What is Zollinger-Ellison Syndrome?
Zollinger-Ellison syndrome (ZES) is a condition that involves serious stomach ulcers, acid reflux, and ongoing diarrhea. It is caused by a tumor, often located in the small intestine or pancreas, that produces an excess amount of the hormone gastrin. This hormone stimulates the cells of the stomach to produce more acid. This type of tumor is known as a gastrinoma (see image. Gastrinoma on Distal Pancreas).
While it was initially thought that most gastrinomas occur in the pancreas, we now understand that they are actually more likely to be found in the small intestine, especially in the beginning part of it. There are other types of tumors that can also produce gastrin, but usually not in amounts sufficient to cause significant symptoms.
ZES primarily occurs on its own, in almost 80% of the cases, and is related to a genetic disorder known as multiple endocrine neoplasia type 1 (MEN1) in about 20% to 25% of cases, according to multiple scientific reports. Hence, if a healthcare provider suspects ZES, they might look for signs of MEN1 too, as half the patients with MEN1 can have ZES.
Diagnosing ZES can take a while, with an average of 8 years from the appearance of symptoms to diagnosis, largely because of the common usage of medications known as proton pump inhibitors (PPIs). PPIs can effectively control the symptoms of ZES, which unfortunately can delay diagnosis. In fact, one study involving two referral centers in Italy and the USA showed a 62% decrease in ZES diagnosis due to the widespread use of PPIs.
ZES was first described in a medical journal in 1955 by two surgeons from Ohio State University, Dr. Robert M. Zollinger and Edwin H. Ellison. They reported cases of patients with ulcers in the small intestine and excessive stomach acid production that were resistant to medicine and surgical treatment, including the removal of the stomach. The condition ultimately linked to excessive stomach acid production and repeated stomach ulcers turned out to be caused by a specific type of tumor in the pancreas. This discovery sparked interest and led to further studies to understand the connection between gastrin-secreting tumors and ZES.
What Causes Zollinger-Ellison Syndrome?
Zollinger-Ellison Syndrome (ZES) happens when a special kind of abnormal tumor, known as an ectopic neuroendocrine gastrin-secreting tumor, stimulates the cells in the stomach that produce acid. Gastrin is a hormone that aids in digestion. In this case, it leads to stomach lining damage, which can develop into sores or ulcers.
Risk Factors and Frequency for Zollinger-Ellison Syndrome
Proton Pump Inhibitors (PPIs) are used more often nowadays, making it hard to diagnose Zollinger-Ellison Syndrome (ZES) early. ZES is quite rare, with only 0.1% to 1% of people with peptic ulcer disease (PUD) having this condition. It’s noted that between 25% and 30% of ZES patients also have Multiple Endocrine Neoplasia Type 1 (MEN1), a condition causing growth of abnormal cells or tumors in the pituitary, parathyroid, and pancreatic islet cells. This could trigger an excess production of stomach acid due to high calcium levels. The overlap between ZES and PUD makes estimating the incidence rate of ZES difficult, and an accurate rate cannot be specified. However, gastrinomas (tumors that produce excessive amounts of the hormone gastrin) are found in about 0.1 to 3 people per million. Interestingly, ZES has been reported more in females than males, and is seen in all age groups.
Signs and Symptoms of Zollinger-Ellison Syndrome
Zollinger-Ellison Syndrome (ZES) is a condition that often starts with long-lasting symptoms due to an excess of gastrin, a hormone that stimulates stomach acid. The most common sign of ZES is abdominal pain. However, patients may also experience diarrhea and heartburn. Due to malabsorption, these individuals often go through periods of excessive acid secretion that can lead to weight loss and chronic diarrhea. In some cases, patients can test negative for Helicobacter pylori and may still have symptoms even after taking Proton Pump Inhibitors (PPIs). It’s also possible for ZES to occur with another condition called MEN1, which can result in a family history of endocrine disorders or persistent Peptic Ulcer Disease (PUD) at a young age. These endocrine issues may include unusually high calcium levels and kidney stones caused by overactive parathyroid glands or tumors.
