Zollinger Ellison Syndrome

Also known as Strom-Zollinger-Ellison syndrome

The Zollinger Ellison syndrome (ZES) is the result of excessive production of gastrin that produces excessive gastric acidity. It can occur as a component of type 1 multiple endocrine neoplasia syndrome, abbreviated to MEN1 or it can occur in isolation.

The tumour is usually in the duodenum, the pancreas or abdominal lymph nodes but can be at distant sites. It stimulates hyperplasia of the acid secreting cells and continual high output, even at times of normal rest.

This syndrome is the major cause of morbidity in MEN1.

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 20 and 7% after 60.¹

Gastrinomas are the commonest functioning tumour of the pancreas. In addition to secreting high levels of gastrin, these tumours may produce other hormones such as 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.

ZES represents no more than between 1 in 100 and 1 in 1,000 cases of duodenal ulcer.

• 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 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.

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 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.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 ZES and should arouse suspicion. Ulcers larger than 2cm 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.

• 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 commoner causes of H pylori negative dyspepsia. If it is positive but eradication does not cure the disease this may also be suggestive but other commoner conditions such as GORD 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 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 and a 6 step algorithm is suggested:

• Check fasting gastrin level on at least 3 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.³
• Check gastric acid secretion and if basal acid output is >15mEq/hour with basal gastric secretory volume >140 mL with gastric pH <2, a gastrinoma is suggested. If gastric pH is >2 in the absence of acid suppression medication, ZES is most unlikely.
• If provocation tests are required, a secretin stimulation test is best because of its higher sensitivity.
• Perform somatostatin receptor scintigraphy.
• Use imaging studies to stage and localize the gastrinoma.
• Assess if the tumour is amenable to resection.

Imaging

There are a number of potential imaging techniques.

• CT may be used to locate the primary tumour and to detect metastases. It will detect only about half of primary tumours and small ones 1cm diameter or less are often missed.
• MRI and ultrasound are not as good as CT.
• Somatostatin receptor scintigraphy is the most sensitive technique to detect both primary and metastatic lesions^4,5 and is very much the investigation of choice⁶ although it may be combined with endoscopic ultrasonography.^7,8
• Endoscopic ultrasound 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.⁹

If ZE syndrome 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 NICE guidelines on the management of dyspepsia.¹⁰

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 40mg daily, is required.
• Patients with sporadic ZES without metastases should have surgical resection of the tumour as this decreases the risk of liver metastases.¹¹
• 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 2.5cm.
• A single liver metastasis may be resected.¹² For metastatic disease, chemotherapy, interferon, and octreotide may be helpful.¹³ The response to these agents in most studies has been low.

• 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 embolization 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 ZES so that presentation is later and more advanced.^14,15

• ZES is due to a malignancy and it can metastasise. Tumours over 2 to 3cm 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 less 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 5 years. Annual assessment with somatostatin receptor scintigraphy 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 5 years, between 20 and 40% are disease free.

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

Robert Zollinger was born 1903 and died 1992.¹⁶ 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 1918.¹⁷ 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 1955.¹⁸