What Is Zollinger-Ellison Syndrome?

Zollinger-Ellison syndrome (ZES) is a rare condition that causes heartburn and severe ulcers in the stomach and small intestine. The name comes from the two surgeons — Dr. Zollinger and Dr. Ellison — who discovered the disease in the 1950s. Two patients had severe, untreatable stomach ulcers. During surgery, the surgeons found the source of the problem: a tumor called a gastrinoma. 

ZES typically affects men in their 30s to 50s, but women can be affected, too. ZES can be hereditary (but not always) and the tumors that cause it are often cancerous. In this article, we review the causes, symptoms, diagnosis, and treatment of ZES.

What causes Zollinger-Ellison syndrome?

ZES is caused by a neuroendocrine tumor (gastrinoma) that releases gastrin. Gastrin is a normal hormone that triggers stomach cells to release stomach acid, which helps with digestion. We need gastrin and stomach acid to digest food properly. But too much acid can be harmful to the stomach. The acid starts to digest the lining of the stomach itself, causing heartburn and ulcers.

Most gastrinomas are located in the pancreas or the first part of the small intestine, called the duodenum. About 5% to 15% of gastrinomas spring up in other locations. And 60% to 90% of gastrinomas are cancerous and may spread to other organs (metastasize).

Is Zollinger-Ellison syndrome hereditary?

Sometimes. About 20% to 30% of ZES cases are related to Multiple Endocrine Neoplasia Type 1 (MEN1). MEN1 is a genetic condition associated with tumors. These tumors come from endocrine glands, which make hormones. MEN1 is caused by a mutation (change) in the MEN1 gene. The mutation can be inherited from your birth parents or happen by chance.

The majority of ZES cases (about 80%) are sporadic. That is, they just happen. These aren’t related to an underlying genetic condition.

What are the symptoms of Zollinger-Ellison syndrome?

The symptoms of ZES make sense when we think about the root of the problem, specifically too much stomach acid. 

When too much acid drenches the stomach, symptoms include:

• Heartburn (acid reflux or GERD), which is a burning, gnawing sensation from the upper chest to the throat

• Nausea and vomiting

• Abdominal pain

• Stomach or intestinal bleeding, which can be caused by severe ulcers

When gastric acid overflows into the small intestine, symptoms include:

• Chronic diarrhea: Gastric acid shuts down enzymes in the small intestine that digest food, and it damages cells that absorb nutrients. When food isn’t digested or absorbed properly, diarrhea results.

• Weight loss: When food isn’t digested or absorbed properly, it’s hard to get all the nutrients we need. This results in weight loss.

How is it diagnosed?

The toughest part of diagnosing ZES is suspecting it in the first place. The average time to diagnosis of ZES is 5 years. But why is that? Well, heartburn (or GERD) is super common. First-choice treatment involves acid-lowering medications, which are cheap and effective for most people. These medications can help treat ZES symptoms, which further delays testing. Also, ZES is a rare cause of heartburn, so it doesn’t make sense to test for it right away.

When people have ongoing symptoms of GERD, they may have a procedure called upper endoscopy. This involves inserting a small camera into the stomach to take a look at the stomach lining. Upper endoscopy can give providers a better idea of what the inside of the stomach looks like, and it can help diagnose ulcers. 

Testing for ZES might make sense if you have:

• Multiple ulcers

• Ulcers below the first part of the small intestine (duodenum)

• Ulcers that don’t improve with maximum dose acid-lowering medication

• Ulcers and chronic diarrhea

• A known diagnosis of MEN1

• Ulcers and a family history of MEN1

Tests for ZES include blood tests and stomach acid tests. Even when ZES is suspected, testing isn’t that straightforward. Acid-lowering medications can affect test results, making ZES hard to catch. 

If testing does suggest ZES, the next step is finding the tumor. Gastrinomas are notoriously hard to find, so several different tests might be needed. Tests to locate gastrinomas include: 

• Upper endoscopy

• CT or MRI scans

• Octreotide scans, a radioactive substance that sticks to gastrinomas is injected into your vein, and then a special scan finds where the octreotide went

• Exploratory surgery (laparotomy), a procedure in which a surgeon opens up your belly to physically look for the tumor

What tests are needed to determine if Zollinger-Ellison is hereditary?

Since 20% to 30% of ZES is hereditary, testing for MEN1 is important for all people with ZES. And, if ZES is hereditary, treatment options change. 

Testing involves a blood test that looks for mutations in the MEN1 gene. Even if you have no family history of MEN1, testing is still needed. That’s because 10% of people with MEN1 have no family history of it. The gene mutation just happened on its own.

How do you treat Zollinger-Ellison syndrome?

Treatment of ZES involves acid-lowering medications, surgery, or both. What’s needed depends on whether:

• ZES is hereditary

• The tumor has stayed in one place or has metastasized

Current guidelines recommend surgery for people with sporadic ZES (not hereditary) that has not metastasized. Surgery might be curative for 20% to 45% of these people. 

If ZES is hereditary or tumors have metastasized, surgery is typically not recommended. Surgery is unlikely to cure disease in this case, so the risks of surgery often outweigh the benefits. Instead, treatment includes medications. Examples include:

• Proton pump inhibitors (PPI’s) — like pantoprazole (Protonix) or lansoprazole (Prevacid) — which block the production of stomach acid

• Histamine-2 antagonists (H2 blockers), like famotidine, which also block stomach acid production, though not as well as PPIs 

Can Zollinger-Ellison syndrome be cured?

When surgery is an option, it may cure ZES for 20% to 45% of people. Even when surgery isn’t an option, medications can help extend and improve the quality of life of people with ZES. A small percentage of ZES cases can be aggressive, so frequent follow-up with your healthcare provider is important.

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Written by:

Samantha C. Shapiro, MD

Samantha Shapiro, MD, is a board-certified rheumatologist and internist with expertise in autoimmune and inflammatory conditions. She founded the division of rheumatology at Dell Medical School at The University of Texas at Austin.

Edited by:

Mandy Armitage, MD

Mandy Armitage, MD, has combined her interests in clinical medicine with her passion for education and content development for many years. She served as medical director for the health technology companies HealthLoop (now Get Well) and Doximity.

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