PEPTIC ULCER DISEASE JOHN R SALTZMAN, MD Director of Endoscopy Brigham and Women s Hospital Professor of Medicine Harvard Medical School
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Overview Causes of peptic ulcer disease Clinical manifestations Current diagnostic tests Recommended therapies New strategies to treat H. pylori Complications including GI bleeding
Peptic ulcer disease Ulcers are defects in gastrointestinal mucosa that extend beyond muscularis mucosa Arise when mucosal defenses are impaired in presence of gastric acid and pepsin Overall incidence declining worldwide Lifetime prevalence 5-10% Complications GI bleeding (10-20%) Perforation (5%) Obstruction (2%)
Causes of peptic ulcers Helicobacter pylori infection Aspirin and NSAIDs Rare causes: Neoplasia (carcinoma, lymphoma, leiomyosarcoma) Acid hypersecretion (Zollinger-Ellison syndrome) Granulomatous disease (Crohn s, sarcoidosis) Systemic mastocytosis Infectious (CMV, HSV, TB) Familial Idiopathic (No H. pylori, NSAID or other identifiable cause)
Additional Risk Factors Older age Prior history of peptic ulcers Smoking proportional to amount smoked Medications in combination with NSAIDs Corticosteroids, anticoagulants, antiplatelets, SSRIs, bisphosphonates
Helicobacter pylori Gram-neg spiral, urease producing bacteria H. pylori is the most common chronic bacterial infection in humans Infection mainly acquired in childhood (<10 years) Risk factors include Low socioeconomic status Household crowding Country of origin and ethnicity Cover TL, Blaser MJ. Gastroenterology 2009;136(6):1863-73; Bruce MG Epidemiol Infect 2015;143(6):1236-4
H. pylori and peptic ulcers H. pylori associated with up to 80% duodenal ulcers H. pylori associated with up to 70% gastric ulcers Prevalence of H. pylori Undeveloped countries 80% by age 20 Developed countries 10% by age 20 Incidence of peptic ulcers declining in developed countries due to less H. pylori 50% to 60% to
H. pylori eradication results in long-term remission of peptic ulcer disease Duodenal ulcer % Patients in remission 100 H. pylori eradicated 75 Gastric ulcer % Patients in remission 100 H. pylori eradicated 75 50 50 25 H. pylori-positive 25 H. pylori-positive 0 0 0.5 1 1.5 2 Years after termination of treatment 0 0 2 4 6 8 10 12 Months after termination of treatment Miehlke S. Eur J Gastroenterol Hepatol 1995;7(10):975-8; Axon AT. BMJ 1997;314(7080):565-8
NSAIDs and peptic ulcers Responsible for majority of ulcers not due to H. pylori (>100,000 hospitalizations/year) Increased risk for significant GI event (bleeding, perforation and obstruction) and silent ulcers Surreptitious NSAID use is common, especially in refractory / complicated ulcers Co-therapy of NSAIDs with corticosteroids, anticoagulants, other NSAIDs, low dose aspirin, selective serotonin reuptake inhibitors (SSRIs) and alendronate increases the risk of ulcers
Risk of ulcer complications with ASA and NSAIDs ASA + ASA + > > ASA + NSAIDs COX-2 inhibitor placebo ASA alone causes a 2-3 fold increase in ulcer bleeding Long term ASA use does not reduce risk of ASA-induced ulcer bleed (Meta-analysis of 24 RCTs) Enteric coated or buffered ASA does not protect against ulcers due to systemic effects Garcia Rodriguez LA. Gastroenterology 2007;132(2):498-506; Derry S, Loke YK. BMJ 2000;321(7270):1183-7
Risk factors for NSAIDinduced peptic ulcers Risk Factor Relative Risk 95 Percent CI Overall 2.74 2.54-2.97 Anticoagulants 12.7 6.3-25.7 High dosage (>2x normal) 10.1 4.6-22.0 Age (>60) 5.52 4.63-6.60 Prior PUD 4.76 4.05-5.59 Corticosteroids 4.4 2.0-9.7
Other causes of peptic ulcers Gastric acid hypersecretion Zollinger-Ellison syndrome Cigarette smoking Increased rate of ulcers in patients with H. pylori More difficult to treat ulcers Neoplasia (carcinoma, lymphoma) Familial (polygenic inheritance)
Zollinger-Ellison Syndrome Neuroendocrine tumor (duodenum, pancreas) Hypergastrinemia acid secretion PUD (duodenum, jejunum), diarrhea, GERD Usually sporadic MEN1 syndrome in 25% of cases Diagnosis gastrin, cross-sectional imaging Ddx hypergastrinemia hypochlorhydria from PPI or atrophic gastritis
