GI Physiology, Pathology, and Motility

GI Reasoning Map

GI physiology on Step 1 rewards tracing the first disturbed signal. Acid secretion is a three-input parietal cell system. Acetylcholine from vagal postganglionic neurons binds M3 receptors, gastrin from antral G cells binds CCK-B receptors, and histamine from enterochromaffin-like cells binds H2 receptors. All converge on the apical H/K ATPase, but through different second messengers: acetylcholine and gastrin raise intracellular calcium, while histamine raises cAMP. Their effects are synergistic, which is why blocking one arm can sharply lower acid output.

Gastrin is released by peptides, amino acids, gastric distention, and vagal GRP; it is inhibited by low antral pH through somatostatin from D cells. Prostaglandins protect mucosa by increasing mucus and bicarbonate and decreasing acid. NSAIDs remove that protection, increasing ulcer risk even without excess acid. Zollinger-Ellison syndrome produces gastrin-mediated acid hypersecretion, recurrent ulcers distal to the duodenal bulb, thickened gastric folds, diarrhea from acid inactivating pancreatic enzymes, and low gastric pH despite high gastrin.

Secretin testing classically raises gastrin in gastrinoma but suppresses or minimally changes physiologic gastrin release. Peptic ulcer location reflects pathophysiology. Duodenal ulcers are commonly related to H pylori antral gastritis, reduced somatostatin, increased gastrin, and increased acid delivery to the duodenum; pain often improves with meals. Gastric ulcers can result from impaired mucosal defense, NSAIDs, or H pylori corpus-predominant inflammation; pain can worsen with meals, and malignancy must be excluded when an ulcer is suspicious.

H pylori has urease, which generates ammonia and buffers acid locally. It also causes chronic active gastritis with lymphoid aggregates; long-standing infection increases risk of intestinal-type gastric adenocarcinoma and MALT lymphoma. Autoimmune metaplastic atrophic gastritis targets parietal cells and intrinsic factor in the body and fundus, causing achlorhydria, high gastrin from loss of acid feedback, pernicious anemia from B12 deficiency, and risk of gastric carcinoid tumors through enterochromaffin-like cell hyperplasia. GI hormones integrate digestion.

CCK is released by I cells in the duodenum and jejunum in response to fatty acids and amino acids. It contracts the gallbladder, relaxes the sphincter of Oddi, stimulates pancreatic enzyme secretion, slows gastric emptying, and promotes satiety. Secretin is released by S cells in response to duodenal acid; it increases pancreatic and biliary bicarbonate and decreases gastric acid. GIP is released by K cells in response to oral glucose, fatty acids, and amino acids; it increases insulin in a glucose-dependent manner and reduces gastric acid.

GLP-1 from L cells increases insulin, decreases glucagon, slows gastric emptying, and increases satiety. Motilin from small intestine M cells drives migrating motor complexes during fasting. Somatostatin broadly inhibits endocrine and exocrine secretion, including gastrin, acid, pancreatic enzymes, and splanchnic blood flow. VIP relaxes intestinal smooth muscle, increases chloride and water secretion, and decreases acid; VIPoma causes watery diarrhea, hypokalemia, and achlorhydria. Swallowing and motility questions require knowing which muscle and plexus failed.

The upper third of the esophagus is skeletal muscle, the lower third is smooth muscle, and the middle is mixed. The myenteric plexus coordinates peristalsis and sphincter relaxation. Achalasia is failure of lower esophageal sphincter relaxation and aperistalsis from loss of inhibitory myenteric neurons that release nitric oxide and VIP. It causes dysphagia to solids and liquids, regurgitation, a bird-beak narrowing, and increased squamous cell carcinoma risk. Chagas disease can mimic achalasia through destruction of enteric ganglia.

Scleroderma causes smooth muscle atrophy and fibrosis with low lower esophageal sphincter tone and hypomotility, leading to reflux and strictures rather than a tight sphincter. Hirschsprung disease is congenital absence of submucosal and myenteric ganglion cells from failed neural crest migration, usually in the rectosigmoid colon; the aganglionic distal segment remains contracted, causing functional obstruction, delayed meconium passage, abdominal distention, and risk of enterocolitis. Absorption is region-specific.

