You are in: eMedicine Specialties > Radiology > GASTROINTESTINAL Zollinger-Ellison SyndromeArticle Last Updated: Aug 7, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: Praveen K Roy, MD, Assistant Professor of Medicine, Associate Director of Research, Division of Gastroenterology, Department of Internal Medicine, University of Missouri at Columbia; Chief of Gastroenterology, Harry Truman Veteran Affairs Memorial Hospital Praveen K Roy is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and Canadian Association of Gastroenterology Coauthor(s): Jack Bragg, DO, FACOI, Assistant Professor, Department of Clinical Medicine, University of Missouri School of Medicine; Mohamed Othman, MD, Staff Physician, Department of Internal Medicine, University of New Mexico School of Medicine; Jehad Barakat, MD, Assistant Professor of Medicine, Gastroenterology and Hepatology, University of New Mexico School of Medicine; Consulting Staff, Department of Medicine, Albuquerque Veterans Affairs Medical Center; Brian Rich, MD, Consulting Staff, Department of Radiology, Blue Mountain Medical Group, PLLC; Gautam Dehadrai, MD, Consulting Staff, Section Chief, Department of Interventional Radiology, Veterans Affairs Medical Center, Albuquerque Editors: Zahir Amin, MBBS, MRCP, MD, FRCR, Consulting Staff, Department of Imaging, The Middlesex Hospital, University College London Hospitals Trust; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Udo P Schmiedl, MD, PhD, Clinical Professor, Department of Radiology, University of Washington; Consulting Staff, Swedish Medical Center, University of Washington Medical Center, Seattle Radiologists; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center Author and Editor Disclosure Synonyms and related keywords: gastrinoma, ZES, fulminating peptic ulcer disease, gastric acid hypersecretion, non-beta islet cell tumor, hypergastrinemia, multiple endocrine neoplasia type 1, MEN 1 INTRODUCTIONSection 2 of 12
  BackgroundZollinger-Ellison syndrome is caused by non-beta islet cell gastrin-secreting tumors of the pancreas. These tumors stimulate acid-secreting cells of the stomach to maximal activity, with consequent gastrointestinal (GI) mucosal ulceration. In 1955, Zollinger and Ellison first described the classic triad of fulminating peptic ulcer disease, gastric acid hypersecretion, and non-beta islet cell tumors.1 The diagnosis of Zollinger-Ellison syndrome is made based on a combination of criteria, including the clinical presentation, gastrin radioimmunoassay findings, gastric acid secretory testing, and diagnostic imaging evaluation. Imaging tests play an important role in evaluating the extent of the tumor and in directing therapy. In addition, imaging is important for monitoring patients following surgical resection of the tumors. Zollinger-Ellison syndrome can be either sporadic, developing on its own, or familial, secondary to the genetic disorder multiple endocrine neoplasia type 1 (MEN 1) syndrome. MEN 1 syndrome is a condition that includes parathyroid, pancreatic, and pituitary tumors. For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education article Peptic Ulcers. PathophysiologyThe symptoms of Zollinger-Ellison syndrome are secondary to hypergastrinemia, which causes hypertrophy of the gastric mucosa and leads to an increase in the number of parietal cells (as many as 6 times the reference range value) and increased maximal acid output. On its own, gastrin also stimulates acid secretion, resulting in increased basal acid secretion. The increased acid production leads to mucosal ulceration of the GI tract, diarrhea, or malabsorption. Malabsorption in patients with Zollinger-Ellison syndrome is usually multifactorial and is caused by direct mucosal damage (caused by increased stomach acid), inactivation of the pancreatic enzymes, and the precipitation of bile salts. FrequencyUnited StatesZollinger-Ellison syndrome occurs in approximately 0.1-1% of patients with duodenal ulcers in the InternationalThe annual frequency in Mortality/MorbidityCurrently, the morbidity and mortality rates of Zollinger-Ellison syndrome are low. Fewer than 5% of patients develop complications, such as abdominal perforation, gastric outlet obstruction, or esophageal stricture. RaceAll races can be affected equally. SexA slight male predominance exists, with a male-to-female ratio of 1.3:1. AgeThe mean age for the onset of Zollinger-Ellison