-body tumor content during a single test. See the following images.

Somatostatin receptor scintigraphy in a young pati Somatostatin receptor scintigraphy in a young patient with Zollinger-Ellison syndrome. Besides physiologic uptake in the kidneys and the spleen, 2 pathologic hot spots are present, one in the area of the duodenum and another next to the pancreas.
Somatostatin receptor scintigraphy in a young pati Somatostatin receptor scintigraphy in a young patient with Zollinger-Ellison syndrome whose gastrinomas were resected. The LEFT (big) tumor was a periduodenal lymph node gastrinoma; the RIGHT tumor was a pancreatic gastrinoma. Despite negative findings on the scan, the patient remained hypergastrinemic, probably because of microscopic disease that escaped diagnostic imaging and surgical exploration.

Conventional Radiologic Studies

CT scanning with intravenous (IV) contrast and magnetic resonance imaging (MRI) are highly specific for gastrinoma, with reports of 83-100% specificity using MRI. However, sensitivities range from 20% to 59%.

Transabdominal ultrasonography has a sensitivity of 0-28%, but this imaging modality may be useful in screening for metastatic disease of the liver, with reported sensitivities of 14-63%. Specificity ranges from 92-100%.

Angiography has been used with limited success because of difficulties in discriminating between the relative vascularity of the gastrinoma lesion and the surrounding tissue. This technique has a sensitivity of 28-68%.

In one study, intra-arterial secretin stimulation with hepatic venous sampling yielded a sensitivity rate of 89%; however, because of its invasive nature, angiography is only used when other imaging techniques are ineffective.

Flexible Endoscopy and Endoscopic Ultrasonography

Endoscopy may be used to evaluate recurrent abdominal pain with or without gastrointestinal (GI) bleeding. Regular flexible endoscopy may reveal prominent gastric rugal folds. Ulcers typical of Zollinger-Ellison syndrome (ZES) and histologic findings may help to confirm the diagnosis. Endoscopy is also indicated to stage peptic ulcer disease (PUD). If findings are consistent with Zollinger-Ellison syndrome, immediate treatment with proton pump inhibitors (PPIs) and further diagnostic studies are indicated to localize the tumor.

Endoscopic ultrasonography (EUS) may reveal structures as small as 2 mm, mainly in the pancreas.[19] Reported sensitivities are 58-100%. One study found a sensitivity of 93% and a specificity of 95% for pancreatic lesions. Specificity is reported to be 84-100%. Unfortunately, EUS is limited in its ability to reveal duodenal gastrinomas and can fail to visualize up to 50% of them. The successful and safe use of EUS in pediatrics, which requires special equipment, has been described in children aged 4-16 years.

Portal venous sampling has been described in adults with Zollinger-Ellison syndrome but not in children, with a positive yield of 46-90%; however, it is associated with a complication rate of 10% and is recommended only as a last resort.

Histologic Findings

Because patients with multiple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome (ZES) are at risk for developing enterochromaffin-like (ECL) cell tumors, they require regular gastroscopy with multiple biopsies of all parts of the stomach and systematic biopsies of all mucosal lesions to detect these carcinoids.[20] Both the clinical and laboratory factors and the biopsy results can be used to identify a subgroup of patients that need to be followed more closely, because they have a higher risk for developing carcinoids.

Neuroendocrine tumors (NETs), including gastrinomas, are composed of homogenous sheets of cells with small compact nuclei and prominent nucleoli. The tumors can be glandular or trabecular. Gastrin-producing cells are often well differentiated.

Immunohistochemistry staining may be positive for chromogranin A, neuron-specific enolase, and synaptophysin, as well as for pancreatic peptide, somatostatin, adrenocorticotropic hormone (ACTH), and vasoactive intestinal polypeptide (VIP).

In a series of 57 patients with multiple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome (ZES), no patient had consistently normal gastric biopsy findings, and 47% had diffuse hyperplasia as the most advanced gastric enterochromaffin-like (ECL) cell changes, 25% had linear hyperplasia, 3.5% had micronodular hyperplasia, and 1.8% had dysplasia. In 23% of the patients, (average age at biopsy, 47 y) a carcinoid was found.

 

Treatment

Approach Considerations

Exclude multiple endocrine neoplasia type 1 (MEN-1) with tumors of the parathyroids, pancreatic islets, and pituitary. If hyperparathyroidism is present, the hypercalcemia, which is present in 95% of MEN-1 cases with gastrinomas, must be corrected with parathyroidectomy before abdominal surgery is considered.

