Monjur Ahmed a, b, c, Sarah Ahmed a, b
a Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
b Both authors contributed equally to write the manuscript.
c Corresponding Author: Monjur Ahmed, Sidney Kimmel Medical College, Thomas Jefferson University, 132 South 10th Street, Main Building, Suite 468, Philadelphia, PA 19107, USA
Manuscript submitted September 6, 2019, accepted September 23, 2019
Short title: Gastrointestinal Hormones
doi: https://www.frankenthalerfoundation.org
Gastrointestinal (GI) hormones are essential to many physiologic functions in our body. They have many GI and extra-GI functions. Some of the functions of these hormones, which have GI and extra-GI sources, are still unknown. Specific GI hormones can affect the brain to control food intake, while others can proliferate normal and neoplastic tissue when their receptors are expressed in certain neoplasms. GI hormones also have many diagnostic and therapeutic roles. Physiologic and pathophysiologic aspects as well as the diagnostic and therapeutic values of GI hormones are elaborated in this review.
Keywords:Gastrointestinal hormones; Functions of gut hormones; Diagnostic roles of gut hormones; Therapeutic roles of gut hormones; Effect of gut hormones on neoplastic proliferations
Gastrointestinal (GI) hormones are a group of peptides secreted by the endocrine cells, also known as endocrinocytes, in different parts of the GI mucosa and pancreas. Most of these are secreted after a meal, after which they are released into blood and circulate to different organs. Some of the functions of GI hormones on the GI tract, pancreas and nervous system include the regulation of secretion, digestion, absorption, GI motility, appetite as well as trophic effects on GI mucosa and certain neoplasms. The GI hormones are first classified and then each hormone is discussed separately.
Based on chemical structure, GI hormones can be divided into the following groups as shown in Table 1.
Excluding the above hormones, there are certain hormones which are not mentioned in the above classification. These include gastrin-releasing peptide (GRP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), gastric leptin, oxyntomodulin and uroguanylin.
Gastrin is secreted mainly from G cells of the gastric antrum. Occasionally, G cells can be found in duodenum, pancreas and pituitary gland. Gastrin is released into the circulation in response to gastric antral distension, food containing aromatic amino acids, small peptides, vagal stimulation, hypercalcemia and GRP. Gastrin secretion is inhibited by increased acidity of the stomach (pH 3 or below), low-level gastric distension and somatostatin. Gastrin works on the parietal cells to stimulate acid secretion and has a trophic effect on the oxyntic mucosa. The precursor of gastrin is progastrin which is synthesized and stored in the secretory granules of antral G cells. Three forms of gastrin are released into the circulation after processing (amidation and cleavage): G-34 or big gastrin, G-17 or little gastrin and G-14 or small gastrin. G-34 and G-17 are bioactive. Most of the G-17 are produced after cleavage from G-34.