- Abdominal pain
- Diarrhea
- Heartburn
- Weight loss
- Chronic diarrhea
- Persistent symptoms despite medication
- Possible history of endocrine disorders or peptic ulcers
Testing for Zollinger-Ellison Syndrome
To diagnose Zollinger-Ellison syndrome (ZES), a condition where one or more tumors in your pancreas cause ulcers in the stomach and small intestine, you’ll need to stop taking certain medications, such as Proton Pump Inhibitors (PPIs) for at least a week, or H2-receptor antagonists for 48 hours. The first step in diagnosis involves testing your blood for a chemical called gastrin when you haven’t eaten recently.
This test is highly accurate and people with a specific type of tumor called gastrinoma typically show gastrin levels above 100 pg/ml, and it’s extremely likely to be gastrinoma if the level is above 1000 pg/ml. However, for people who have genetic condition multiple endocrine neoplasia type 1 (MEN1) and have had a surgery to remove the parathyroid glands, the levels of gastrin in their blood may return to normal even though they still have ZES.
Other tests include the basal acid output test, which measures the amount of acid in your stomach and gastric pH, which evaluates the acidity of the stomach. These are also highly accurate. Depending on the circumstance, the gastric acid levels can give solid indications of gastrinoma. Another common test, the secretin stimulation test, measures your body’s gastrin levels for up to 15 minutes after you’ve been given secretin, a hormone that causes your stomach to release a digestive juice. If the test shows a gastrin level of 200 pg/ml or more, it’s likely you have ZES.
If your doctor suspects you have ZES, they might also do some tests to look for MEN1. These tests may include measuring the levels of substances in your blood like calcium, parathyroid hormone, prolactin, and pancreatic polypeptide. MEN1 is suspected if you have high levels of calcium in your blood, a condition known as hyperparathyroidism, and surgery to remove the parathyroid glands is often recommended.
Your doctor might also want to take pictures of the inside of your body to look for the gastrinoma or any places it may have spread to. There are many ways to do this – CT scans, MRI scans, a test that is more sensitive than CT and MRI which involves a drug called octreotide that attaches to the gastrinoma cells, or a PET scan to look for any gastrinoma that has spread to other parts of the body. Additionally, procedures like endoscopic ultrasound to have a closer look at the pancreas and esophagogastroduodenoscopy to see any abnormalities in your esophagus, stomach, and the first part of your small intestine can be done.
Treatment Options for Zollinger-Ellison Syndrome
Before the 1970s and 1980s, the only available treatment for Zollinger-Ellison Syndrome (ZES) was a total removal of the stomach, known as a total gastrectomy. Thanks to the discovery of medications called H2-receptor antagonists and proton pump inhibitors (PPIs), treatments expanded.
Proton pump inhibitors, such as oral omeprazole and intravenous pantoprazole, help to decrease stomach acid production. These are usually taken twice daily on an empty stomach. The dose needs to be adjusted for every patient to ensure that stomach acid production is reduced to a safe level. For the small number of patients who cannot tolerate PPIs, H2-receptor antagonists, another type of drug that reduces stomach acid, are an option.
Patients with ZES often have an associated condition called multiple endocrine neoplasia type 1 (MEN1), which can cause overactivity in the parathyroid glands leading to high calcium levels in the blood, known as hypercalcemia. This can make the symptoms of ZES worse as it increases gastrin levels, a hormone that stimulates acid secretion in the stomach. Surgery to remove most of the parathyroid glands, known as a subtotal parathyroidectomy, can improve symptom control and may even normalize abnormal gastrin levels.
It’s important to note that patients with ZES and MEN1 often have multiple tumors with a low cure rate. Therefore, a tumor is only removed if its size is greater than 2 cm. Surgical exploration is an option for patients with sporadic gastrinomas, a rare condition where a tumor forms in the cells that make gastrin, due to the high chance of the tumor spreading to the liver, lymph nodes, and other distant organs.