Families of patients who have Zollinger-Ellison syndrome with MEN-1 should not only be informed about the disease, but they should be also screened for MEN-1.

Consultations

Because gastrinomas in children are extremely rare, only pediatric institutions should deal with the disease. In addition, children with Zollinger-Ellison syndrome benefit from a multidisciplinary approach that involves pediatric gastroenterologists, surgeons, endocrinologists, and radiologists.[16, 21]

Clinical Management

Since the introduction of effective antisecretory medications such as proton pump inhibitors (PPIs) and histamine H2-receptor antagonists, treatment paradigms for Zollinger-Ellison syndrome (ZES) have changed. Medical therapy is also indicated before surgery when patients present with metastatic disease and in patients who refuse or cannot undergo surgical resections. Measures are designed to prevent peptic ulcer disease (PUD) due to gastric acid hypersecretion.

Proton pump inhibitors

PPIs have become the first-line treatment in Zollinger-Ellison syndrome since their approval in the late 1980s. These agents are the most effective antisecretory medication available, because they block the hydrogen potassium/adenosine triphosphate (ATPase) pump, the final common pathway, regardless of the stimulus.

The acid environment in the stomach allows for the release of the prodrug granules, which are then absorbed in the duodenum. Once in the systemic circulation, they are taken up by gastric parietal cells and diffuse into the extracellular canaliculus. The PPI then covalently and irreversibly binds to the proton pump. PPIs require acid for accumulation and activation, which is why they are most efficacious on an empty stomach.

PPIs are rapidly and almost completely absorbed. The peak plasma concentration is reached in 1-3 hours. The prodrug is quickly metabolized by the liver, primarily by cytochrome P-450 isoenzyme CYP2C19, resulting in a half-life of roughly 1 hour.

Despite the short half-life of PPIs, the irreversible covalent bonding to the proton pump provides sustained antisecretory effects; therefore, the effect is not due to plasma concentration of the drug but rather the area under the plasma concentration curve.

Little information about the metabolism and distribution of PPIs in children is available, but some data suggest decreased metabolism in newborns, a metabolic rate in children aged 1-9 years that is higher than that of adults, and more rapid absorption and clearance in children.

Of note, PPIs can mask the clinical symptoms of Zollinger-Ellison syndrome due to gastric acid hypersecretion and may cause a delay in diagnosis.[22]

H2-receptor antagonists

H2-receptor antagonists are no longer indicated for this condition, because PPIs provide more effective antisecretory effects, and prolonged use of H2-receptor antagonists leads to tachyphylaxis.

Somatostatin analogues

Somatostatin analogues such as octreotide decrease gastrin and gastric acid secretion and can be used to treat the symptoms associated with gastrinoma. Small studies in adults using weekly subcutaneous octreotide acetate for 1-48 months led to a decrease in abdominal pain and diarrhea in most patients.

Metastatic gastrinomas

For the medical management of metastatic gastrinomas, long-acting somatostatin analogues alone or in combination with alfa-interferon (3 times per wk) are now the recommended initial antitumor treatments.[23] Chemotherapy with streptozocin, doxorubicin, and/or 5-fluorouracil can decrease tumor size in some patients but has not been shown to prolong survival and may have considerable toxicity profiles. Because gastrinomas have a high density of somatostatin receptors present, studies have investigated the use of radiolabeled somatostatin analogues for their cytotoxic antitumor effects.[23] Patients with metastatic or inoperable tumors who are treated with111 In-DTPA octreotide;90 Y –DOTA0, Tyr3; or177 Lu-DOTA0, Tyr3 octreotate have symptomatic improvement and tumor regression.[24]

Dietary considerations

Special diets are not required for children with Zollinger-Ellison syndrome. However, special considerations may be necessary for children with severe diarrhea or symptoms who are unable to take in essential calories for normal growth on a regular diet.[9]

Although some studies indicate decreased vitamin B-12 levels in patients who receive long-term proton pump inhibitor (PPI) therapy, no evidence of clinical significance has been reported.

Current data are insufficient to support administration of cobalamin.

Surgical Intervention

Total gastrectomy was the standard of care for gastrinomas until at least the mid 1970s, when the first histamine H2-receptor antagonists were introduced. This procedure is no longer recommended, because medical therapy with proton pump inhibitors (PPIs) is effective in virtually all patients. Rather, surgery is now focused on staging (when gastrinomas are not revealed by imaging) and reducing tumor burden to decrease metastases and improve disease-free survival.

