Zollinger-Ellison syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Aravind Reddy Kothagadi M.B.B.S[3]

Patients with Zollinger-Ellison syndrome may experience abdominal pain and diarrhea. The diagnosis is also suspected in patients without symptoms who have severe ulceration of the stomach and small bowel, especially if they fail to respond to treatment. Gastrinomas may occur as single tumors or as multiple, small tumors. About one-half to two-thirds of single gastrinomas are malignant tumors that most commonly spread to the liver and lymph nodes near the pancreas and small bowel. Nearly 25 percent of patients with gastrinomas have multiple tumors as part of a condition called multiple endocrine neoplasia type I (MEN I). MEN I patients have tumors in their pituitary gland and parathyroid glands in addition to tumors of the pancreas. Development of Zollinger-Ellison syndrome is the result of increased levels of gastrin due to an existing gastrinoma in the duodenum or pancreas. Zollinger-Ellison syndrome must be differentiated from gastric antrum syndrome, antral G-cell hyperplasia, peptic ulcer, gastroesophageal reflux disease (GERD), and hypergastrinemia. The incidence of gastrinoma, which can cause Zollinger-Ellison syndrome, is approximately 0.5-2 persons per 100,000 individuals worldwide. Pharmacologic medical therapies for Zollinger-Ellison syndrome include proton pump inhibitors, H2-receptor antagonists, chemotherapy, and hormonal therapy. Effective measures for the primary prevention of Zollinger-Ellison syndrome include genetic testing, if family history presents.

In 1955, Zollinger and Ellison published their seminal paper on gastrinomas wherein the Zollinger-Ellison syndrome was first discussed.

Development of Zollinger-Ellison syndrome is the result of increased levels of gastrin due to an existing gastrinoma in the duodenum or pancreas.

The cause of Zollinger-Ellison syndrome has not been identified. However, 25 to 30 percent of gastrinomas, which can cause Zollinger-Ellison syndrome, are caused by multiple endocrine neoplasia type 1 (MEN1).

Zollinger-Ellison syndrome must be differentiated from gastric antrum syndrome, antral G-cell hyperplasia, peptic ulcer, gastroesophageal reflux disease (GERD), and hypergastrinemia.

The incidence of gastrinoma, which can cause Zollinger-Ellison syndrome, is approximately 0.05-0.2 per 100,000 individuals worldwide. About 25 to 30 percent of gastrinomas are caused by multiple endocrine neoplasia type 1 (MEN1). Zollinger-Ellison syndrome is a disease that tends to affect the middle-aged adult population. Males are more commonly affected with Zollinger-Ellison syndrome than females.

If left untreated, patients with Zollinger-Ellison syndrome may progress to develop abdominal pain, diarrhea, and heartburn. Common complications of Zollinger-Ellison syndrome include upper gastrointestinal bleeding, anemia, and duodenal ulcer perforation. Prognosis is generally good, and the 5 and 10-year survival rate of patients with Zollinger-Ellison syndrome is approximately 94% and 75%, respectively.

Symptoms of Zollinger-Ellison syndrome include diarrhea, odynophagia, nausea, and hematemesis .

Common physical examination findings of Zollinger-Ellison syndrome include epigastric tenderness, pallor, and jaundice.

An elevated concentration of fasting serum gastrin level and secretin stimulation test may be helpful in the diagnosis of Zollinger-Ellison syndrome.

Abdominal CT scan may be helpful in the diagnosis of Zollinger-Ellison syndrome caused by gastrinoma. Gastrinomas are frequently multiple and often extrapancreatic (90% located in the gastrinoma triangle). Thus, they can be difficult to locate. For this reason, multiphase contrast enhanced thin slice cross-sectional imaging is ideal. Findings on Abdominal CT scan suggestive of gastrinoma include clearly defined, well-enhanced mass.

Abdominal MRI may be helpful in the diagnosis of Zollinger-Ellison syndrome caused by gastrinoma. Findings on abdominal MRI suggestive of Zollinger-Ellison syndrome include solitary lesion or multiple lesions.

Abdominal ultrasound may be helpful in the diagnosis of Zollinger-Ellison syndrome caused by gastrinoma.

