Pathophysiology of Biochemistry Pharmacy PHM 143 PUD, GERD and IBD March 25, 2024 - FINAL SUBMITTED 24.03.24.pdf

Lecture 1: Gastrointestinal DISCLOSURE Pathophysiology Peptic Ulcer Disease and Gerd Relevant relationships...

Lecture 1: Gastrointestinal DISCLOSURE Pathophysiology Peptic Ulcer Disease and Gerd Relevant relationships None with commercial entities Pathophysiology & Clinical Biochemistry Pharmacy Program – PHM 143 March 25, 2024 Potential for conflicts of interest within this None IN CLASSROOM LECTURE - MSB, RM 3153 presentation Maria Cino, Hon BSc, MSc, MD, FRCP, CAGF Associate Professor, University of Toronto Division of Gastroenterology, Department of Medicine Steps taken to review and Slides reviewed by peer mitigate potential bias 1 2 1  CanMEDS Roles Covered in this Academic Half-Day Session OBJECTIVES Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical ! knowledge, clinical skills, and professional attitudes in their provision of patient-centered care. Medical Expert is the central physician Role in the CanMEDS framework.) Identify major causes of upper GI bleeding Communicator (as Communicators, physicians effectively facilitate the doctor-patient relationship and the dynamic exchanges that occur before, during, and after the medical encounter.) Understand pathophysiology of peptic ulcer Collaborator (as Collaborators, physicians effectively work within a healthcare team to achieve optimal disease & GERD ! patient care.) Manager (as Managers, physicians are integral participants in healthcare organizations, organizing Identify prognostic factors for rebleeding sustainable practices, making decisions about allocating resources, and contributing to the effectiveness of the healthcare system.) Health Advocate (as Health Advocates, physicians responsibly use their expertise and influence to ! advance the health and well-being of individual patients, communities, and populations.) Discuss the complications of GERD Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning, as well as the creation, dissemination, application and translation of medical knowledge.) Management of upper GI bleeding, peptic Professional (as Professionals, physicians are committed to the health and well-being of individuals and society through ethical practice, profession-led regulation, and high personal standards of ulcer disease & GERD behaviour.) 3 4 2  GASTROINTESTINAL BLEEDING CLINICAL PRESENTATION: OVERT BLEEDING § Hematemesis: vomiting blood, black (coffee grounds) or bright § Acute vs Chronic red/ suggests source proximal to ligament of Treitz A § Overt vs Occult (blood you § Melena: tarry black stool, transit A can see vs. Bleeding you time in GI tract >14 hrs, 50 - 100 suspect) cc blood into UGI tract / proximal to ileocecal valve B B § Hematochezia: rectal bleeding, bright red or maroon – colon or small bowel/ massive UGI bleed Bezobchuk, S and Grainek, IM Clin Gastrointest Endo, 3rd Edition, 2019:190-201 5 6 3  GASTROINTESTINAL BLEEDING CLINICAL PRESENTATION: OCCULT BLEEDING § Upper GI bleed: source proximal to ligament of Treitz A § Blood work: Iron deficiency anemia § Middle or small bowel: proximal A § Stool test: FIT test (fecal immunochemical to ileocecal valve, not within the test) reach of the colonoscope B B § Lower GI bleed: colon +/- distal terminal ileum 7 8 4  CAUSES OF UPPER GI BLEED NATURAL HISTORY COMMON UNCOMMON § bleeding risk: duodenal > gastric ulcer, 2:1 § peptic ulcer disease § gastric antral § 75 % non-variceal bleeding spontaneously stop bleeding § gastric vascular ectasia § 25 % rebleed, majority in 8 hrs § duodenal § Dieulafoy lesion § Morbidity & mortality in non-variceal upper GI § esophagitis § gastric malignancy bleeding is associated with underlying illnesses, § Mallory-Weiss tear (adenocarcinoma, i.e. cardiovascular disease § varices lymphoma) § unchanged mortality rate x 3 decades: 