L19 Non-neoplastic GI Diseases

• Reflux oesophagitis


  Inflammation of the lower oesophagus caused by reflux of gastric contents, clinically presents as gastro-oesophageal reflux disease (GORD or GERD)
• Oesophageal epithelium


  • Stratified squamous mucosa for protection against abrasion and friction
• Gastric epithelium


  • Simple columnar mucosa for protection against gastric secretions
• Reflux of gastric secretions into the oesophagus causes a chemical injury, inducing inflammation of the oesophagus experienced as heart burn
• Aetiology of reflux oesophagitis

  • Relaxation of the lower oesophagus induced by vagal pathway in response to gastric distention
  • Abrupt changes in abdominal pressure (e.g. coughing, straining)
  • Alcohol, smoking, obesity, pregnancy, delayed gastric emptying, CNS depressants

  
• Reflux oesophagitis


  • Scattered intraepithelial eosinophils and mild basal zone expansion
  • Multiple erosions within the squamous oesophageal epithelium, and metaplastic mucosa (Barrett oesophagus)

  
• Barrett oesophagus


  Columnar (intestinal) metaplasia of the oesophagus, with stratified squamous mucosa replaced with simple columnar mucosa
• Barrett oesophagus can occur as a complication of chronic GORD
• Barrett oesophagus occurs in ~10% of patients with symptomatic GORD, and ~2% of the general population

  
• Barrett oesophagus is considered a precancerous or premalignant lesion, with mutations found in Barrett oesophagus also found in oesophageal adenocarcinoma
• Although Barrett oesophagus increases risk of oesophageal adenocarcinoma, not all patients with Barrett oesophagus will develop cancer

  
• Barrett oesophagus


  • Small islands of residual pale squamous mucosa
  • Low grade dysplasia
  • High grade dysplasia
• Majority of oesophageal cancers are either adenocarcinoma or squamous cell carcinoma (SCC), with SCC the most common worldwide
• Oesophageal adenocarcinoma is rising in developed countries, possibly due to increased incidence of obesity-related GORD and Barrett oesophagus
• Peptic ulcer disease (PUD)

  Ulceration of the mucosa lining the stomach (gastric ulcer), or small intestine (duodenal ulcer)

  
• Aetiology of peptic ulcer disease

  Imbalance between damaging and protective factors at mucosal surface

  
• Aetiological factors of peptic ulcer disease

  • H. pylori infection
  • Gastric hyperacidity
  • Oral NSAIDs
  • Alcohol/smoking
  • Duodenal-gastric reflux
• PUD most commonly occurs secondary to chronic gastritis induced by H. pylori, in combination with an increase in gastric acidity
• Symptoms of peptic ulcer disease

  • Epigastric pain, especially after meals, relieved by antacids
  • Nausea and vomiting
  • Bleeding and anaemia

  
• Most commonly affects the lesser curvature of the antrum in the stomach, or the first portion of the duodenum
• Helicobacter pylori


  Gram-negative spiral (helical) shaped curved rod bacteria which induces acute and chronic inflammation of the gastric mucosa (gastritis)
• Dr Barry J. Marshall won the Nobel prize for discovering the link between H. pylori and peptic ulcer disease, by experimenting on himself!
• Adaptations of H. pylori


  • Flagella – Used to burrow through the gastric mucus to reach the mucosal surface
  • Adhesins – Adheres to epithelial cell membranes
  • Urease – Produces ammonia from urea, neutralizing acid around the bacterium
• Most patients with gastric H. pylori have asymptomatic gastritis, but only 10-20% of patients with chronic gastritis develop peptic ulcer disease

  
• Treatment of H. pylori-induced peptic ulcer disease

  • Omeprazole (proton-pump inhibitor) to reduce gastric acidity
  • Clarithromycin and amoxicillin to treat the H. pylori infection
• Other than peptic ulcer disease, H. pylori induced gastritis increases the risk of gastric adenocarcinoma and lymphoma

  
• Gross peptic ulcer


  • H. Pylori-induced antral gastritis
  • Gastric ulcer with punched out straight edges, and base haemorrhage
  • Flattened rugae from remodelled fibrotic tissue

  
• Peptic ulcer histology


  • Muscularis, Necrotic Debris/Slough, Inflammation, Vascular Granulation Tissue, Fibrosis/Scar

  
• Healing of a peptic ulcer involves a combination of mucosal regeneration and fibrosis within the submucosa and deeper tissue layers

  
• Chronic bleeding occurs in 15-20% of patients, may present as anaemia and/or hematemesis (vomiting blood), and accounts for 25% of deaths
• Perforation of the gastric wall occurs in ~5% of patients, can penetrate into adjacent organs, and accounts for 2/3 of deaths
• Although there is an increased risk of gastric adenocarcinoma in patients with peptic ulcer disease, this is associated with the H. pylori-induced chronic gastritis rather than the actual peptic ulceration

  
• Inflammatory bowel disease (IBD)


  Chronic inflammatory condition affecting the bowel with two distinct presentations; ulcerative colitis or Crohn disease
• Aetiology of IBD


  • Genetics (e.g. NOD2 mutations)
  • Anti-microbial peptide secretion (e.g. α-defensin)
  • Intestinal microflora dysbiosis
  • Autoimmune?* Some other immune dysfunction?
• Note: Although many sources still list IBD as a type of autoimmune disease, recent research suggests that autoimmunity may not be involved in IBD
• Microflora dysbiosis in Crohn disease

  Mutations in NOD2 reduces the ability of paneth cells to detect microbial peptides (MDP), reducing the secretion of anti-microbial peptides (AMPs)

  
• Crohn disease (CD)


  • Inflammation in Crohn disease is transmural, affecting all layers of the bowel wall, and involves a TH1-predominated immune response
  • Skip lesions are separated by healthy intervening bowel
  • Strictures can form in affected bowel from fibrosis
• Crohn disease can present throughout the gastrointestinal tract, mouth-to-anus, but most commonly affects the terminal ileum, ileocecal valve, and cecum
• Crohn disease


  • Cobblestones
  • Granulomas
  • Fissures
• Patients with Crohn disease also have an increased risk of developing colorectal cancer