Helicobacter Pylori & Gastric Cancer - An Evidence Based Approach for Primary Care
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The document discusses the relationship between Helicobacter pylori (H. pylori) and gastric cancer, including its epidemiology, diagnosis, and treatment. It highlights the significant risk H. pylori poses for gastric cancer, detailing effective eradication strategies and the importance of testing specific patient populations. Evidence supports that eradicating H. pylori can reduce gastric cancer risk, particularly in patients with relevant risk factors.
Helicobacter Pylori & Gastric Cancer - An Evidence Based Approach for Primary Care
- 1. Helicobacter Pylori & Gastric Cancer An Evidence Based Approach for Primary Care Maastricht IV 2012, Asia Pacific 2009, ACG 2007 Dr Jarrod Lee Gastroenterologist & Advanced Endoscopist Mt Elizabeth Novena Hospital
- 2. Scope • Overview & Epidemiology • Clinical Conditions • Diagnosis • Treatment • Gastric Cancer 2
- 3. Overview • First isolated by Warren & Marshall in 1983 • Gram negative bacterium on gastric epithelium • Survives in acidic environment due to high urease activity, which converts urea in gastric juice to alkaline ammonia 3
- 4. Marshall & Warren Nobel Prize in Medicine 2005 4
- 6. Epidemiology • HP infects 50% of global population • Usually contracted in first few years of life • Persists indefinitely unless treated • Associated with a number of important upper GI conditions: chronic gastritis, PUD, gastric cancer • Prevalence – Closely tied to socio-economic conditions – Varies widely – Associated with gastric cancer prevalence 6
- 7. Prevalence of HP & Gastric Cancer in Asia 7
- 8. Which of the following patients should have HP tested and eradicated? A. 70 year with IHD on long term ASA, with past history of PUD 5 years ago B. 60 year with newly diagnosed rheumatoid arthritis, now wants to start NSAIDs for pain C. 45 year with ankylosing spondylitis on long term NSAIDs, who now wants to increase NSAID dose D. 60 year with “gastritis” on OGD 6 months ago, mother had gastric cancer at 65 years E. 40 year patient, father just diagnosed with gastric cancer at 60 years, now worried about cancer 8
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- 10. Functional Dyspepsia • Large population studies show increased incidence of HP infection in patient with FD; significance unclear • Most recent Cochrane meta-analysis of 17 RCTs (2006): significant symptom relief with NNT 14 • HEROES trial1: large RCT, primary care setting – HP eradication vs PPI + placebo – 50% symptom improvement at 1yr: 49% vs 36.5% – P=0.01, NNT 8 101. Arch Int Med 2011; 171: 1929-36
- 11. HP Eradication in Asians • Meta-analysis of 7 Chinese RCTs1: OR 3.61 benefit • Recent Chinese study using Rome III criteria2 – Benefit for epigastric pain & epigastric burning: 60.8-65.7% vs 33.3-31.8%; P<0.05 • 2x Singapore RCTs – CGH (2006)3: 31% complete symptom resolution; 62% global symptom resolution – NUH (2009)4: 39% symptom resolution if HP eradicated; 3% if HP persistent 11 1. Helicobacter 2007; 12: 542-6 2. World J Gastroenterol 2011; 17: 3242-7 3. J Gastroenterol 2006; 41: 647-53 4. Eur J Gastroenterol Hepatol 2009; 21: 417-24
- 12. Gastritis • HP eradication may increase, decrease or have no effect on acid secretion • Antral predominant gastritis: – High acid production due to low somatostatin production in antrum, leading to higher acid production in body • Body predominant & atrophic gastritis: – Low acid production – Associated with increased gastric cancer risk • HP eradication resolves both types of gastritis; may correct acid state 12
- 13. NSAIDs • NSAIDs & HP are independent risk factors for PUD • NSAIDs & HP are synergistic risk factors: – OR 60 for PUD, OR 6 for bleeding • If NSAID naïve, HP eradication reduces PUD: OR 0.26 – Beneficial before starting NSAIDs – Mandatory in patients with history of PUD • No benefit if already on long term NSAID – Maintenance PPI more effective 13Vergara et al. Aliment Pharmacol Ther 2005; 21: 1411-8