6-10% § aortoenteric fistula § esophageal § 0.6% : age < 60 yrs, no comorbid illness § hematobilia § gastric § 15% : age > 60 yrs, +/- comorbid illness 9 10 5  PROGNOSTIC FACTORS § age > 60 yrs § comorbid illnesses (i.e. cardiac, respiratory, renal) § severity of initial hemorrhage PEPTIC ULCER DISEASE § # units transfused blood, Hb < 80 g/L § hemodynamic instability § RED blood in hematemesis +/- stool § onset during hospitalization for another reason § endoscopic criteria (appearance) 11 12 6  PARIETAL CELL SCHEMATIC DIAGRAM OF AN ULCER apical H+ K+ clean base non-bleeding H+- K+ ATPase visible vessel H+ K+ Cl- mucosa crater M3 H2 submucosa CCK muscle acetylcholine gastrin histamine vessel basolateral provided by Cino, M 13 14 7  PEPTIC ULCER ETIOLOGY PEPTIC ULCER ETIOLOGY AGGRESSIVE FACTORS > EPITHELIAL DEFENSE MECHANISMS The 2 most common causes: (protective) § Non-steroidal anti-inflammatory agents § acid (NSAIDs) or ASA § pepsin (breakdown § mucous/ from pepsinogen) bicarbonate layer § Helicobacter pylori (H. Pylori) infection § prostaglandins (mucosal blood flow) > > 15 16 8  HELICOBACTER PYLORI ULCER RECURRENCE < 10%/YR § Infection transmission: fecal – oral FOLLOWING H. PYLORI ERADICATION § Location: gastric mucosa, mucous 60 Layer, over epithelium % ulcer recurrence 50 40 § Histological antral gastritis 100%: 30 § association: DU, 90% > GU, 70% 20 10 § Acquisition increases with age 0 H.p. neg H. p. pos § Inverse relationship to socioeconomic status Laine et al. Am J Gastro 1998; 93: 1409-1415 17 18 9  LOW-DOSE ASA COMBINED WITH COXIB HAS SIMILAR PUD RATE VS. NSAIDS ALONE A. GENERAL: HISTORY 17.1 12-wk % cumulative incidence ulcers 18 16.1 abdominal pain 16 14 placebo e.g. ulcer, mesenteric ischemia, malignancy ASA 12 retching (Mallory-Weiss tear) 10 ASA + COXIB 8 7.3 medications: NSAID / ASA / COX inhibitor 5.8 NSAID 6 family or personal history of coagulopathy 4 2 comorbid illness i.e. liver, cardiac disease 0 prior surgery for PUD, arterial bypass graft medication Laine,L et al. Gastro 127:395-402, 2004 19 20 10  MANAGEMENT OVERVIEW PROTON PUMP INHIBITORS General Measures Specific Measures § Reduce acid secretion (increase pharmacotherapy pH), block final step in acid production Resuscitation: proton pump inhibitors by inhibition of H+- K+ ATPase fluids octreotide (variceal) § High pH promotes a stable clot: transfusion endoscopy to localize § acid inhibits platelet function, +/- treat required for clot formation Correct Coagulation § pepsin (formed from pepsinogen at status Failure of above low pH) destroy clot that has interventional radiology formed INR, platelets surgery Aliment Pharmacol Ther 106:1565-84, 1999 21 22 11  RATIONALE FOR EMPIRIC PPI USE INTRAVENOUS PPI: HIGH RISK LESIONS § Current guidelines1 recommend IV bolus dose of PPI followed by continuous infusion ü Treatment of common etiologies § Many stuidies2 have shown that intermittent of UGI bleeding and PPI therapy do not differ: ü Overall, safe, effective, § Rebleeding @ 3 & 30 days reduce re-bleeding rate & need § Mortality for surgery § Need for urgent interventions § Blood transfusion ü IV or oral formulation § Length of hospital stay § Can downgrade the lesion (higher to lower risk) Barkun, AN, et al. Ann Intern Med 2019; 171(11): 805-822 Khuroo et al. NEJM 336: 1054-1058, 1997; Kau et al. NEJM 2000 Sachar, H. et al. JAMA Intern Med 2014 174(11):1755-1762 23 24 12  ENDOSCOPY: 3 KEY ROLES ENDOSCOPIC PREDICTORS OF III REBLEEDING & MORTALITY: FORREST CLASSIFICATION IIc DIAGNOSIS PROGNOSIS THERAPY Ulcer Base Rebleed Surgery Mortality Identify the Risk-stratify the Treat the lesion bleeding lesion lesion (achieve hemostasis) III Clean base 5 0.5 2 IIc Flat spot 10 6 IIb IIb Adherent clot 22 10 7 IIa Visible vessel 43 34 11 IIa Ia Active bleed 55 35 11 At endoscopy: III, Iic No intervention/ IIb consider intervention/ Ia, IIa intervention Ia Image