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Board Review Lecture Class of 2012

Board Review Lecture Class of 2012. Colin W. Howden, MD May 19, 2010. Disclaimer. I know practically NOTHING about USMLE I’ve seen the “ First Aid ” pages. Selected GI-related topics for review. Esophagus Pathophysiology of GERD and motility disorders Pharmacology of drugs for GERD

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Board Review Lecture Class of 2012

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  1. Board Review LectureClass of 2012 Colin W. Howden, MD May 19, 2010

  2. Disclaimer • I know practically NOTHING about USMLE • I’ve seen the “First Aid” pages

  3. Selected GI-related topics for review • Esophagus • Pathophysiology of GERD and motility disorders • Pharmacology of drugs for GERD • Stomach / duodenum • “Gastritis”; H. pylori • Pathophysiology of peptic ulcer • Intestine • Celiac disease • IBD – pathology / clinical features • Q&A

  4. PLUS ………….. I will comment on some of the “information” given to you in the First Aid …… …. because it ain’t all true!

  5. Anatomy Dr. Howden last studied anatomy in 1975 Enough said …………

  6. Pathophysiology of GERD • Transient LES relaxations • Low LES resting pressure • Increased intra-abdominal pressure • Delayed gastric emptying • Hiatus / hiatal hernia – reservoir for re-reflux • Reflux of (acidic) gastric contents into esophagus • Pepsinogen requires acid for conversion to pepsin • Pepsin biologically active on esophageal mucosa at pH < 4 Less important

  7. Ach NO LESP Neurogenic Myogenic LES Basal Pressure

  8. Esophageal motility disorders • Many are poorly characterized • Important to know about achalasia

  9. Abnormalities in achalasia • Impaired deglutitive relaxation • Aperistalsis • Increased LESP • Increased intra-esophageal pressure • Dilation of esophagus • Poor esophageal emptying • Beaking of distal esophagus MANOMETRIC RADIOLOGIC

  10. Achalasia DILATION “BIRD’S BEAK”

  11. Achalasia • Dysphagia (duh!!) • Chest pain / discomfort • Choking, coughing, aspiration • Sleep disturbance • Weight loss • Increased risk of distal squamous cancer of the esophagus • NOTE – NOT adenocarcinoma

  12. “Esophageal pathologies”(First Aid page 316) • Mallory-Weiss syndrome – not always “painful” • Bleeding generally follows repeated episodes of vomiting • Vomitus initially “clear” – then becomes bloody • Bleeding usually trivial / mild • Esophageal strictures • NOT just associated with “lye ingestion and acid reflux” • Can occur following pill esophagitis

  13. Pill esophagitis Tetracyclines, qunidine, NSAIDs, bisphosphonates, iron, vitamin C Chest pain, odynophagia, dysphagia Lesion may appear “trivial” on endoscopy Can heal with development of scarring / stricture

  14. “Esophageal pathologies”(First Aid page 316) “BARRett’s = Becomes Adenocarcinoma, Results from Reflux” Most patients with Barrett’s esophagus will NEVER develop esophageal adenocarcinoma BUT …………. Most cases of esophageal adenocarcinoma develop in patients with Barrett’s esophagus

  15. “Esophageal cancer”(First Aid) • A B C D E F • A = alcohol = squamous • A = achalasia = squamous • B = Barrett’s = adenocarcinoma • C = cigarettes = squamous • D = “diverticuli” (sic) = squamous (?????) • PLURAL OF DIVERTICULUM IS ………??? • E = esophageal web (Plummer Vinson) = squamous • F = familial = squamous (tylosis)

  16. Tylosis

  17. “Esophageal cancer”(First Aid) • Squamous – upper and middle thirds • Adenocarcinoma – distal third • Also note marked racial differences • Squamous – predominantly non-white • Adenocarcinoma – predominantly white (and male)

  18. Pharmacology of drugs for GERD • Antacids • Chemical neutralization • Al, Ca – constipation / Mg - diarrhea • H2-receptor antagonists • Competitive antagonists at a receptor • Proton pump inhibitors (PPIs) • Irreversible inhibitors of an enzyme

  19. Acid MUCOSA LUMEN H+ K+ ATPase cAMP Ca2+ Ca2+ Parietal Cell pH ACh Gastrin Vagus Nerve Histamine ECL Cell G Cell ACh Gastrin = = Feedback Inhibition D Cell Somatostatin Gastric Secretion and Feedback

  20. H2-receptor antagonists • Dr. Silinsky’s lecture is consistently one of the highest rated in the entire course • Any further questions? • Drug interactions? • Pharmacological tolerance? • Rebound acid hypersecretion?

