Zollinger-Ellison syndrome is a condition that occurs when one or more tumors—called gastrinomas, which are located mainly in your pancreas or duodenum—cause your stomach to make too much acid. Too much acid in your stomach can lead to symptoms, such as diarrhea, and health complications, including peptic ulcer disease and gastroesophageal reflux disease (GERD).

The pancreas and the first part of the small intestine, called the duodenum

Zollinger-Ellison syndrome is rare. Only 0.5 to 3 out of every 1 million people are diagnosed with Zollinger-Ellison syndrome each year.

While anyone can have Zollinger-Ellison syndrome, the condition is most often diagnosed in people ages 20 to 50 years old. Zollinger-Ellison syndrome is slightly more common in men than in women.

About 80% of cases of Zollinger-Ellison syndrome is unrelated to other conditions, but 20% to 25% of cases occur in people who have a rare, genetic disorder called multiple endocrine neoplasia type 1 (MEN1). People with a family history of MEN1 are more likely to have MEN1 and Zollinger-Ellison syndrome.

Tumors, called gastrinomas, that form mainly in the pancreas and duodenum cause Zollinger-Ellison syndrome. Gastrinomas release large amounts of a hormone called gastrin. Normally, your body releases a small amount of gastrin after you eat, and gastrin triggers your stomach to make acid. When gastrinomas release large amounts of gastrin, your stomach makes too much acid, which leads to Zollinger-Ellison syndrome.

In most cases of Zollinger-Ellison syndrome, experts don’t know what causes the gastrinomas to form. In about 20% to 25% of cases, a rare genetic disorder called MEN1 causes gastrinomas to form.

Normal Function

The MEN1 gene provides instructions for making a protein called menin. This protein acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. Although the exact function of menin is unclear, it is likely involved in several important cell functions. For example, it may play a role in copying and repairing DNA and regulating the controlled self-destruction of cells (apoptosis). The menin protein is present in the nucleus of many different types of cells and appears to be active in all stages of development.

Menin interacts with many other proteins, including several transcription factors. Transcription factors bind to specific areas of DNA and help control whether particular genes are turned on or off. Some of these genes likely play a role in cell growth and division. Researchers are working to identify the proteins that interact with menin and determine its specific role as a tumor suppressor.

Health Conditions Related to Genetic Changes

Familial isolated hyperparathyroidism

Mutations in the MEN1 gene have been found in some cases of familial isolated hyperparathyroidism, a condition characterized by overactivity of the parathyroid glands (primary hyperparathyroidism). These glands help control the normal balance of calcium in the blood. This balance is disrupted in familial isolated hyperparathyroidism, which can lead to high blood calcium levels (hypercalcemia), kidney stones, thinning of bones, nausea and vomiting, high blood pressure (hypertension), weakness, and fatigue. Primary hyperparathyroidism is the most common sign of another condition called multiple endocrine neoplasia type 1 (described below); however, familial isolated hyperparathyroidism is diagnosed in people with hyperparathyroidism but not the other features of multiple endocrine neoplasia type 1.

Many of the mutations in the MEN1 gene that are associated with familial isolated hyperparathyroidism change single protein building blocks (amino acids) in the menin protein. It is thought that these amino acid changes impair menin's ability to interact with other proteins. Without normal menin function, cells likely divide too frequently, leading to the formation of tumors involving the parathyroid glands. Researchers speculate that the mutations that cause familial isolated hyperparathyroidism have a milder effect on the function of menin than the mutations that cause multiple endocrine neoplasia type 1. Occasionally, individuals with familial isolated hyperparathyroidism later develop features of multiple endocrine neoplasia type 1, although most never do. Familial isolated hyperparathyroidism caused by MEN1 gene mutations may be an early or mild form of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia

More than 1,300 mutations in the MEN1 gene have been found to cause multiple endocrine neoplasia type 1. Multiple endocrine neoplasia typically involves the development of tumors in two or more of the body's hormone-producing glands, called endocrine glands. These tumors can be noncancerous or cancerous. The most common endocrine glands affected in multiple endocrine neoplasia type 1 are the parathyroid glands, the pituitary gland, and the pancreas, although additional endocrine glands and other organs can also be involved.