syndrome is the fifth decade of life. Patients with MEN 1 syndrome and Zollinger-Ellison syndrome usually present 1 decade earlier than those solely with Zollinger-Ellison syndrome. Fewer than 3% of patients are younger than 20 years, while 7% are older than 60 years. AnatomyThe most frequent locations of the primary tumor are the pancreas and duodenum, followed by the nearby lymph nodes. More than 90% of gastrinomas are located in the gastrinoma triangle, which is bound by the porta hepatis, the neck of the pancreas, and the third part of the duodenum. Ectopic locations include the ovaries, bile duct, heart, and kidneys. These tumors are often small and, if in the duodenum, are usually less than 1 cm in diameter. They can be multiple in 20-40% of cases (in patients with MEN 1 syndrome), and two thirds are malignant. Clinical DetailsA high index of suspicion is needed to make an early diagnosis of Zollinger-Ellison syndrome. Presenting symptoms include the following:
Physical examination findings may be normal, or they may include the following:
Preferred ExaminationImaging studies are essential for planning an appropriate strategy for the treatment of patients with Zollinger-Ellison syndrome. First and foremost, imaging studies determine tumor extent. The presence of diffuse metastatic disease is a contraindication for surgical resection. In addition, identification of the primary site of the tumor helps in planning the surgical procedure. After appropriate biochemical diagnosis of Zollinger-Ellison syndrome, the initial imaging of choice is somatostatin-receptor scintigraphy (SRS); however, this technique is not commonly available. Computed tomography (CT) scans of the abdomen can be performed first. Ultrasonography or magnetic resonance imaging (MRI) of the abdomen can also be performed if CT scans demonstrate negative findings. Once Zollinger-Ellison syndrome has been biochemically proven, an SRS should be performed. Endoscopic ultrasound may be useful if other imaging studies have failed to detect a lesion. Limitations of TechniquesSonography, MRI, and CT scans are all limited by low sensitivity; small primary lesions can be easily missed by these imaging tests. SRS is only available in major medical centers. DIFFERENTIALSSection 3 of 12
Small-Bowel Obstruction Other Problems to Be ConsideredRetained antrum
RADIOGRAPHSection 4 of 12
FindingsPlain abdominal images are not useful in the routine evaluation of patients with Zollinger-Ellison syndrome. In patients presenting with complications stemming from Zollinger-Ellison syndrome, evidence of abdominal visceral perforation can be seen. Evidence of gastric outlet obstruction may be seen. Upper GI series findings may reveal esophageal stricture, duodenal ulcers, duodenal strictures, and hypertrophic gastric and duodenal folds.Degree of ConfidenceThe presence of hypertrophic gastric folds on plain radiographs has a sensitivity of 94% for Zollinger-Ellison syndrome. CT SCANSection 5 of 12
FindingsOn nonenhanced CT scans, a small hypoattenuating nodule may be seen in the duodenum or pancreas. Gastrinomas may occasionally be calcified. They are usually transiently hyperattenuating during arterial phase contrast-enhanced CT scans. Liver metastases may be seen; these are usually hypervascular and are best seen on arterial phase scanning. Degree of ConfidenceCT scans help detect 38-75% (with a mean of 50%) of extrahepatic gastrinomas, while 42-76% of hepatic metastasis are seen on CT scans. The detection rate is higher for gastrinomas located in the pancreas or for larger tumor sizes (30% for 1- to 3-cm tumors compared to greater than 95% for tumors larger than 3 cm). CT scans have a specificity of 95%, a positive predictive value of 96%, and a negative predictive value of 54%. For gastrinomas that have metastasized to the liver, CT scans of the abdomen have a sensitivity of 54%, a specificity of 98%, a positive predictive value of 96%, and a negative predictive value of 54%. False Positives/NegativesSmaller tumors are frequently missed on CT scans. MRISection 6 of 12
