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• The study notes cover gastrointestinal (GI) disorders and liver assessment, lab tests, and markers of injury.
• Lecture 2.1 provides an introduction to GI disorders and the anatomical specializations that enable function along the length of the GI tract.
• Lecture 2.2 focuses on esophageal disorders, while Lecture 2.3 discusses gastric disorders.
• Pancreas disorders are discussed in Lecture 2.5
• Small intestine disorders are investigated in Lecture 2.6
• Disorders of the large intestine are covered in Lecture 2.7
• The notes also include information on the functions of the liver and the pathogenesis of cirrhosis

Intro to GI Disorders

• The mouth is responsible for mechanical digestion (chewing).
• The salivary glands' amylase breaks down carbs, and lipase breaks down fats/lipids.
• The esophagus uses peristalsis to move food down to the stomach.
• The stomach is responsible for mechanical digestion (mixing via peristalsis) and contains HCl (Parietal cells) and Pepsin & Lipase (Chief cells).
• The liver and gallbladder produce and store bile, respectively.
• The pyloric sphincter is located between the stomach and duodenum of the small intestine.
• The duodenum facilitates further digestion, while the pancreas produces amylase, trypsin, chymotrypsin, and lipase, along with bicarbonate, which neutralizes stomach acid.
• The jejunum and ileum are responsible for nutrient absorption.
• The ileocecal sphincter is located between the small and large intestines. -The colon (large intestine) is responsible for the absorption of water and fiber.

GI Anatomy

• The GI tract is composed of four layers:
  • Mucosa: innermost layer, most variable and contains:
    • Epithelium: cells that line the lumen.
    • Lamina Propria: connective tissue hosting immune cells.
    • Muscularis Mucosa: thin muscle layer that provides structure and is important in secretion.
  • Submucosa: dense connective tissue containing glands, blood & lymphatic vessels to take up nutrients.
  • Muscularis: circular & longitudinal smooth muscle layers with myenteric plexus (enteric neurons) needed for gut motility.
  • Serosa: mesothelium lining the organ to produce a moist environment and prevent damage while cells rub together.

GI Tract Function

• The main functions of the GI tract include:
  • Digestion: breakdown of food into macronutrients.
  • Secretion: exocrine & endocrine (e.g. CCK).
  • Absorption: uptake of nutrients, water, and ions from the lumen into the body.
  • Motility: mixing & movement of food to facilitate digestion & absorption.
  • Defense: immune barrier against harmful components.
  • Hosting the gut microbiome: with numerous roles in various diseases.

Main Symptoms of GI Disorders

• The main symptoms of GI disorders include pain, altered ingestion, and altered bowel movements.
• Pain pathways/signaling involve:
  • Ascending pathway: which senses damage and sends neural information along the spinal cord to the thalamus, relaying the perception of pain to the somatosensory cortex.
  • Descending pathway: inhibits the ascending signals at the level of the spinal cord.
• Visceral pain: is poorly localized and often referred to somatic structures.
• Altered ingestion includes nausea (feeling of sickness in the stomach with an inclination to vomit) and Vomiting (forcible ejection of undigested GI content from the mouth and a defense mechanism involving relaxation of the LES (lower esophageal sphincter) and ↑ intra-abdominal pressure via contraction of the diaphragm & abdominal muscles along with Closing of the epiglottis).
• Other symptoms include dysphagia (difficulty swallowing), odynophagia (painful swallowing), anorexia (lack of appetite, either primary like Anorexia Nervosa, or secondary as a consequence of disease like GERD or Peptic ulcer), and altered bowel movements (diarrhea or constipation).
• GI tract bleeding diagnosis: based on location & color of blood:
  • Stool: bright red coating (hematochezia - Rectum), dark blood mixed (hematochezia – Colon), or black/tarry stool (Melena - Esophagus/Stomach/Duodenum).
  • Vomit: bright red (Esophagus/Stomach) or "coffee-grounds" appearance -(Stomach/Duodenum).
  • Signs of fatigue/anemia: may indicate occult blood.

