Zollinger-Ellison syndrome

Synonyms: Strom-Zollinger-Ellison syndrome

What is Zollinger-Ellison syndrome?

Zollinger-Ellison syndrome (ZES) is an endocrinopathy characterised by gastrin-secreting tumours, which cause multiple, refractory and recurrent peptic ulcers in the distal duodenum and proximal jejunum. There are two main variants:¹

• Sporadic (isolated).

• Associated with parathyroid and pituitary tumours as part of the genetic disorder multiple endocrine neoplasia type 1 (MEN1).

The tumour (gastrinoma) is usually in the duodenum (60-65%) or the pancreas (30%).² See also the separate article on Pancreatic Endocrine Tumours. In rare cases, gastrinomas occur in other abdominal locations (eg, the stomach, liver, bile duct, ovary) and also extra-abdominal locations (eg, the heart, lung - small cell lung cancer).³

How common is Zollinger-Ellison syndrome? (Epidemiology)

• The incidence of Zollinger-Ellison syndrome is rare, ranging from is 0.1-3/million population/year.⁴

• 20-30% of patients have ZES as part of MEN1, an autosomal dominant disorder.⁵

• Mean age of presentation is around 40, being younger in MEN1 patients than sporadic cases. Only about 3% present before age 20 and 7% after age 60.

• Gastrinomas are the most common functioning tumour of the pancreas. In addition to secreting high levels of gastrin, these tumours may produce other hormones such as adrenocorticotrophic hormone (ACTH), vasoactive intestinal polypeptide (VIP), and glucagon.⁶ They can also produce various peptides such as insulin, chromogranin A and the alpha and beta subunits of human chorionic gonadotrophin.

Zollinger-Ellison syndrome symptoms⁷

Patients with ZES as part of the MEN1 syndrome present at an earlier age (approximately 10 years earlier) and may have relatively mild symptoms which can be misdiagnosed or overlooked.

• Epigastric pain suggestive of peptic ulceration is common, especially in men and in sporadic cases of ZES.⁸

• The other major feature is diarrhoea and this particularly occurs in MEN1 and in women.

• There is often both abdominal pain and diarrhoea.

• Pain of gastro-oesophageal reflux, nausea, vomiting and weight loss may also occur.

• Gastrointestinal (GI) bleeding is the presenting symptom in about 25% of patients.

• Most children with the disease present with complications such as perforation or bleeding.

Other features suggestive of MEN1 should be sought.

If there is hepatomegaly, this suggests liver metastasis. Liver metastases occur much more frequently with pancreatic gastrinomas than with duodenal gastrinomas.⁶

Clinical suspicion

There are a number of features that may arouse clinical suspicion. It is very common for it to be treated initially as a simple peptic ulcer.

• The combination with diarrhoea may suggest the diagnosis.

• Persistent recurrence of the condition after treatment should arouse suspicion.

• Nearly all cases of duodenal ulcer and many of gastric ulcer are associated with infection with Helicobacter pylori but, in this condition, it is not required, as the high acid alone will cause ulceration.

• As up to 50% of the population aged over 50 may be infected with H. pylori, the two may co-exist. However, there is evidence that the very high acid may kill the organism.

• The presence of H. pylori may also predispose to gastric ulcers and reduce the level of acid secretion.

• If endoscopy is performed, it may show a duodenal ulcer further down the duodenum than usual. This is typical of ZES and should arouse suspicion. Ulcers larger than 2 cm in diameter and multiple ulcers are also suggestive. Endoscopy may also show that gastro-oesophageal reflux has caused lower oesophageal stenosis or Barrett's oesophagus.

Investigations

Biochemical serum evaluation for elevated gastrin, followed by radiological or nuclear localisation of the primary lesion, is necessary for establishing the diagnosis.¹

Hypergastrinaemia is defined as fasting serum gastrin concentration >100 pg/ml and is seen frequently in clinical conditions other than ZES - eg, proton pump inhibitor (PPI) or H2-receptor antagonist therapy, post-vagotomy, renal failure and chronic atrophic gastritis.⁹

• FBC may show evidence of iron-deficiency anaemia due to bleeding.

• Ferritin may be low in non-anaemic iron deficiency.

• As parathyroid hyperplasia is a common feature of MEN1, calcium may be elevated.¹⁰

• Clinical suspicion of duodenal ulcer should lead to testing for H. pylori. If it is negative, that may point to the syndrome, although there are many more common causes of H. pylori-negative dyspepsia. If it is positive but eradication does not cure the disease, this may also be suggestive but other more common conditions, such as gastro-oesophageal reflux disease, should be considered.

• Endoscopy may show both gastric and duodenal ulceration along with hypertrophied gastric folds. The last was found in 94% of a large series. A more distal ulcer, or a large ulcer or multiple ulcers, have been mentioned above.

• If ZES is confirmed, it is important to consider MEN1, and calcium, parathormone and prolactin levels should be checked.

If the diagnosis is suspected, then more specific tests are required - these should be performed in a specialist setting. The following diagnostic algorithm is taken from consensus guidelines on the management of functional pancreatic neuroendocrine tumours:¹¹

• Check fasting serum gastrin (FSG) level - if this is raised, check gastric pH level.

• If pH level is ≤2, consider how raised the FSG is.

• If the FSG is 10x the expected level - and you can rule out retained gastric antrum tissue (post surgery) as a cause of high gastrin levels - the diagnosis is Zollinger- Ellison syndrome.

• If the FSG is less than 10x, a provocation test - ideally the secretin test - should be done. If this is positive, the diagnosis is Zollinger-Ellison syndrome.

• The next stage is to check for multiple endocrine neoplasia (do parathyroid hormone, calcium and prolactin levels) and locate the site of the tumour with CT/MRI and/or somoatostatin receptor scintigraphy - see below.

