Peptic Ulcer Disease Peptic Ulcer Disease Timothy C. Wang, M.D. Chief, Digestive and Liver Diseases Columbia University Med Center 1
(body/corpus) (low acid) (antral) (high acid) 2
Simple versus Complicated Peptic Ulcer Disease • Lifetime PUD • Simple ulcers prevalence of 10% – Symptomatic • In past, DU 5X as – Asymptomatic common as GU • Complicated ulcers • Incidence of GU – Bleeding increases with age – Perforation • Overall PUD has been – Death declining Bleeding ulcer 3
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Causes of Peptic Ulcer Disease • H. pylori infection * • NSAIDs * • Stress ulcers (Cushing’s, Curling’s, ischemia) • Increased gastrin: (Zollinger-Ellison, retained gastric antrum, antral G-cell hyperplasia) • Increased histamine: Systemic mastocytosis, foregut carinoid tumors, leukemia • Massive small bowel resection, renal failure, cirrhosis, COPD 5
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No Acid, No Ulcer • Schwarz (1910): “Ohne saueren Magensaft, kein pepticsches Geschwur” • Hyperacidity only in some patients (e.g.DU, ZE) but acid is a factor in most patients with PUD Role of acid (HCl) in the stomach • Helps to kill prey that is ingested live • Small role in protein digestion through activation of pepsin • Some bacteriostatic action - helps to sterilize the gastric contents • Gastric juice also contains bicarbonate, pepsinogen, intrinsic factor, prostaglandins, K+, Na+, mucins, and trefoil proteins 8
Effect of pH on intragastric bacteria Intragastric pH 7 Intragastric pH 1.5 Fundamentals of acid secretion • The human stomach produces 1-1.5 liters of gastric juice per day • Highly acidic with pH of ~0.8 (160 mM H+) • Acid secreted across a concentration gradient of 2.5 million fold • Active transport process requiring tremendous energy • Transport achieved by H+K+ATPase pump 9
Parietal cells • Human stomach contains ~ 1 billion parietal cells • Large (25 μ m in diameter) oval shaped cells located in mid region of oxyntic glands • Major function is the secretion of acid • Three main ultrastructural features: – numerous mitochondria – tubulovesicles – secretory canaliculi 10
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Integrated control of acid secretion Three levels of regulation of acid secretion: • Neural control - acetylcholine – cephalovagal and local intragastric reflex arcs • Hormonal control – endocrine (gastrin) or paracrine (somatostain, histamine) • Local direct factors – positive (+) factors - amines/amino acids, gastric distention – negative (-) factors - increased acid or low pH Histamine is the final common mediator of acid secretion 12
Phases of gastric acid secretion •Interdigestive phase –basal acid secretion -vagal regulation 5%, gastrin, a.a. 50%, gastrin 35-40%, vagal 13
Why the stomach does not digest itself • Acid is through a mucus gel layer through narrow “viscous fingers” which prevent back diffusion of acid due to a change in viscosity at the lower lumenal pH. Bhaskar KR et al, Nature 1992;360:458 Mucous layer Protective Factors Mucous layer thickness pH gradient Cell membrane hydrophobicity Bicarbonate secretion Mucosal blood flow Cell renewal 14
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Normal Gastric Normal Gastric Protective Mechanisms Protective Mechanisms Acid and pepsin Acid and pepsin Stomach Stomach lumen Protective factors: Protective factors: lumen pH pH < 2 < 2 HCL HCL HCL HCL all are all are PG PG dependent dependent Mucous layer thicknes Mucous layer thicknes Š HCO HCO HCO 3Š Š HCO HCO 3Š HCO 3Š Š HCO HCO 3Š Š Mucous layer Mucous layer 3 3 3 3 Gastric Gastric pH gradient pH gradient epithelium epithelium pH7 pH7 Cell membrane Cell membrane hydrophobicity Gastric pit Gastric pit hydrophobicity Bicarbonate secretion Bicarbonate secretion Mucosal Mucosal blood flow blood flow Collins, 1990. Collins, 1990. Mechanisms of NSAID Injury Mechanisms of NSAID Injury • Topical injury – Ion trapping: rapid, compound specific – Enterohepatic recirculation • Prostaglandin depletion – Systemic effect • Neutrophil Activation – Increased neutrophil vascular adherence mediated by increased TNF α and ICAM • Combination renders mucosa vulnerable to acid 17
