How to recognise Zollinger-Ellison syndrome

Once in a lifetime: Continuing our series on conditions that GPs may only encounter once in a career, gastroenterology resident doctors Dr Kevin Jacob, Dr Sana Mallick, Dr Belinda Eze and consultant gastroenterologist Dr Andrew Poullis provide an overview of the rare disorder known as Zollinger-Ellison syndrome (ZES)

What is Zollinger-Ellison syndrome?

Zollinger-Ellison syndrome (ZES) is a rare disorder characterised by the development of gastrin-secreting tumours, known as gastrinomas, predominately in the pancreas and duodenum. It can develop sporadically or as a manifestation of multiple endocrine neoplasia type 1 (MEN 1), which accounts for around 25% of cases. The majority of gastrinomas are malignant, and 60% have metastasised at the time of diagnosis.

Symptomatically, ZES manifests with features of peptic ulcer disease and hypergastrinemia. The common presenting complaints include abdominal pain (75% of patients); diarrhoea (73%); persistent heartburn and regurgitation (50%); nausea; vomiting; weight loss; and complications of excessive acid secretion: gastrointestinal bleeding, stricture formation, fistulisation or perforation.

The pathophysiology of diarrhoea is due to large volumes of gastric acid secretion causing a low intestinal pH that damages intestinal villi and inactivates pancreatic enzymes, leading to poor emulsification of fat and bile acid, resulting in malabsorption.

How rare is it?

ZES has an annual incidence of 0.5-2 per million population. Men are more commonly affected than women, with most patients being diagnosed between the ages of 20 and 50 years of age.

Gastrinomas most frequently arise in the duodenum (50-88% of sporadic cases of ZES and 70-100% of ZES cases associated with MEN1). Around 25% of gastrinomas arise in the pancreas and are more likely to metastasise to the liver (22-33% of pancreatic gastrinomas versus 0-10% of duodenal). More rarely they may also arise in the stomach, liver, bile ducts, heart, lungs and ovaries.

Often confused with…

ZES is often confused with peptic ulcer disease, irritable bowel syndrome and coeliac disease, in view of presentations with diarrhoea and malabsorption. Other differentials may include antral G-Cell hyperplasia, where serum gastrin may similarly be elevated as in ZES. However, imaging studies will not show a gastrinoma, and there will be a poor response to the secretin stimulation test.

ZES should be considered as a differential diagnosis in patients who have previously undergone a sleeve gastrectomy and are presenting with recurrent peptic ulceration. These patients may exhibit retained antrum syndrome, which arises due to the incomplete excision of the gastric antrum from the duodenum. The secretin stimulation test in this case will be negative, and hypergastrinemia is reversible with excision of the retained antral remnant.

Red flags

While a rare pathology, GPs should include ZES in their differential in patients with the following:

Multiple or refractory peptic ulcers in patients who test negative for Helicobacter pylori.
Patients presenting with a combination of peptic ulcer disease and secretory diarrhoea, which persists despite fasting. This is due to elevated levels of gastrin which inhibit sodium and water reabsorption, leading to this type of diarrhoea.
Weight loss in combination with the above.
Diarrhoea that improves with PPIs.
A strong family history of peptic ulcer disease or MEN1.

How can GPs pick it up?

Early diagnosis of ZES can be challenging due to its nonspecific symptoms that overlap with common gastrointestinal disorders. Average time from onset of symptoms to diagnosis is over 5 years. If the patient history contains clinical features or the red flags outlined previously, urgent referral to secondary care should be initiated.

Initial investigations for GPs should encompass a comprehensive patient history, with particular emphasis on medications that may predispose individuals to peptic ulceration or diarrhoea. Additionally, it is important to gather a family history regarding MEN1 or any familial occurrences of pituitary adenomas, pancreatic cancers or parathyroid cancers.

Examination will often be normal, although you may find epigastric tenderness and cachexia. If part of MEN1, then hypercalcemia due to parathyroid adenoma or visual field changes due to a pituitary lesion compressing the optic chiasm may be found.

Patients with a family history of MEN1 (first-degree relatives of known MEN1) and with clinical manifestations suggestive of MEN1 (diagnosis of primary hyperparathyroidism before age 40 or other tumour types associated with MEN1 – eg, parathyroid, anterior pituitary, or pancreatic islet) should be screened for MEN1 syndrome.

Investigations should include H. pylori testing, faecal calprotectin, faecal elastase and routine blood tests, including coeliac serology, thyroid function and liver function, to assess for possible liver metastases and referral for an upper gastrointestinal endoscopy.

Upper gastrointestinal endoscopy is essential to evaluate peptic ulcer disease. There may also be thickened gastric folds in ZES, reflective of gastric mucosal hyperplasia.

The gold standard test for ZES is a fasting serum gastrin concentration and measurement of gastric pH and this will usually be done in secondary care. Markedly elevated gastrin levels (>1,000picograms/mL) in the presence of a gastric pH <2 is diagnostic of ZES. Higher levels are more likely with pancreatic (as opposed to duodenal) tumours, increased tumour sizes and the presence of metastatic disease.

Two-thirds of patients with ZES have serum gastrin levels less than 10 times the upper limit of normal (200-1,000 picograms/mL). Furthermore, patients receiving PPIs often have elevated serum gastrin levels. In these cases, a secretin stimulation test can be performed to differentiate gastrinomas from other causes of hypergastrinaemia. The test involves administering secretin intravenously and measuring serum gastrin levels before and after administration; an increase in gastrin levels by more than 200picograms/mL confirms a diagnosis of ZES.

Tumour localisation and staging is performed through computed tomography (CT), magnetic resonance imaging (MRI) or somatostatin receptor-based imaging (SRS). Endoscopic ultrasound should be considered if imaging modalities are negative because of its greater sensitivity in detecting small tumours and the ability to perform fine-needle aspiration for histological identification.

Treatment and prognosis

Medical management in ZES aims to limit the complications of peptic ulcer disease, using high-dose proton-pump inhibitors (PPIs) to control acid hypersecretion and prevent complications. Somatostatin analogues, such as octreotide, may be considered where PPIs fail. H2 receptor antagonists are used less frequently than PPIs, with a failure rate of 50%.

Surgical resection of gastrinomas is the definitive management, especially for localised tumours. For liver metastases, ablation, embolisation or resection may be considered.

Prognosis for ZES depends on whether the tumour is benign or malignant and the extent of disease involvement. The most common site of metastasis in malignant gastrinoma is the liver (around 24% of patients). In patients without metastases, the 10-year survival rate is over 90%, but this drops to 30% for those with liver metastases.

Dr Andrew Poullis is consultant gastroenterologist and Dr Kevin Jacob, Dr Sana Mallick and Dr Belinda Eze are gastroenterology resident doctors at St George’s University Hospital NHS Foundation Trust