Even in cases in which no tumor is identified before surgery, an exploratory laparotomy is indicated, because it offers the only chance of cure.

Surgical exploration

The surgical exploration includes a careful bidigital palpation of the liver, pancreas, stomach, and lymph node groups along the pancreas and duodenum after mobilization of the duodenum and pancreatic head by a Kocher maneuver. Some authorities recommend a duodenotomy, because it allows full exploration through palpation of the duodenal wall, where 60% of gastrinomas are present. However, others argue that duodenotomy-related complications, such as leakage and fistula formation, do not justify the procedure.

Local tumor excision is currently the procedure of choice.

Lymph node sampling

Lymph node sampling is also an important aspect of surgery, because primary lymph node gastrinomas have been reported and a high rate of lymph node metastases is observed. Removal of all regional lymph nodes is recommended in patients with sporadic Zollinger-Ellison syndrome.[12, 25]

Other procedures

Major surgical resections, including duodenopancreatectomy, have been performed in adults but not in children. The subgroup of patients that may benefit from extensive resections has not yet been identified.

Some investigators report that intraoperative endoscopic transduodenal illumination of the duodenum is helpful in discovering additional gastrinomas of the duodenal wall.

Intraoperative ultrasonography of the pancreas may help to localize small tumors in the pancreas.

For patients with diffuse metastases limited to the liver, liver transplantation is being considered in younger patients.[3]

Postprocedure management

Continue PPIs after surgical resections until reliable measurements of basal acid output (BAO) are performed (see Basal Acid Output levels under Workup). Acid hypersecretion may persist after curative surgery for 6-12 months.

Long-Term Monitoring

Postoperative normogastrinemia does not mean long-term cure. Almost 50% of patients with postoperative normogastrinemia experience recurrence of the disease within 5 years.

Progression of the disease should be monitored with somatostatin receptor scintigraphy (SRS) on a yearly basis.

Even after surgery and assumed complete gastrinoma resection, patients with Zollinger-Ellison syndrome (ZES) should be kept safe on acid inhibitory medication until a secretin test has been performed and the basal acid output (BAO) has been determined.

Biochemical study results that are within the reference range, including serum gastrin levels less than 115 pg/mL and a secretin test with a gastrin rise less than 200 pg/mL, do not exclude a prolonged elevation of the basal acid output. As much as 6 months may pass before the basal acid output decreases to reference range levels because of hypertrophy of the parietal cell mass acquired during the active phase of the disease.

Thus, long-term proton pump inhibitor (PPI) use should be continued as indicated based on the basal acid output.

In cases with advanced metastatic disease, chemotherapy with a combination of streptozocin, 5-fluorouracil, and doxorubicin may be used. A response rate of 65% can be expected.

 

Medication

Medication Summary

Inhibition of gastric acid secretion with proton pump inhibitors (PPIs) is mandatory to prevent complications of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome (ZES). PPIs have proven to be safe, without side effects even after long-term use. The goal is to reduce basal acid output (BAO) to levels less than 10 mEq/h 1 hour before the next dose in patients without gastric acid–reducing surgery and less than 5 mEq/h in patients with previous acid-reducing gastric surgery.

Proton Pump Inhibitors

Class Summary

Proton pump inhibitors (PPIs) are used to reduce gastric acid hypersecretion. Dosing should be adequate to achieve a basal acid output (BAO) of less than 10 mEq/h. Dosing may vary in each patient. Children may require relatively higher doses per kilogram than adults.

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 intravenous (IV) formulation, oral (PO) caps, or solutabs. 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.

Somatostatin Analogues

Class Summary

Somatostatin analogues are synthetic analogues of somatostatin that inhibit growth (GH) secretion, thereby leading to a decrease in chloride secretion, sodium absorption, and decreased fluid losses. These agents are used to treat secretory diarrhea in Zollinger-Ellison syndrome.[26]

Octreotide (Sandostatin)

Octreotide acts primarily on somatostatin receptor subtypes II and V. This agent inhibits growth hormone (GH) secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, vasoactive intestinal peptide (VIP), and gastrointestinal (GI) peptides. Octreotide controls diarrhea in 80% of patients, but progressive increases in dosage may be necessary. In adults, Mozell et al reported success with 100 mcg subcutaneously (SC) 3 times/wk for 1-48 months.