Pediatric Zollinger-Ellison Syndrome Workup
- Author: Tiffany J Patton, MD; Chief Editor: Carmen Cuffari, MD more...
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.
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.
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.
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%. 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.
Conventional Radiologic Studies
Computed tomography (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. 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.
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. 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.
Massaro SA, Emre SH. Metastatic Gastrinoma in a Pediatric Patient With Zollinger-Ellison Syndrome. J Pediatr Hematol Oncol. 2013 Feb 15. [Medline].
Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004 Jan. 83(1):43-83. [Medline].
Imamura M, Komoto I, Ota S. Changing treatment strategy for gastrinoma in patients with Zollinger-Ellison syndrome. World J Surg. 2006 Jan. 30(1):1-11. [Medline].
Passaro E, Howard TJ, Sawicki MP, et al. The origin of sporadic gastrinomas within the gastrinoma triangle: a theory. Arch Surg. 1998 Jan. 133(1):13-6; discussion 17. [Medline].
Debelenko LV, Emmert-Buck MR, Zhuang Z, et al. The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology. 1997 Sep. 113(3):773-81. [Medline].
Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med. 1999 Mar 18. 340(11):858-68. [Medline].
Riff BP, Leiman DA, Bennett B, Fraker DL, Metz DC. Weight Gain in Zollinger-Ellison Syndrome After Acid Suppression. Pancreas. 2015 Jul 8. [Medline].
Norton JA, Fraker DL, Alexander HR, et al. Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med. 1999 Aug 26. 341(9):635-44. [Medline].
Nord KS, Joshi V, Hanna M, et al. Zollinger-Ellison syndrome associated with a renal gastrinoma in a child. J Pediatr Gastroenterol Nutr. 1986 Nov-Dec. 5(6):980-6. [Medline].
Morrow EH, Norton JA. Surgical management of Zollinger-Ellison syndrome; state of the art. Surg Clin North Am. 2009 Oct. 89(5):1091-103. [Medline].
Eire PF, Rodriguez Pereira C, Barca Rodriguez P, Varela Cives R. Uncommon case of gastrinoma in a child. Eur J Pediatr Surg. 1996 Jun. 6(3):173-4. [Medline].
Heikenen JB, Pohl JF, Werlin SL. Octreotide in pediatric patients. J Pediatr Gastroenterol Nutr. 2002 Nov. 35(5):600-9. [Medline].
Kim HU. Diagnostic and Treatment Approaches for Refractory Peptic Ulcers. Clin Endosc. 2015 Jul. 48 (4):285-90. [Medline].
Berna MJ, Hoffmann KM, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore). 2006 Nov. 85(6):295-330. [Medline].
Berna MJ, Hoffmann KM, Long SH, Serrano J, Gibril F, Jensen RT. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore). 2006 Nov. 85(6):331-64. [Medline].
Proye C, Malvaux P, Pattou F, et al. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery. 1998 Dec. 124(6):1134-43; discussion 1143-4. [Medline].
Norton JA, Melcher ML, Gibril F, Jensen RT. Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment. Surgery. 2004 Dec. 136(6):1267-74. [Medline].
Epelboym I, Mazeh H. Zollinger-Ellison syndrome: classical considerations and current controversies. Oncologist. 2014 Jan. 19 (1):44-50. [Medline].
Corleto VD, Annibale B, Gibril F, et al. Does the widespread use of proton pump inhibitors mask, complicate and/or delay the diagnosis of Zollinger-Ellison syndrome?. Aliment Pharmacol Ther. 2001 Oct. 15(10):1555-61. [Medline].
Jensen RT. Gastrinomas: Advances in Diagnosis and Management. Neuroendocrinology. 2004. 80 Suppl 1:23-27. [Medline].
Kwekkeboom DJ, de Herder WW, van Eijck CH, et al. Peptide receptor radionuclide therapy in patients with gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2010 Mar. 40(2):78-88. [Medline].
Citak EC, Taskinlar H, Arpaci RB, Apaydin FD, Gunay EC, Tanriverdi H, et al. Primary lymph node gastrinoma: a rare cause of abdominal pain in childhood. J Pediatr Hematol Oncol. 2013 Jul. 35(5):394-8. [Medline].
Mozell EJ, Cramer AJ, O'Dorisio TM, Woltering EA. Long-term efficacy of octreotide in the treatment of Zollinger-Ellison syndrome. Arch Surg. 1992 Sep. 127(9):1019-24; discussion 1024-6. [Medline].
Berna MJ, Annibale B, Marignani M, et al. A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors. J Clin Endocrinol Metab. 2008 May. 93(5):1582-91. [Medline].
Ellison EC, Johnson JA. The Zollinger-Ellison syndrome: a comprehensive review of historical, scientific, and clinical considerations. Curr Probl Surg. 2009 Jan. 46(1):13-106. [Medline].
Gibril F, Jensen RT. Advances in evaluation and management of gastrinoma in patients with Zollinger-Ellison syndrome. Curr Gastroenterol Rep. 2005 May. 7(2):114-21. [Medline].
Quatrini M, Castoldi L, Rossi G, et al. A follow-up study of patients with Zollinger-Ellison syndrome in the period 1966-2002: effects of surgical and medical treatments on long-term survival. J Clin Gastroenterol. 2005 May-Jun. 39(5):376-80. [Medline].