from: product-https://www.medicalexpo.com/product-manufacturer/olympus-video-endoscope-49115- 36.htmlmanufacturer/olympus-video-endoscope-49115-36.html Laine L, Peterson WLN Engl J Med 1994; 331:717-727 25 26 13  ENDOSCOPIC THERAPY PROTON PUMP INHIBITORS: 1. Medications POST-ENDOSCOPY HIGH RISK LESION § Injection (diluted epinephrine) 2. Thermal Hemostatic Devices PPI IV bolus (80 mg) followed by IV § Bipolar probe (electrical) infusion (8 mg/h x 72h) > placebo § Argon plasma coagulation § Heater probe (thermal) 3. Mechanical § Hemoclips § Banding 4. Hemospray@ (proprietary spray) Laine, L et al, NEJM 1994: 331:717-27 http://www.wjgnet.com/esps/Pub/10.4253/v8/i4/WJGE-8-205-g001.jpg Lau et al. N Engl J Med. 2000;343:310-316 Barkun, AN, et al. Ann Intern Med 2019; 171(11): 805-822 27 28 14  RESCUE MEASURES FOR FAILED PROTON PUMP INHIBITOR CONTROL OF BLEEDING VIA ENDOSCOPY THERAPY POST DISCHARGE PPI bid x 2 weeks, high risk lesions, § Angiography with embolization then once daily x 8 weeks Long term use Large ulcers Severe erosive esophagitis § Surgery (infrequently / rarely required) Need for long-term NSAID, anticoagulation use www.mghradrounds.org/clientuploads/august_2007/figure4.jpg http:// Barkun, AN et al. Ann Intern Med 2019; 171(11): 805-822 29 30 15  ? GASTROESOPHAGEAL REFLUX DISEASE 31 32 16  GASTROESOPHAGEAL REFLUX DISEASE GERD Increased # transient LES relaxations (TLES) 82% § Definition: failure of the Hypotensive LES anti-reflux barrier, allowing reflux of Disruption of diaphragmatic sphincter & crural fibers (loss of GE junction gastric contents into competence) esophagus Reduced esophageal clearance (impaired peristasis) § 2 Subsets: § endoscopic lesions Delayed gastric emptying § non-erosive Obesity § m = f, but esophagitis > in male (2 - 3 : 1) Hiatus hernia > 5 cm http://images.medicinenet.com/images/illustrations/gastroesophageal_reflux.jpg 33 34 17  INVESTIGATION CLINICAL PRESENTATION 24-hr esophageal pH monitoring Typical Atypical Frequency, duration: low pH Relationship: symptoms § heartburn § cough & episodes of acid reflux § regurgitation § wheezing Endoscopy § belching § chest pain § hoarseness § odynophagia www.hopkinsmedicine.org 35 36 18  LOS ANGELES (LA) CLASSIFICATION A.. One or more mucosal breaks < 5 mm in maximum length MILD B. One or more mucosal breaks, > 5 mm, but not extending across 2 folds > 5 mm C. Non-circumferential mucosal breaks, continuous between 2 folds D. Mucosal break involving > 75% of > 2 folds esophageal circumference SEVERE Armstrong D et al. Gastroenterology 1996; 111:85-92 Lundell L et al. Gut 1999; 45:172-180 Lundell L et al. Gut 1999; 45:172-180Gut 1999 37 38 19  COMPLICATIONS Barrett’s Esophagus Erosive Esophagitis acquired N O injury to squamous R epithelium in the lower M Ulceration esophagus A L normal squamous Peptic Stricture epithelium is replaced by B metaplastic columnar A epithelium R R Barrett’s esophagitis tissue at risk for dysplasia, E T adenocarcinoma T’ S Falk, GW Gastro 112:1569, 2002; Spechler NEJM 346: 836, 2002 39 40 20  THERAPY § Lifestyle changes HEALING RATES BY LA CLASSIFICATION § elevation head bed (nocturnal Sx) § avoid bedtime meals / drinks 100 § avoid cigarettes, EtOH, caffeine 80 § low fat diet / weight loss 60 § Histamine 2 Receptor Antagonists: mild % 8 weeks intermittent symptoms 40 6 months § Proton pump inhibitor agents: prolonged acid 20 suppression 0 § Prokinetic agents: Domperidone, A B C D Metoclopramide (D2 Receptor Antagonists) Lauritsen K et al. Aliment Pharmacol Ther 2003;17:333 § Surgery - fundoplication Castell DO et al. Am J Gastroenterol 2002;97:575 41 42 21  PPI Therapy Reduces the Incidence SUMMARY Rates of Barrett’s Dysplasia § Majority of PUD is associated with H. pylori § NSAIDs & COXIBs account for the majority of H. pylori-negative ulcers, exacerbated by ASA § Proton pump inhibitors – Peptic ulcer disease § Endoscopic