Review Article: Strategies to Determine Whether Hypergastrinaemia Is Due to Zollinger-Ellison Syndrome Rather Than a More Common Benign Cause

S.V.M. Murugesan; A. Varro; D.M. Pritchard

Disclosures

Aliment Pharmacol Ther. 2009;29(10):1055-1068. 

In This Article

Gastrin Physiology

Since its discovery by Edkins in 1905, gastrin has been shown to regulate not just gastric acid secretion but also parietal cell maturation and gastric epithelial organization. Gastrin is initially synthesized as a precursor molecule (preprogastrin), which is subsequently enzymatically cleaved to generate the intermediate hormones progastrin and glycine-extended gastrins. In the endocrine G cells of the gastric antrum, these peptides are subsequently amidated to form G34 amide and G17 amide. Amidated forms of gastrin bind specifically to two receptors CCK-1 and CCK-2 or (CCKB), which both belong to the G protein coupled receptor family. However, gastrin exhibits a much higher affinity for CCK-2 rather than CCK-1 receptors. CCK-2 receptors are located on the surface of parietal cells and enterochromaffin-like (ECL) cells in the gastric corpus, as well as in certain cells in the pancreas, smooth muscle and brain. The effect of direct gastrin binding to CCK-2 receptors located on gastric parietal cells is still under investigation, but recent evidence suggests that it plays a role in the regulation of parietal cell maturation.[8,9]

Gastrin is released by antral G cells in response to various stimuli, including stomach distension following a meal, the presence of luminal contents (especially aromatic amino acids, calcium and dietary amines), vagal stimulation mediated by acetylcholine and by the neurotransmitter, gastrin releasing peptide (GRP).[10] Gastrin causes acid secretion by binding to the CCK-2 receptors located on ECL cells (which are located in the neck region of oxyntic glands). This causes the release of histamine, which in turn binds to the H2 receptors on parietal cells, stimulating them to release hydrochloric acid (Figure 1).[10,11] This mechanism appears to be the main route for gastrin-stimulated acid secretion. Gastrin also stimulates the synthesis and storage of histamine by ECL cells, by inducing histidine decarboxylase expression and also promotes the sequestration of histamine in secretory vesicles by stimulating the expression of vesicular monoamine transporter-2 (VMAT-2) in ECL cells.[12]

Figure 1.

Regulation of gastric acid secretion.

There are several inhibitors of gastrin secretion including somatostatin, which is secreted by gastric D cells in response to an acidic gastric juice pH. The presence of an acidic gastric pH thus causes negative feedback inhibition of gastrin release. Secretin has also been shown to suppress the release of gastrin in response to a meal in normal subjects and in patients with duodenal ulcer disease. This effect is thought to be secondary to non-competitive inhibition of the action of gastrin at the gastric parietal cell.[13]

In addition to regulating acid secretion, gastrin has a number of other effects upon gastric physiology. For example, this hormone stimulates the proliferation of gastric epithelial cells, which may result in parietal or ECL cell hyperplasia. While some of these effects may result directly from gastrin-CCK-2 receptor stimulation (e.g. ECL-cell hyperplasia in atrophic gastritis), other effects may be due to paracrine stimulation by other growth factors, such as heparin-binding epidermal growth factor (HB-EGF).[14]

The gastrin concentration in serum or plasma is currently usually measured by radioimmunoassay (RIA). Gastrin radioimmunoassay is based on the same principle as that involved in other RIA systems - competitive binding between a radiolabelled peptide (usually 125I) and a standard or unknown peptide to an antibody (of defined specificity).[15] A comprehensive analysis of the biochemical issues involved in gastrin RIA has been described elsewhere.[15] Although RIA has been used for several years to measure serum gastrin concentrations, it has now been replaced by ELISA (Enzyme Linked Immunosorbent Assay) kits in several laboratories. However, as many such commercial kits are specific for gastrin-17, some authors have expressed concern that they may not detect the other forms of gastrin which may be present at increased concentration in certain pathological states such as gastrinoma and thus yield false negative results in this condition.[16]

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