If the gastric pH is >2, consideration needs to be given to whether the patient is taking a proton pump inhibitor (PPI). If they are, the PPI may have affected their pH result and lowering the dose, changing the frequency the PPI is taken (or stopping it), can be tried with repeat pH measurements, before making a diagnosis.

Imaging¹²

There are a number of potential imaging techniques. Tumour localisation studies are required in all patients with biochemically confirmed ZES. An initial upper gastrointestinal endoscopy with careful inspection of the duodenum is recommended, followed by CT or by MRI and somatostatin receptor scintigraphy (SRS).

• CT scan may be used to locate the primary tumour and to detect metastases. It will detect only about half of primary tumours, and small ones of 1 cm diameter or less are often missed.

• MRI and ultrasound scans are not as good as CT scan.

• SRS is more sensitive for detecting ZES lesions.⁴ It may be combined with endoscopic ultrasonography (EUS).

• EUS is used for locating gastrinomas. Many tumours are in the head of the pancreas. Detection of pancreatic tumours is very good but less reliable outside the pancreas.

Provocation tests

Secretin stimulation tests⁶

• Secretin is normally stimulated by food in the stomach, leading to release of bicarbonate-rich fluid from the pancreas which neutralises gastric acid. This leads to both inhibition of further secretin release and antral gastrin secretion, but with increased gastrin release from gastrinoma cells.

• Secretin is administered (IV) and blood collected for gastrin levels at 0, 2, 5, 10, 15 and 20 minutes.

• A positive test is when serum gastrin concentration increases by >200 pg/ml 15 minutes after the dose is given.

• This has been reported to have a sensitivity of 94% and specificity of 100%.

Calcium stimulation test

• Calcium also causes the release of gastrin stored in gastrinoma cells.

• 10% calcium gluconate (dose of 5 mg/kg body weight) is given IV over three hours and gastrin levels determined at 0, 30, 60, 90, 120, 150 and 180 minutes.

• A test is positive when gastrin increases >395 pg/ml from baseline.

• Sensitivity is poor but specificity is excellent.

• This test may be useful in patients with strong history suggestive of ZES but negative secretin test.

Differential diagnosis

If ZES is confirmed, other features of MEN1 should be sought, including a family history.

It is a rare condition but there must be awareness of it. Follow the National Institute for Health and Care Excellence (NICE) guidelines on the management of dyspepsia.¹³

Zollinger-Ellison syndrome treatment and management¹⁴

Once the diagnosis has been made, management is within tertiary centres by multidisciplinary teams.¹⁵ Management includes medical suppression of gastric acid production and surgical resection of primary tumour for the prevention of malignant transformation and metastatic complications.¹

In patients with liver metastases, surgery should be considered if all identifiable tumour can be safely removed.¹⁶ Liver surgery is the best treatment for endocrine liver metastases, but it is often impossible due to diffuse disease. Systemic chemotherapy is poorly effective. Hepatic arterial embolisation and chemoembolisation may be considered.¹⁷

Drug treatment⁶

• Oral PPIs will be effective in maintaining acid secretion at an acceptable level but a higher dose than usual, such as omeprazole 40 mg daily, is required.

• Oral doses of histamine H₂ receptor antagonists can also be effective, but high, frequent dosing is required.³

• Chemotherapy may be tried for metastatic disease.⁵

Surgical treatment¹⁸

• Due to the efficacy of PPIs, total or partial gastrectomy is no longer routinely indicated.

• For sporadic gastrinomas, surgery, including complete resection of the primary and involved lymph nodes, is the only curative treatment.

• Laparoscopic resection of gastrinomas is controversial and not generally recommended.

• Patients with sporadic ZES without metastases should have surgical resection of the tumour, as this decreases the risk of liver metastases.¹⁴

• Surgery in MEN1 is more contentious, as it rarely achieves cure but it may reduce the risk of metastasis. It is recommended for tumours over 2.0 cm.

• A single liver metastasis may be resected.

Postoperative surveillance involves measurement of gastrin level, with imaging if an elevation of gastrin levels is detected. Re-excision of recurrent or resection of metastatic disease is controversial but aggressive excision is usually considered if feasible.¹

Complications

• Complications of ulceration include gastrointestinal bleeding and perforation.

• Acid reflux can cause oesophagitis and oesophageal stricture.

• The very high acid levels can inactivate pancreatic enzymes and precipitate bile salts so that malabsorption occurs.

• Control of acid secretion limits complications.

• Metastases: approximately 30-40% of gastrinomas are associated with liver metastases. At diagnosis, 5-10% of duodenal gastrinomas and 20-25% of pancreatic gastrinomas are associated with liver metastases.³

It has been argued that the widespread use of PPIs may delay the diagnosis of ZES so that presentation is later and more advanced.

Prognosis⁷

The most significant factor in pancreatic gastrinoma is the presence of liver metastasis. Patients with liver metastasis have 15% 10-year survival but those without have 95% 20-year survival.

Other factors in poor prognosis include:

• Advanced tumour, node and metastasis (TNM) classification status; lymph node metastases, bone metastases.

• Inadequate control of gastric acid hypersecretion.

• Female gender.

• Absence of MEN1.

• Short disease history from onset to diagnosis.

• Markedly increased fasting gastrin levels.

• Presence of a large primary tumour; pancreatic primary gastrinoma.

• Development of ectopic Cushing’s syndrome.

• Histological features, including angioinvasion, perineural invasion, poor differentiation.

Ectopic Cushing’s syndrome develops in 5-15% of patients with advanced metastatic disease and has a very poor prognosis.¹⁹

Prevention

If MEN1 is diagnosed, genetic counselling and genetic testing of family members are recommended.