therapy is guided by ulcer base characteristics § H. pylori eradication reduces recurrence of PUD § Longstanding GERD is a risk factor for Barrett’s esophagus... risk factor for adenocarcinoma § PPI therapy after the Dx of Barrett’s esophagus El-Serag,H.B. Am J. Gastro 99:1877, 2004 may reduce the risk of dysplasia in Barrett’s 43 44 22  OBJECTIVES zLECTURE 2: GASTROINTESTINAL PATHOPHYSIOLOGY - INFLAMMATORY BOWEL DISEASE Crohn's Disease & Ulcerative Colitis Pathophysiology & Clinical Biochemistry Pathogenesis Pharmacy Program 143 March 25, 2024 Clinical Manifestations IN CLASSROOM Lecture, MSB 3153 Maria Cino, HBSc, MSc, MD, FRCPC, CAGF Key principles of management Associate Professor, University of Toronto Division of Gastroenterology, Department of Medicine 45 46 23  INFLAMMATORY BOWEL DISEASE INFLAMMATORY BOWEL DISEASE § Chronic inflammatory disorders of the § bimodal: intestinal tract, variable systemic peak 20s – 30s, 2nd peak age 60s involvement § high in N. America, Europe, low in S.A., § Crohn’s disease: affects any portion of the Asia, Japan GI tract § Ulcerative colitis: limited to colon & rectum § Prevalence: § Indeterminate colitis: (features of both) up Crohn’s Disease - 2-100 / 100,000/yr to 15% cannot be classified as either CD Ulcerative Colitis - 10-150 / 100,000/yr or UC 47 48 24  PATHOGENESIS: AUTOIMMUNITY Definition: immune r esponse against self Genetic Host antigen Susceptibility Immune CD > UC Response Development of 16 (NOD-2) autoimmunity reflects Click Clicktotoadd addtext text Click Click to addtext to add text a combination Environmental of susceptibility Luminal Factors genes & Bacteria smoking environmental triggers ? fish oil ? stress Guilherme Piovezani, R, Papadakos, KA. 2019 Jan;94(1):155-165.doi: 10.1016/j.mayocp.2018.09.013. 49 50 25  PATHOGENESIS Regulatory DIAGNOSIS T cells activated T cells tolerance § Crohn’s disease versus ulcerative colitis Healed intestine § Extent of disease lumen bacteria § Disease behavior acute inflammation normal immune dysregulation § Severity of disease impaired bacterial clearance Chronic inflammation Sartor, B. Nat Clin Practice Gastro & Hepatology 3: 390-407, 2006 51 52 26 Feature Crohn’s Disease Ulcerative Colitis Feature Crohn’s Disease Ulcerative Colitis endoscopy mouth to anus, continuous or diffuse gross transmural injury superficial: mucosal and segmental inflammation pattern of pathology (deep ulcers, submucosal injury “skip lesions”, inflammation, extends fissures) serosal cobblestone, from anus (normal erythema, creeping fat pseudopolyps small bowel) Any part of GI Limited to the colon tract: ileocolonic 50%; Defined by location small bowel 30%; colon 20% LOCATION 55% rectum 35% left colon 15% pancolitis N CD UC http://www.hopkins-gi.org http://www.hopkins-gi.org/Upload/200710261526_42614 49208 _000.jpg 53 54 27 Feature Crohn’s Disease Ulcerative Colitis Crohn’s Disease: microscopic patchy architectural architectural distortion, pathology distortion, granulomas gland destruction, crypt Common Clinical Manifestations (non-caseating) abscess § abdominal pain § diarrhea § inflammatory mass RLQ § obstruction (usually partial) § weight loss § fever § perianal disease (fissures, fistula) Podolsky, D. Nature 448: 427-432, 2007 55 56 28  Natural History of Crohn’s Disease Crohn’s Disease: Common Complications stricture fistula Pariente, B.et al. Inflamm Bowel Dis. 2011 Jun; 17(6): 1415–1422. Published online 2010 Nov 28. doi: 10.1002/ibd.21506 57 58 29  ULCERATIVE COLITIS: ULCERATIVE COLITIS: COMMON CLINICAL MANIFESTATIONS COMPLICATIONS Toxic Megacolon § abdominal pain Malignancy Risk § duration > 8-10 yrs § diarrhea, frequent, small volume § extensive disease § rectal bleeding § co-morbid liver disease (primary sclerosing § mucous cholangitis or PSC) § Indolent, persistent chronic active disease http://www.radpod.org/wp-content 59 60 30  EXTRAINTESTINAL