Zollinger Ellison syndrome (gastrinoma)

Discuss Zollinger Ellison syndrome (ZES)?

The ZES is characterized by peptic ulcers of the upper GIT refractory to medical therapy caused by severe gastric acid hyper secretion associated with non-beta islet cell tumors of the pancreas.

Gastrinomas arise from the neuroendocrine cells. Most gastrinomas arise from the duodenum (about 75%), whereas they are localized in the pancreas in 25% of cases. Occasionally gastrinomas occur from other sites including extra abdominal sites. Gastrin is the predominant peptide secreted by the gastrinoma cells.

Majority of the Gastrinomas are sporadic (about 80%), whereas others are associated with multiple endocrine neoplasia type 1. The diagnosis is usually made between the ages of 30 and 50 years. There is no clear sex prevalence.

Discuss the clinical features of ZES?

Excessive gastrin secretion from a gastrinoma stimulates parietal cells leading to high gastric acid output.

  • Majority of patients present with peptic ulcer disease. In a third of cases, the ulcers are multiple or in an unusual site. The ulcer can appear as a common duodenal ulcer, but it is usually less responsive to therapy with respect to ulcers in patients without gastrinomas.
  • Diarrhea is the second most common symptom occurring in 50% or more patients. The cause of diarrhoea is maldigestion and malabsorption caused by the high acid output. The acid inactivates pancreatic digestive enzymes, interferes with the emulsification of fat by bile acids and damages intestinal epithelial cells and villi.

Discuss the diagnosis of ZES?

Diagnosis should be suspected in patients with multiple or refractory ulcers, or ulcer location distal to the duodenum, diarrhoea, or a personal or family history of MEN 1.
Step 1- Check fasting serum gastrin. If it is elevated on PPIs, you want to discontinue the PPIs for seven days and then re check
Step 2- if high need to exclude secondary causes of hypergastrinemia (achlorhydria in pernicious anaemia or atrophic gastritis) – pH of the gastric juice can be obtained during endoscopy or through a nasogastric tube.  In the presence of gastric acid (i.e., a gastric pH below 5.0), a serum gastrin value greater than 1000 pg/mL (475 pmol/L) is virtually diagnostic of the disorder.
Step 3- If fasting gastrin levels are not diagnostic i.e. if the pH is <5 and the plasma gastrin concentration is between 100 and 1 000 pg/mL, a secretin test must be carried out. Secretin stimulates the release of gastrin by gastrinoma cells, and therefore patients with gastrinoma’s have a dramatic rise in serum gastrin in response to a secretin infusion. Secretin test is performed by the administration of 2 IU/kg of secretin intravenously in 2 min, after having taken a blood sample in order to perform the basal gastrin concentration; after the injection, blood samples are taken after 2.5, 5, 10, 15 and 30 min. An increase of plasma gastrin >200 pg/mL is diagnostic of ZES. The secretin test can give a false negative result in 10% of patients with ZES, and this is usually associated with a malignant course of the disease.

More than 90% of gastrinomas can be localized using Octreoscan and/or EUS. CT and MRI also have high sensitivity in localizing the gastrinomas.

Discuss the treatment of ZES?

Two main principal therapeutic objectives: control the gastric acid hypersecretion and to control the growth of the tumor. Medical therapy is the current standard of care for most patients with ZES as part of the MEN 1 syndrome. In contrast, many patients with sporadic ZES are candidates for surgical therapy.

Control of gastric acid hyper secretion
- High dose PPI’s are used using symptoms to titrate the dose. Somatostatin analogs like octreotide can inhibit the secretion of gastrin. However, due to the unpredictability of the response, they are not used as first-line agents for symptomatic patients.
Surgery- to resect the tumour should be offered to patients with a sporadic gastrinoma with no evidence of metastases. Successful resection of sporadic gastrinomas protects against the possibility of eventual morbidity and mortality from metastatic spread of the tumour.
Treatment of metastatic disease- Liver and bone is the commonest site of metastases. PPI and somatostatin analogues may be used as above. Isolated liver metastases can be resected. Unresectable liver disease can be treated with chemoembolisation, RFA etc.
Discuss the prognosis of ZES?

Mortality largely depends upon whether the gastrinoma is benign or malignant and the extent of disease involvement.
Do we need to rule out ZE syndrome in non-HP, non-NSAID ulcer disease?  Is it reasonable?  Is it worthwhile?

The incidence of ZES is 0.1to 1% in patients with peptic ulcer disease.  If we test, we are going to test more than 1000 people unnecessarily in order to identify one Z-E patient.   If we do not test, the worry is “Will we delay the diagnosis of Z-E?”  Most importantly, if we delay the diagnosis will that lead to more advanced disease?
There is no good study which has evaluated this.

So who should be tested?

I would suggest that it may be reasonable to test

  • Duodenal ulcer patient’s refractory to PPIs
  • Concomitant diarrhoea
  • Endocrinopathy like parathyroid disease or
  • Multiple ulcers perhaps in unusual locations

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