What Is Zollinger-Ellison Syndrome?

  • Helen Maginnis MBChB, BSc. (MedSci) Genetics, University of Glasgow
  • Rajni Sarma MBBS, MD from North-Eastern Hill University, India
  • Nick Gibbins BSc (Hons) Biochemistry, University of Sussex, UK

We all produce gastric (stomach) acid, which is essential for the digestion of food and as a protective mechanism against germs that might otherwise make us unwell. Usually, the production of gastric acid is a tightly regulated process that prevents unpleasant symptoms that can arise when it is overproduced.1

Sometimes, the normal regulation of gastric acid production goes awry. Zollinger-Ellison Syndrome (ZES) describes a group of symptoms that occur when the cells that produce stomach acid are overstimulated by abnormally high levels of a hormone called gastrin. The excess gastrin is produced by a hormone-secreting tumour of the duodenum (part of the small intestine) or pancreas called a gastrinoma.2 In this article, we’ll explore the typical symptoms of ZES, how the condition develops, and what options there are for treatment. 

Overview

Zollinger-Ellison syndrome (ZES) is a condition characterised by the classic symptoms of severe peptic ulcer disease, gastroesophageal reflux disease (GORD; also known as acid reflux), and chronic diarrhoea.2 

ZES arises when a hormone-secreting tumour of the duodenum or pancreas, called a gastrinoma, produces high levels of the hormone gastrin. Gastrin, in turn, stimulates specialised cells in the stomach to produce abnormally high levels of gastric acid, leading to the development of the symptoms described.2

Treatment for ZES comprises treatment for the symptoms of the condition (usually by using medication to suppress gastric acid production) and the treatment of the gastrinoma that is driving the condition.2

Gastrinoma - the driver of zollinger-ellison syndrome 

Most (80%) cases of ZES arise randomly in the population, whilst a significant minority (20%) are linked to the genetic condition multiple endocrine neoplasia type 1 (MEN1).2 In both cases, the condition is driven by the presence of a hormone-secreting tumour, or gastrinoma, that secretes the hormone gastrin.2

Levels of gastric acid in the stomach are carefully regulated, in part by hormones that stimulate or suppress its production. Gastrin stimulates specialised cells in the stomach, called parietal cells, to produce gastric acid.3 

Ordinarily, the increase in stomach acid within the stomach is recognised by another type of cell called a D cell. D cells then secrete a hormone called somatostatin, which suppresses the production of gastric acid by parietal cells both directly and by preventing the release of further gastrin. This balancing act between gastrin and somatostatin allows the production of gastric acid to be tightly controlled.3

The presence of a gastrinoma in the duodenum or pancreas means that extra gastrin is produced that can stimulate parietal cells to produce gastric acid.2

Although D cells in the stomach recognise that the stomach is becoming increasingly acidic, their subsequent release of somatostatin does not stop the gastrinoma from continually producing gastrin. It is this escape from normal feedback mechanisms that means we see the continual production of gastric acid in individuals with ZES.3 In addition, the increased levels of gastrin cause the number of parietal cells to increase, further increasing levels of gastric acid.4

What are the symptoms of zollinger-ellison syndrome?

The stomach is lined with special mucus-producing cells. Ordinarily, this mucus protects the stomach from the acidic gastric acid within it. However, the very high levels of gastric acid found in those with ZES disrupt this mucus barrier, causing damage to the stomach lining underneath.5 As a result, the following symptoms commonly develop:

Severe peptic ulcer disease

Over 99% of people who develop a peptic ulcer do not have ZES. Those with ZES are more likely to have multiple ulcers, which often do not respond to typical treatments.4

Abdominal pain

This is the most common symptom amongst those with ZES and arises due to the presence of peptic ulcers.2 It occurs in around 75% of patients.6

Diarrhoea

High levels of gastrin and gastric acid make it difficult for the body to absorb water and salt from the gut. This leads to diarrhoea in around three-quarters of patients.6 Diarrhoea means that less nutrients are absorbed from food, so some people with ZES lose weight.2

Gastro-oesophageal reflux disease (GORD)

It is also known as acid reflux or heartburn and occurs commonly amongst those with ZES due to high levels of gastric acid.2

How is zollinger-ellison syndrome diagnosed?

If your healthcare team suspect that you could have ZES based on the symptoms you report and their findings on examination, they may suggest the following tests:

Blood tests

A blood test to measure the levels of gastrin in the blood whilst you fast will reveal very high levels of the hormone if you have ZES.2

Tests of pH level within the stomach

Acids have a low pH value. It’s important to measure the pH found within the stomach if ZES is suspected to ensure that high levels of gastrin in the blood have not arisen appropriately (in response to insufficient acid in the stomach). If a person has ZES, the pH within the stomach will be lower than 2. Stomach acid can be obtained using a nasogastric tube or through endoscopy.7 Very high levels of gastrin in the blood combined with a low pH (lower than 2) in the stomach is diagnostic from ZES.7 The next step seeks to locate the gastrinoma that is driving the condition. 

