GIT Hormones- Gastrin

Gastrin is one of the five established gastrointestinal (GI) hormones, playing a pivotal role in the regulation of upper GI function, particularly gastric acid secretion and mucosal growth. The word "hormone" itself was coined by Starling in 1905 to describe substances like gastrin, conveying the concept of bloodborne chemical messengers. Its existence as a polypeptide distinct from histamine was definitively established by Komarov in 1938, and its chemical structure was identified and synthesized in 1964.

I. Glands of Secretion (Distribution and Release)

Gastrin is a peptide hormone primarily released from specialized endocrine cells within the GI tract.

• G cells: These are the primary cells responsible for gastrin synthesis and release.

    ◦ Location: G cells are most abundant in the antral mucosa (pyloric gland area) of the stomach, which is the distal 20% of the gastric mucosa.

    ◦ They are also found in significant amounts in the proximal duodenum.

    ◦ Release Pattern: Most gastrin is released from the antrum under physiological conditions. After a meal, a large quantity of antral gastrin, primarily "little gastrin" (G 17), is released, providing most of the stimulus for gastric acid secretion. During the interdigestive (basal) state, the major component of gastrin immunoactivity in human serum is "big gastrin" (G 34), released in small amounts from both antral and duodenal mucosa.

• Ultrastructure: GI endocrine cells, including G cells, have hormone-containing granules concentrated at their bases, close to capillaries. They also possess microvilli on their apical borders, which are presumed to contain receptors for sampling the luminal contents and triggering hormone secretion.

II. Composition and Forms of Gastrin

Gastrin, like other peptide hormones, is heterogeneous and exists in various molecular forms.

• Major Forms:

    ◦ Little Gastrin (G 17): A 17-amino acid peptide, it is the predominant form released from the antrum after a meal and accounts for 90% of antral gastrin. Its half-life in plasma is approximately 7 minutes.

    ◦ Big Gastrin (G 34): A 34-amino acid peptide, it is the major form in human serum during the basal (interdigestive) state. Its half-life is 38 minutes.

    ◦ Both G 17 and G 34 are equipotent.

    ◦ An additional gastrin molecule, G 14, a C-terminal tetradecapeptide, has also been isolated from tissue.

• Structural and Functional Features:

    ◦ All biologic activity of gastrin resides in its four carboxyl-terminal (C-terminal) amino acids. This tetrapeptide is the minimum fragment for strong activity.

    ◦ Gastrin and Cholecystokinin (CCK) share an identical sequence of their five C-terminal amino acids.

    ◦ Gastrin is synthesized as a large, biologically inactive precursor called progastrin. It undergoes endoproteolytic processing to a glycine-extended (G-Gly) form, which is then amidated to mature gastrin. The C-terminal amide moiety is required for full biologic activity.

    ◦ The N-terminus of gastrin is pyroglutamyl, and its C-terminus is phenylalamide, with alterations that protect the molecules from peptidases and inactivation as they pass through the liver.

• Receptors: Gastrin acts primarily by binding to CCK-2 receptors (previously called CCK-B receptors).

III. Functions of Gastrin

Gastrin's actions primarily focus on stimulating gastric functions and promoting growth within the GI tract.

• Stimulation of Gastric Acid (HCl) Secretion: This is the primary and most important physiological action of gastrin.

    ◦ Direct action on parietal cells: Gastrin can directly stimulate parietal cells, though this effect is less important.

    ◦ Indirect action via Histamine: Gastrin primarily stimulates HCl secretion by causing the release of histamine from enterochromaffin-like (ECL) cells in the stomach. Histamine then acts in a paracrine manner on H2 receptors on nearby parietal cells to stimulate acid secretion. Gastrin also increases histamine synthesis and storage in ECL cells.

• Trophic Activity (Stimulation of Growth): Gastrin is an important regulator of the growth of the oxyntic gland mucosa (body and fundus of the stomach).

    ◦ It stimulates the synthesis of ribonucleic acid (RNA), protein, and deoxyribonucleic acid (DNA).

    ◦ It promotes the growth of the mucosa of the small intestine and colon, as well as the exocrine pancreas.

    ◦ Continued hypersecretion of gastrin leads to ECL cell hyperplasia.

    ◦ The G-Gly form of gastrin also has trophic effects, activating its own receptor and potentially working with gastrin to regulate gut development.

• Stimulation of Pepsinogen Secretion: Gastrin is usually listed as a pepsigogue, increasing pepsin secretion. In humans, it may have a weak direct pepsigogic effect.

• Gastric Motility: Gastrin increases contractions of the stomach.

• Other Potential Actions (Less Physiological): Large doses of gastrin can stimulate gallbladder contraction, but this is likely not a primary physiological role in humans. It can also stimulate glucagon and insulin release, but these mechanisms are generally not considered physiologically important in normal GI physiology.

IV. Regulation of Secretion

Gastrin secretion is meticulously regulated by a combination of neural and chemical stimuli, with crucial feedback inhibition.