Clinical manifestations of peptic ulcer disease Dyspepsia: epigastric pain most common Duodenal ulcer symptoms Epigastric pain (burning, gnawing or hunger-like), 2 to 5 hours after meal or on empty stomach (without a food buffer) Nocturnal between 11 PM and 2 AM (circadian stimulation of acid maximal) Symptom relief with food or antacids Gastric ulcer symptoms: Pain soon after meals with less relief by food or antacids Ulcers can be asymptomatic (up to 70%)
Differential diagnosis of peptic ulcer disease Functional nonulcer dyspepsia Gastroesophageal reflux disease Gastric cancer Pancreatic and biliary diseases
Alarm symptoms Weight loss Persistent vomiting Dysphagia Anemia Hematemesis Palpable abdominal mass Family H/O upper GI carcinoma Previous gastric surgery
Diagnosis of peptic ulcer disease Suspect by symptoms and history Ask about alarm symptoms Consider blood tests CBC, LFT s, calcium and lipase Test for H. pylori infection Consider endoscopy
Upper endoscopy for PUD Upper endoscopy gold standard test Best in patients over the age of 45 years or with alarm symptoms Allows biopsy (for H. pylori or to R/O cancer) Sensitive, specific and safe Best initial test in most patients
Gastric ulcer
Antisecretory therapy for PUD H 2 -blockers 90% effective after 8 weeks Proton pump inhibitors More rapid healing than H 2 -blockers 90% effective at 4 weeks Large ulcers (>2 cm) take longer to heal Gastric ulcers confirm healing and exclude malignancy in 8 to 12 weeks Continue maintenance PPIs in patients with non H. pylori, non NSAID ulcers
Diagnostic tests for H. pylori infection
Endoscopy-based methods of detecting H. pylori Method of Diagnosis Main Indication Sensitivity (%) Specificity (%) Histology Diagnosis 90 90-95 Culture Rapid urease test (CLO) H. pylori antibiotic sensitivities Rapid results in endoscopy room 80-90 95-100 90 90
Gastric biopsies with H. pylori
Noninvasive methods of detecting H. pylori Method of Diagnosis Main Indication Sensitivity (%) Specificity (%) Serology Screening 85 79 Urea breath test Stool antigen test Screening and confirm eradication Screening and confirm eradication 95 96 93 94
Principle of 13 C + 14 C-urea breath test
General principles of treating PUD Heal ulcer by decreasing gastric acid using PPIs or H 2 RAs Treat the underlying cause: Test and eradicate H. pylori infection For NSAID-related ulcers - Discontinue or switch to non-nsaid analgesic - For patients who require chronic NSAIDs, consider co-therapy with PPI (or misoprostol)
Established recommendations for H. pylori eradication Strong evidence to treat Gastric or duodenal ulcers (current or H/O untreated H. pylori) MALT lymphoma Also recommended (limited evidence of benefit) Atrophic gastritis / intestinal metaplasia Gastric adenocarcinoma in early stages 1st degree relatives of patients with gastric cancer Maastricht IV Consensus Report. Gut 2012;61(5):646-64; Liang X. Clin Gastroenterol Hepatol 2013;11(7):802-7
New recommendations for H. pylori eradication Any patient with a positive test not previously treated Non-ulcer dyspepsia Under the age of 60 years without alarm features who undergo nonendoscopic testing and found to have H. pylori Those who undergo endoscopy and are found to have H. pylori Prior to long-term NSAID or ASA use to reduce risk of bleeding (in patients with H. pylori) Patients with unexplained iron deficiency anemia despite an appropriate evaluation (in patients with H. pylori) Adults with idiopathic thrombocytopenic purpura (ITP) should be tested for and treated if H. pylori present Chey WD. Am J Gastroenterol 2017;112:212 238
Treatment of H. pylori Multiple regimens and durations evaluated Treatment must be effective, have acceptable costs, side effects and ease of administration Commonly used regimens have frequent side effects (usually mild) including metallic taste, diarrhea and allergic reactions Be aware of clarithromycin and metronidazole resistance and do not repeat Rx with these drugs Best regimens eradicate organism > 90%
H. pylori eradication therapies Clarithromycin triple therapy PPI BID+ 2 antibiotics including clarithromycin Determine if patient had previous macrolide exposure Clarithromycin may be used if local resistance low (resistance <15%) Bismuth quadruple therapy PPI BID+ Bismuth salt + 2 antibiotics Other first line regimens Salvage therapy Avoid initial antibiotics and offer to those with persistent infection after initial therapy Liang X. Clin Gastroenterol Hepatol 2013;11(7):802-7; Chey WD. Am J Gastroenterol 2017;112:212 238
