Zollinger-Ellison syndrome

• Zollinger-Ellison syndrome is the clinical consequence of a gastrin-secreting neuroendocrine tumour called a gastrinoma, usually arising in the duodenum or pancreas.
• Unchecked gastrin drives massive gastric acid secretion, producing refractory or unusual-site peptic ulcers, reflux and oesophagitis, and a secretory diarrhoea that can be the first or only clue.
• The diagnosis is biochemical, not radiological: an elevated fasting serum gastrin together with acid gastric juice, ideally a gastric pH under 2.
• High-dose proton pump inhibitors control the acid and are the immediate life-saving treatment; surgery of the tumour matters for long-term survival in sporadic, localised disease.
• About a quarter of patients have multiple endocrine neoplasia type 1, which changes the evaluation, the surgical plan and the prognosis.

By the end of this page you should be able to:

1. Define Zollinger-Ellison syndrome and gastrinoma, and contrast sporadic disease with MEN1-associated disease.
2. Explain why each symptom occurs, from tumour to gastrin to acid to ulcer, diarrhoea, oesophagitis and weight loss.
3. List the causes of hypergastrinaemia, grouped by acid status, and interpret a fasting gastrin level with a gastric pH and a secretin test.
4. Choose first-line and confirmatory tests and the right localisation studies, with a sound reason for each.
5. Outline management of acid control, MEN1 screening, localised sporadic disease, MEN1 disease and metastatic disease, including doses and targets.
6. State the prognosis and outline acceptable management where tests or drugs are scarce.

A few distinctions matter throughout.

• Gastrinoma is the tumour. Zollinger-Ellison syndrome is the state of acid hypersecretion and its consequences.
• Sporadic disease accounts for roughly three-quarters of cases. Sporadic gastrinomas arise in the duodenum in 50 to 88% of cases, in the pancreas in much of the remainder (other, non-duodenal abdominal or extra-abdominal sites 5 to 15%). ^[2]
• MEN1-associated disease accounts for 20 to 30% of cases. In these patients the gastrinomas are almost always duodenal (70 to 100%), usually multiple, and arise from diffuse gastrin cell hyperplasia of the duodenal mucosa. ^[2]
• Duodenal gastrinomas are usually small (mean size about 0.9 cm, and most are under 1 cm), whereas pancreatic gastrinomas are generally larger (mean about 3.8 cm). ^[2]
• In WHO 2010 terminology these are well-differentiated neuroendocrine neoplasms, grade 1 to 2, expressing gastrin on immunohistochemistry. ^[2]

Gastrinomas have a strong preference for a small region of the right upper abdomen. At surgery 70 to 85% lie in the "gastrinoma triangle", bounded by the cystic duct superiorly, the second and third parts of the duodenum inferiorly and the neck of the pancreas medially. ^[2] This explains why a surgeon operating for gastrinoma explores that triangle so carefully, including transillumination and opening of the duodenum.

The condition is rare, with an incidence of 0.5 to 2 new cases per million population per year; one 2021 review gives 1.0 to 1.5. ^[1][2] It is the second most common functioning gastroenteropancreatic neuroendocrine tumour syndrome after insulinoma, and it is the commonest one that is malignant. ^[2]

• Age. Sporadic disease presents at a mean age of 48 to 55 years; MEN1-associated disease presents at a mean age of 32 to 35 years, roughly fifteen years earlier. ^[2]
• Sex. Sporadic disease is slightly more common in men, 54 to 56% of cases, with a male to female ratio of about 1.5 to 2 to 1. ^[2]
• MEN1. Multiple endocrine neoplasia type 1 is an autosomal dominant syndrome present in 20 to 30% of people with Zollinger-Ellison syndrome. ^[2] The syndrome is covered in its own topic; briefly, it combines parathyroid, pancreatic-duodenal and pituitary neoplasia. Up to 40% of people with MEN1-associated gastrinoma have no family history, so every patient with Zollinger-Ellison syndrome must be screened. ^[2][4]
• Diagnostic delay. The mean delay between first symptoms and diagnosis is 5.2 years, largely because proton pump inhibitors control symptoms so well. ^[2]
• Metastases at diagnosis. Overall 30 to 40% of gastrinomas are associated with liver metastases; at the time of diagnosis liver metastases are present in 5 to 10% of duodenal and 20 to 25% of pancreatic primaries. ^[2]
• Proliferation. Prospective studies show aggressive growth in about 25% of sporadic and 15% of MEN1-associated cases. ^[2]