Endoscopic ultrasound and somatostatin receptor scintigraphy (SRS) (octreotide scan) may be helpful in the diagnosis of Zollinger-Ellison syndrome caused by gastrinoma.

Other diagnostic studies for Zollinger-Ellison syndrome include upper endoscopy, which demonstrates erosive esophagitis, thickened gastric folds, and antral erosions.

Pharmacologic medical therapies for Zollinger-Ellison syndrome include proton pump inhibitors, H2-receptor antagonists, chemotherapy, and hormonal therapy.

The feasibility of surgery depends on the stage of gastrinoma causing Zollinger-Ellison syndrome at the time of diagnosis. However, all patients diagnosed with Zollinger-Ellison syndrome with no metastasis should be offered surgical exploration and resection.

Effective measures for the primary prevention of Zollinger-Ellison syndrome include genetic testing, if family history is positive.

Secondary prevention strategies following Zollinger-Ellison syndrome include surgical resection of gastrinoma to prevent malignant trasformation and distant metastasis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shadan Mehraban, M.D.[2]

In 1955, Zollinger and Ellison published their seminal paper on gastrinomas wherein the Zollinger-Ellison syndrome was discussed for the first time.

• In 1955, Zollinger and Ellison announced their concept about ulcerogenic islet cell tumor which caused marked ulcer diathesis due to gastric hyperacidity.^[1]
• Dr. Robert M. Zollinger and Dr. Edwin H. Ellison announced their theory at the annual meeting of American Surgical Association in Philadelphia in April 1956.^[2]
• This concept raised from clinical case of two women who presented with perforated jejunal ulcers accompanied with severe ulcer diathesis.
• One of the patients was a 36 year-old woman with past history of 8 years abdominal pain and diarrhea. A laparotomy revealed perforated jejunal ulcers with severe recurrent hemorrhage. Although she underwent two subtotal gastric resections, transabdominal vagotomy, and transthoracic vagotomy, her symptoms were constantly persistent. Finally she underwent total gastrectomy; however, she died due to anastomic leakage from the surgery. Her autopsy was in favor of non-beta pancreatic islet cell tumor.^[3]
• The other patient was a 19 year-old woman with 2 years of upper abdominal pain. She underwent a surgery in July 1953 and was diagnosed with two perforated jejunal ulcers. A truncal vagotomy and a radical subtotal gastrectomy were performed in January 1954. This operation was called a dream operation for ulcers by Zollinger. Due to unsuccessful results of the operation, she had to go through radiation therapy to her stomach. Eventually, total gastrectomy was performed. The results described a non-beta islet cell carcinoma with lymph node metastasis.
• In 1956, Ben Eiseman of Denver, Colorado, presented the same experience with one of his patients and called the condition “Zollinger-Ellison syndrome”.^[4]
• Discovery of insulinoma in 1927 and malignant carcinoid syndrome in 1953, have exceeded the presentation and discovery of Zollinger-Ellison syndrome.^[5][6]
• In the 1960s, gastrin was described to be involved in the pathogenesis of gastric hyperacidity by Dr. Lester.^[7]
• Roderic Gregory and Hilda Tracy of Liverpool proved that gastrin is the cause of Zollinger-Ellison syndrome. ^[8]
• Radioimmunoassay was developed for assessment of gastrin level in 1967 and 1968.^[9][10]
• Histamine-2 blocking drugs (H2) were introduced as the first effective medical therapy for Zollinger-Ellison syndrome in 1975.^[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2] Mohamad Alkateb, MBBCh [3]

Zollinger-Ellison syndrome results from increased levels of gastrin due to an existing gastrinoma in the duodenum or pancreas.

• Chemotransmitters, which are delivered to the gastric mucosa, have a main role in the stimulation and inhibition of gastric acid and pepsin production.^[1]
• Gastric acid is responsible for protein digestion, absorption of calcium, iron, vitamin B12, thyroid hormones and some drugs (itraconazole and ketoconazole).^[2]
• Gastric acid is responsible for lowering gastric pH.
• Acidic pH kills microorganisms, reduces bacterial growth, and prevents intestinal infection and bacterial peritonitis.^[3][4]
• Acid secretion has 3 phases:^[5]

1. Cephalic

• Mediated by vagal stimulation during thinking about, smelling, and seeing food.

