Zollinger-Ellison syndrome is gastrointestinal neuroendocrine tumors (NETs). Zollinger-Ellison syndrome is caused by gastrinoma (tumor of stomach) that results in hypergastrinemia that cause gastric acid hyper secretion. Gastrinoma is a neuroendocrine tumor that secretes large quantities of gastrin. Due to secretion of excess gastrin there is chronic gastric acid hyper secretion which leads to growth of the gastric mucosa with increased numbers of parietal cells and proliferation of gastric cells.

What are the clinical manifestations of Zollinger-Ellison syndrome?

Due to gastric acid hyper secretion peptic ulcer disease (PUD) is the common problem of Zollinger-Ellison syndrome. Generally PUD of Zollinger-Ellison syndrome is severe and refractory, which is very difficult to manage along with diarrhea. The most common symptoms of Zollinger-Ellison syndrome are abdominal pain (which is seen in 70-100% of patients of Zollinger-Ellison syndrome and the pain may be burning sensation in stomach to frank abdominal pain), diarrhea (seen in 40-70% of patients of Zollinger-Ellison syndrome) and GERD or gastroesophageal reflux disease (seen in approximately one third of patients of Zollinger-Ellison syndrome). Some patients with Zollinger-Ellison syndrome may present only with diarrhea (10-20% of patients). Abdominal pain is generally due to peptic ulcer, which usually occurs in duodenum, but can occur in unusual locations in gastrointestinal tract in patients with Zollinger-Ellison syndrome.

Gastrinomas are generally present in the duodenum (50-70% of gastrinomas), followed by the pancreas (20–40%) and less commonly in other locations of abdomen and extremely rarely in outside abdomen. Approximately 20-25 % of patients of gastrinima have MEN-1 (endocrinopathy, family history of ulcer or endocrinopathy, nephrolithiases or stone in kidney) and it should be diagnosed if possible in all cases of Zollinger-Ellison syndrome. More than two third of the gastrinomas are malignant, sometimes with distant metastasis.

How to diagnose Zollinger-Ellison syndrome?

Zollinger-Ellison syndrome should be suspected if there is peptic ulcer disease in association with diarrhea, PUD which is refractory to standard treatment, peptic ulcer in unusual location with multiple ulcers, peptic ulcer without Helicobacter pylori infection (Helicobacter pylori is present in more than 90% of idiopathic peptic ulcers, but less than 50% in Zollinger-Ellison syndrome), peptic ulcer in association with MEN-1 or multiple endocrine neoplasia (endocrinopathy, family history of ulcer or endocrinopathy, nephrolithiases) etc. Sometimes unexplained long duration diarrhea can also suggest Zollinger-Ellison syndrome.

The appropriate diagnosis of gastrinoma (Zollinger-Ellison syndrome) requires demonstration of fasting hypergastrinemia and an increased basal gastric acid output (BAO) or hyperchlorhydria. More than 98% of patients with gastrinoma have hypergastrinemia, which is more than 10 folds (although approximately half of patients have less than 10 fold increase). So if gastrinoma (Zollinger-Ellison syndrome) is suspected by clinical presentation, a fasting gastrin level should be determined first. For determining fasting gastrin level, it is important to stop proton pump inhibitor drugs (long duration drugs like omeprazole, esmoprazole, lansoprazole etc.) or other anti secretory drugs at one week prior to testing. Along with demonstration of increased gastrin level, it is also important to show that the increase was during gastric pH level of less than 2. If the fasting gastrin level is more than 10 fold increased (more than 1000 nanogram/liter) and pH is less than 2, the diagnosis of gastrinoma (Zollinger-Ellison syndrome) can be established after ruling out any retained antrum syndrome by history. If the fasting gastrin level increase is less than 10 fold (less than 1000 nanogram/liter), the diagnosis is made by considering other conditions like H. pylori infections, gastric outlet obstruction, gastric antral hyperplasia etc. and determination of BAO and a secretin stimulation test should be done to confirm diagnosis (the BAO is usually more than 90% elevated i.e., more than 15 milli equivalent/hour). The secretin stimulation test is also usually positive, with more than 120 nanogram/liter increase over the basal level.

Once the diagnosis of gastrinoma is established the tumor should be located by use of imaging techniques like CT scan.

How gastrinoma is treated?

The symptomatic treatment of gastrinoma(Zollinger-Ellison syndrome) include control of gastric acid hyper secretion by use of potent anti secretory drugs like proton pump inhibitors (omeprazole, pantoprazole, esmoprazole, lansoprazole etc.), histamine H₂-receptor antagonists (ranitidine, cimetidine, roxatidine etc.). Due to high efficacy and requirement of less frequent administration (once a day) the PPIs (proton pump inhibitors) are the drug of choice in Zollinger-Ellison syndrome. If patients also have MEN-1 with hyperparathyroidism, correction of the hyperparathyroidism is essential as it increases the sensitivity to gastric antisecretory drugs and decreases the basal acid output.

Patients with Zollinger-Ellison syndrome generally die from tumor-related causes. At the time of diagnosis of gastrinoma (Zollinger-Ellison syndrome) a careful imaging like CT scan should be done to locate the tumor (gastrinoma). If the tumor is located in a position which can be removed surgically, it should be removed after carefully locating the tumor. If there is metastasis as seen with hepatic metastases the disease may be limited, so that surgical resection may be possible. Surgical cure is possible in approximately one third of patients with gastrinoma (Zollinger-Ellison syndrome). Therefore if possible all the patients should undergo surgery by experienced surgeon.