Sporadic gastrinoma has no known modifiable risk factor. It is a well-differentiated neuroendocrine neoplasm, and most lesions stain strongly for gastrin.

Multiple endocrine neoplasia type 1 is the one risk factor that matters and that you must not miss. In MEN1, 20 to 61% of mutation carriers (about 42% on average) develop a gastrinoma, usually duodenal and usually multiple. ^[4] Hyperparathyroidism is the commonest first manifestation of MEN1 overall, and hypercalcaemia worsens acid secretion. In a patient with chronic peptic disease and diarrhoea, an unexplained raised calcium should prompt MEN1 exclusion before anything else, and successful parathyroidectomy reduces both gastrin and acid output and may lower the required acid-suppressing dose. ^[2][4]

Carney complex and other inherited neuroendocrine tumour syndromes are rare differential considerations, but gastrinoma is overwhelmingly sporadic or MEN1.

Everything follows from one biochemical fact: gastrin is the principal stimulus of gastric acid. It acts directly on cholecystokinin-2 (CCK2) receptors on parietal cells and indirectly by releasing histamine from enterochromaffin-like (ECL) cells. The result is a basal acid output that is markedly elevated (over 15 milliequivalents per hour in 87 to 90% of patients) ^[2] while the fasting gastric pH is below 2 in essentially all patients, and fasting serum gastrin is elevated in over 97%. ^[2]

Gastrin also has trophic effects on gastric mucosa, which explains the prominent gastric folds visible endoscopically in about 92% of patients, and the tendency to gastric neuroendocrine (type 2 carcinoid) tumours in MEN1. ^[2]

From the acid load, each symptom follows directly.

• Peptic ulceration. Unneutralised acid injures mucosa. In Zollinger-Ellison syndrome ulcers are often multiple and in unusual sites, beyond the duodenal bulb, in the third part of the duodenum or the jejunum. ^[4] They bleed, penetrate and perforate more readily than ordinary ulcers, and Helicobacter pylori is present in only 24 to 48% of cases compared with over 90% in idiopathic ulcer disease, so an ulcer with no H. pylori and no non-steroidal drug should raise suspicion. ^[2]
• Diarrhoea and steatorrhoea. Acid entering the small bowel inactivates pancreatic lipase and denatures bile salts, so fat is not digested. Acid also damages mucosa and accelerates transit. Up to three-quarters of patients have diarrhoea, and diarrhoea that promptly resolves when acid is suppressed is itself a diagnostic clue. ^[2]
• Reflux and oesophagitis. The acid load exceeds the capacity of the lower oesophageal sphincter, and the oesophagus is bathed in acid; strictures can result.
• Weight loss. Anorexia, malabsorption and the pain and energy cost of diarrhoea combine to produce weight loss in 7 to 53% of patients. ^[2]

Acid suppression also explains the clinical trap: proton pump inhibitors relieve almost all of this, which masks the disease and delays diagnosis for years.

Common presenting symptoms, with approximate frequencies from the ENETS consensus series. ^[2]

• Abdominal pain, mainly from peptic ulcer or reflux, in 75 to 98% of cases.
• Diarrhoea in 30 to 73%.
• Heartburn and reflux in 44 to 56%.
• Gastrointestinal bleeding in 44 to 75%.
• Nausea and vomiting in 12 to 30%.
• Weight loss in 7 to 53%.