Drug Mechanisms for GI Symptoms

• Mechanisms of action of drugs combating the main symptoms of GI disorders include:
  • Pain:
    • Opioids: inhibit the signal sent from the damaged tissue to the brain via the ascending pathway and stimulate the descending pathway.
    • NSAIDs: inhibit at the tissue damage level.
  • Vomiting Reflex Mechanism & Medication:
    • 5-HT3 Receptor Antagonists (e.g. Ondansetron): blocks 5-HT3-R on Chemoreceptor Trigger Zone, preventing transmitter release, and vomiting, and blocks 5-HT3-R in the gut, blocking stimulation of the Vagus nerve and ACh release.
    • D2 Receptor Antagonists (e.g. Prochlorperazine): block Dopamine D2-R on Chemoreceptor Trigger Zone, and prevent transmitter release and vomiting.
    • Muscarinic Receptor Antagonist (e.g. Scopolamine – patch for motion sickness): blocks Muscarinic Receptor on the Vomiting Center and prevents ACh from binding and results in preventing Vomiting Reflex.
  • Anorexia (Secondary Anorexia – NOT anorexia nervosa):
    • CGRP Receptor Antagonist: Blocks CGRP release from parabrachial nucleus to prevent its action in Central Amygdala and facilitate food intake.

Esophageal Function and Achalasia

• The function of the esophagus: transporting swallowed food to the stomach with 2 main actions:
  • Propulsive Functions (Peristalsis): transferring food to the esophagus by the pharynx then transporting the bolus from the pharynx to the stomach, and permitting entry into the stomach.
  • Protective Effects: protecting the airway via protection of the UES from swallowed material and backflow and clearing materials with the esophagus while the LES protects the esophagus via backflow.
• Peristalsis: wavelike movement of the bolus and controlled by enteric neurons between tunica muscularis layers that contract muscles via stimulartory and inhibitory processes.
• Achalasia is from over-contraction of the LES that can lead to Incomplete LES relaxation leading to a difficult traversment in the esophagus from food material,
  • It can be caused by the inflammation of the myenteric plexus of the esophagus from viral/toxic agents and combined w/ genetic predisposition, ↓ in NO synthase, cytotoxic autoimmune T cells, ultimately the LES fails to relax

Esophageal Epithelium

• The normal epithelium in the esophagus is stratified squamous epithelium, which benefits due to constant abrasion of food allowing the top cells to be sequentially sloughed off and replaced without exposing the basement membrane
• Esophageal Epithelium in Barrett's Esophagus is composed of Single Columnar epithelium, like the stomach, and GERD caused by a defective LES, causes acid reflux, elevated intragastric pressure, or elevated acid & pepsin.
• Prolonged GERD: metaplasia of esophageal cells will transforms into columnar tissue, can evolve in esophagittis and peptic ruptures.

GERD Treatment

• GERD treatment targets include mechanisms and involve pathophysiological features:
  • ↓LES tone: Defective LES fails to prevent acid reflux.
  • ↑ Intragastric Pressure: Which makes it easier for acid to reflux into the esophagus.
  • ↑ Acid & Pepsin leads to ↑ likelihood for acid to reflux into the esophagus.
• Treatments include:
  • Proton Pump Inhibitor (PPI): inhibits the H+-K+ Antiporter responsible for secreting H+ & HCl and decreases acid .secretion
  • H2 Receptor Antagonists: Block Histamine H2-Rs on the Parietal to prevents histamine (secreted by ECL cells) from generating proton's pump
  • Antacids: Reduce acicd.
• Behavioral mods:
  • Weight loss: controls gastric volume since it's known fat can apply pressure.
  • Meals: reduces stomach space and volume.

Regulation of Acid Secretion

Liver Disorders

• The liver, produces bile acid for lipid digestion and stores energy
• Major processing steps take place
• Glycogenesis
• Gluconeogenesis
• Lipogenesis
• Urea cycle

Cirrhosis

• Cirrhosis causes inflammation in the Space of Disse which can ultimately effect the flow of blood in the liver - major processes are
• Inflammation
• Collagen deposition
• Vasoconstriction (portal hypertension)
• Hepatocyte injury

Liver Disease

• Viral hepatitis ABCDE
• Alcoholic and non alcoholic
• Genetic e.g. wilsons

What is the role of the large intestine in fluid absorption? What cells are involved? What is the

mechanism of fluid absorption? Main function of the large intestine is absorption of water, bile salts, and electrolytes Fluid is critical for intestinal function – GI tract secretes a HUGE volume of fluid each day: Permits contact of food w/ digestive enzymes Diffusion of digested nutrients to site of absorption Fluidity of contents allows transit without damage to the epithelium Large intestine is very efficient in conserving fluid Cells Involved: Enterocytes (w/o villi/microvilli) – Absorption of water, bile salts, and electrolytes