Ion Trapping of Ion Trapping of Acidic Acidic NSAIDs NSAIDs Gastric Lumen Gastric Lumen pH = 1-2 pH = 1-2 AH AH A – A – + H+ + H+ pH = 2 pH = 2 Mucous Gel Layer Mucous Gel Layer AH AH – + H + A – A + H + pH = 7 pH = 7 Gastric Epithelium A – – + H + H + + Gastric Epithelium A pH = 7.4 pH = 7.4 AH AH A – – + H + H + + AH AH A pH = 7.4 pH = 7.4 Blood Blood Schoen Schoen . Am J . . 1989;86:449. . 1989;86:449. Am J Med Med Indirect Topical Exposure Via Indirect Topical Exposure Via Enterohepatic Enterohepatic Circulation Circulation Liver Liver NSAIDs Excreted NSAIDs Excreted in Bile in Bile Absorption Absorption Indomethacin Indomethacin Diclofenac Diclofenac Stomach Stomach Naproxen Naproxen Reflux (with bile) Reflux (with bile) Piroxicam Piroxicam Sulindac Sulindac Gallbladder Gallbladder Oxaprozin Oxaprozin Ketorolac Ketorolac Reabsorption Reabsorption Intestinal Intestinal Damage Damage 18
Pathogenesis of Pathogenesis of NSAID-Induced Ulcer NSAID-Induced Ulcer Epithelial effects (due to Epithelial effects (due to Endothelial effects Endothelial effects • direct toxicity direct toxicity • prostaglandin depletion) prostaglandin depletion) “ion trapping” “ion trapping” • stasis stasis ischemia ischemia • _ _ HCl HCl secretion • secretion • ⎠ ⎠ mucin mucin secretion • secretion • ⎠ ⎠ HCO HCO secretion • 3 secretion • 3 ⎠ ⎠ surface active surface active phospholipid • phospholipid • secretion secretion ⎠ epithelial cell proliferatio ⎠ epithelial cell proliferation • • HEALING (spontaneous HEALING (spontaneous Acid Acid ULCER ULCER or therapeutic) or therapeutic) EROSIONS EROSIONS Cyclooxygenase Cyclooxygenase Isoenzymes Isoenzymes Physiologic Physiologic Inflammatory Inflammatory Stimulus Stimulus Stimulus Stimulus Platelets Macrophages 8 Platelets 8 Macrophages 8 8 8 Endothelium Endothelium 8 Leukocytes Leukocytes 8 8 COX-1 COX-1 COX-2 COX-2 Constitutive Inducible Constitutive Inducible 8 Stomach Stomach 8 Fibroblasts Fibroblasts 8 8 Kidney Endothelial cell 8 Kidney TXA PGI PGE PGI PGE 8 Endothelial cell TXA PGI PGE PGI PGE 8 8 2 2 2 2 2 2 2 2 2 2 Inflammation Inflammation “Housekeeping” “Housekeeping” 19
Risk factors for serious NSAID-related Risk factors for serious NSAID-related Peptic Ulcer Disease Peptic Ulcer Disease – Age > 60 years – History of previous ulcer or GI bleeding – Concomittant use of anticoagulants or glucocorticoids – High dose NSAID therapy – Use of multiple NSAIDs – Severity of underlying disease • High (9%) risk of major complications if 4 or more risk factors • PPI prophylaxis for patients at high risk for NSAID ulcers H. pylori Timeline • Early 1900’s Discovery of human gastric bacteria • 1920-1980 Rediscovery of gastric bacteria • 1982 Isolation and culture of C. pyloridis by Marshall and Warren • 1987 Eradication reduces DU recurrence • 1989 Bacteria are renamed H. pylori • 1990’s Association of H. pylori with gastric cancer and MALT lymphoma • 1997 Complete genome sequence of H. pylori Marshall & Warren Helicobacter pylori 20
Epidemiology of H. pylori • Universal in developing countries but declining in incidence in industrialized nations • Cohort effect explains higher rates in older adults in the U.S. • Early childhood the major window for acquisition; low rates in older children & adults • Transmission is person-to-person – Familial clustering (passed among siblings older-younger) – High rates in institutions with crowding & poor sanitation • Fecal-oral versus oral-oral transmission H. pylori belongs to a larger family of Helicobacter sp. Humans Rat Woodchuck • H. pylori • H. trogontum • H. marmotae • H. bilis • H. heilmanni Gerbil Chicken Mouse • H. bilis • H. pullorum • H. hepaticus • H. hepaticus Hamster • H. bilis Dog • H. cinaedi • H. rodentium • H. fennelliae • H. cholecystus • H. typhlonius • H. canis • H. aurati • H. ganmani Other • H. mesocricetorum • H. rappini • H. canadensis Cat Ferret • H. winghamensis • H. felis • H. mustaelae 21
CagA Protein from Helicobacter pylori Is a Trojan Horse to Epithelial Cells Type IV Secretion System • Keys for survival – Acid tolerant (urease, UreI) – Motile (multiple flagella) • Important attributes – Attachment (32 Hop adhesins, including Src BabA) – Other virulence factors: VacA, picB/cagE Shp-2 – Genes regulated by slipped-strand mispairing – Uses molecular hydrogen for energy H. pylori : Natural History Ingestion of H. pylori Childhood (gastroenteritis/diarrhea) Early adulthood Chronic, active gastritis Fe deficiency anemia Asymptomatic Body Menetrier’s (90%) gastritis Hyperplastic polyps (<1%) Duodenal Late adulthood ulcer (5%) Gastric MALT Gastric lymphoma ulcer (3%) cancer (0.5%) (<1%) 22
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