A classic vignette is a 45-year-old man with "reflux that does not respond to a double dose" and loose stools that disappear during every course of omeprazole. The disappearance of diarrhoea with acid suppression is itself a diagnostic clue. ^[2]

Red flags that should make you think of the syndrome: ulcers in unusual sites (beyond the duodenal bulb, in the third part of the duodenum or the jejunum) or multiple at once; ulcers that bleed, penetrate or perforate without clear cause; peptic disease with negative H. pylori and no non-steroidal drug; peptic disease with concurrent endocrinopathy, nephrolithiasis or hypercalcaemia; reflux that produces oesophageal strictures; and chronic secretory diarrhoea that settles with acid suppression. ^[2]

There may be nothing specific to see. Epigastric tenderness is common but unhelpful. Look for weight loss, anaemia from chronic or acute bleeding, and skin or other features of MEN1 (angiofibromas, collagenomas, lipomas). Tenderness alone does not help.

The symptoms are common and the differential is broad. The key distinction is between appropriate hypergastrinaemia, where gastrin rises because acid is genuinely low, and inappropriate hypergastrinaemia, where gastrin is secreted despite an already acidic stomach.

The first fork in the diagnostic approach is therefore not the gastrin level but the gastric pH or basal acid output. A high gastrin with a gastric pH under 2 means inappropriate hypergastrinaemia and narrows the list to Zollinger-Ellison syndrome and its mimics. A high gastrin with a high pH means the stomach is under-acid and the cause is appropriate.

Proton pump inhibitors deserve special mention: they are the commonest cause of hypergastrinaemia overall, usually raising gastrin modestly (200 to 400 picograms per millilitre is typical) ^[3] for months or years, and because they control symptoms so well they can delay the diagnosis of Zollinger-Ellison syndrome for years.

Fasting serum gastrin, drawn after an overnight fast, is the screening test. Because a single level fluctuates, repeat it on a separate day. It should, wherever it is safe, be taken after stopping proton pump inhibitors for at least one week. Histamine H2-receptor antagonists can cover the gap because they have a shorter duration of action, and can usually be continued up to the evening before. ^[2][4]

Gastric pH can be measured at endoscopy by aspirating gastric juice and reading it with pH paper or a meter. Recent descriptions of this method may make it easier outside specialist centres. A markedly raised pH suggests hypochlorhydria or achlorhydria; a pH under 2 is what is expected in Zollinger-Ellison syndrome. ^[2][3]

When the fasting gastrin is less than ten-fold elevated with gastric pH below 2, a secretin test and basal acid output are performed. ^[2] Gastrin is measured before and at intervals after an intravenous infusion, starting with a basal sample.

A rise in gastrin of more than 120 picograms per millilitre over the basal value is positive, with an approximate sensitivity of 94% and a specificity of 100%. ^[2][4] Some protocols use a 1-hour infusion of 3 units per kilogram and assess acid output as well. Calcium stimulation of gastrin release is an alternative where secretin is unavailable, but it has lower sensitivity, lower specificity and more side effects, so it is reserved for cases with a negative secretin test and strong suspicion. ^[2]

Recent European guidance reports that the secretin test and basal acid output measurement have largely disappeared from routine practice in expert centres, which instead rely on fasting gastrin with gastric pH and imaging, and that acid control is set by an empirical proton pump inhibitor dose range with higher totals (80 to 120 mg of omeprazole equivalent per day) in MEN1-related disease. ^[8] Secretin doses differ between sources and preparations: 2 units per kilogram as a rapid infusion is one standard, and 1 to 2 micrograms per kilogram is another, depending on whether porcine or recombinant product is available. ^[2][3]

False positive secretin tests occur with proton pump inhibitor use, so Zollinger-Ellison syndrome cannot reliably be diagnosed while taking one. ^[2]

