Epidemiology

About 75% of cases are sporadic and 25% associated with MEN1. Although MEN1 has an equal sex distribution, this syndrome has a slight male preponderance at about 1.3:1. 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.^[1]

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 adrenocorticotropic hormone (ACTH), vasoactive intestinal polypeptide (VIP), and glucagon. They can also produce various peptides, such as insulin, pancreatic polypeptide, glucagon, chromogranin A, neuron-specific enolase, and the alpha and beta subunits of human chorionic gonadotropin.

Zollinger-Ellison syndrome (ZES) represents no more than between 1 in 100 and 1 in 1,000 cases of duodenal ulcer.

Presentation

• Epigastric pain suggestive of peptic ulceration occurs in 75%, especially in men and in the sporadic cases.
• The other major feature is diarrhoea and this also occurs in 73% but especially in MEN1 and in women.
• In 55% there is both abdominal pain and diarrhoea.
• Pain of gastro-oesophageal reflux occurs in 44%
• Nausea, vomiting and weight loss can occur and were found in 17%.
• Gastrointestinal (GI) bleeding is the presenting symptom in 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.

The figures given above are based on a series of 261 cases.^[1] A single symptom was the presentation in only 11%. Multiple symptoms should increase the diagnostic suspicion.

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 coexist. However, there is evidence that the very high acid may kill the organism.^[2]
• The presence of H. pylori may also predispose to gastric ulcers and reduce the level of acid secretion.^[2]
• If endoscopy is performed, it may show a duodenal ulcer further down the duodenum than usual. This is typical of Zollinger-Ellison syndrome (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

Hypergastrinaemia is defined as fasting serum gastrin concentration >100 pg/ml and is seen frequently in clinical conditions other than Zollinger-Ellison syndrome (ZES), eg proton pump inhibitor (PPI) or H2-receptor antagonist therapy, post-vagotomy, renal failure and chronic atrophic gastritis.^[3]

• 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.
• 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.^[1] 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 - the following is one algorithm from Liverpool:^[3]

• Check fasting gastrin level - levels >1000 pg/ml with acidic gastric juice (pH<2) suggest ZES and the patient should undergo tumour localisation and further tests to rule out MEN1.^[3]
• More often though levels of between 100-1000 pg/ml are encountered.^[3] In this case it may help to test on at least three different days. The higher the level of gastrin, the worse the prognosis in sporadic cases but not in MEN1, where prognosis is better than in sporadic cases.^[4]
• If the level of gastrin is <1000 pg/ml, the patient should go on to have provocation tests to determine if ZES likely, eg secretin test (first-line) and calcium test (if secretin test negative), which are both discussed below.
• If gastric acid pH >2 with a raised gastrin level and patient is on acid suppressing drugs, then stop treatment and recheck one week later.^[3] If gastrin level still elevated, then check gastric pH and decide as above as to whether provocation tests are needed. If the pH is >2 and the patient is not taking any acid suppressants, then a gastric biopsy is needed; if this shows atrophy, then further tests may be indicated, such as autoantibodies, B12 level and H. pylori.

Imaging

There are a number of potential imaging techniques.

• 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 the most sensitive technique to detect both primary and metastatic lesions^[5][6] and is very much the investigation of choice^[7] although it may be combined with endoscopic ultrasonography (EUS).^[8][9]
• EUS is a new technique for locating gastrinomas. Many tumours are in the head of the pancreas. Detection of pancreatic tumours is extremely good at 93% but, outside the pancreas, it is less reliable.^[10]

Provocation tests^[3]

Secretin stimulation tests

• 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 positive test is when gastrin increases >395 pg/ml from baseline.
• Sensitivity poor at 62% and specificity of 100%.
• This test may be useful in patients with strong history suggestive of ZES but negative secretin test.

Differential diagnosis

If Zollinger-Ellison syndrome (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 Clinical Excellence guidelines on the management of dyspepsia.^[11]

Management

Medical management is aimed at control of hyperacidity. Surgical intervention is aimed at removing the gastrin-secreting tumours, although emergency surgery may be required for complications such as bleeding or perforation.

Pharmacological agents to suppress acid secretion have made an enormous impact on this condition but the H2-receptor blockers have been superseded by the even better PPIs. Surgery is still required to remove the gastrinoma but total gastrectomy is no longer recommended. Subcutaneous octreotide may help the abdominal pain and diarrhoea.

In the acute condition, an intravenous PPI can be used to gain control of gastric secretion.

• 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.
• Patients with sporadic Zollinger-Ellison syndrome (ZES) without metastases should have surgical resection of the tumour as this decreases the risk of liver metastases.^[12]
• 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 2.5 cm.
• A single liver metastasis may be resected.^[13] For metastatic disease, chemotherapy, interferon, and octreotide may be helpful.^[14] The response to these agents in most studies has been low.

Complications

• Complications of ulceration include GI bleeding and perforation.
• Acid reflux can cause oesophagitis and stricture.
• The very high acid levels can inactivate pancreatic enzymes and precipitate bile salts so that malabsorption occurs.
• Control of acid secretion limits complications.
• Tumours may metastasise, especially in MEN1. For patients with hepatic metastasis, initial expectant observation and medical management of symptoms is appropriate in view of the long and indolent course of the disease. Hepatic arterial embolisation is the preferred palliative procedure for pain and hormonal symptoms.

It has been argued that the widespread use of PPIs may delay the diagnosis of Zollinger-Ellison syndrome (ZES) so that presentation is later and more advanced.^[15][16]

Prognosis

• Zollinger-Ellison syndrome (ZES) is due to a malignancy and it can metastasise. Tumours over 2-3 cm in diameter carry a worse prognosis, as does metastasis to lymph nodes or liver. In patients with a pancreatic gastrinoma around 60% have hepatic metastasis at diagnosis compared with fewer than 10% with a duodenal gastrinoma.
• Normal gastrin levels after surgery do not indicate cure and 50% of patients with normal levels will have recurrence within five years. Annual assessment with SRS is indicated.
• If acid suppression is incomplete, long-term treatment with a PPI is indicated.
• In advanced metastatic disease, chemotherapy with a combination of streptozocin, 5-fluorouracil, and doxorubicin may achieve a response rate of 65%.
• At diagnosis, around 60% of gastrinomas have no sign of metastasis but diagnosis is difficult as they are usually so small. At five years, between 20 and 40% are disease-free.

Prevention

If MEN1 is diagnosed, genetic counselling and screening of family members is required.

Historical note

Robert Zollinger was born in 1903 and died in 1992.^[17] He was Professor of Surgery at Ohio State University until he retired in 1974. He was was president of several professional bodies, including the American Surgical Association, the American Board of Surgery and the American College of Surgeons. He was was the editor-in-chief of the American Journal of Surgery from 1958 to 1986.

Edwin Homer Ellison was born in 1918.^[18] He studied at Ohio and was Professor of Surgery at Marquette School of Medicine, Milwaukee from 1967 until he committed suicide in 1970.

They published together in 1955.^[19]