Physiology of gastrin

INTRODUCTION — Gastrin is the major hormonal regulator of gastric acid secretion [1]. Its discovery in 1905 was based upon its profound effect on meal-stimulated acid secretion, making it one of the first hormones to be described [2]. The study of gastrin accelerated with the isolation and characterization of the peptide in 1964, after which it was found to promote growth of the gastric mucosa and have proliferative effects on cells that express the gastrin receptor [3]. The cloning and characterization of the gastrin receptor has provided keen insights into physiology and pathophysiology of gastrin [4].

This topic will review the physiology of gastrin. Zollinger-Ellison syndrome and the physiology of gastric acid secretion are discussed in detail elsewhere. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)" and "Physiology of gastric acid secretion".)

GASTRIN PHYSIOLOGY

Molecular forms — Human gastrin is the product of a single gene located on chromosome 17. The active hormone is generated from a precursor peptide "preprogastrin" (figure 1). Human preprogastrin contains 101 amino acids (AA) including a signal peptide (21 AA), spacer sequence (37 AA), gastrin component (34 AA), and a 9 AA extension segment at the carboxyl terminus. The enzymatic processing of preprogastrin produces all of the known physiologically active forms of gastrin.

Preprogastrin is processed into progastrin and gastrin peptide fragments of various sizes by sequential enzymatic cleavage (figure 1). Like other hormones, gastrin is synthesized on rough endoplasmic reticulum, processed in the Golgi apparatus, and packaged in secretory granules, where final modifications occur [5]. In endocrine cells of the gut (enteroendocrine cells), the glycine residue at the carboxyl terminus is cleaved and the terminus is amidated to form the mature gastrin peptide.

Two major forms of gastrin are secreted (G-17 and G-34), although larger N-terminal extended forms (eg, G-71) and smaller forms (eg, G-6) exist. The common feature of all gastrins is an amidated tetrapeptide (Try-Met-Asp-Phe-NH2) at the carboxyl terminus that imparts full biological activity. Modification by sulfation at tyrosine residues produces alternative gastrin forms. The circulating half-life of gastrin is affected by the size of the various molecular forms. The full physiologic response is determined by the presence of the biologically active tetrapeptide and the time available for receptor interaction. (See "Overview of gastrointestinal peptides in health and disease".)

Gastrin can be ectopically expressed in tumors. However, because these cells lack secretory vesicles, prohormone convertases, and amidating enzymes, the main forms of gastrin secreted are progastrins including glycine-extended gastrin. These forms of gastrin may have growth-promoting effects on certain tumors. (See 'Unclear clinical implications of hypergastrinemia' below.)

Tissue distribution — The vast majority of gastrin is produced in gastrin-expressing cells (G cells) of the gastric antrum [6]. Much smaller amounts of gastrin are produced in other regions of the gastrointestinal tract including the nonantral stomach, duodenum, jejunum, ileum, and pancreas. Gastrin has also been found outside of the gastrointestinal tract including the brain, adrenal glands, respiratory tract, and reproductive organs, although its biological role in these sites is unknown (table 1).

Regulation of gastrin — Gastrin release is profoundly influenced by the pH of the stomach. Fasting and increased gastric acid in the stomach inhibit its release, whereas a high gastric pH provides a strong stimulus for its secretion. The G cells are tightly regulated by two counterbalancing transmitters, the neurotransmitter gastrin-releasing peptide (GRP) and the paracrine regulator somatostatin, which exert stimulatory and inhibitory effects, respectively. Physiological regulation of gastrin secretion is highest when nutrients are in direct contact with G cells. Consequently, diversion of food from the antrum of the stomach, as with Roux-en-Y gastric bypass, has been associated with low blood levels of gastrin [7].

