Gastrointestinal Disorders Lecture 6

Disorders of Upper GI

Gastric Phase

• Food triggers vagovagal reflexes, stimulating gastrin secretion
• Acidification of the gastric antrum stimulates somatostatin production
• Somatostatin inhibits gastrin release and acid secretion
• Vagal acetylcholine inhibits somatostatin production

NSAIDs and Gastric Mucosa

• NSAIDs reduce acid secretion
• Disruption of protective mechanisms leads to gastropathy/gastritis
• Inhibition of COX by NSAIDs, inhibition of gastric bicarbonate transporters by ammonium ions, reduced mucin and bicarbonate secretion, and decreased oxygen delivery

H. Pylori and Gastric Cancer

• H. pylori is implicated in almost all non-NSAID-induced GI mucosal inflammation
• H. pylori causes type B gastritis (antrum and body of the stomach)
• Almost all patients with gastric cancer have had H. pylori or gastric ulcer

Carcinoid Tumors

• Carcinoid tumors secrete serotonin
• Serotonin is secreted into the hepatic portal circulation

Bile Composition and Jaundice

• Major components of bile: bilirubin, bile salts, cholesterol, phospholipids
• Normal serum bilirubin: 0.3-1.2 mg/dL
• 2-2.5 mg/dL and above: jaundice
• Unconjugated bilirubin is insoluble and cannot be excreted in urine
• Conjugated bilirubin is water-soluble and bound to serum albumin, allowing excretion in urine

GI Tract Layers

• Mucosa: specialized epithelial cells lining the lumen
• Lamina propria: contains small blood and lymphatic vessels, immune cells, and nerve fibers
• Muscularis mucosa: used to determine if cancer of the GIT is still localized
• Submucosa: contains larger blood and lymphatic vessels
• Muscularis: responsible for motility of the GIT
• Serosa: outermost layer

Enteric Nervous System

• Enteric neurons are organized into submucosal and myenteric plexuses
• PNS efferents stimulate intestinal motility and exocrine secretion

Hormones and Paracrine Factors

• Gastrin: stimulates acid secretion and growth of gastric oxyntic gland
• CCK: stimulates gallbladder contraction, pancreatic enzyme and bicarbonate secretion, and growth of exocrine pancreas
• Secretin: stimulates pancreatic bicarbonate secretion, growth of exocrine pancreas, and pepsin secretion
• GIP: stimulates insulin release and inhibits gastric acid secretion
• Motilin: stimulates gastric and duodenal motility
• Somatostatin: inhibits release of most other peptide hormones
• Prostaglandins: promote blood flow, increase mucus and bicarbonate secretion from gastric mucosa
• Histamine: stimulates gastric acid secretion
• Serotonin: increases intestinal motility and secretion
• VIP: relaxes sphincters and gut circular muscle, stimulates intestinal and pancreatic secretion

Diseases of the Upper GI

• Zollinger-Ellison syndrome: gastrin-producing tumors
• GERD: complication of Barrett's esophagus
• Barrett's esophagus: GI metaplasia of the lower esophagus that results from chronic GERD-induced esophagitis
• Achalasia: caused by degeneration of neurons in the esophageal wall → loss of inhibitory innervation in the LES### Gastrointestinal Diseases

• Clostridioides difficile (C. diff) Infection: + Presents with watery diarrhea (≥3 loose stools in 24 hrs), lower abdominal pain, fever + Toxin released by C. diff causes ribosylation of small GTPases, leading to disruption of the epithelial cytoskeleton, tight junction barrier loss, cytokine release, and apoptosis + Labs: leukocytosis, hypoalbuminemia, and lactic acidosis (in severe cases) + Diagnosis: stool studies + Risk factors: recent antibiotic use (clindamycin most common), hospitalization, age > 65

Malabsorption Disorders

• Celiac Disease: + Immune-mediated disorder triggered by ingestion of gluten-containing foods (wheat, rye, or barley) + Gliadin peptides interact with HLA-DQ2 or HLA-DQ8 on antigen-presenting cells, stimulating CD4+ T cells to produce cytokines that exacerbate tissue damage + Almost all people with celiac disease carry the class II HLA-DQ2 or HLA-DQ8 allele + Presents with diarrhea, fatigue, weight loss, and malabsorption of nutrients

Intestinal Obstruction

• Intussusception: + Occurs when a segment of the intestine telescopes into the immediately distal segment + Most common cause of intestinal obstruction in children younger than 2 years old + Etiology: idiopathic, viral infection, and rotavirus vaccines + 1% of patients with cystic fibrosis develop intussusception

β-Lipoproteinemia

• Abetalipoproteinemia: + Rare autosomal recessive disease caused by mutation in microsomal triglyceride transfer protein (MTP) + Presents in infancy with failure to thrive, diarrhea, and steatorrhea + Triglyceride accumulation in epithelial cells leads to acanthocytosis (red cells with spiky membrane protrusions)

Inflammatory Bowel Disease (IBD)

• Crohn's Disease: + Chronic inflammatory condition characterized by transmural inflammation, which can affect any area of the gastrointestinal tract + May produce transmural inflammation, leading to complications such as bowel obstruction, fistulas, and malabsorption • Ulcerative Colitis: + Limited to the colon and rectum, involving only the mucosa and submucosa + High risk for colon cancer + Associated with primary sclerosing cholangitis and pyoderma gangrenosum

Irritable Bowel Syndrome (IBS)

• Chronic Functional Disorder: + Characterized by recurrent abdominal pain, changed bowel habits (diarrhea or constipation), and bloating + Pathophysiology involves altered gut motility, visceral hypersensitivity, and psychosocial factors

Pancreatitis

• Acute Pancreatitis: + Reversible inflammatory disorder that varies in severity, from focal edema to widespread hemorrhagic necrosis + Caused by autodigestion of the pancreas by intraacinar activation of pancreatic enzymes + Elevated serum lipase and amylase levels + Common causes: gallstones, chronic excessive alcohol use, and hypertriglyceridemia

Liver Diseases

• Portal Triads: + Portal vein, hepatic artery, and bile duct + Blood from the portal vein and hepatic artery mixes in the sinusoids + Drains into the central vein, which forms the hepatic veins • Space of Disse: + Space between hepatocytes and endothelial cells + Contains interstitial fluid + Stellate (Ito) cells are located here and store vitamin A • Zone 1: + Region with the greatest delivery of oxygen and nutrients + Preferentially undertakes oxidative metabolism, ureagenesis, and bile acid production

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