  21. PPIs • Acid-labile pro-drugs • Need to be protected from gastric acid • Absorbed systemically • Preferential uptake by parietal cells • Chemically converted within parietal cell • Extruded from apical membrane of parietal cell • Bind covalently to –SH groups on membrane-bound H+/K+-ATPase

  22. PPIs (2) • Currently the most effective agents for GERD • This is illogical! • No development of tolerance • Profound inhibition of acid – NOT achlorhydria • Long-term safety issues • Hypergastrinemia – no longer considered a concern • B12 absorption • Increased risk of hip (and ? other) fractures • Interaction with clopidogrel (?)

  23. Acid  Acid  Acid X H+/K+ X X H+/K+ ATPase ATPase Increased parietal cell mass(ECL cell hyperplasia) PPI PPI withdrawal Effects of prolonged PPI use Blockade Hyperplasia Rebound

  24. PPI use as a risk factor for hip fracture Yang et al., JAMA 2006; 296: 2947

  25. B12 absorption • Most dietary B12 is bound to food protein • Meat and eggs • Gastric acid helps to release B12 from food protein • B12 then binds to salivary R-proteins • Pancreatic enzymes release B12 from salivary R-proteins • B12 binds to intrinsic factor • Absorbed from terminal ileum

  26. Causes of low B12 • Strict vegan diet • Absence of gastric acid / IF • Pernicious anemia • Pancreatic insufficiency • Competition for B12 in GI tract • Bacterial overgrowth (B12 LOW / folate HIGH) • Disease / resection of terminal ileum

  27. 0 What is H. pylori? • Gram-negative, curved or spiral bacterium • Flagellated – highly motile • Ideally adapted to survive in the human stomach • potent producer of urease, which breaks down ureain gastric juice to produce carbon dioxide and two ammonium ions – protects it from highly acidic environment

  28. 0 Epidemiology of H. pylori infection • Usually acquired in childhood • becomes chronic if not cleared or treated • M = F • Inverse relationship with socioeconomic status • more common in developing than developed countries • May be spread within families or among young children (e.g., day-care centers) • Possible fecal-oral or gastric-oral routes of transmission

  29. 0 Transmission of H. pylori and risk factors for acquisition • Transmission • fecal-oral, gastric-oral • water • fecal contamination of water supply • Risk factors • family members infected • increased number of siblings (>2 siblings) • crowded living conditions • clustering in institutions, day-care centers, health care workers • poor sanitation (fecal contamination of water supply) • poor hygiene

  30. 0 Disease associations • Gastritis (histological) – 100% • Peptic ulcer in around 1:7 individuals • Gastric adenocarcinoma 2-3 fold higher risk • group 1 carcinogen (World Health Organization / International Agency for Research on Cancer) • high incidence areas such as Japan • Gastric mucosa-associated lymphoid tissue (MALT) lymphoma • Dyspepsia – controversial

  31. H. pylori seen microscopically on a gastric biopsy from a patient with a duodenal ulcer • H. pylori organisms are stained black (Warthin-Starrysilver stain) • H. pylori can usually also be seen with routine stains (e.g., H&E)

  32. Natural history of H. pylori infection Acid production High Duodenal ulcer Antral-predominantgastritis MALT lymphoma Non-atrophicpangastritis Chronic H. pylori infection Asymptomatic H. pylori infection Normal gastric mucosa Corpus-predominant atrophic gastritis Acute H. pylori infection Gastric ulcer Intestinal metaplasia Dysplasia Gastric cancer Low Childhood Advanced age

  33. Probable mechanism of H. pylori infection as a cause of DU H. pylori colonizes gastric antrum D cells inhibited; SST gastrin Acid hypersecretion Duodenal gastric metaplasia H. pylori migrates; colonizes DGM

  34. “Peptic ulcer disease”(First Aid Page 319) • “Ugh!!” • Cannot distinguish GU from DU on basis of history • (Cannot really distinguish PUD from NUD / FD either) • H. pylori prevalence grossly over-estimated • Weight gain not typical of DU • Should not be any confusion between DU and cancer ………..