In fasting humans, normal plasma concentrations of gastrin are 10 to 30 pmol/L and consist primarily of G-34, which has a circulating half-life five times longer than G-17. After a meal consisting of a mixture of protein, fat, and carbohydrates, peak gastrin levels increase two- to threefold by 30 to 60 minutes and consist primarily of G-17 [8]. Thus, gastrin circulates as a mixture of peptides ranging from G-17 to G-71, although G-17 and G-34 predominate [9]. Standard commercial antibodies used in clinical assays bind both G-17 and G-34.  

Gastrin receptors — The receptors for gastrin and cholecystokinin (CCK) share considerable sequence homology and constitute the CCK/gastrin receptor family. Gastrin binds to the CCK2 receptor (formerly known as the CCK-B or gastrin receptor). CCK2 has equal affinity for gastrin and CCK peptides, which have an identical pentapeptide terminal sequence [4]. The CCK2/gastrin receptor is found on parietal cells and enterochromaffin-like (ECL) cells in the stomach, in the brain, and on pancreatic islet cells. The CCK1 receptor is abundant in the pancreas and gallbladder and has a 1000-fold higher affinity for CCK than for gastrin.  

Gastrin receptors have also been found on somatostatin-secreting D cells. However, this receptor is CCK1, which has much greater affinity for CCK than for gastrin [10]. This difference in receptor affinity may explain why gastrin is so much more effective as a stimulant of acid secretion, while CCK induces greater release of the inhibitor somatostatin [11]. Knockout mice genetically engineered to be deficient in CCK2 receptors have low acid secretion, while double knockout mice (deficient in both CCK1 and CCK2 receptors) have robust acid secretion in response to vagal stimulation or exogenous histamine [12]. These findings indicate that CCK1 receptors exert inhibitory effects on acid secretion in vivo and are likely mediated by release of endogenous somatostatin.

The localization of the receptors responsible for trophic actions of gastrin remains uncertain; the primary receptor appears to be on the ECL cell, although receptors may also be present on gastric stem cells.

Complex mechanisms control gastrin release from the antral G cells.

●Gastric distension impacts gastrin secretion, and the effect varies with the degree of distension [13]. Low-grade distention activates vasoactive intestinal peptide neurons, which stimulate somatostatin release and inhibit gastrin secretion. Higher grade distention causes cholinergic activation, which reverses the pattern to one of increased gastrin and reduced somatostatin secretion.

●Dietary amino acids induce gastrin release by directly acting on G cells and indirectly through activation of both cholinergic neurons and GRP neurons [14]. GRP released from mucosal nerves directly stimulates the G cell [15].

●Gastrin inhibits its own secretion by enhancing the secretion of somatostatin [14].

●Hypercalcemia stimulates gastrin secretion through activation of the calcium-sensing receptor on G cells [16].

Biologic actions

Gastric acid secretion — Gastrin is a primary physiologic mediator of gastric acid secretion and is the major hormonal regulator of the secretory response to a protein meal. Gastric acid secretion is influenced by the central, peripheral, and enteric nervous systems mediated by the neurocrine transmitter GRP and neurotransmitter acetylcholine.    

The major cellular determinants of acid secretion involve the antral gastrin-secreting G cell, the ECL cell of the stomach that secretes histamine, and the somatostatin-secreting D cell. The acid-secreting parietal cell possesses receptors for acetylcholine, histamine, and gastrin. Although activation of all three receptors can stimulate acid secretion, the most important mechanism of acid release occurs via stimulation of the ECL cell to secrete histamine, which in turn stimulates the parietal cell [17,18]. The ECL cell receives stimulatory signals from gastrin and inhibitory signals from somatostatin (figure 2). Somatostatin also provides inhibitory signals to antral G cells and, therefore, inhibits gastric acid secretion.

Other biologic effects — Gastrin is also the best identified trophic regulator of parietal cell mass in humans. This relationship is evidenced by the presence of gastric hypertrophy in gastrinoma patients who have chronic exposure to elevated gastrin levels (picture 1), and atrophy of the parietal cell mass with antrectomy, which decreases gastrin levels. Gastrin activates several mitogenic pathways, including epidermal growth factor receptor signaling, phosphoinositide 3-kinase (PI3K), and MAPK activity [19].

