Zollinger–Ellison syndrome
Zollinger–Ellison syndrome is a disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.
The syndrome is caused by the formation of a gastrinoma, a neuroendocrine tumor that secretes a hormone called gastrin. High levels of gastrin in the blood trigger the parietal cells of the stomach to release excess gastric acid. The excess gastric acid causes peptic ulcer disease and distal ulcers. Gastrinomas most commonly arise in the duodenum, pancreas or stomach.
In 75% of cases, Zollinger–Ellison syndrome occurs sporadically, while the remaining 25% of cases are due to an autosomal dominant syndrome called multiple endocrine neoplasia type 1.
Signs and symptoms
Patients with Zollinger–Ellison syndrome may experience abdominal pain and diarrhea. If left untreated, the condition could result in severe gastroesophageal reflux disease and refractory peptic ulcer disease. The diagnosis is also suspected in patients who have severe and recurrent ulceration of the stomach and small bowel, especially if they fail to respond to treatment.- Chronic diarrhea, including steatorrhea
- Pain in the esophagus, especially between and after meals at night
- Nausea
- Wheezing
- Vomiting blood
- Malnourishment
- Loss of appetite
- Malabsorption
Nearly 25 percent of patients with gastrinomas have multiple tumors as part of a condition called multiple endocrine neoplasia type 1. MEN I patients have tumors in their pituitary gland and parathyroid glands, in addition to tumors of the pancreas.
Pathophysiology
Gastrin works on the parietal cells of the gastric glands, causing them to secrete more hydrogen ions into the stomach lumen. In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell hyperplasia. Normally, hydrogen ion secretion is controlled by a negative feedback loop by gastric cells to maintain a suitable pH, however, the neuroendocrine tumor that is present in individuals with Zollinger–Ellison Syndrome has no regulation, resulting in excessively large amounts of secretion. Thus, there is an increase in the number of acid-secreting cells, and each of these cells produces acid at a higher rate. The increase in acidity contributes to the development of peptic ulcers in the stomach, duodenum and occasionally the jejunum, the last of which is an 'atypical' ulcer.Diagnosis
Zollinger–Ellison syndrome may be suspected when the above symptoms prove resistant to treatment when the symptoms are especially suggestive of the syndrome, or when endoscopy is suggestive. The diagnosis is made through several laboratory tests and imaging studies:- Secretin stimulation test, which measures evoked gastrin levels. Note that the mechanism underlying this test is in contrast to the normal physiologic mechanism whereby secretin inhibits gastrin release from G cells. Gastrinoma cells release gastrin in response to secretin stimulation, thereby providing a sensitive means of differentiation.
- Fasting gastrin levels on at least three occasions
- Gastric acid secretion and pH
- An increased level of chromogranin A is a common marker of neuroendocrine tumors.
Diagnosis can sometimes be very difficult, especially considering patients who take a proton pump inhibitor medication for gastric reflux, which constitute a large and increasing proportion of people who develop Zollinger–Ellison syndrome. PPIs inadvertently increase gastrin production, which may cause a false positive for elevated gastrin levels. This can occur even in patients who have been off their medication for weeks, due to the long duration of effects of these medications.