MANIFESTATIONS EVALUATION * § Clinical history: travel Hx, antibiotic use, diet, * Parallel disease activity sexual Hx, FHx of IBD, extraintestinal § eye (episcleritis) manifestations § skin (erythema nodosum) § Physical examination: abdomen, perianal § mouth ulcers § Laboratory data: § musculoskeletal: CBC, iron, folate, vitamin B12, c-reactive * peripheral arthritis protein, ESR, stool for leukocytes, fecal calprotectin, infectious work-up (ova & parasites (E. Histolytica on selected patients), c. difficile toxin, culture http://www.hopkins-gi.org/Upload/200710261533_18552_000.jpg 61 62 31  EVALUATION GOALS OF THERAPY CT or MR enterography to BIOLOGIC CLINICAL ULTIMATE GOALS GOALS GOALS determine disease extent Crohn's Disease MR pelvis if symptoms of or suspect perianal Suppress Induction of Mucosal healing disease Basic Laboratory Data : inflammatory remission Quality of life CBC, lytes, liver enzymes, albumin, calcium, Fecal Calprotectin Colonoscopy +/- upper endoscopy Evaluate small bowel, CT Consider capsule response Maintenance of Normal Normal or MR enterography endoscopy study Suppress remission immune Disease Ulcerative colitis Acute setting: Abdominal x-ray or CT tomogram response monitoring/ relapse prevention/ treat complications 63 64 32  MEDICATION OPTIONS CD: PRINCIPLES OF THERAPY CLASS DELIVERY Medication § Extent of disease burden 5-ASA Mesalamine Oral § ileocolonic 50% Rectal: suppository, enema Corticosteroids Prednisone Oral, Intravenous § small bowel 30% Rectal: suppository, enema § colon 20% Budesonide Oral, Rectal enema Immunosuppressant Azathioprine or 6-Mercaptopurine Oral § Severity Methotrexate Oral, Subcutaneous Cyclosporin Oral, intravenous Immunobiologic Anti TNF: Intravenous 1, Subcutaneous 2 § Disease behavior: Infliximab 1, Adalimumab 2 Fistulizing Anti-Integrin (a 4, b 7): Vedolizumab Intravenous Non-fistulizing Anti- IL-12, 23 Subcutaneous Ustekinumab Anti-IL23 Subcutaneous § Complications Risankizumab § stricture Immunotherapy (smal Janus Kinase Inhibitors (JAK) - Oral § fistula l molecules) Tofacitinib, Upatacitinib § perianal disease 65 66 33  CROHN'S DISEASE: REMISSION CLASS INDUCTION REMISSION ENDOSCOPIC HEALING 5-ASA (Cochrane + + Analysis, overall no role, ? Mild ileal disease) Corticosteroids + - Immunosuppressant Azathioprine or 6-MP - (3.4 mo) + Methotrexate + + Cyclosporine - - Immunobiologic Anti TNF: + + Infliximab, Adalimumab ileum Anti-Integrin (a 4, b 7): + + Vedolizumab pre-Infliximab… post… Anti- IL-12, 23 + + Ustekinumab Anti- IL-23 + + Risankizumab 67 68 34  ULCERATIVE COLITIS : REMISSION UC: PRINCIPLES OF THERAPY CLASS INDUCTION REMISSION § extent of disease 5-ASA + + Corticosteroids + - § proctitis (28%), left-sided Immunosuppressant - (25%), pancolitis (47%) Azathioprine or 6-MP - Methotrexate Cyclosporine + Safety profile, use § severity other agents § # bowel movements Immunobiologic Anti TNF: + + § rectal bleeding Infliximab, Adalimumab Anti-Integrin (a 4, b 7): + + § fever, tachycardia Vedolizumab Anti- IL-12, 23 + + § anemia Ustekinumab Anti- IL-12 Risankizumab + + Immunotherapy § complications Janus Kinase Inhibitors (JAK) - + + Tofacitinib, Upatacitinib 69 70 35  BOTTOM UP VS. TOP DOWN THERAPY BIOSIMILAR IMMUNOBIOLOGIC AGENTS Biologically similar to SEVERE Anti-TNF agents, immunotherapy, original biologic drug IV corticosteroids already authorized for sale MODERATE Similar benefit and side Anti-TNF agents, effect profile immunosuppressant Currently: only anti-TNF agents, oral MILD corticosteroids agents have biosimilar drugs 5-ASA, Budesonide www.freepik.com 71 72 36  OVERALL GOAL Mucosal Change Prevent Healing disease Complications course Dialogue-V11_Iss05- 2015_Figure-1.jpg www.mentoringinibd.com/optimizing-management-using-the-treat-to-target-approach/ 73 74 37  AI & IBD Stidham, RW & Takenaka, K, Gastroenterology 2022;162:1493–1506 Freepik.com images 75 38