Gastrin is the major hormonal regulator of pepsinogen secretion from gastric chief cells [20].

The CCK2 receptor can be found on pancreatic islet cells, and hypergastrinemia has been associated with islet cell hyperplasia and enhanced insulin secretion [21]. In animals, coadministration of gastrin and glucagon-like peptide-1 can restore normoglycemia in diabetic mice, suggesting that gastrin may have incretin-like effects [21]. Gastrin acting on CCK2 receptors in the proximal tubule exerts natriuretic effects [22]. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Gastrointestinal peptides'.)

HYPERGASTRINEMIA

Causes of hypergastrinemia — Since gastrin secretion is strongly influenced by intraluminal gastric pH, it is helpful to interpret hypergastrinemia in relation to gastric acid production. Hypergastrinemia is observed in a number of settings, of which use of acid-suppressive medications and chronic atrophic gastritis are by far the most common (table 2). In these conditions, gastric acid is reduced resulting in alkalinization of gastric contents. Sensing the elevated pH, G cells secrete gastrin. Hypoacidity also accounts for the increased plasma gastrin levels often associated with Helicobacter pylori infection [23]. Less common causes of hypergastrinemia associated with reduced acid production are renal insufficiency and truncal vagotomy.

Secretion of gastrin by a gastrinoma (Zollinger-Ellison syndrome) is a rare but important cause of hypergastrinemia (picture 1). Most patients with Zollinger-Ellison syndrome have serum gastrin concentrations between 150 and 1000 pg/mL (71 and 475 pmol/L). In this condition, ectopic gastrin secretion is independent of gastric pH, thus circulating gastrin levels are high despite excessive gastric acid production (table 2). (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)

The highest gastrin levels (>1000 pg/mL), although rare, are seen with gastrin-secreting tumors or chronic atrophic gastritis accompanying pernicious anemia. Modest elevations in serum gastrin (approximately 200 to 400 pg/mL) are much more common and are often due to acid-suppressive medications (ie, H2 blockers or proton pump inhibitors [PPIs]) or H. pylori-associated gastritis.

Elevated gastrin levels are often seen following small bowel resection due to the loss of enterogastrones (hormones such as secretin that tend to inhibit gastric acid secretion). With loss of enterogastrones, there is an increase in gastric acid secretion and gastric pH is low. 

Other rare causes of achlorhydria-associated hypergastrinemia may occur in the absence of gastritis. For example, impaired potassium secretion into the gastric lumen can reduce hydrogen-potassium proton pump activity on the apical surface of parietal cells, resulting in low acid secretion [24]. Patients with Jervell and Lange-Nielsen syndrome caused by mutations in the potassium channel gene KCNQ1 not only have cardiac arrhythmias due to QT prolongation but have gastric achlorhydria, iron deficiency anemia, and hypergastrinemia as a consequence of impaired potassium ion secretion [25].

Unclear clinical implications of hypergastrinemia — The clinical significance of chronic elevation in serum gastrin levels (as may be seen in patients taking PPIs long-term) is uncertain. Gastrin receptors have been detected on a variety of tumor cells, and gastrin has trophic effects on the stomach and intestine, suggesting that it may have a role in the development of gastrointestinal malignancies [26,27]. The degree to which this might contribute to oncogenesis has not been defined. Gastrin has both antiapoptotic and mitogenic effects in various gastrointestinal malignancies. These effects are mediated by CCK2, which is expressed in human gastric neuroendocrine neoplasms and gastric, pancreatic, and colorectal adenocarcinomas [28-31].

●Gastric adenocarcinoma – Gastric cancer cells express CCK2, which appears to mediate the direct effects of gastrin. The ability of gastrin to stimulate cancer has been demonstrated on gastric cancer cells in vitro and human gastric cancer xenografts.