FindingsUseful sequences are fat-saturated T1- and T2-weighted sequences, as well as dynamic gadolinium-enhanced sequences. The primary tumor is usually hypointense on T1-weighted images and hyperintense on T2-weighted images, and they typically show early arterial enhancement. Ring enhancement may be present, and the tumors are occasionally hypovascular and show no enhancement. Lesions may be seen in the duodenal wall, pancreas, liver, or bones. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving Degree of ConfidenceFor extrahepatic primary gastrinomas, MRI has a sensitivity of 20-25%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 11%. For metastatic gastrinoma to the liver, MRI has a sensitivity of 43%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 81%. MRI is highly sensitive for bone metastases. False Positives/NegativesPrimary tumors located in the duodenum or pancreas are frequently missed on MRI. ULTRASOUNDSection 7 of 12
FindingsThe primary tumor may be seen as a hypoechoic nodule in the head of the pancreas, in the duodenum, or in adjacent structures. Occasionally, the primary tumor is hyperechoic. Hyperechoic or isoechoic metastases with a hypoechoic halo may also be seen. Degree of ConfidenceEndoscopic sonography is more sensitive than transabdominal ultrasonography, and high sensitivities have been reported for pancreatic gastrinoma detection (>90%). It is less sensitive for duodenal gastrinoma detection; however, endoscopic sonography is not widely available and requires considerable expertise in order to localize these small tumors. Lesions seen on sonograms must be confirmed via another imaging study, especially if lesions are seen in the liver. Tumor size and location are critical to the sonographic detection rate. Overall, ultrasonography has a poor sensitivity for extrahepatic lesions (23%); however, sensitivity increases for larger tumor sizes and tumors confined to the pancreas. The positive predictive value of sonography for extrahepatic gastrinoma is 92%, and the negative predictive value is 25%. For hepatic lesions, the sensitivity is higher (76%). Lesions missed on CT scans or angiograms can be detected by using sonograms; therefore, sonography has a role in the initial workup of patients with gastrinoma. For the detection of hepatic metastases, ultrasonography has sensitivity comparable to that of CT scanning (≤63%), with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value to 89%. False Positives/NegativesHepatic hemangiomas may be mistaken for liver metastases. NUCLEAR MEDICINESection 8 of 12
FindingsSRS is the study of choice for the initial evaluation of patients with Zollinger-Ellison syndrome. Hot spots, indicating increased uptake of the octreotide, are seen in the tumor. This can be seen either at the primary site of the tumor or in the metastases (liver or bone). Degree of ConfidenceSRS has the highest sensitivity compared to conventional imaging studies. SRS has a higher sensitivity (58-77%; mean, 67%) than conventional imaging studies (CT, ultrasonography, MRI) for extrahepatic gastrinomas and a specificity equal to all of these studies combined (SRS specificity, 84-94%). For hepatic metastases, the sensitivity is 92-100%. The sensitivity for localizing duodenal gastrinoma is lower than that for localizing pancreatic gastrinoma. False Positives/NegativesFalse-positive findings have been reported to occur in granulomatous disease (sarcoid, Wegner disease, tuberculosis), thyroid diseases (Graves disease, thyroiditis), various forms of arthritis, lymphomas (Hodgkin lymphoma, non-Hodgkin lymphoma), and activated lymphocytes secondary to infections. ANGIOGRAPHYSection 9 of 12
FindingsAngiography can be a useful tool in localizing neuroendocrine tumors. Degree of ConfidenceMost gastrinomas are hypervascular, and the reported sensitivity of arteriography is 60-100%; however, small hypovascular tumors may be missed. Hepatic venous sampling after intra-arterial secretin stimulation can also be used; this modality has a sensitivity of 77%. INTERVENTIONSection 10 of 12
All patients with the sporadic form of Zollinger-Ellison syndrome and without any metastatic disease should be offered surgical resection of the primary tumor. In patients with Zollinger-Ellison syndrome and MEN 1 syndrome, the role of surgical resection is controversial, since these patients tend to have multiple primary tumors and, therefore, a surgical cure is not feasible; however, patients with both syndromes and a primary tumor greater than 2.5 cm should have surgical resection, since the risk of developing hepatic metastases is increased with large primary tumors. MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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