Gastrointestinal Pathology PDF

Gastrointestinal Pathology Major Functions of the GI • • • • • • • • • Ingest and prepare food for digestion Mechanical and chemical digestion Regulated absorption of nutrients Metabolism of endogenous and exogenous chemicals Immune surveillance Regulated secretion of hormones, enzymes, lubricant...

Gastrointestinal Pathology Major Functions of the GI • • • • • • • • • Ingest and prepare food for digestion Mechanical and chemical digestion Regulated absorption of nutrients Metabolism of endogenous and exogenous chemicals Immune surveillance Regulated secretion of hormones, enzymes, lubricants and water Microbiome functions Propulsion of waste Regulated defecation Regions of the GI • Upper GI tract: mouth, esophagus, stomach • Middle GI tract: (small bowel) duodenum (9”), jejunum (2.5 m), ileum (3 m) • Lower GI tract: (large bowel) cecum, colon (ascending, transverse, descending), rectum • Sphincters between segments (6) • Accessory structures: salivary glands, liver, pancreas, gall bladder List of Sphincters Sphincters of the GI • Upper esophageal sphincter (pharyngoesophageal) • Lower esophageal sphincter (gastroesophageal) • Pyloric sphincter (gastroduodenal) • Ileocecal valve/sphincter • Internal anal sphincter • External anal sphincter Gross Anatomy of the GI Tract Layers of the of GI Tract Layers the GI • • • • • • • • • Tract Serosa Longitudinal muscle Myenteric (Auerbach’s) nerve plexus Circular muscle Submucosa Submucosal (Meissner’s) nerve plexus Muscularis mucosae Mucosa Epithelial lining GI Cross Section ENS, Enteric Nervous System Enteric Nervous System (ENS) Enteric Nervous System (ENS) • Location – Gut wall from esophagus to anus • Composition – Cell bodies, axons, dendrites, nerve endings • Innervation – Gut cells, sensory nerves, other • Integration – Can occur entirely within ENS – Can function independent of ANS • Transmitters – Many excitatory and inhibitory neurons Neural Control of GI Tract Neural Control of ENS • Intrinsic Control—Enteric nervous system - Myenteric (Auerbach’s) plexus - Submucosal (Meissner’s) plexus • Extrinsic Control—Autonomic nervous system - Parasympathetic – mainly stimulates (Ach) - Sympathetic – mainly inhibits (NE) Enteric Nervous System Enteric Nervous System (ENS) (ENS) Mechanics of Digestion Mouth -Mastication breaks food into small segments -Food mixed with saliva from three pairs of salivary glands (sublingual, submandibular and parotid) -Release of saliva under autonomic control (~1.2 L/d) -Saliva contains amylase (begins carbohydrate digestion) and lingual lipase (triglycerides to partial glycerides and FFA) -Saliva has pH ~7.4, which inhibits bacterial growth in the oral cavity and neutralizes acid from stomach (hence the need to rinse the mouth after vomiting to prevent erosion of teeth) Mechanics of Digestion Esophagus • Esophagus is a muscular tube 20-30 cms long • Swallowing begun by expansion of upper esophageal sphincter and peristaltic movement mediated by muscle • Upper 1/3 of esophagus has skeletal muscle and is voluntary. Remainder is smooth muscle and under autonomic control • Food takes 5-7 seconds to traverse esophagus. Important to tell patients to drink fluids with pills • Relaxation of a lower esophageal sphincter permits movement of food into stomach; contraction prevents reflux of gastric content Mechanics of Digestion Stomach • Function of stomach is to mix the food (chyme) with acid and digestive enzymes • HCl is formed by parietal cells and aids in digestion, provides optimal pH for pepsin, and kills organisms consumed with food • Parietal cells also produce intrinsic factor, essential for absorption of vitamin B12 • Pepsin is produced by chief cells as pepsinogen; it requires a low pH (~2.0) for optimal activity • Gastrin produced in stomach stimulates production of HCl and pepsinogen • Gastric digestion is inhibited by sympathetic innervation (in response to fear, pain, aggression, unpleasant taste or smell). Digestion enhanced under vagal control (para) • Mucosa of stomach protected by mucus, production of which is stimulated by prostaglandins. Prostaglandin