Clarithromycin triple therapy Proton pump inhibitor twice daily Amoxicillin 1 gram twice daily Clarithromycin 500 mg twice daily All given for 14 days Can substitute Metronidazole 500 mg twice daily if penicillin allergic
Bismuth quadruple therapy Proton pump inhibitor twice daily Bismuth subcitrate or subsalicylate 2 tablets 4 times daily Tetracycline 500 mg 4 times daily Metronidazole 250-500 mg 4 times daily All given with meals for 10-14 days First line therapy if prior macrolide exposure or penicillin allergy
2017 H. pylori Treatment Guidelines American College of Gastroenterology (ACG) Chey WD. Am J Gastroenterol 2017;112:212-238
Levofloxacin triple therapy Proton pump inhibitor twice daily Amoxicillin 1 gram twice daily Levofloxacin 500 mg once daily All given for 10-14 days
Concomitant therapy Proton pump inhibitor twice daily Amoxicillin 1 gram twice daily Clarithromycin 500 mg twice daily Nitroimidazole (metronidazole or tinidazole) 500 mg twice daily All given for 10-14 days
Confirmation of H. pylori eradication Recommended for all treated patients Serologic testing not useful Urea breath testing or stool antigen testing Repeat testing 4-6 weeks after therapy Patients need to avoid using antibiotics, bismuth compounds and PPIs (for 1-2 weeks) which can cause false negative results
Salvage regimens Use for recurrent or persistent H. pylori If clarithromycin used as first line therapy Bismuth quadruple therapy x 14 days Levofloxacin triple therapy x 14 days If Bismuth used as first line therapy Clarithromycin triple therapy x 14 days Levofloxacin triple therapy x 14 days Concomitant therapy alternative option
Treatment recommendations for NSAID-related peptic ulcers Heal ulcer with acid lowering medications Test and eradicate any H. pylori infection Discontinue or switch to non-nsaid analgesic For patients requiring chronic NSAIDs consider strategies to prevent recurrent ulcers
Preventing recurrent ulcers in patients requiring chronic NSAIDs Use lowest dose of NSAID and provide cotherapy with either PPI or misoprostol (prostaglandin E1 analogue) Switch to a selective COX-2 inhibitor Effective anti-inflammatory agents Less ulcer complications than nonselective NSAIDs Increases cardiovascular events (RR =1.42) Sung JJ. Gut 2011;60(9):1170-7; Laine L. Aliment Pharmacol Ther 2009;30(7):767-74
Complications of peptic ulcers Gastrointestinal bleeding 10-20% Gastric outlet obstruction 2% Perforation/fistulalization 5% Usually occur in chronic peptic ulcers May develop in days - weeks of NSAIDs May occur heralded by symptoms or may occur in silent ulcers
Bleeding peptic ulcers Accounts for over 50% severe UGI bleeding Overall mortality rate 2-14% Resuscitation is critical Restrictive transfusion strategy (Hgb < 7 g/dl) Acid suppression with PPIs Endoscopy within 24 hours Crooks C. Gastroenterology 2011;141(1):62-70; Villanueva C. N Engl J Med 2013;368(1):11-21
Restrictive vs. liberal transfusion strategy 921 patients with acute upper GI bleeding Restrictive: Transfuse when Hgb < 7 g/dl Liberal: Transfuse when Hgb < 9 g/dl Further GI bleed Adverse events 10% 16% (P=0.01) 40% 48% (P=0.02) Survival at 6 weeks 95% 91% Hazard ratio: 0.55 (95%CI:0.33 to 0.92 ; P=0.02) Villanueva C. N Engl J Med 2013;368(1):11-21
Overall Survival (%) Survival according to transfusion strategy Days
Event rate (%) RCT of aspirin vs. placebo after peptic ulcer bleed Sung JJ. Ann Intern Med 2010;152:1-9
Resumption of aspirin after upper GI bleeding American College of Gastroenterology Guidelines If given for secondary prevention (i.e. established CV disease) then aspirin should be resumed as soon as possible after bleeding ceases in most patients: ideally within 1-3 days and certainly within 7 days Laine L, Jensen DM. Am J Gastroenterol 2012;107:345-60
Summary NSAIDs/ASA and H. pylori are the major causes of peptic ulcers Test for and eradicate H. pylori using established treatments regimens For ulcer patients requiring chronic NSAIDs Treat with PPI (misoprostol) or COX2 NSAID For bleeding ulcer patients requiring ASA Restart ASA within 7 days with a PPI