Most of the MEN1 gene mutations that cause multiple endocrine neoplasia type 1 lead to the production of an abnormally short, inactive version of menin or an unstable protein that is rapidly broken down. As a result of these mutations, one copy of the MEN1 gene in each cell makes no functional protein. If the second copy of the MEN1 gene is also altered, the cell has no working copies of the gene and does not produce any functional menin. For unknown reasons, a second mutation occurs most often in cells of the endocrine glands. Without menin, these cells can divide too frequently and form a tumor. Although menin appears to be necessary for preventing tumor formation, researchers have not determined how a lack of this protein leads to the specific tumors characteristic of multiple endocrine neoplasia type 1.

Primary macronodular adrenal hyperplasia

MedlinePlus Genetics provides information about Primary macronodular adrenal hyperplasia

Other tumors

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the MEN1 gene have been identified in several types of nonhereditary (sporadic) tumors. Specifically, MEN1 gene mutations have been found in a significant percentage of noncancerous tumors of the parathyroid glands (parathyroid adenomas); pancreatic tumors called nonfunctioning neuroendocrine tumors, gastrinomas, and insulinomas; and cancerous tumors of the major airways in the lungs (bronchi) called bronchial carcinoids. Many of these tumor types are also found in people who have multiple endocrine neoplasia type 1 (described above). As in multiple endocrine neoplasia, tumors occur only when both copies of the MEN1 gene are inactivated in certain cells.

Other Names for This Gene

• MEAI
• MEN1_HUMAN
• menin
• multiple endocrine neoplasia I

Genomic Location

Extra stomach acid can cause symptoms similar to those of peptic ulcer disease and GERD, as well as other symptoms. Common symptoms of Zollinger-Ellison syndrome include

• diarrhea, which may sometimes be the only symptom
• burning or dull pain in the abdomen, or belly, between the navel and middle of the chest
• heartburn
• nausea or vomiting
• weight loss

You should see a doctor right away if you have symptoms such as

• chest pain
• persistent vomiting
• problems breathing
• problems or pain while swallowing
• signs of bleeding in the digestive tract
• sudden, sharp stomach pain that doesn’t go away
• weakness or feeling faint

These could be signs of a complication or another serious health problem.

The extra stomach acid caused by Zollinger-Ellison syndrome can lead to peptic ulcer disease or GERD. Without treatment, these diseases can lead to complications such as

• bleeding or perforation in the upper digestive tract
• a blockage that can stop food from moving from your stomach into your duodenum
• esophagitis or esophageal stricture

The tumors that cause Zollinger-Ellison syndrome are sometimes cancerous and may spread to other parts of your body. If the cancer spreads, it most often spreads to lymph
nodes near the tumor and later to the liver and bones.

Doctors will perform a physical exam and ask about your symptoms, medical history, and family medical history. Your doctor may suspect you have Zollinger-Ellison syndrome if you have certain symptoms and signs, such as

• chronic diarrhea that occurs along with GERD or peptic ulcer disease
• peptic ulcer disease that usually is chronic, comes back repeatedly, and is severe or leads to complications
• peptic ulcer disease without Helicobacter pylori (H. pylori) infection or without a history of nonsteroidal anti-inflammatory drug (NSAID) use
• personal or family history of MEN1 or MEN1 symptoms

If your doctor suspects you may have Zollinger-Ellison syndrome, he or she will order tests to diagnose this condition.

Doctors may order the following tests to diagnose Zollinger-Ellison syndrome and find the tumors that cause this condition.

Blood tests

For a blood test, a health care professional will take a blood sample from you and send the sample to a lab.

Doctors may order a blood test to check gastrin levels in your blood after you fast—have nothing to eat or drink except water—for several hours. High gastrin levels could be a sign of Zollinger-Ellison syndrome. Doctors may order another blood test to check gastrin levels after you receive intravenous (IV) secretin—a hormone that causes gastrinomas to produce more gastrin.

Your doctor may ask you to stop or change the medicines you take before these tests. Certain medicines, such as proton pump inhibitors (PPIs), may raise your gastrin levels.

Stomach acid tests

Doctors may order a test to check the pH—or acidity—of your stomach fluids. A health care professional will insert a tube through your nose, down your throat, and into your stomach to take a sample of fluid. Doctors may also measure your stomach acid pH during an upper gastrointestinal (GI) endoscopy.

In some cases, doctors may order additional tests to measure the amount of acid your stomach makes.

Upper GI endoscopy

Upper GI endoscopy is a procedure during which a doctor uses an endoscope—a flexible tube with a camera—to see the lining of your upper GI tract, including your esophagus, stomach, and duodenum. Upper GI endoscopy may show signs of Zollinger-Ellison syndrome or its complications. Doctors may also order this test to look for the tumors that cause Zollinger-Ellison syndrome.