inhibitors (eg., NSAIDs) may induce gastric erosion Gastric Mucosal Barrier Mechanics of Digestion Stomach • Muscles of stomach provide thorough mixing with acid and enzymes, progressively liquefying the content • Peristaltic contractions ~3/min, gain force as they approach the pyloric sphincter • Excessive loss of gastric fluids (eg, through vomiting) may increase loss of sodium and potassium, causing hyponatremia and hypokalemia • Chyme enters the duodenum through the pyloric sphincter, relaxation of which is coordinated with the stomach peristaltic wave Mechanics of Digestion Small Intestine • Chyme enters the duodenum, where it is neutralized by mixing with bile, pancreatic juice and intestinal enzymes (maltase, lactase, sucrase, trypsin and chymotrypsin), and bicarbonate from Brunner’s glands • Rate of digestion is regulated by secretin, cholecystokinin, motilin and gastric inhibitory peptide • Bile and pancreatic fluid enter the duodenum via the common duct through the ampulla of Vater, which is regulated by the sphincter of Oddi • The mucosal surface of the small intestine is modified to enhance absorption of nutrients, minerals, vitamins, etc • Movement of chyme is result of coordinated haustral segmental contraction of inner smooth muscle and longitudinal peristaltic movements. These movements are controlled by both the autonomic and regional NS, and peptide-producing paraneurons • Movement of intestine in place is facilitated by the serosal secretion; limited by the omentum • Majority of nutrient absorption occurs in small intestine • Contents of small intestine pass through liver via the portal system before entering systemic circulation, hence 1st-pass metabolism of drugs taken by mouth. Mechanics of Digestion Large Intestine • Chyme enters the cecum via the ileocecal valve • Some digestion continues in proximal large intestine, but primary function is to recover water and control the fluidity of the feces • Defecation is signaled by distention of the distal sigmoid colon and rectum • Defecation requires the coordinated relaxation of two sphincters: the internal anal sphincter (autonomic control) and external anal sphincter (more or less voluntary control) • 30% of fecal mass is bacteria • Internal ecology of GI bacteria (microbiome) critical for health • Rectal blood does not return via the liver Gastrointestinal Microbiome • • • • • • • • • • Microbiome: aggregate of all microbiota residing on or within tissues May be bacteria, fungi or viruses (majority are bacteria) Organisms may be commensal, mutualist or pathogenic GI tract has the broadest diversity of organisms Composition of microbiome established at birth: vaginal delivery results in largely non-pathogenic microbiota resembling mother’s. Caesarian delivery results in more pathogenic organisms and delays the establishment of a normal GI microbiome Mutualistic organisms contribute to normal GI function through cooperative synthesis (eg. Vit K) and metabolism Composition of microbiome changes with age, diet, and health Changes in microbiome implicated in diseases ranging from diabetes, obesity, IBD, neurological diseases (eg. Parkinson’s), antibiotic-mediated colitis to colon cancer Reconstitution of ‘normal’ microbiome by fecal microbiome transplants has high efficacy in some diseases Hot area of therapeutic research: “eco-pharmaceutics” • • • • • Major Diseases of the GI Tract Basic Constipation Diarrhea (including traveler’s diarrhea) Drug-induced hepatic disorders Gastroesophageal reflux disease Nausea & vomiting, simple (e.g., acute viral gastroenteritis, overindulgence, motion sickness) Constipation Diarrheal Disease • • • Diarrhea is defined as the passage of loose or watery stools, typically of amounts greater than 200 grams per day. Worldwide, diarrheal diseases are estimated to cause the deaths of 1.5 to 2 million children under 5 years of age annually. Diarrhea is a common symptom of many intestinal diseases, including those due to infection, inflammation, ischemia, malabsorption, and nutritional deficiency Subclassified into four major categories: – • Secretory diarrhea is characterized by isotonic