Gastrin
G17 (little gastrin), G34 (big gastrin), gastrin-17, human gastrin I, pentagastrin (synthetic C-terminal analogue)
Gastrin is the hormone that drives stomach acid secretion. It is released from G-cells in the gastric antrum in response to protein, stomach distension and vagal stimulation, and acts on CCK2 receptors to trigger histamine release and, through that, parietal cell acid output. It is also trophic to the gastric mucosa, which is why chronically raised gastrin causes enterochromaffin-like cell hyperplasia and, in some settings, gastric neuroendocrine tumours.
Mechanism
Gastrin circulates in two principal forms: gastrin-17 (little gastrin), a 17-residue peptide with a pyroglutamate N-terminus and an amidated C-terminus, and gastrin-34 (big gastrin), an N-terminally extended form. Both share the C-terminal tetrapeptide Trp-Met-Asp-Phe-NH2, which carries the full biological activity and is identical to the C-terminus of cholecystokinin. Each exists in sulfated (gastrin II) and non-sulfated (gastrin I) forms; unlike cholecystokinin, sulfation makes little difference to potency at the gastrin receptor.
Gastrin acts at the CCK2 receptor, a class A G-protein-coupled receptor. The dominant route to acid secretion is indirect: CCK2 receptors on enterochromaffin-like (ECL) cells in the oxyntic mucosa trigger histamine release, and histamine acts on H2 receptors on parietal cells to activate the H+/K+-ATPase proton pump. Gastrin also has a smaller direct effect on parietal cells. Secretion is switched off by antral acidification through somatostatin release from D-cells, a negative feedback loop that is the key to understanding hypergastrinaemia. Anything that removes acid from the antrum, whether a proton pump inhibitor or autoimmune destruction of parietal cells in atrophic gastritis, releases that brake and drives gastrin higher. Gastrin is also a growth factor for ECL cells and oxyntic mucosa; sustained hypergastrinaemia therefore produces ECL hyperplasia and can progress to type 1 gastric neuroendocrine tumours.
What the research shows
Gastrin was isolated and sequenced by Gregory and Tracy in 1964, and the identification of its C-terminal tetrapeptide as the active fragment led directly to pentagastrin, which became the standard provocative agent for gastric acid secretion testing and, separately, for stimulating calcitonin release in medullary thyroid carcinoma. Both uses have largely been superseded (acid secretion testing by endoscopy and pH studies, calcitonin provocation by more sensitive assays), and pentagastrin has been withdrawn from most markets.
The clinically productive modern research on gastrin has been about blocking it. Netazepide is an orally active, selective CCK2 receptor antagonist. In a two-centre, 12-week open-label nonrandomised trial in 16 patients with autoimmune chronic atrophic gastritis, hypergastrinaemia and multiple type 1 gastric neuroendocrine tumours, netazepide reduced tumour number and size and normalised circulating chromogranin A; longer-term open-label follow-up reported eradication of tumours in some patients, with recurrence after stopping. Those are small, open-label studies in a rare condition, and netazepide is not licensed anywhere. But they represent proof of concept that gastrin's trophic effect on ECL cells is druggable and reversible. It is important to set against them the one properly randomised controlled trial of netazepide, conducted in patients with non-dysplastic Barrett's oesophagus by Abrams and colleagues in 2021: it was negative, with netazepide failing to reduce cellular proliferation. Gastrin blockade is therefore promising in the specific setting of gastrin-driven ECL tumours and unproven elsewhere. The parallel clinical question, whether long-term proton pump inhibitor-induced hypergastrinaemia carries neoplastic risk, has been examined in large observational datasets without a convincing causal signal, though it remains a subject of legitimate debate.
Evidence assessment
Limited evidence
Gastrin is not a therapeutic agent and has never been tested as one in controlled trials. Its synthetic analogue pentagastrin held diagnostic licences historically but has been withdrawn from most markets. Human evidence exists in abundance as physiology, diagnostics and disease pathology, but therapeutic-grade evidence for administering gastrin does not exist. The clinical trial evidence in this record concerns blocking gastrin, not giving it. And the one randomised controlled trial of that approach, in Barrett's oesophagus, was negative.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
The constitution and properties of two gastrins extracted from hog antral mucosa Preclinical only
Isolated and sequenced gastrin, identifying the two forms and the C-terminal tetrapeptide as the seat of biological activity, the work that made pentagastrin and, much later, CCK2 antagonists possible.
Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis Preclinical only
Netazepide reduced the number and size of type 1 gastric neuroendocrine tumours and normalised circulating chromogranin A. Open-label, nonrandomised and small, but the clearest demonstration that these tumours are gastrin-dependent and that the effect is reversible.
Netazepide, a gastrin/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis Preclinical only
Extended treatment eradicated tumours in some patients, with recurrence after stopping, indicating that continuous gastrin blockade is required and that the driver is gastrin itself.
Randomized controlled trial of the gastrin/CCK2 receptor antagonist netazepide in patients with Barrett's esophagus Preclinical only
NEGATIVE. Netazepide did not reduce cellular proliferation in patients with non-dysplastic Barrett's oesophagus, contrary to the chemoprevention hypothesis. This is the only properly randomised trial of gastrin blockade in the record and it did not support benefit outside the neuroendocrine tumour setting.
Safety
Gastrin itself is not administered therapeutically. Pentagastrin, when it was in use, commonly caused flushing, nausea, abdominal cramps, an urge to defecate, dizziness and transient hypotension or hypertension; like the related CCK-4, it can provoke intense anxiety or panic in susceptible individuals, and this limited its acceptability. The clinically important safety issues around gastrin concern chronic elevation rather than administration: sustained hypergastrinaemia from autoimmune atrophic gastritis, chronic proton pump inhibitor use or a gastrinoma drives ECL cell hyperplasia and can lead to type 1 gastric neuroendocrine tumours. Markedly raised fasting gastrin with acid hypersecretion should prompt investigation for Zollinger-Ellison syndrome. Anyone finding gastrin peptides offered for sale should understand there is no therapeutic indication, no licensed product and no rationale for stimulating gastric acid secretion outside a supervised diagnostic setting.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Gastrin is not a licensed medicine. Pentagastrin injection formerly held a UK licence for gastric acid secretion testing and for provocative testing in medullary thyroid carcinoma, but has been withdrawn from the UK market. Fasting serum gastrin measurement remains a routine investigation for Zollinger-Ellison syndrome and atrophic gastritis. Gastrin peptides offered for sale to consumers are unlicensed research chemicals. |
| United States | Gastrin is not an approved medicine. Pentagastrin injection, the synthetic C-terminal analogue, was formerly FDA-approved as a diagnostic agent for evaluating gastric acid secretory capacity but has been discontinued and is no longer commercially available. Serum gastrin measurement remains a standard diagnostic test. |
| WADA (sport) | Not listed on the WADA Prohibited List. There is no performance-enhancing rationale for stimulating gastric acid secretion. |
Questions
Gastrin release is switched off by acid in the gastric antrum, acting through somatostatin from D-cells. Proton pump inhibitors remove that acid, so the brake comes off and G-cells secrete more gastrin. The same happens in autoimmune atrophic gastritis, where the acid-producing parietal cells are destroyed.
Gastrin is trophic to enterochromaffin-like cells, and sustained very high gastrin (as in autoimmune atrophic gastritis or a gastrinoma) causes ECL hyperplasia that can progress to type 1 gastric neuroendocrine tumours. That link is well established. Whether the more modest hypergastrinaemia from long-term proton pump inhibitor use carries meaningful neoplastic risk is much less clear, and large observational studies have not produced a convincing causal signal.
No. Cholecystokinin also activates CCK2 receptors, because the two hormones share an identical C-terminal five amino acids. The receptor was originally named CCK-B for that reason. In the stomach gastrin dominates; in the brain, cholecystokinin does.
No. There is no licensed therapeutic use for gastrin, and none has been established in controlled trials. The synthetic analogue pentagastrin was used diagnostically for decades but has been withdrawn from most markets. The promising work in this area involves blocking the gastrin receptor rather than stimulating it. And even there, the only randomised controlled trial, in Barrett's oesophagus, was negative.