Pediatric Zollinger-Ellison Syndrome Treatment & Management

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]}

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.

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.

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.