stool and persists during fasting. – • Osmotic diarrhea, such as that occurring with lactase deficiency, is due to osmotic force exerted by unabsorbed luminal solutes. The diarrheal fluid is at least 50 mOsm more concentrated than plasma and the condition abates with fasting. – • Malabsorptive diarrhea caused by inadequate nutrient absorption is associated with steatorrhea and is relieved by fasting. – • Exudative diarrhea is due to inflammatory disease and characterized by purulent, bloody stools that continue during fasting. Gastroesophageal Reflux Disease (GERD) Nausea and Vomiting Major Diseases of the GI Tract Advanced •Cirrhosis, end-stage liver disease, and complications (e.g., portal hypertension, ascites, varices, hepatic encephalopathy, hepatorenal syndrome) •Inflammatory bowel disease (Crohn disease, ulcerative colitis) •Irritable bowel syndrome •Nausea & vomiting, complex (e.g., postoperative, chemotherapy-induced) •Nonalcoholic steatohepatitis •Peptic ulcer disease (including stress-related mucosal injury, gastrointestinal bleeding) •Pancreatitis (acute, chronic, and drug-induced) Most Advanced •Celiac disease •Liver diseases, metabolic (e.g., hemochromatosis, Wilson disease) ADVANCED Clinical Manifestations of Gastric Disease • • • • Pain and dyspepsia Loss of appetite Bloating and distention Bleeding/vomiting (if slow, black, ‘coffee grounds’ emesis. If rapid, bright red blood) • ‘Mass’ effect mimicking satiety • Outlet obstruction (pyloric stenosis) with profuse vomiting – Hypokalemic alkalosis Gastric Inflammations • Gastritis (acute and chronic) • Associated with enhanced gastric secretion and/or impaired gastric defenses – Alcohol, smoking, infections (Helicobacter pylori, Herpes, Salmonella), corticosteroids and NSAIDS, stress, CNS trauma, shock, serious illnesses • Chronic gastritis associated with anemia; common in elderly patients – H. pylori is most common cause; 90% of patients with chronic gastritis are infected – Autoimmunity H. pylori • H. pylori produces urease, increasing ammonia production; this is the basis of the urea breath test • H. pylori toxic to mucosal cells; ‘hides’ in mucous layer • Stimulates gastric emptying, thus overwhelming bicarbonate buffering Mechanisms of Gastritis Peptic Ulcer Disease • Occurs anywhere mucosa is exposed to acid gastric juice (esophagus, stomach, duodenum) • Often chronic, frequently recurrent • Most common site is duodenum (70%); M:F ratio ~3:1 • ‘true’ gastric ulcers occur in older individuals (~60+) • Extremely common (lifetime incidence up to 10%) • Duodenal ulcers most common age 20-40 years • Most common in patients with blood type O • Signs/symptoms: ‘burning or gnawing’ epigastric pain with transient reduction of pain upon eating, bleeding, belching Pain worse 1-3 hours after eating; at night • INFECTION WITH HELICOBACTOR in >65% of patients with gastric ulcer; 85-100% of patients with duodenal ulcers • Genetic and systemic factors can contribute • Gastric ulcers resemble carcinomas; all should be biopsied • Gastric ulcer erosions may cause peritonitis or catastrophic hemorrhage Clinical Manifestations of Intestinal Disease • • • • • • • Malabsorption Obstruction/constipation ‘Paralytic’ bowel Ischemia Perforation Hemorrhage Diarrhea-rapid movement, often high volume, extremely dangerous in young and old • Dysentery-blood and mucous • Steatorrhea Inflammatory Bowel Syndrome (IBS) Inflammatory Bowel Disease (IBD) • Idiopathic colitis • Crohn disease • Ulcerative colitis • IBDs are usually idiopathic with multi-factorial origins • Most IBDs arise from mucosal immune activation and interaction between gut microbiome • Both Crohn and UC more common in females, often presenting in teens and 20’s • Both Crohn and UC have increased long-term risk of Ca • Hygiene Hypothesis? Crohn Disease • F>M; rare in young children. Most common in whites • Etiology unknown; can be triggered by stress • Clinical signs: highly variable, acute: pain, diarrhea, fever – chronic: relapse and remission, weight loss, obstruction, malabsorption Anatomic: full thickness inflammation, ‘skip’ lesions, luminal narrowing (‘lead-pipe’ bowel, string-sign on Xray) Lesions may occur anywhere (mouth to anus) but are most common in terminal ileum (‘terminal ileitis’) • Common in US and Western Europe • Multiple surgeries often required leading to ‘short bowel syndrome’ • Suppression of inflammatory response used but has side-effects, particularly activation of Herpes virus Ulcerative Colitis • • • • • • • • Most common in 20-30 year old group F>M Most common in US and Western Europe Etiology unknown; episodes may be precipitated by psychological stress Disease involves primarily rectum; inflammation involves only the mucosa ‘Sloughing’ of contiguous sheets of mucosa, with bleeding Clinical presentation: pain, bloody diarrhea, pain and fever, exacerbations and remissions Increased risk of aggressive rectal adenocarcinoma after 8-10 years of disease Non-Alcoholic Steatohepatitis (NASH) IF THERE IS TIME: OTHER DISEASES Oral Diseases • Infections (bacterial, fungal, viral), frequent in immunosuppressed hosts • Cancers (95% squamous cell Ca) – Oral squamous cancer has poor prognosis <50% 5-year survival – Up to 70% of oral cancers are result of HPV infections, particularly HPV 16 & 18. The National Cancer Institute recommends HPV vaccination of children as young as 9 years – HPV-related cancers in tonsils or tongue – Other risk factors (smoking, alcohol, poor oral care, excessive dryness) Clinical Effects of Esophageal Disease • Retrosternal pain unassociated with swallowing. May be confused with MI • Hematemesis (bright red blood) • Dysphagia/obstruction to Patients may subconsciously change diet reduce problems with swallowing Esophageal Cancer • Primarily carcinoma; sarcoma very rare • Squamous cell carcinoma – M:F ratio 4:1; occurs after 45 years of age • Incidence of adenocarcinoma is increasing rapidly, particularly in distal 1/3, as result of Barrett esophagus. AdenoCa is 7:1 M:F; whites • Risk factors: alcohol, smoking, GERD • Prognosis bleak: ~65% mortality in 1 year • 9% 5-year survival squamous, ~25% adenoCa • Metastasis early to local lymph nodes • Most patients present with dysphagia, generally indicating an nonresectible lesion. Most patients display cachexia Gastric Cancer • Shows geographical variance; incidence has decreased 85% in US over last 70 years • Usually diagnosed late as it’s asymptomatic early in development. Mean age at presentation 55 yrs • Most commonly adenocarcinoma (~90%); 2:1 M/F • Prognosis depends upon stage: >stage II prognosis is poor • Metastasis usually present at diagnosis • Metastasis to ovaries (Krukenberg tumor) or to left supraclavicular node (Virchow’s node). 5-year survival <30% • CLINICAL SIGNS: Rare or nonspecific early signs (eg., dysphagia, dyspepsia). Late signs include anorexia, anemia and weight loss Colorectal Cancer • Most common in >60 age group • Strong correlation to diet • Multiple mutational events have been identified, including mutation of p53 tumor suppressor gene, loss of DCC (‘deleted in colon cancer’ gene) • Frequently arises from adenoma (benign) precursors • Second only to lung cancer for total deaths from cancer • Common in both M and F – Rectal cancer slightly more common in M – Colon cancer F:M 2:1 • Recto-sigmoid ~50% • If iron-deficiency anemia presents in postmenopausal female or older male, expect right-side GI cancer • Clinical: blood in stool, anemia, obstruction • Prognosis: excellent if caught early, poor if Stage III or IV • Metastasis to liver, extension through bowel wall • Importance of digital exam, colonoscopy, family history Appendicitis • Remains difficult diagnosis • 20% missed dx; 15-40% overdx’ed • Peak incidence 10-12 years • Starts as diffuse pain, this becomes localized. Rebound tenderness classic, with guarding • Clinical signs: WBC>10,000/mL • Fever >99.5F • Pain in right lower quadrant with rebound tenderness • CT scans good dx if available • Danger is rupture with peritonitis; this occurs in ~90% <3 years old • Treatment is surgery BEFORE rupture Infections • Viruses Noroviruses --Rotoviruses -- • Bacteria • • • • --Typhoid --Salmonella --Cholera --Campylobacter • Helminths • --Ascaris • --Echinococcus • --Hookworm