• Basal acid output. Over 15 milliequivalents per hour in over 85% of untreated patients without previous gastric surgery. ^[2] All patients have a gastric pH below 2.
• The 10-fold rule. If the fasting gastrin is more than ten times the upper limit of normal and the gastric pH is below 2, the diagnosis can be made (retained antrum is usually excluded by history). Sixty percent of patients have a smaller rise, in the range that overlaps with other conditions and with proton pump inhibitor use, and these need a secretin test plus basal acid output. ^[2]
• Repeated testing. Fewer than 1 in 200 patients with the syndrome have entirely normal values on every test. ^[2]
• Chromogranin A is often raised but is not diagnostic; it is mainly a marker for monitoring. ^[2]
• Assay quality. Only five of twelve commercial gastrin assays studied measured plasma gastrin accurately; the rest over- or under-reported. Send to a reliable laboratory. ^[2]
• Helicobacter pylori testing. Its presence is 24 to 48% in Zollinger-Ellison peptic disease versus over 90% in idiopathic ulcer disease. ^[2]

Once the biochemical diagnosis is secure, the aims are to locate the primary, define metastases and decide on resectability. Results vary widely between centres, depending on expertise and equipment, and no single modality is 100% effective. ^[2]

• Contrast-enhanced CT. Useful for lesions larger than 1 cm, pancreatic head lesions and liver metastases; reported sensitivity 59 to 78% and specificity 95 to 98% for the primary or for liver disease. ^[1] It is fast and widely available.
• MRI. Sensitive for detecting liver metastases from endocrine tumours, and generally preferred over CT for liver staging. ^[2]
• Somatostatin receptor imaging. Gastrinomas over-express somatostatin receptor 2. Scintigraphy localises 30 to 70% of primary tumours and 70 to 95% of liver and distant metastases, and bone metastases should be sought with scintigraphy together with an MRI of the spine. ^[2] Tumours under 1 cm are missed in more than half of cases, which matters because most duodenal gastrinomas are under 1 cm. ^[2]
• Gallium-68 DOTA-somatostatin analogue PET combined with CT appears to have higher sensitivity and specificity than scintigraphy and is increasingly used. ^[1] ENETS 2012 regarded these tracers as still investigational, ^[2] but they are now part of routine practice in many centres.
• Endoscopic ultrasound. Excellent for pancreatic lesions, but it misses up to half of duodenal gastrinomas, which is where most of them are. ^[2]
• Other modalities. Where first-line studies are negative and surgery is being considered, selective angiography with secretin stimulation and hepatic venous gastrin sampling can be used in experienced centres. ^[2]

At surgery, intraoperative ultrasound, duodenal transillumination and routine duodenotomy are essential, because duodenotomy can detect up to half of duodenal tumours that imaging missed. ^[2]

Bone metastases occur in up to one-third of patients with liver metastases and should be sought with somatostatin receptor imaging and spinal MRI. ^[2]

For MEN1 the picture is different: lesions are smaller, more numerous and duodenal, so conventional imaging misses many. Multi-slice CT, MRI and endoscopic ultrasound are used together, and careful surgical exploration is often needed for final staging.

Because 20 to 30% of people with Zollinger-Ellison syndrome have MEN1, and up to 40% of them have no family history, every patient must be screened biochemically at diagnosis and then yearly. ^[2][4] The recommended tests are intact parathormone, ionised calcium and prolactin. Ionised calcium is preferred because total or albumin-corrected calcium can miss mild hypercalcaemia. ^[2][4]

Genetic testing for MEN1, preceded by counselling, is appropriate where the family history is positive, where other endocrinopathies are present, or where multiple tumours raise the possibility. ^[2][4] Also ask about personal or family history of renal colic, nephrolithiasis, hypercalcaemia and other endocrine disease. Type 2 gastric neuroendocrine tumours and carcinoid tumours of the thymus or lung are much more common in MEN1 and should also prompt testing. ^[2]

