GI Secretions & Physiology

Gastric secretion

Parietal cells. Located in the gastric body and fundus, parietal cells secrete HCl and intrinsic factor. Three stimulators converge on them: gastrin (via the CCK-B receptor), acetylcholine from the vagus (M3), and histamine from enterochromaffin-like (ECL) cells (H2). Gastrin and ACh signal through Gq and Ca²⁺, histamine through Gs and cAMP, so together they potentiate one another.

Intrinsic factor. Intrinsic factor binds vitamin B12 and carries it to the terminal ileum for absorption. Autoimmune destruction of parietal cells causes pernicious anemia: megaloblastic anemia plus achlorhydria.

The proton pump. The apical H⁺/K⁺ ATPase is the final common step of acid secretion and is irreversibly blocked by proton pump inhibitors (omeprazole). H2 blockers (ranitidine, now withdrawn; famotidine, cimetidine) act one step upstream, on histamine. Because ECL-cell histamine is the dominant amplifier of acid secretion, H2 blockade works well even though gastrin and ACh remain.

Chief and mucous cells. Chief cells secrete pepsinogen, which the low gastric pH converts to pepsin to begin protein digestion. Surface mucous (foveolar) cells secrete mucus and bicarbonate, forming a protective gel that keeps acid off the epithelium; prostaglandins sustain this barrier, which is why NSAIDs promote ulcers.

GI hormones

Gastrin and Zollinger-Ellison syndrome. Gastrin is released by distension, peptides and amino acids, and vagal GRP, and raises acid mostly by making ECL cells release histamine. Acid shuts it off: antral pH <1.5 stimulates somatostatin, which suppresses gastrin. This feedback explains why gastrin is appropriately high when acid is low (chronic PPI use, atrophic gastritis). A gastrinoma escapes feedback and causes Zollinger-Ellison syndrome: refractory, multiple, or distal (jejunal) ulcers plus diarrhea, because acid inactivates pancreatic enzymes. Fasting gastrin is markedly elevated, and IV secretin paradoxically raises it further. Gastrinomas are associated with MEN1.

The duodenal responders. CCK and secretin tailor the duodenal environment to the meal. Fat and protein release CCK, which empties the gallbladder and pancreatic enzymes into the duodenum (Cholecystokinin: Contracts gallbladder, Kicks out pancreatic enzymes) and acts largely through vagal afferents. Acid releases secretin, "nature's antacid," which drives bicarbonate from pancreatic ductal cells so the duodenum is neutralized and pancreatic enzymes work at the right pH.

Incretins. GIP and GLP-1 (from L cells of the ileum and colon) potentiate insulin release in response to enteral nutrients, which is why oral glucose triggers more insulin than an equal IV load. GLP-1 agonists and DPP-4 inhibitors exploit this pathway in diabetes.

Somatostatin and octreotide. Somatostatin is the universal off-switch of the gut and islets. Its analog octreotide treats variceal bleeding, acromegaly, and VIPoma/carcinoid.

Motilin and VIP. Fasting motilin surges generate the migrating motor complex, the between-meal "housekeeper" contractions that sweep debris and bacteria out of the stomach and small bowel; erythromycin is a motilin-receptor agonist used as a prokinetic. VIP relaxes smooth muscle and drives intestinal water and electrolyte secretion. A VIPoma (pancreatic islet tumor) causes WDHA: watery diarrhea that persists with fasting, hypokalemia, and achlorhydria.

Pancreatic enzymes and brush-border digestion

Zymogens. The pancreas secretes its proteases as inactive zymogens (trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase) so it does not digest itself. Amylase and lipase are secreted already active. Premature activation of trypsin inside the pancreas is the key step in acute pancreatitis.

Brush border. Brush-border enzymes finish digestion at the enterocyte surface. Disaccharidases (maltase, sucrase, lactase, isomaltase) yield monosaccharides, and peptidases complete protein breakdown. Glucose and galactose enter enterocytes by sodium-coupled SGLT1, fructose by GLUT5, and all exit through GLUT2. Lactase is the most easily lost disaccharidase, causing lactose intolerance, including transiently after mucosal injury such as gastroenteritis.

Bile and the enterohepatic circulation

Composition. Bile contains bile salts (made from cholesterol, with cholesterol 7α-hydroxylase as the rate-limiting enzyme, and conjugated to glycine or taurine), phospholipids, cholesterol, and bilirubin.

Functions. Amphipathic bile salts form micelles that allow absorption of fats and the fat-soluble vitamins (A, D, E, K). Bile is also the body's main route for excreting cholesterol and bilirubin.

Enterohepatic circulation. About 95% of bile acids are reabsorbed in the terminal ileum and returned to the liver through the portal vein. Losing the terminal ileum (Crohn disease, resection) wastes bile acids, causing fat malabsorption with fat-soluble vitamin deficiency, and also predisposes to cholesterol gallstones and calcium oxalate kidney stones.

Appetite: ghrelin and leptin

Opposing signals to the hypothalamus. Ghrelin from the stomach rises before meals to stimulate appetite. It is elevated in Prader-Willi syndrome and falls after gastric bypass. Leptin from adipose tissue rises with fat mass and signals satiety to the hypothalamus; common obesity reflects leptin resistance rather than deficiency. Sleep deprivation lowers leptin and raises ghrelin, a hormonal push toward weight gain.