ERCP

Endoscopic retrograde cholangiopancreatography (ERCP) is a procedure that combines upper GI endoscopy and x-rays to examine the bile ducts and pancreatic ducts.

Imaging tests

Doctors may order imaging tests to help find the tumors that cause Zollinger-Ellison syndrome. Small gastrinomas may be hard to see, and doctors may order several types of imaging tests, including

• computed tomography (CT), which uses a combination of x-rays and computer technology to create images
• magnetic resonance imaging (MRI), which takes pictures of your body’s internal organs and soft tissues without using x-rays
• radionuclide scanning, in which you receive an injection of a small amount of radioactive material, and a special camera takes pictures that highlight the radioactive material in gastrinomas
• endoscopic ultrasound, in which a doctor uses an endoscope with an ultrasound attachment to create pictures
• angiography, a special kind of x-ray in which a doctor threads a catheter through your large arteries to inject a special dye that will show up on x-rays

Predictive genetic testing may be available to people with a family history of a genetic condition who have a potential risk of eventually developing the condition. Depending on the condition, a predictive test may show whether a person will definitely develop the condition (pre-symptomatic testing) or has an increased chance to develop the condition (susceptibility testing). Predictive testing may be considered if:

• the condition can be prevented or its symptoms can be treated
• the condition cannot be prevented or treated, but knowing the chance of getting the condition may help with important life decisions (such as decisions about health care, employment, or having children)
• a person can lower the risk to develop the condition by making lifestyle changes, having regular screening, taking preventative drugs, or having preventative surgery (e.g., for some hereditary cancer syndromes)
• a person prefers to live with certainty rather than uncertainty regarding knowing whether they will develop the condition

Even when a predictive test result is positive, it is usually not possible to predict the exact age that symptoms will develop, how fast symptoms will progress, or how a person will be affected. Because there is no going back after a person gets results, it is important to think through some of the main issues before deciding whether to have testing. Each person may have specific concerns relevant to their own situation.Some questions to think about before making a decision may include:

• How might the test results affect me emotionally?
• How might I react if the result reveals that I carry the changed gene? For some people, even a result which shows that they have the changed gene is preferable to the stress and anxiety caused by not knowing.
• How might I react if the result reveals that I do not carry the changed gene?
• What might the test results mean for my children (or future children)? The results of a genetic test will not only tell you about your risk of developing the condition, it will also tell you more about your children's risk.
• What are the implications for other family members? Many family members share the same genes, so testing for one family member may have implications for others.

People who are considering having a predictive genetic test should speak with a genetics professional. Genetics professionals can provide the information needed in order for each person to make the decision that is right for them. They can explain the advantages and disadvantages of having the test; help to discuss any emotions that may arise; and address questions or concerns, including those about reproductive decision-making, privacy, and insurance.

Doctors treat Zollinger-Ellison syndrome with medicines and surgery.

Medicines

Doctors treat Zollinger-Ellison syndrome with PPIs. PPIs lower the amount of acid your stomach makes, which can relieve symptoms and promote healing. Doctors may prescribe a higher dose of PPIs when starting treatment and may lower the dose over time. Many people with Zollinger-Ellison syndrome need lifelong treatment with PPIs.

PPIs are generally safe and effective. Side effects, while uncommon, may include headache, diarrhea, and upset stomach. Long-term use of PPIs to treat Zollinger-Ellison syndrome may lead to low levels of vitamin B12. Experts are still studying the effects of taking PPIs for a long time or in high doses. Talk with your doctor about the risks and benefits of these medicines.

Surgery

Doctors may recommend surgery to remove the tumors that cause Zollinger-Ellison syndrome in people who don’t have MEN1. In some cases, removing the gastrinomas will cure Zollinger-Ellison syndrome and prevent the tumors from spreading to other parts of the body. After surgery, people may still need to take PPIs to control stomach acid.

In people who have MEN1, doctors don’t typically recommend surgery to remove the tumors that cause Zollinger-Ellison syndrome, especially if the gastrinomas are relatively small. People with MEN1 often have many small tumors, making it difficult for surgeons to find and remove them all. Doctors may recommend surgery to remove any larger tumors, which have a higher chance of spreading to other parts of the body.

Treating Zollinger-Ellison syndrome reduces the amount of acid in the stomach, which can help prevent or treat complications related to peptic ulcers or acid reflux.

If gastrinomas are cancerous and spread to the liver, bone, or other parts of the body, doctors may recommend chemotherapy, surgery, or other cancer treatments.