Questions
Question 1 A 47 year old man presents with a bleeding gastric ulcer with biopsies showing H. pylori infection. He is treated with clarithromycin triple therapy including a PPI, amoxicillin and clarithromycin. At 8 weeks repeat upper endoscopy shows that the ulcer has healed but H. pylori is still present. His next course of H. pylori treatment should avoid use of the following medication: a) Proton pump inhibitors b) Amoxicillin c) Clarithromycin d) Metronidazole e) Bismuth subsalicylate
Question 1 A 47 year old man presents with a bleeding gastric ulcer with biopsies showing H. pylori infection. He is treated with clarithromycin triple therapy including a PPI, amoxicillin and clarithromycin. At 8 weeks repeat upper endoscopy shows that the ulcer has healed but H. pylori is still present. His next course of H. pylori treatment should avoid use of the following medication: a) Proton pump inhibitors b) Amoxicillin c) Clarithromycin d) Metronidazole e) Bismuth subsalicylate
The answer is C Commonly used regimes to treat H. pylori include clarithromycin triple therapy (PPI BID + 2 antibiotics including clarithromycin) and Bismuth quadruple therapy (PPI BID, Bismuth + 2 antibiotics) Clinicians need to be aware of clarithromycin and metronidazole resistance If a patient is previously treated with clarithromycin or metronidazole, a repeat treatment for H. pylori should not use these drugs Maastricht IV Consensus Report. Gut 2012;61(5):646-64; Chey WD. Am J Gastroenterol 2017;112:212 238
Question 2 A 62 year old male presents with abdominal pain, nausea, and passage of dark black stools. He has diabetes, hypertension, and coronary artery disease and takes aspirin daily for secondary prophylaxis. An upper endoscopy shows a duodenal ulcer with a visible vessel that is treated with endoscopic hemostasis. Biopsies of the stomach show no H. pylori present. He remains stable for 3 days and starts treatment with oral PPI therapy. What are your recommendations about further antiplatelet therapy? a) Discontinue aspirin therapy b) Switch aspirin therapy to clopidogrel c) Continue an oral PPI and restart aspirin at this time d) Continue an oral PPI and restart aspirin therapy after 4 weeks
Question 2 A 62 year old male presents with abdominal pain, nausea, and passage of dark black stools. He has diabetes, hypertension, and coronary artery disease and takes aspirin daily for secondary prophylaxis. An upper endoscopy shows a duodenal ulcer with a visible vessel that is treated with endoscopic hemostasis. Biopsies of the stomach show no H. pylori present. He remains stable for 3 days and starts treatment with oral PPI therapy. What are your recommendations about further antiplatelet therapy? a) Discontinue aspirin therapy b) Switch aspirin therapy to clopidogrel c) Continue an oral PPI and restart aspirin at this time d) Continue an oral PPI and restart aspirin therapy after 4 weeks
The answer is C The patient has significant cardiovascular disease requiring continued anti-platelet therapy The use of a PPI given with aspirin is superior to switching to clopidogrel alone in reducing recurrent ulcer bleeding He should continue oral PPI therapy and restart aspirin as soon as possible This strategy significantly reduces mortality as compared to restarting aspirin several weeks later Sung JJ. Ann Intern Med 2010;152:1-9
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References Chey ED. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 2017;112:212 238 Graham DY. History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol 2014;20:5191-204 Kumar NL. Initial management and timing of endoscopy in nonvariceal upper GI bleeding. Gastrointest Endosc 2016;84(1):10-7 Lau JY. Challenges in the management of acute peptic ulcer bleeding. Lancet 2013;381:2033-43 Malfertheiner P. Management of Helicobacter pylori infection-the Maastricht IV/ Florence Consensus Report. Gut 2012;61(5):646-64 Laine L Jensen DM. Am J Gastroenterol 2012;107:345-60 Villanueva C. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368(1):11-21