Most of the gastrin released following food intake is G-17. But as G-17 is quickly cleared from the circulation, most of the gastrin seen in the circulation during the fasting state is G-34. Both G-17 and G-34 can stimulate the enterochromaffin-like (ECL) cells of the oxyntic mucosa to synthesize and release histamine, as well as parietal cells to secrete acid through the cholecystokinin B receptors (CCKBRs, formerly known as gastrin/CCK2 receptors). Histamine binds to H2 receptors on parietal cells and induces acid secretion. Gastrin can increase both ECL and parietal cell mass. Parietal cells or oxyntic cells are present throughout the length of gastric glands located in gastric fundus and gastric body. They secrete hydrochloric acid (keeping gastric pH between 1.5 and 3.5) and intrinsic factor which aids the absorption of vitamin B12 from the terminal ileum. Chief cells or zymogenic cells are present in the basal part of gastric glands and they secrete inactive pepsinogen (PG) which becomes active pepsin on exposure to acid. Pepsin partially digests protein into peptides only in the acidic medium. Chief cells are activated by gastrin, secretin, vasoactive intestinal peptide (VIP), acetylcholine and epinephrine. The gastric corpus chief cell mass is decreased in patients with multifocal atrophic gastritis (MAG), i.e. foci of gastric atrophy and intestinal metaplasia starting at the junction of gastric corpus and antrum and extending into the adjacent mucosa of both with time. In gastric antral atrophy, there is a decrease in serum concentration of G-17 which is mainly secreted by antral glands. Gastrin has trophic effect on gastric, small bowel and probably colonic mucosa. It also increases gastric mucosal blood flow, gastric motility, and to a lesser extent, small intestinal and gall bladder motility. As mentioned before, G cells can be present in the duodenal wall and pancreatic islet cells, where patients can develop a gastrinoma. Patients with gastrinoma secrete huge amount of gastrin leading to severe hypergastrinemia. Of the gastrinomas, 85-90% are located in the gastrinoma triangle bounded superiorly by the cystic duct and common bile duct, inferiorly by the second and third part of duodenum and medially by the neck and body of pancreas. Of gastrinomas, 40-50% occur in the duodenal wall. Various imaging studies (computerized axial tomography, magnetic resonance imaging and octreotide scan) and endoscopic ultrasound can detect the location of gastrinomas. Other causes of significant hypergastrinemia (serum gastrin > 150 pg/mL) include H2 blocker and proton pump inhibitor therapy, H. pylori infection, chronic atrophic gastritis, renal failure, gastric outlet obstruction, retained gastric antrum, antral G cell hyperplasia and vagotomy.
Secretin suppression test is a provocative test used to evaluate hypergastrinemia suspected of gastrinoma. Normally, secretin suppresses the release of serum gastrin. However, in a gastrinoma (Zollinger-Ellison syndrome), there is a paradoxical rise of serum gastrin after intravenous administration of exogenous secretin 0.4 µg/kg as a single dose.
Pentagastrin is a synthetic pentapeptide analogue of natural gastrin comprised of the first five amino acids of gastrin. Like gastrin, it can stimulate the secretion of acid, pepsin and intrinsic factor. Pentagastrin was studied to investigate the secretory response of acid and pepsin in peptic ulcer disease. In response to the administration of pentagastrin, the secretion of acid and pepsin was markedly higher in duodenal ulcers, slightly higher in pyloric ulcers and slightly lower in gastric ulcers. Men secreted more acid per kilogram of body weight than women both in healthy individuals and patients with peptic ulcer disease.
The pentagastrin stimulation test is also used in the early diagnosis of medullary carcinoma of the thyroid gland (MCT) in the presence of an equivocal or slightly high serum calcitonin level. Pentagastrin binds to CCKBRs on parafollicular cells of MCT and increases serum calcitonin level by > 100 pg/mL. This test is also used in determining the necessity of surgical resection of MCT and investigating any residual MCT after surgery. Pentagastrin stimulation test can also be used for assessment of completeness of vagotomy by measuring peak acid output (PAO) of the stomach.
CCK is a peptide hormone secreted by the enteroendocrine I cells located within the crypts of Lieberkuhn of the duodenum and jejunum in response to partially digested food (amino acids, proteins and fats). It stimulates gallbladder contraction, pancreatic enzyme secretion and bowel motility, inhibits gastric emptying, potentiates insulin secretion and has trophic effects on the intestinal mucosa and pancreas. CCK suppresses hunger by inhibiting expression of orexigenic peptides in the hypothalamus and preventing stimulation of specialized neurons by ghrelin. It also induces satiety by interacting with CCK-1 receptors in the hind brain. The diagnostic and therapeutic roles of CCK are as follows.
Secretin is a polypeptide hormone secreted by the enteroendocrine S cells located within the crypts of Lieberkuhn in the duodenum and proximal jejunum in response to the presence of acidic pH in the lumen. It stimulates pancreatic acinar cells to secrete water and bicarbonate to be drained through the pancreatic duct into the duodenum. As a result, the acidic environment is quickly neutralized.
