Serum Gastrin

Gastrin is a peptide hormone made by the G cells of the gastric antrum and the duodenum. It stimulates gastric acid secretion from parietal cells and trophic growth of gastric mucosa, and acid in the antrum feeds back to switch it off. It circulates mainly as gastrin-17 and gastrin-34 and is measured by immunoassay on fasting serum, reported in ng/L (pg/mL) or pmol/L (1 pmol/L is about 2.1 ng/L).

The test is used to diagnose gastrin secreting tumours (Zollinger-Ellison syndrome), to explain recurrent or refractory peptic ulcer, and as a marker of atrophic gastritis. Interpretation always needs knowledge of gastric acid status, since acid lowering medicines are the commonest cause of a raised level.

Gastrinoma is rare, with an incidence of 0.5 to 2 per million people a year. About 80% occur in the gastrinoma triangle (duodenum and pancreas), 60 to 90% are malignant, and about 20 to 25% occur with multiple endocrine neoplasia type 1 (MEN 1). Hypergastrinaemia from acid suppression, atrophic gastritis and Helicobacter pylori infection is far commoner.

Indications. Recurrent, multiple, distal or refractory peptic ulceration, ulcer without H. pylori infection and without non-steroidal anti-inflammatory drug use, ulcer with complications, severe oesophagitis, chronic watery diarrhoea with ulcer disease or high gastric output, thick gastric folds on endoscopy, MEN 1 or hypercalcaemia with ulcer, and assessment of autoimmune gastritis with pernicious anaemia.

Specimen. Fasting serum after at least 12 hours without food, separated promptly and frozen if delayed (gastrin degrades at room temperature). Stop proton pump inhibitors for at least 1 to 2 weeks and H2 antagonists for 48 to 72 hours before sampling where it is safe to do so. In a patient with severe disease, stopping acid suppression is done under supervision, because ulcer complications can occur within days.

Reference range. Fasting gastrin under 100 ng/L (under 48 pmol/L) in most assays.

Interpretation of fasting gastrin.

• Over 1000 ng/L (10 times the upper limit) with a gastric pH under 2: diagnostic of Zollinger-Ellison syndrome. This occurs in about 40 to 60% of patients.
• 100 to 1000 ng/L: indeterminate, since gastrinoma, H. pylori gastritis, atrophic gastritis and drug effects all cause it. Gastric pH and a secretin test are needed.
• Raised with a gastric pH over 4 or 5: hypochlorhydria or achlorhydria, found in atrophic gastritis, pernicious anaemia and acid suppression.
• Normal fasting gastrin on repeat testing makes gastrinoma very unlikely.

Gastric pH. A pH under 2 on a gastric aspirate with raised gastrin indicates inappropriate acid secretion. Basal acid output over 15 mmol/hour (or over 5 mmol/hour after acid reducing surgery) supports gastrinoma.

Secretin stimulation test. After an overnight fast, secretin 2 units/kg is given intravenously with samples for gastrin at baseline and at 2, 5, 10, 15 and 30 minutes. A rise of 120 ng/L or more over baseline within 15 minutes has sensitivity of about 90% and specificity of 100% for gastrinoma. Normal and antral G-cell hyperplasia responses show no rise or a fall.

Calcium infusion test. Used when the secretin test is negative and suspicion remains, with a rise of over 395 ng/L supporting gastrinoma. It is now rarely used.

Causes of hypergastrinaemia.

• With raised acid: gastrinoma, antral G-cell hyperplasia, retained antrum after gastric surgery, gastric outlet obstruction, renal failure, and short bowel.
• With low acid: proton pump inhibitors and H2 antagonists (two to four times the upper limit), atrophic gastritis, autoimmune gastritis, pernicious anaemia (levels often over 1000 ng/L), vagotomy, and H. pylori infection.
• Other: chronic kidney disease, rheumatoid arthritis, diabetes, phaeochromocytoma, and hypercalcaemia (which also stimulates release).

Critical values and findings needing immediate action.

• Gastrin over 1000 ng/L with a gastric pH under 2 and recurrent ulcer disease: the diagnosis is made, and acid control with high dose proton pump inhibition is started at once.
• Bleeding, perforation or obstruction in suspected Zollinger-Ellison syndrome.
• Hypercalcaemia or raised prolactin with gastrinoma, which indicates MEN 1.
• Hypokalaemia and dehydration from severe diarrhoea, which needs fluid and potassium replacement.

Interferences and pitfalls.

• Proton pump inhibitors cause a false positive rise and also mask diagnostic gastrin response, and stopping them is needed for a reliable result, with the risk managed.
• A pH measurement is essential. A raised gastrin without acid measurement cannot be interpreted.
• Gastrin is unstable in unfrozen samples, giving falsely low results.
• Different assays recognise different molecular forms and give different results.
• Heterophile antibodies cause false elevation.
• The secretin test can be falsely negative in patients on high dose acid suppression (a small number) and falsely positive in hypochlorhydria.
• Pernicious anaemia and atrophic gastritis can mimic the picture, and the pH separates them.
• Secretin is not available in all regions.

Special groups.

• MEN 1: gastrinoma is often multiple and small, and screening with gastrin yearly starts in the teens.
• Older adults: hypochlorhydria and acid suppression are common, so a high gastrin is frequently benign.
• Children: very rare, and ulcers in children usually follow H. pylori or other causes.
• Pregnancy: no major change, and acid suppression is used.
• Regions: H. pylori is highly prevalent, and gastrin is often modestly raised.

Follow up tests. Gastric pH or acid output, secretin stimulation test, H. pylori testing (stool antigen, urea breath test), upper endoscopy with biopsy, chromogranin A, serum calcium and parathyroid hormone, prolactin and pituitary hormones, MEN1 gene testing, somatostatin receptor PET-CT, endoscopic ultrasound, contrast CT or MRI of the abdomen, intrinsic factor antibodies and vitamin B12, and parietal cell antibodies.