●Fundic gland polyps – Long-term treatment with PPIs has been associated with the development of gastric fundic polyps and hyperplasia of the oxyntic mucosa. The clinical significance of these observations is uncertain, and their pathogenesis is incompletely understood [32]. Infection with H. pylori may have a role since gastrin has a growth-promoting effect [33]. (See "Gastric polyps", section on 'Fundic gland polyps'.)

●Gastric carcinoid tumors – Although prolonged hypergastrinemia from potent antisecretory therapy has been associated with the development of enterochromaffin-like (ECL) cell carcinoid tumors in rodents, the incidence of gastric carcinoid tumors is low in adults exposed to short-term or periodic acid suppression. The risk of developing a gastric carcinoid is greatest in patients treated with PPI drugs for more than 10 years and those with chronic H. pylori infection and gastric atrophy [34]. The role of gastrin appears to be central in the development of ECL carcinoids associated with atrophic gastritis since the gastrin receptor antagonist netazepide has been shown to induce regression of these carcinoids [35]. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Hypergastrinemia'.)

Studies in patients with gastrinoma and pernicious anemia who develop carcinoids suggest that carcinoid tumor formation requires not only hypergastrinemia but another cofactor, such as loss of the tumor suppressor gene, menin (the genetic defect in multiple endocrine neoplasia type 1 [MEN-1]), or overexpression of a tumor growth promoter such as BCL-2, which occurs in the setting of chronic inflammation and atrophic gastritis [36]. This hypothesis is supported by the observation that carcinoid tumors have been reported in up to 30 percent of patients with MEN-1 and 5 percent of patients with atrophic gastritis and pernicious anemia. However, carcinoid tumors occur in only 1 percent of patients with sporadic gastrinomas [37,38].

●Colon cancer – It remains controversial whether circulating gastrin has a significant role in the development of human colon cancer. Gastrin has been implicated in colon cancer based upon laboratory and epidemiologic evidence [39-43]. Elevated gastrin levels were associated with an increased risk of colorectal malignancy [41], although this association may be due to the production of gastrin by most colon cancers [44]. However, an increased rate of colon cancer has not been observed in patients with gastrinoma, pernicious anemia, or in those taking acid-suppressive medications [45]. It is likely that chronic hypergastrinemia by itself is not carcinogenic, but its proliferative effects may expand the pool of cells that could be at risk for carcinogenesis in susceptible patients. One group of patients at risk may be those infected with H. pylori [41,46].

The following observations illustrate some of the laboratory findings:

•Gastrin increases the proliferation of colon cancer cell lines and the tumor burden in mice with colon cancer [47].

•Gastrin and glycine-extended gastrin have growth-promoting effects on human colon cancer in vivo and in vitro [48].

•A specific inhibitor of glycine-extended gastrin inhibited the growth of human colon cancer, suggesting that receptor blockade may be a strategy for treating patients with colon cancer [49].

•Progastrin, glycine-extended gastrin, and amidated gastrin have been detected in cell extracts of gastrointestinal malignancies, suggesting that gastrin may be an autocrine or paracrine growth regulator [50-52].

•Immunostaining reveals that 80 to 90 percent of colon polyps contain gastrin [53].

•Gastrin inhibits apoptosis [54] and enhances angiogenesis [55].

Although gastrin could be a potential target in the treatment of colorectal cancer, receptor antagonists and antisecretory agents have been ineffective [44].  

●Pancreatic cancer – The CCK2 receptor is rare in a normal pancreas but appears in pancreatic intraepithelial neoplasia (PanIN) lesions of the pancreas and is highly expressed in pancreatic adenocarcinoma [56]. A role for gastrin in the proliferation of pancreatic cancer cells is supported by the observation that growth of cultured human pancreatic cancer cells can be inhibited by antisense oligonucleotides to gastrin [57] and activation of CCK2 potentiates cancer growth [27]. This effect is believed to be autocrine or paracrine since gastrin and its messenger RNA have been identified in cancers of the human pancreas [58]. Gastrin has also been implicated in a mouse model of pancreatic cancer metastasis [59].