2. Gastric

• The major mediator for acid secretion due to stomach distension and chemical effects related to the food.

3. Intestinal

• Small mediator for acid secretion due to chemical effects of food

• Acid secretion mediated by some pathways:^[6][7]
  • Parietal cells
    • Contains the hydrogen-potassium-ATPase acid-secreting pump which controls acid secretion
  • Gastrin^[8]
    • Main hormone involved in acid secretion
    • Gastrin-expressing cells (G cells) are located in the antrum and are responsible for gastrin secretion.
    • Gastrin stimulates gastrin secretion from parietal cells by histamine release from enterochromaffin-like (ECL) cells.
    • Gastrin activates cholecystokinin (CCK) 2 receptor and somatostatin-secreting D cells.^[9][10]
• Acid secretion is stimulated by histamine release, gastrin release, and acetylcholine release.^[11].
• Acid secretion is inhibited by somatostatin secretion from oxyntic glands and antral D cells.

• Embryologic endoderm produces enteroendocrine cells and these cells are considered as the origin of gastrinomas.^[12]
• Symptoms of Zollinger-Ellison syndrome are related to hypergastrinemia.^[13]
• Hypertrophy of gastrin mucosa results in hypergastrinemia.
• Gastric acid secretion increases four to six-fold.
• Hypergastrinemia results from increase activity of parietal cells and histamine-secreting enterochromaffin-like cells.
• Gastric acid secretion overrides the mucosal defense of the gastric and duodenal wall which may cause ulceration and inactivation of pancreatic enzymes.
• The majority of patients have large and multiple peptic ulcers located in distal duodenum and proximal jejunum.^[14]
• Inactivation of pancreatic enzymes leads to fat malabsorption and diarrhea.^[15]
• High gastric acid secretion does not reabsorb in small intestine and colon; therefore, it results in chronic diarrhea.^[13]
• Sodium and water do not reabsorb in presence of high volume of gastric acids which results in secretory diarrhea.
• The major factors related to fat malabsorption are as following:^[16]
  • Gastric mucosal damage
  • Inactivation of Pancreatic enzymes
  • Bile salts precipitation

• Approximately 75% of Zollinger-Ellison syndrome (ZES) patients develop sporadically. ^[17]
• Approximately 25% of patients are associated with Multiple Endocrine Neoplasia-type 1 syndrome.^[18]
• MEN-1 is considered as an autosomal dominant disorder defining by tumors of the pituitary, the parathyroid, and the pancreas.^[19]
• MEN1 results from mutations in an 10-exon gene at chromosome 11q13. ^[20]

• Multiple endocrine neoplasia type 1 (MEN 1)^[21]
• Gastrinoma (duodenal gastrinoma and pancreatic gastrinomas)^[22]
• Usually these gastriomas are small (less < 1 cm), multiple ones,less often to metastasize to liver rather than pancreatic gastrinomas.
• Peptic ulcer disease

• Gross pathology presents as enlarged fundic mucosal folds with cerebriform pattern.

• A well-differentiated neuroendocrine tumor (NET) histologically typically shows an organ like arrangement of cells with nesting, trabecular, or gyriform patterns. ^[23]
• The tumor cells are usually round with regular bland nuclei which produce large number of secretory granules with diffuse immunoexpression of neuroendocrine markers where as, the poorly differentiated neuroendocrine tumor (NET) shows a atypical, sheet-like, diffuse and irregular nuclei, less cytoplasmic secretory granules, and limited biomarker immunoexpression. ^[23]
• Immunostaining for chromogranin A and synaptophysin is an important step in the diagnosis of neuroendocrine tumors. In order to differentiate from other neuroendocrine tumors gastrin immunostaining may be used. somatostatin scintigraphy is considered an effective localizing tool as gastrinomas tend to express a high density of somatostatin receptors. ^[23]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2] Mohamad Alkateb, MBBCh [3]

The cause of Zollinger-Ellison syndrome has not been identified. However, 25 to 30 percent of gastrinomas, which can cause Zollinger-Ellison syndrome, are caused by multiple endocrine neoplasia type 1 (MEN1).