Those with advanced disease may need to explore non-surgical options, involving a team of healthcare professionals. These options can include chemotherapy with drugs such as everolimus or sunitinib, somatostatin analogs, interferon, and procedures such as chemoembolization, radioembolization, and radiofrequency ablation.
What else can Zollinger-Ellison Syndrome be?
Hypergastrinemia is a medical condition where there’s an excess of the hormone gastrin in the blood. Several factors or conditions could be the cause of this, including:
- Surgery involving cutting the vagus nerve (vagotomy)
- Peptic ulcer disease (PUD) arising from a Helicobacter pylori infection
- Regular use of nonsteroidal anti-inflammatory drugs (like ibuprofen or aspirin)
- Obstruction in the stomach passage
- Kidney diseases
- Short bowel syndrome
- Autoimmune gastritis, a type of chronic inflammation in the stomach
The overuse of nonsteroidal anti-inflammatory drugs like ibuprofen and aspirin can cause peptic ulcers. It might be tricky for a doctor to differentiate between stomach pain from ulcers and Zollinger-Ellison Syndrome (ZES) because they have similar symptoms. However, ZES also results in diarrhea and esophageal disease.
Helicobacter pylori, a type of bacteria, produces an enzyme called urease that interacts with cells in your stomach causing inflammation and imbalance in the stomach function. If your stomach outlet becomes obstructed, it causes your stomach to stretch and indirectly induces more gastrin production.
People with chronic or severe kidney disease, including those undergoing dialysis, often have high levels of gastrin because the kidney is less effective in clearing the hormone from the blood. Studies on rat models have shown increased cell growth in the stomach when kidneys are not functioning properly, causing less protection in the stomach lining.
Similarly, blocking of the stomach outlet can cause the stomach to enlarge, which causes more gastrin to be produced.
What to expect with Zollinger-Ellison Syndrome
Zollinger-Ellison Syndrome (ZES) is a condition that involves a tumor known as gastrinoma. The seriousness of this disease can depend on the stage of the cancer. Gastrinomas are often quite severe, with 60% to 90% of these tumours spreading to lymph nodes, liver, or other organs in the body. About half of the gastrinomas that start in the pancreas end up in the liver, while this number is about 10% for gastrinomas that start in the upper part of the small intestine (duodenum).
The effect of these gastrinomas on survival rates can be significant. For example, pancreatic gastrinomas that spread to the liver directly impact survival rates. Patients with liver involvement typically have a 15% chance of survival 10 years after surgery. However, if the cancer has not spread to the liver, the survival rate jumps up to 95% after 20 years. This is a significant observation. In contrast, while duodenal gastrinomas have a higher chance of spreading to lymph nodes than pancreatic gastrinomas (70% versus 40%), this does not impact survival if the liver is not involved.
Possible Complications When Diagnosed with Zollinger-Ellison Syndrome
Complications related to acid production can include bleeding and perforation or holes in the digestive tract, which includes the esophagus, stomach, and duodenum. Serious complications could also occur such as death during surgery aimed at removing a type of tumor called a gastrinoma or other cancers associated with a condition known as MEN1.
Common Complications:
- Bleeding in the digestive tract
- Perforation or holes in the esophagus, stomach, or duodenum
- Severe issues occurring from surgery to remove tumours such as gastrinomas
- Death during surgery
Preventing Zollinger-Ellison Syndrome
Doctors need to advise their patients on the importance of taking Proton Pump Inhibitors (PPIs) as directed to help manage the symptoms of Zollinger-Ellison Syndrome (ZES). ZES is a condition characterized by the overproduction of stomach acid. PPIs are medications that reduce the production of stomach acid. In addition to medication, patients should consistently get lab tests done to measure how effective the medications are. Regular testing and medication adherence can help lower the chances of ZES recurring or causing other complications.
Although ZES, particularly when associated with Multiple Endocrine Neoplasia Type 1 (MEN1, a condition that affects the body’s glands and hormone production), has a relatively low cure rate, it’s crucial for patients to keep up regular meetings with their doctors. Seeking help and staying engaged with their healthcare, even if a complete cure isn’t always possible, can still significantly improve their quality of life.
