Zollinger–Ellison syndrome (Z-E syndrome) is a disease in which tumors cause the stomach to produce too much acid, resulting in

peptic ulcer Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines ...

s. Symptoms include

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

and

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

. The syndrome is caused by a

gastrinoma Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger–Ellison syndrome (ZES). A large number of gastrinomas develop in the pancreas or duod ...

, a

neuroendocrine tumor Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine ( hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lu ...

that secretes a hormone called

gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gast ...

. Too much gastrin in the blood (hypergastrinemia) results in the overproduction of

gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...

by parietal cells in the stomach. Gastrinomas most commonly arise in the duodenum, pancreas or stomach. In 75% of cases Zollinger–Ellison syndrome occurs sporadically, while in 25% of cases it occurs as part of an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

syndrome called

multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. It was first d ...

(MEN 1).

Signs and symptoms

Patients with Zollinger–Ellison syndrome may experience abdominal pain and diarrhea. The diagnosis is also suspected in patients who have severe ulceration of the stomach and small bowel, especially if they fail to respond to treatment. * Chronic diarrhea, including

steatorrhea Steatorrhea (or steatorrhoea) is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may o ...

(fatty stools) * Pain in the esophagus, especially between and after meals at night * Nausea * Wheezing * Vomiting blood * Malnourishment * Loss of appetite *

Malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety ...

Gastrinoma Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger–Ellison syndrome (ZES). A large number of gastrinomas develop in the pancreas or duod ...

s may occur as single tumors or as multiple small tumors. About one-half to two-thirds of single gastrinomas are

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

tumors that most commonly spread to the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

and to

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...

s near the pancreas and small bowel. Nearly 25 percent of patients with gastrinomas have multiple tumors as part of a condition called

(MEN 1). MEN I patients have tumors in their

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...

and parathyroid glands, in addition to tumors of the pancreas.

Pathophysiology

Gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gast ...

works on the parietal cells of the

gastric glands The gastric glands are glands in the lining of the stomach that play an essential role in the process of digestion. All of the glands have mucus-secreting foveolar cells. Mucus lines the entire stomach, and protects the stomach lining from the ...

, causing them to secrete more

hydrogen ion A hydrogen ion is created when a hydrogen atom loses or gains an electron. A positively charged hydrogen ion (or proton) can readily combine with other particles and therefore is only seen isolated when it is in a gaseous state or a nearly particle ...

s into the stomach lumen. In addition, gastrin acts as a

trophic factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...

for parietal cells, causing parietal cell

hyperplasia Hyperplasia (from ancient Greek ὑπέρ ''huper'' 'over' + πλάσις ''plasis'' 'formation'), or hypergenesis, is an enlargement of an organ or tissue caused by an increase in the amount of organic tissue that results from cell proliferatio ...

. 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

s in the stomach,

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

(first portion of the small bowel) and occasionally the jejunum (second portion of the small bowel), 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 An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are inse ...

is suggestive. The diagnosis is made through several laboratory tests and imaging studies: *

Secretin Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the du ...

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

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 (normal basal gastric acid secretion is less than 10 mEq/hour; in Zollinger–Ellison patients, it is usually more than 15 mEq/hour) * An increased level of chromogranin A is a common marker of neuroendocrine tumors. In addition, the source of the increased gastrin production must be determined using MRI or somatostatin receptor scintigraphy.

Treatment

Proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...

s (such as omeprazole and lansoprazole) and histamine

H2-receptor antagonist H2 antagonists, sometimes referred to as H2RAs and also called H2 blockers, are a class of medications that block the action of histamine at the histamine H2 receptors of the parietal cells in the stomach. This decreases the production of st ...

s (such as famotidine and ranitidine) are used to slow acid secretion. Once gastric acid is suppressed, symptoms normally improve. Surgery to remove peptic ulcers or tumors might also be considered.

Epidemiology

The condition most commonly affects people between the ages of 30 and 60. The prevalence is unknown, but estimated to be about 1 in 100,000 people.

History

Sporadic reports of unusual cases of peptic ulceration in the presence of pancreatic tumors occurred prior to 1955, but R. M. Zollinger and E. H. Ellison, surgeons at

Ohio State University The Ohio State University, commonly called Ohio State or OSU, is a public land-grant research university in Columbus, Ohio. A member of the University System of Ohio, it has been ranked by major institutional rankings among the best pub ...

, were the first to postulate a causal relationship between these findings. The American Surgical Association meeting in Philadelphia in April 1955 heard the first public description of the syndrome, and Zollinger and Ellison subsequently published their findings in '' Annals of Surgery''.

References

External links

{{DEFAULTSORT:Zollinger-Ellison syndrome Disorders of endocrine pancreas Syndromes affecting the gastrointestinal tract Diseases of oesophagus, stomach and duodenum Steatorrhea-related diseases Rare diseases