Imaging

Using CT or MRI scanning in combination with a specialised form of PET scanning is a reliable way to locate a gastrinoma and check for tumour spread (metastases).  Small tumours that might not be picked up easily may be detected through endoscopic ultrasound scanning. A sample of any suspicious areas can also be taken during the endoscopy.7 

Genetic testing

If your healthcare team suspects you may have developed ZES as a result of having the genetic condition MEN1, they will discuss the option of a genetic test with you. Only a subset of patients with ZES will be tested for MEN1, usually those with:7

  • More than one type of primary tumour is associated with MEN1 (i.e. these tumours will have arisen separately and not be the result of spread from one original tumour).
  • Additional abnormalities on blood testing suggestive of MEN1 (such as high levels of calcium). 
  • Those with features suggestive of MEN1 who have a parent, child or sibling with the condition. 

If you want to read about MEN1 in more detail, click here.

How is zollinger-ellison syndrome treated?

Treating the symptoms of ZES

The mainstay of treatment for symptoms of ZES is a high dose of a medication called a proton pump inhibitor (PPI). PPI, like omeprazole, reduce the levels of acid in the stomach and controls symptoms for most people with ZES.6, 8 

Treating the gastrinoma

In addition to treating the symptoms of ZES, it’s important to address the root cause - gastrinoma. If the tumour is in an early stage and hasn’t spread, you will likely be offered surgery to remove it. Afterwards, you will be monitored through blood testing and imaging to ensure that the gastrinoma hasn’t recurred.4

Unfortunately, for some people, their gastrinoma can spread to other parts of the body, forming secondary tumours called metastases. Some metastases can be removed surgically if they are localised within an area of the liver. If the metastases are more widespread, you will likely be offered treatment such as chemotherapy to manage symptoms and prolong your life.4

People with ZES associated with MEN1 are more likely to have multiple kinds of primary tumours, as we discussed above. This means that surgery is less likely to cure the condition, and so medical treatment may be preferred.4 If you have ZES associated with MEN1, then speak to your healthcare team to find out more about the best treatment option for you.

What are the complications of zollinger-ellison syndrome?

The main complications from ZES arise from peptic ulcers. They may bleed, causing anaemia, or erode through the lining of your stomach or intestine to cause a perforation. A perforation requires emergency surgery to repair the hole to prevent contents from the gut from entering the abdominal cavity.2 

What is the prognosis for zollinger-ellison syndrome?

Only small studies looking at survival rates of gastrinoma have been conducted. A 2019 Dutch study showed that almost 85% of people live for 5 years or more after diagnosis. 65% of people survive for 10 years or longer.9

Summary

Zollinger-Ellison syndrome occurs when a hormone-secreting tumour called a gastrinoma secretes the hormone gastrin, leading to excess gastric acid production in the stomach. This excess acid erodes the normal protective mucus found in our gastrointestinal tract and damages the tissue beneath. This leads to the development of peptic ulcers, acid reflux symptoms, and chronic diarrhoea. 

The condition is diagnosed through a combination of blood tests, tests on stomach acid, and imaging. Symptoms of ZES are treated with high doses of proton pump inhibitors. If the gastrinoma driving ZES is a solitary tumour, it will be surgically removed, with medical follow-up to monitor for recurrence. For those with metastases, medical treatment to manage symptoms and prolong life, such as chemotherapy, will be offered. 

References

  1. Antunes C, Aleem A, Curtis SA. Gastroesophageal reflux disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK441938/ 
  2. Cho MS, Kasi A. Zollinger-Ellison syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK537344/ 
  3. Phan J, Benhammou JN, Pisegna JR. Gastric hypersecretory states: investigation and management. Curr Treat Options Gastroenterol [Internet]. 2015 Dec [cited 2023 Sep 16];13(4):386–97. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633316/ 
  4. Cingam SR, Botejue M, Hoilat GJ, Karanchi H. Gastrinoma. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK441842/ 
  5. Hsu M, Safadi AO, Lui F. Physiology, stomach. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 17]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK535425/ 
  6. Aamar A, Madhani K, Virk H, Butt Z. Zollinger-ellison syndrome: a rare case of chronic diarrhea. Gastroenterology Res [Internet]. 2016 Dec [cited 2023 Sep 17];9(6):103–4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191898/ 
  7. Rossi RE, Elvevi A, Citterio D, Coppa J, Invernizzi P, Mazzaferro V, et al. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies. World J Gastroenterol [Internet]. 2021 Sep 21 [cited 2023 Sep 17];27(35):5890–907. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475006/ 
  8. Ahmed A, Clarke JO. Proton pump inhibitors(Ppi). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Sep 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557385/ 
  9. van Beek DJ, Nell S, Pieterman CRC, de Herder WW, van de Ven AC, Dekkers OM, et al. Prognostic factors and survival in MEN1 patients with gastrinomas: Results from the DutchMEN study group (DMSG). J Surg Oncol. 2019 Nov;120(6):966–75. 
This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Helen Maginnis

MBChB, BSc. (MedSci) Genetics, University of Glasgow

Helen is a former NHS doctor living in Scotland. She discovered her love for medical writing while working in the charity sector with families affected by Huntington’s disease. She has a special interest in rare genetic disorders and has conducted laboratory research examining the impact of collagen IV gene mutations in mice. Helen values diversity in all its forms and is a passionate LGBTQ+ rights advocate.

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