CLINICAL APPLICATIONS OF GASTRIN

●Pentagastrin – The gastrin analog, pentagastrin, has been used clinically to stimulate histamine and gastric acid secretion in diagnostic tests of acid secretory capacity [60].

Parafollicular C cells of the thyroid gland and medullary thyroid carcinoma are neural crest in origin and secrete calcitonin, which regulates calcium homeostasis. By virtue of their expression of CCK2 receptors, C cells and medullary carcinomas secrete calcitonin in response to exogenous pentagastrin. This response is sufficiently sensitive that intravenous injection of pentagastrin is used as a provocative test in the biochemical diagnosis of medullar thyroid cancers [61,62]. (See "VIPoma: Clinical manifestations, diagnosis, and management" and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Evaluation'.)

Pentagastrin has been used to provoke symptoms and stimulate 5-hydroxytryptamine release in patients with carcinoid syndrome [63]. Profound responses in some patients require that the test be conducted under careful medical monitoring [64].

●Gastrin receptor antagonists – Gastrin receptor antagonists have the theoretical advantage of blocking gastrin-induced gastric acid secretion, while obviating concern for the trophic effects related to hypergastrinemia. In addition, they could have a role in the treatment and prevention of certain gastrointestinal malignancies that express gastrin receptors. In one study, a gastrin receptor antagonist reduced tumor size in patients with neuroendocrine tumors associated with autoimmune atrophic gastritis [65]. Other ongoing or recently completed clinical trials are evaluating gastrin antagonists on gastric carcinoids and Barrett's esophagus. Other than investigative studies, gastrin antagonists have not been approved for clinical use. (See 'Hypergastrinemia' above.)  

SUMMARY

●Human gastrin is the product of a single gene located on chromosome 17. The active hormone is generated from a precursor peptide "preprogastrin" (figure 1). (See 'Molecular forms' above.)

●The vast majority of gastrin is produced in hormone-producing cells of the gastric antrum (G cells). Much smaller amounts of gastrin are produced in other regions of the gastrointestinal tract including the nonantral stomach, duodenum, jejunum, ileum, and pancreas. Gastrin has also been found outside of the gastrointestinal tract including the brain, adrenal glands, respiratory tract, and reproductive organs, although its biological role in these sites is unknown (table 1). (See 'Tissue distribution' above.)

●The receptors for gastrin and cholecystokinin (CCK) are related and constitute the CCK/gastrin receptor family. The CCK1 receptor is abundant in the pancreas and gallbladder and has a 1000-fold higher affinity for CCK than for gastrin. The CCK2/gastrin receptor is found on parietal cells and enterochromaffin-like (ECL) cells in the stomach, in the brain, and on pancreatic islet cells.

●Gastrin is released from G cells into the circulation in response to a meal or to a high gastric pH. The G cells are tightly regulated by two counterbalancing hormones, gastrin-releasing peptide and somatostatin, which exert stimulatory and inhibitory effects, respectively. (See 'Gastrin physiology' above.)

●Gastrin is a primary physiologic mediator of gastric acid secretion. Gastrin stimulates ECL cells, which then secrete histamine, which in turn stimulates parietal cells to secrete acid (figure 2). (See 'Gastrin physiology' above.)

●The clinical significance of chronic elevation in serum gastrin levels (as may be seen in patients taking proton pump inhibitors long-term) is uncertain. Gastrin receptors have been detected on a variety of tumor cells, and gastrin has trophic effects on the stomach and intestine, suggesting that it may have a role in the development of gastrointestinal malignancies. However, the degree to which this might contribute to oncogenesis has not been defined. (See 'Unclear clinical implications of hypergastrinemia' above.)

●The gastrin analog, pentagastrin, has been used clinically to stimulate histamine and gastric acid secretion in diagnostic tests of acid secretory capacity. This test has been used to assess the extent of surgical vagotomy and to screen for thyroid C-cell hyperplasia and medullary carcinomas. (See "VIPoma: Clinical manifestations, diagnosis, and management" and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Evaluation'.)