There is no single cut-off. The diagnosis rests on inappropriate gastrin secretion in the setting of acid hyperchlorhydria. ^[2]

• Fasting gastrin over 1,000 pg/mL together with gastric pH below 2 is considered diagnostic. ^[1][2]
• If fasting gastrin is more than ten-fold elevated and gastric pH is below 2, the diagnosis can be made. ^[2]
• Sixty percent of patients have a less than ten-fold elevation, in the range that overlaps with ordinary reflux or ulcer disease treated with acid suppressants. In these patients the secretin test and basal acid output are needed. ^[2]
• A basal acid output over 15 mEq per hour in someone who has not had gastric surgery supports the diagnosis; all patients have gastric pH below 2. ^[2]
• If initial tests are normal but suspicion remains high, repeat the fasting gastrin on another day; fewer than 1 in 200 patients with the syndrome have all normal values. ^[2]

Where proton pump inhibitors have been used for a long time, every step is complicated. The usual practice is to switch the patient to an H2-receptor antagonist for at least one week before testing, under specialist supervision, because acid hypersecretion on withdrawal can cause bleeding or perforation. ^[2]

Two goals run in parallel: correct the acid, then deal with the tumour. Acid control has priority in every patient, because acid produces most of the morbidity and, before proton pump inhibitors existed, most of the mortality. Tumour control determines long-term survival.

Proton pump inhibitors are the drugs of choice. They are potent, long-acting and well tolerated even in high doses, and they removed the need for total gastrectomy.

The usual empiric high-dose start, divided twice daily: ^[1]

• omeprazole 60 mg per day;
• esomeprazole 120 mg per day;
• lansoprazole 45 mg per day;
• rabeprazole 60 mg per day;
• pantoprazole 120 mg per day.

These doses are higher than those used for ordinary reflux disease. The dose is then titrated. Where acid-output testing is available, aim for a basal acid output below 10 mEq per hour in a patient with an intact stomach, and below 5 mEq per hour after previous gastric surgery. ^[1][2] Where it is not, titrate to symptom control and, when possible, to a gastric pH below 2 on endoscopic aspiration. Once control is achieved, a gradual dose reduction is usually possible.

In MEN1, where hypercalcaemia worsens acid secretion, start omeprazole 40 mg twice daily with reduction to 20 mg twice daily if possible, and assess parathyroid disease in parallel. ^[4]

Histamine H2-receptor antagonists can be used, for example when proton pump inhibitors must be withdrawn before testing, but they are weaker and often require high, frequent doses, and they are never first line. ^[2] Intravenous proton pump inhibitors are available for patients with upper gastrointestinal bleeding. Long-term proton pump inhibitor use can lower vitamin B12 in some patients, so check levels during prolonged treatment.

Treat the parathyroid glands where indicated, because normocalcaemia improves acid control and may allow lower proton pump inhibitor doses. Screen and monitor pituitary function. Genetic counselling and family testing follow where appropriate. Zollinger-Ellison syndrome can be harder to diagnose after successful parathyroidectomy because calcium, gastrin and acid output can all fall, so a strong clinical suspicion should still be reassessed. ^[2][4]

Sporadic, localised disease. Surgery is the only potentially curative treatment of the tumour and should be offered to all fit patients with sporadic gastrinoma and no metastatic disease. ^[2] Resection reduces the later development of liver metastases, which is the main determinant of survival, and can reduce or remove the need for long-term acid suppression.

