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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 is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...
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. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
and
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
. The syndrome is caused by the formation of 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 duo ...
, 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. ...
. High levels of gastrin in the blood (hypergastrinemia) trigger the
parietal cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions o ...
s of the stomach to release excess
gastric acid Gastric acid or stomach acid is the acidic component – hydrochloric acid – of gastric juice, produced by parietal cells in the gastric glands of the stomach lining. In humans, the pH is between one and three, much lower than most other a ...
. 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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
syndrome called multiple endocrine neoplasia type 1 (MEN 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 (GERD) 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 Steatorrhea (or steatorrhoea) is the presence of excess fat in Human feces, 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 incon ...
(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 varie ...
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 duo ...
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; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
tumors that most commonly spread to the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
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 multiple endocrine neoplasia type 1 (MEN 1). MEN I patients have tumors in their
pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
and
parathyroid gland Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...
s, 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. ...
works on the
parietal cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions o ...
s of the gastric glands, 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 particl ...
s into the stomach lumen. In addition, gastrin acts as a trophic factor 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 Tissue (biology), organic tissue that results from ...
. Normally, hydrogen ion secretion is controlled by a
negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
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 ulcer Peptic ulcer disease is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...
s in the stomach,
duodenum The duodenum is the first section of the small intestine in most vertebrates, including mammals, reptiles, and birds. In mammals, it may be the principal site for iron absorption. The duodenum precedes the jejunum and ileum and is the shortest p ...
(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 insert ...
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 duodenum ...
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 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. ...
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 Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
or somatostatin receptor scintigraphy. Diagnosis can sometimes be very difficult, especially considering patients who take a
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. The body eventually synthesizes ne ...
(PPI) 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 A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test resu ...
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.


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. The body eventually synthesizes ne ...
s (such as omeprazole and lansoprazole) and histamine H2-receptor antagonists (such as
famotidine Famotidine, sold under the brand name Pepcid among others, is a histamine H2 receptor antagonist medication that decreases stomach acid production. It is used to treat peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–E ...
and
ranitidine Ranitidine, previously sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It was commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellis ...
) 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 Robert M. Zollinger and Edwin H. Ellison, surgeons at
Ohio State University The Ohio State University (Ohio State or OSU) is a public university, public Land-grant university, land-grant research university in Columbus, Ohio, United States. A member of the University System of Ohio, it was founded in 1870. It is one ...
, were the first to postulate a causal relationship between these findings. The
American Surgical Association The American Surgical Association is the oldest surgical organization in the United States. History It was founded in 1880. Their publication, ''Annals of Surgery'', was started in 1885. A collection of the association's papers are held at the Na ...
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 The ''Annals of Surgery'' is a monthly peer-reviewed medical journal of surgery, surgical science and practice. It was started in 1885 by Lippincott Williams & Wilkins (United States, United Kingdom). See also * List of medical journals Referen ...
''.


References

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