• Stimulants for Gastrin Release:

    ◦ Peptides and Amino Acids: The presence of protein digestion products (small peptides and single amino acids, especially aromatic ones like phenylalanine and tryptophan) in the lumen of the stomach are potent stimuli for gastrin release. These substances likely bind directly to receptors on the apical membrane of G cells.

    ◦ Distention of the Stomach: Physical distention of the stomach wall activates antral mechanoreceptors, initiating both long vagovagal reflexes and local intramural reflexes that lead to gastrin release. While effective, the contribution of distention to total gastrin release in humans is considered minor.

    ◦ Vagal Stimulation: This is a major neural pathway. Vagal efferents release gastrin-releasing peptide (GRP), also known as bombesin, which directly stimulates gastrin release from G cells. This vagally mediated release of gastrin is not blocked by atropine, distinguishing it from acetylcholine's direct action on parietal cells. Vagal activation also inhibits somatostatin release, further contributing to gastrin stimulation.

    ◦ Other Chemical Stimuli: Calcium (Ca2+), decaffeinated coffee, and wine can also stimulate gastrin release.

• Inhibition of Gastrin Release:

    ◦ Luminal Acidification (Low pH): When the pH in the antral lumen falls below 3 (and is totally prevented below 2), gastrin release is inhibited. This is a crucial negative feedback mechanism.

        ▪ This inhibition is mediated by somatostatin (SS), a paracrine factor released from D cells (found throughout the gastric and duodenal mucosa and pancreas). Acid directly stimulates somatostatin release, which then inhibits gastrin release from neighboring G cells, inhibits histamine release from ECL cells, and directly inhibits acid secretion from parietal cells. Vagal stimulation actually inhibits somatostatin release.

    ◦ Enterogastrones: Hormones released from the duodenal mucosa (such as secretin and gastric inhibitory peptide (GIP)) in response to acid, fatty acids, or hyperosmotic solutions can inhibit gastric acid secretion and sometimes gastrin release. While these are important in general gastric inhibition, their specific physiological role in directly inhibiting human gastrin release is debated.

    ◦ Other Hormones: Secretin and glucagon can inhibit gastrin release, but their physiological importance in humans is uncertain.

• Phases of Gastrin Secretion (coordination with digestion):

    ◦ Cephalic Phase: Accounts for approximately 20% of the pancreatic response to a meal (in dogs). Stimulated by the sight, smell, taste, chewing, and swallowing of food. Vagal afferent impulses lead to vagal efferents stimulating G cells (via GRP) and parietal cells (via ACh).

    ◦ Gastric Phase: Accounts for at least 50% of the total acid response to a meal. Triggered by food in the stomach. Distention and protein digestion products (amino acids, peptides) in the lumen stimulate gastrin release through both vagovagal and local reflexes.

    ◦ Intestinal Phase: While largely inhibitory for gastric acid secretion via enterogastrones, the proximal duodenum is rich in gastrin (G 34), which contributes to the serum gastrin response to a meal. This phase accounts for approximately 5% of the acid response.

V. Applied Physiological Aspects (Clinical Significance)

Dysregulation of gastrin secretion or action can lead to significant clinical conditions.

• Zollinger-Ellison Syndrome (Gastrinoma):

    ◦ Caused by gastrin-producing tumors (gastrinomas), typically in the pancreas (non-β-cell tumors) or duodenum, which continually release gastrin into the blood.

    ◦ Results in severe hypergastrinemia and subsequent hypersecretion of gastric acid.

    ◦ The hypersecretion occurs due to two main mechanisms:

        1. Trophic action: Gastrin's trophic effect leads to increased parietal cell mass (hypertrophy and hyperplasia of gastric mucosa) and acid secretory capacity. This can also cause ECL cell hyperplasia.

        2. Constant stimulation: Elevated gastrin levels continuously stimulate acid secretion from the hyperplastic mucosa.

    ◦ Clinical Complications: The constant presence of large amounts of acid in the small bowel overwhelms the neutralizing capacity of the pancreas, leading to severe complications:

        ▪ Fulminant peptic ulceration (in esophagus, stomach, and duodenum).

        ▪ Diarrhea.

        ▪ Steatorrhea (excessive fat in stool) due to inactivation of pancreatic lipases by the low duodenal pH.

        ▪ Hypokalemia.

• Inverse Relationship with Acid Secretory Capacity: Generally, serum gastrin levels are inversely related to gastric acid secretory capacity. For example, patients with chronic decreased acid-secreting cells (e.g., in pernicious anemia) may have extremely high serum gastrin concentrations because the absence of gastric acid removes the inhibitory feedback on gastrin release. Patients with gastric ulcer and carcinoma also often have higher than normal serum gastrin levels.

• Pharmacological Effects on Gastrin Secretion: Long-term inhibition of gastric acid production (e.g., with proton pump inhibitors or H2 receptor blockers) can lead to an overgrowth of antral G cells. Antrectomy (surgical removal of the antrum and thus most endogenous gastrin) causes atrophy of the remaining gastric mucosa and the exocrine pancreas, which can be prevented by exogenous gastrin administration.