The tumour is often small and duodenal, so exploration is methodical: full abdominal survey; Kocher mobilisation with careful palpation of the pancreatic head and duodenum; intraoperative ultrasound of the duodenum, pancreas and liver; intraoperative endoscopy with transillumination of the duodenal wall; and duodenotomy with full-thickness excision where lesions are found. Regional lymph nodes are resected routinely, because nodal metastases are common and regional disease matters for staging and prognosis. ^[2] Pancreatic lesions may be enucleated when small and well clear of the main pancreatic duct; lesions closer to the duct need distal pancreatectomy or pancreaticoduodenectomy, with the latter reserved for selected cases because of its higher morbidity. Debulking surgery is reasonable in selected metastatic patients when the majority of tumour burden can be removed, for example with liver-dominant disease. ^[2]

MEN1. Surgery for gastrinoma in MEN1 is controversial. The tumours are many small duodenal lesions rather than one pancreatic mass, and biochemical cure after limited surgery is rare. ^[4] Many authorities recommend intervention for pancreatic neuroendocrine tumours larger than 2 cm and a more aggressive approach only in carefully selected cases, while medical acid control remains the backbone of treatment for most. The decision should be made within a multidisciplinary team at a centre with experience. ^[2][4]

Pancreaticoduodenectomy remains a specialised option for extensive duodenal disease and carries higher morbidity than limited resection.

Roughly a third of patients present with or develop liver metastases. ^[2] Systemic options are those used for other well-differentiated gastroenteropancreatic neuroendocrine tumours, and evidence specific to gastrinoma alone is limited.

• Somatostatin analogues (octreotide, lanreotide) control hormone-mediated symptoms in most functioning tumours and have antiproliferative activity. Octreotide long-acting release 20 to 30 mg by deep intramuscular injection every 4 weeks is the dose usually cited for advanced midgut and enteropancreatic neuroendocrine tumours. ^[5] Because Zollinger-Ellison symptoms are controlled by proton pump inhibitors, the antisecretory role of somatostatin analogues is secondary here; their antiproliferative role matters more.
• Everolimus, an oral mTOR inhibitor, at 10 mg once daily until disease progression, is used for progressive advanced pancreatic and gastrointestinal neuroendocrine tumours. ^[7] Its approved indication text emphasises progressive well-differentiated neuroendocrine tumours of pancreatic origin with unresectable or metastatic disease.
• Sunitinib is another systemic option for advanced progressive pancreatic neuroendocrine tumours, including gastrinoma, based on large neuroendocrine tumour studies. ^[1]
• Peptide receptor radionuclide therapy with lutetium-177 DOTATATE is given as four cycles of 7.4 gigabecquerels at 6 to 10 week intervals, with amino acid infusion for renal protection. It is for somatostatin receptor-positive disease and requires adequate Karnofsky performance status (at least 60) and renal, marrow and liver function. ^[6]
• Cytotoxic chemotherapy (streptozocin-based or temozolomide-based regimens) is an option for progressive pancreatic neuroendocrine tumours.
• Liver-directed therapies (embolisation, ablation, radioembolisation) and, in highly selected cases, liver transplantation may be used for liver-dominant disease.

Follow-up should be lifelong. Monitor acid control rather than symptoms alone: a patient who feels well may still have an acid output above the target. Re-image the tumour and stage regularly. In MEN1, keep to the yearly biochemical screening programme.

Refer promptly to a neuroendocrine tumour centre:

• any patient with a biochemical diagnosis of Zollinger-Ellison syndrome;
• suspected or confirmed MEN1;
• liver metastases, bone metastases or any progressive disease;
• inability to control acid output with high-dose therapy;
• surgical candidates and anyone needing major exploration.

• Refractory and complicated peptic ulcer disease: bleeding, perforation, penetration, obstruction.
• Diarrhoea with dehydration and hypokalaemia.
• Reflux oesophagitis with stricture.
• Gastric neuroendocrine (type 2) tumours, which are far more common in MEN1 than in sporadic disease. ^[2]
• Metastatic spread: 60 to 90% of gastrinomas are malignant; liver metastases occur in 5 to 10% of duodenal and 20 to 25% of pancreatic primaries, and liver metastases are the main determinant of prognosis. ^[2]
• Ectopic Cushing syndrome develops in 5 to 15% of patients with advanced metastatic disease. ^[2]
• Secondary hormonal syndromes in 1 to 10% of patients, especially those with metastatic disease or MEN1. ^[2]
• Failure of acid suppression with ulcer bleeding or diarrhoea and hypokalaemia.