Iron is absorbed in the duodenum and proximal jejunum as Fe2+ through DMT1 after acid and brush-border enzymes help reduce ferric iron. Folate is absorbed in the jejunum. Vitamin B12 binds intrinsic factor from parietal cells and is absorbed in the terminal ileum. Bile salts are also reabsorbed in the terminal ileum and return through enterohepatic circulation. Most carbohydrates enter as monosaccharides after pancreatic amylase and brush-border enzymes; glucose and galactose use SGLT1 with sodium, while fructose uses GLUT5. Amino acids and small peptides use sodium- or hydrogen-dependent transporters.

Fat absorption requires bile salt micelles, pancreatic lipase and colipase, enterocyte re-esterification, chylomicron assembly with apolipoprotein B-48, and lymphatic transport. A defect at any step causes steatorrhea, weight loss, and fat-soluble vitamin deficiency. Diarrhea mechanisms are repeatedly tested. Secretory diarrhea is due to active ion secretion or inhibited absorption, produces large-volume watery stool, has a low stool osmotic gap, and continues during fasting. Cholera toxin ADP-ribosylates Gs, increasing cAMP and CFTR-mediated chloride secretion.

Heat-labile ETEC toxin works similarly; heat-stable toxin raises cGMP. Osmotic diarrhea results from poorly absorbed solutes, improves with fasting, and has a high osmotic gap; lactase deficiency causes bloating, flatulence, acidic stool, and diarrhea after dairy because lactose is metabolized by colonic bacteria. Inflammatory diarrhea has blood, fever, fecal leukocytes, or elevated calprotectin because mucosal invasion or immune inflammation disrupts the barrier. Steatorrhea is bulky, pale, foul-smelling stool from fat malabsorption.

Celiac disease is an immune reaction to deamidated gliadin presented by HLA-DQ2 or HLA-DQ8, with anti-tissue transglutaminase and anti-endomysial antibodies, villous atrophy, crypt hyperplasia, and intraepithelial lymphocytes. It causes iron deficiency early because proximal small bowel is affected, dermatitis herpetiformis from IgA deposition in dermal papillae, and increased enteropathy-associated T-cell lymphoma risk. Tropical sprue can mimic celiac but often follows travel and improves with antibiotics plus folate.

Whipple disease is Tropheryma whipplei infection with PAS-positive foamy macrophages in the lamina propria, migratory arthralgias, diarrhea, weight loss, and neurologic findings. Abetalipoproteinemia impairs ApoB-containing lipoprotein formation, causing fat malabsorption, acanthocytes, neurologic deficits, and low triglycerides. Inflammatory bowel disease is mechanism-rich. Crohn disease can affect any GI site from mouth to anus, especially terminal ileum and colon. Transmural inflammation causes skip lesions, fissures, strictures, fistulas, creeping fat, and noncaseating granulomas.

Terminal ileal disease produces B12 and bile salt malabsorption, gallstones from reduced bile salt pool, and calcium oxalate kidney stones because unabsorbed fatty acids bind luminal calcium, leaving oxalate free for absorption. Ulcerative colitis begins in the rectum and extends continuously through the colon. It is limited mostly to mucosa and submucosa, causing bloody diarrhea, pseudopolyps, crypt abscesses, toxic megacolon, and high colorectal carcinoma risk proportional to duration and extent. Primary sclerosing cholangitis is more strongly associated with ulcerative colitis.

Ischemia and obstruction use vascular anatomy. The splenic flexure and rectosigmoid junction are watershed zones vulnerable to hypoperfusion. Acute mesenteric ischemia often involves the superior mesenteric artery and produces severe pain out of proportion to exam, lactic acidosis, and bowel necrosis if prolonged. Small-bowel obstruction classically causes colicky pain, vomiting, distention, high-pitched bowel sounds early, and air-fluid levels; adhesions and hernias are common causes. Large-bowel obstruction causes distention and constipation, often from cancer, volvulus, or diverticular stricture.

GI cancers follow cumulative mutations and chronic injury. Esophageal squamous cell carcinoma is linked to smoking, alcohol, caustic injury, achalasia, and upper or mid-esophageal lesions. Esophageal adenocarcinoma arises from Barrett metaplasia due to chronic reflux and usually involves the distal esophagus. Colorectal adenocarcinoma often follows APC loss, KRAS activation, and p53 loss in the adenoma-carcinoma sequence, while mismatch repair defects cause microsatellite instability in Lynch syndrome.

Right-sided colon cancers more often cause occult bleeding and iron deficiency; left-sided cancers more often narrow the lumen and cause obstruction or pencil-thin stools.