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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