Prognosis is driven almost entirely by whether liver metastases are present. ^[2]

• Without liver metastases, 10-year survival is 90 to 100%.
• With liver metastases, 10-year survival falls to 10 to 20%.
• Duodenal tumours have a much lower rate of liver metastases (0 to 10%) than pancreatic tumours (22 to 35%), which is one reason the duodenal location carries a better prognosis. ^[2]
• Aggressive growth occurs in about 25% of sporadic and 15% of MEN1-associated cases. ^[2]
• Overall 30 to 40% of gastrinomas are associated with liver metastases. ^[2]

Poor prognostic factors besides liver metastases include inadequate acid control, lymph node metastases, female sex, absence of MEN1, short history from onset to diagnosis, markedly raised fasting gastrin, a large primary (1 to 3 cm), a pancreatic primary, ectopic Cushing syndrome, bone metastases, and adverse histological features (Ki67 over 2, angioinvasion). ^[2]

Medical treatment changed the natural history. Before proton pump inhibitors acid caused most of the deaths; now tumour biology dominates. Surgery, where feasible for sporadic localised disease, improves disease-free survival and lowers the chance of later liver metastases. Total gastrectomy is rarely needed today. ^[2]

Children. Zollinger-Ellison syndrome is rare in children. When it presents young, think of MEN1 and test appropriately. ^[4]

Older adults. Drug interactions, renal function and frailty shape both acid suppression and systemic therapy. Everolimus and sunitinib need dose adjustment for organ dysfunction.

Pregnancy. Evidence is limited to case reports. Management must be multidisciplinary; proton pump inhibitors can usually be continued if needed, and surgery is deferred unless there is a compelling indication.

Families. When MEN1 is confirmed, first-degree relatives should be offered genetic counselling and testing, with biochemical screening in those who carry the mutation. ^[4]

• Diagnosis without instruments. Fasting gastrin and gastric pH at endoscopy (aspirate and measure with pH paper) are cheap and reliable. Many centres can run a basic gastrin assay; if the result is over 1,000 pg/mL with pH below 2, that is sufficient, and if the assay is 5 to 10-fold raised with pH below 2, combine it with endoscopic and clinical evidence. ^[2]
• Secretin testing. If secretin is unavailable, diagnosis rests on fasting gastrin plus gastric pH. Calcium stimulation is an alternative but has lower sensitivity and more side effects. ^[2] Referral to a regional centre is reasonable.
• Acid control first. Start a high-dose proton pump inhibitor using whatever agent is available and affordable; the specific molecule matters less than dose and adherence. H2-blockers are cheaper but weaker and need frequent dosing.
• Surgery. Refer to a surgeon who can explore the gastrinoma triangle. Intraoperative ingenuity (palpation, transillumination, duodenotomy) often finds tumours that imaging did not. ^[2]
• Aftercare. If extended treatment is not affordable, using the lowest effective acid-suppressing dose after initial control is reasonable, with follow-up for recurrent bleeding or weight loss.
• MEN1 clues such as nephrolithiasis, a family history or a known endocrinopathy are free clinical findings and should not be missed. ^[2]

Peptic ulcer disease; gastro-oesophageal reflux disease and reflux oesophagitis; chronic diarrhoea; multiple endocrine neoplasia type 1 (hyperparathyroidism, pituitary and pancreatic-duodenal tumours); gastric neuroendocrine (type 2) tumours; neuroendocrine tumour localisation (CT, MRI, somatostatin receptor PET, endoscopic ultrasound); peptide receptor radionuclide therapy; proton pump inhibitors and long-term acid suppression.