• The cause of Zollinger-Ellison syndrome has not been identified. However, 25 to 30 percent of gastrinomas, which can cause Zollinger-Ellison syndrome, are caused by multiple endocrine neoplasia type 1 (MEN1).^[1]

• Hypergastrinemia (an increased fasting serum gastrin level) is the hallmark of ZES. ^[2]

• Causes of Hypergastrinemia: ^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Zollinger-Ellison syndrome must be differentiated from gastric antrum syndrome, antral G-cell hyperplasia, peptic ulcer, gastroesophageal reflux disease (GERD), and hypergastrinemia.

Zollinger-Ellison syndrome must be differentiated from diseases that cause abdominal pain and chronic diarrhea. The table below summarizes the findings that differentiate watery causes of chronic diarrhea:^{[1][2][3][4][5]}

Zollinger-Ellison syndrome also must be differentiated from diseases that cause dyspepsia:^[6]

Zollinger-Ellison syndrome must be differentiated from:^{[7][8][9][10][11][12][13][14][15]}

Duodenal ulcer

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

The incidence of gastrinoma, which can cause Zollinger-Ellison syndrome, is approximately 0.05 – 0.2 per 100,000 individuals worldwide. About 25 to 30 percent of gastrinomas are caused by multiple endocrine neoplasia type 1 (MEN1).

• The worldwide incidence of gastrinomas is about 5 to 30 cases per 100,000 individuals per year.^[1]
• With improved techniques for tumor detection, the annual incidence has increased.
• About 80% to 90% of these tumors arise in the gastrinoma triangle.

• Zollinger-Ellison syndrome is a disease that tends to affect the middle-aged adult population (20 – 50 years of age).^[2]

• Males are more commonly affected with Zollinger-Ellison syndrome than females.^[2]

• There is no racial predilection to Zollinger-Ellison syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

The most potent risk factor in the development of Zollinger-Ellison syndrome is Multiple endocrine neoplasia type 1 (MEN1). Other risk factors include alcohol abuse.

Common risk factors associated with Zollinger-Ellison syndrome include:^[1][2]

• Multiple endocrine neoplasia type 1 (MEN1)
• Alcohol abuse

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]; Aravind Reddy Kothagadi M.B.B.S[3]

Measurement of fasting serum gastrin levels is the single best screening test for Zollinger-Ellison syndrome (ZES). Other tests such as provocative tests include, the secretin stimulation test, calcium stimulation test, secretin-plus-calcium stimulation tests, bombesin test, and protein meal test.

• Measurement of fasting serum gastrin levels is the single best screening test for Zollinger-Ellison syndrome (ZES).
• It is advised not to take gastric antisecretory medications at the time of the test.
• Serial multiple measurements on different days have been advised as the fasting gastrin levels can fluctuate from day to day and may appear to be normal.
• In untreated ZES, normal levels of serum gastrin are extremely rare (<1%).
• Multiple endocrine neoplasia-type 1 (MEN 1) syndrome should be suspected if serum calcium levels are elevated greater than 12.0 mg/dl accompanied with gastrinoma.
  • Gastric acid secretory test: ZES is suspected in patients with a basal acid output (BAO) is greater than 15 mEq/h. ZES is also suspected in patients with a prior vagotomy and partial gastrectomy whose basal acid output (BAO) is greater than 5 mEq/h.
    • Basal gastric secretory volume greater than 140 mL is considered highly sensitive and specific in patients without any prior gastric acid lowering surgery,
    • Gastric acid pH less than 2.0 in the presence of a large gastric volume greater than 140 mL over 1 hour is highly suggestive of ZES in patients without any prior gastric acid lowering surgery,
  • Provocative tests: ^[1]
    • Secretin stimulation test ^[2]
    • Calcium stimulation test
    • Secretin-plus-calcium stimulation tests
    • Bombesin test
    • Protein meal test
• Secretin stimulation test is the provocative test of choice because of its higher sensitivity. In this test, a 2-U/kg bolus of secretin is administered intravenously after an overnight fast, and serum levels of gastrin are determined at 0, 2, 5, 10, and 15 minutes. An increase in serum gastrin of greater than 200 pg/mL is diagnostic.
• Imaging studies such as Somatostatin receptor scintigraphy (SRS) is helpful in staging and localizing the gastrinoma.
• Screening also helps in determining if the patient is fit to undergo surgery for tumor resection.

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