Zollinger-Ellison Syndrome (ZES)

What happens in Zollinger-Ellison syndrome

Gastrin is a hormone that normally tells the stomach to make acid after a meal. A gastrinoma releases gastrin constantly, regardless of meals and without the usual feedback that switches it off. The stomach lining thickens and pours out acid, often several times the normal amount.

That acid:

• erodes the lining of the stomach, duodenum and even the jejunum, causing ulcers
• inflames the esophagus, causing severe reflux
• overwhelms the small intestine, inactivating the pancreatic enzymes and damaging the lining, which causes diarrhea and poor fat absorption

Where gastrinomas are found

Most gastrinomas (about 60% to 80%) lie in the wall of the duodenum; most of the rest are in the pancreas. Many are small, under 1 cm. More than half are malignant at diagnosis, most often spreading to nearby lymph nodes and later the liver, though they usually grow slowly. They belong to the family of neuroendocrine tumors.

Sporadic vs MEN1-related ZES

Multiple endocrine neoplasia type 1 is an inherited condition. Everyone diagnosed with ZES should have blood calcium and parathyroid hormone checked and be asked about family history; genetic testing is offered when MEN1 is suspected.

Symptoms

• Abdominal pain: burning or gnawing pain in the upper abdomen from peptic ulcers, often recurrent.
• Heartburn and acid reflux, sometimes with esophageal narrowing.
• Diarrhea: watery or fatty, often improves dramatically on proton pump inhibitors. It can be the only symptom in up to 1 in 10 people.
• Nausea, vomiting and weight loss.
• Complications: ulcer bleeding (black stools, anemia), perforation, or narrowing of the stomach outlet.

Clues that point to ZES

• ulcers without H. pylori infection or NSAID use
• multiple ulcers, or ulcers in unusual places (beyond the duodenal bulb, in the jejunum)
• ulcers that do not heal with standard treatment or come back quickly
• ulcers with diarrhea
• thick stomach folds on endoscopy
• ulcers in someone with high calcium, kidney stones or a family history of MEN1

How ZES is diagnosed

1. Fasting serum gastrin: gastrin is high in almost everyone with ZES. However, proton pump inhibitors (PPIs), atrophic gastritis and kidney failure also raise gastrin, so the result must be interpreted with stomach acidity.
2. Gastric pH: a fasting gastrin more than 10 times the upper limit of normal with a stomach pH of 2 or less is essentially diagnostic.
3. Secretin stimulation test: IV secretin normally lowers gastrin; in ZES it causes a sharp rise (an increase of about 120 pg/mL or more). Used when gastrin is only moderately raised.
4. Stopping PPIs: testing is more accurate off PPIs, but stopping them can cause dangerous ulcer complications. This should only be done by a specialist, sometimes switching temporarily to H2 blockers.
5. Endoscopy: shows ulcers, thick folds and esophagitis; biopsies.
6. Tumor localization: somatostatin receptor PET-CT (for example gallium-68 DOTATATE) is the most sensitive scan; contrast CT, MRI and endoscopic ultrasound add detail.
7. Chromogranin A and MEN1 screening tests (calcium, parathyroid hormone, prolactin).

Treatment

Controlling acid

High-dose proton pump inhibitors (such as omeprazole, esomeprazole or pantoprazole), often taken twice daily at doses well above standard, control acid in almost everyone, heal ulcers and stop diarrhea. Treatment is usually lifelong unless the tumor is cured. Long-term high-dose PPIs can lower vitamin B12, so levels are checked.

Surgery

• Sporadic gastrinoma without spread to the liver: surgery to remove the tumor and nearby lymph nodes is recommended because it can cure the disease and reduce the risk of liver spread. Duodenal tumors are often found by opening the duodenum during surgery.
• MEN1-related ZES: tumors are usually multiple and small; surgery is generally reserved for pancreatic tumors larger than about 2 cm. Treating overactive parathyroid glands first can lower gastrin and acid.

Advanced or spread disease

• Somatostatin analogs (octreotide, lanreotide) slow tumor growth and reduce gastrin.
• Peptide receptor radionuclide therapy (PRRT) with lutetium-177 dotatate for tumors that take up somatostatin tracers.
• Targeted drugs such as everolimus or sunitinib, and chemotherapy for pancreatic neuroendocrine tumors.
• Liver-directed treatments: surgery, ablation or embolization of liver metastases.

Outlook

With modern acid control, people rarely die from ulcer complications. Long-term outlook depends on the tumor. When there is no liver spread, 10-year survival is high (around 90% in large series). Spread to the liver lowers survival, but many people still live for years because gastrinomas often grow slowly. Lifelong follow-up with gastrin levels and imaging is needed.

Frequently asked questions

What are the symptoms of Zollinger-Ellison syndrome?

The main symptoms are burning upper abdominal pain from peptic ulcers, heartburn, and chronic diarrhea, often with weight loss. Ulcers tend to be multiple, recurrent or in unusual places. Some people first present with a bleeding or perforated ulcer.

How is Zollinger-Ellison syndrome diagnosed?

Doctors measure fasting gastrin together with stomach acidity. A very high gastrin with a stomach pH of 2 or less strongly suggests ZES. A secretin stimulation test confirms borderline cases, and somatostatin receptor PET scans locate the tumors.

Is Zollinger-Ellison syndrome cancer?

Gastrinomas are neuroendocrine tumors, and more than half are malignant, meaning they can spread to lymph nodes or the liver. They usually grow slowly. Many people live a long time with good treatment, and some are cured by surgery.

What is the link between Zollinger-Ellison syndrome and MEN1?

About 20% to 25% of people with ZES have multiple endocrine neoplasia type 1, an inherited condition that also causes overactive parathyroid glands and pituitary tumors. Everyone with ZES should have calcium and parathyroid hormone tested, and family members may need screening.

Can Zollinger-Ellison syndrome be cured?

Some people with a single sporadic gastrinoma that has not spread to the liver are cured by surgery. In MEN1 or with liver spread, cure is less likely, but high-dose proton pump inhibitors and tumor treatments control symptoms and slow progression for many years.