  35. 0 Number Needed to Treat (NNT) with H. pylori eradication therapy to prevent 1 ulcer recurrence within 1 year:

  36. 0 Methods of testing for H. pylori infection • Non-endoscopic • serology • urea breath test (UBT) • 13C – non-radioactive • 14C – radioactive • stool antigen test • Endoscopic • biopsy urease test • histology • culture NB: Except for serology, all are tests of active infection

  37. 0 Principle of the urea breath test 13CO2 in breath • Can be used to confirm eradication • Pre- and post-treatment accuracy similar • False negative results may occur with recent acid suppression, bismuth, or antibiotic(s) NH2 H2O +13C =O Urease NH2 2NH4+ +13CO2 13CO2 blood

  38. Example of a biopsy urease test (CLOtest™) for H. pylori • Well contains urea and a pH indicator • If H. pylori present in biospy samples, its urease splits urea to produce CO2 and 2NH4+ • NH4+ raises pH and changes color of indicator • yellow = negative • red = positive

  39. “Bismuth, sucralfate”(First Aid Page 332) AVOID ALL OTHER COMBINATIONS! “NO SUBSTITUTIONS ALLOWED!!!!!” • Triple therapy • PPI + clarithromycin + amoxicillin OR • PPI + clarithromycin + metronidazole • Quadruple therapy • Bi + metronidazole + tetracycline + PPI

  40. First Aid Page 332 continued … Ignore “muscarinic antagonists” Antacids – side-effects grossly over-stated Sulfasalazine – UC and Crohn’s (colonic only) Metoclopramide – main use (SHORT-TERM) is as anti-emetic

  41. Celiac disease • a.k.a. celiac sprue • a.k.a. gluten-sensitive enteropathy • Histology • Villous atrophy • Crypt hyperplasia • Increased intra-epithelial lymphocytes • Response to gluten-free diet • Clinical • Serological • Histological

  42. Myths about celiac disease • It’s rare • It’s a condition of childhood • It only occurs in girls and women • It presents with weight loss, diarrhea, steatorrhea and abdominal distension

  43. Serological tests for celiac disease • Anti-gliadin antibody • Poor specificity / unreliable / no longer recommended • IgA anti-endomysial antibody (EMA) • Almost 100% specificity; > 90% sensitivity • Expensive • IgA tissue transglutaminase (TTG) antibody • Check IgG EMA and / or TTG if suspected IgA deficiency • Check serological tests when patient is on an unrestricted diet

  44. IBD in the United States • Incidence: 10 cases per 100,000 per year • Onset: 30% between 10 and 19 years3 • Young children: 2%3 • Prevalence: 100 cases per 100,0001 • More than 1 million cases estimated in U.S. • Ulcerative colitis: 50%2 • Crohn’s disease: 50%2 1. Hanauer SB. Cecil Textbook of Medicine. 20th ed. Philadelphia, Pa: WB Saunders Co; 1996:707. 2. Calkins BM. Digestive Diseases in the United States: Epidemiology and Impact. Bethesda, Md: NIH; May 1994:511. 3. Grand RJ et al. Clin Invest Med. 1996;19:373.

  45. Contiguous involvement Mucosal inflammation Discrete ulcers rare Confined to colon Patchy distribution Transmural inflammation Fistulae, abscess, stenosis Discrete ulcers common Anywhere in GI tract UC vs. Crohn’s disease of colon UC Crohn’s

  46. Ulcerative Colitis: Endoscopy

  47. Crohn’s disease of colon at colonoscopy Aphthous ulcers

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