- 14. Aspirin • PUD risk is dose related; independent of formulation • Bleeding risk in ASA users increases with: – HP infection: OR 4.7 – History of PUD: OR 15.2 • HP eradication reduces recurrent bleeding in ASA users with previous PUD – Long term bleeding risk low after HP eradication even without maintenance PPI • Value of HP eradication uncertain if no previous PUD 14Lanas et al. Aliment Pharmacol Ther 2002; 16: 779-86 Chan et al. Gastroenterology 2011; 140: S173-4
- 15. 15 Diagnosis
- 16. Endoscopy Based Tests • Histology: > 95% sensitivity & specificity – Considered ‘gold’ standard but imperfect – Affected by sampling + medication – Can evaluate pathological changes • Rapid urease test: > 90% sensitivity, > 95% specificity • Cultures: limited sensitivity – Should be considered after 1st failure if endoscopy done, as risk of resistance high (60-70% for clarithromycin) – Should be done for all cases after 2nd failure 16
- 17. Urea Breath Test (UBT) • C13 UBT remains the best test for HP diagnosis • High accuracy • Easy to perform • Non-radioactive • Safe in pregnant & lactating women • > 95% sensitivity & specificity 17
- 18. Stool Antigen Test (SAT) • ELISA test with monoclonal antibody as reagent • Meta-analysis of 22 RCTs; N=2,499 – Pooled sensitivity: 94% – Pooled specificity: 97% • Accuracy considered equivalent to UBT • Rapid in office tests use immunochromatographic technique; have limited accuracy 18Gisbert et al. Am J Gastroenterol 2006; 101: 1921-30
- 19. Serology • IgG detection by ELISA method • Accuracy > 90%; needs to be validated in population • Only test not affected by local changes in stomach that could lead to low bacterial load • Antibodies remain elevated for months to years after HP clearance • Cannot differentiate active from past infection; may need UBT or SAT 19
- 20. Patients on PPI • PPIs widely used for symptomatic relief of dyspepsia & reflux symptoms • Increases gastric pH, resulting in decreased bacterial load, especially in antrum • Results in 10-40% false negative results • All HP tests except serology affected • Stopping PPIs for 2 wks allows HP to repopulate • No study to evaluate washout period after long term PPI 20
- 21. 21 Treatment
- 22. Triple Therapy • ‘Standard’ therapy: PPI-clarithromycin & amoxicillin or metronidazole; both equivalent • Eradication rates previously > 80% • Latest data shows lower efficacy < 70% • Reasons for decreased efficacy: – Increased clarithromycin resistance – Compliance • Empirical treatment should be abandoned when clarithromycin resistance rate > 15-20% 22
- 23. Improving Eradication Rates • Increase PPI dose – High dose PPIs increase cure rates 6-10% vs standard dose – Maximum effect in high dose 2nd generation PPI: 40mg BD of nexium improves eradication by 8-12% • Extend duration: 10-14 days treatment improves eradication by 5% vs 7 days • Add adjuvant treatment: Certain probiotics & prebiotics may reduce adverse effects • Stop smoking: 8.4% difference in eradication rates in meta-analysis of smokers vs non-smokers 23
- 25. Second Line Therapy • Assume selection of a clarithromycin resistant strain • Bismuth based quadruple therapy: – Metronidazole resistance has limited effect on outcome with adequate dosage & duration – Asian study eradication rates: 82.6% (ITT) • Levofloxacin containing triple therapy – Mean eradication rate 80% – Caution with fluoroquinolone resistance 25Lee et al. Helicobacter 2010; 15: 38-45 Gisbert et al. Aliment Pharmacol Ther 2006; 23: 35-44
- 26. Refractory Infection • 2nd line therapy fails in 20% • After 2 failures, consider – Use antibiotics not previously used – Obtain cultures & susceptibility tests • Rifabutin – Promising new antibiotic – 70% eradication rate if used as 4th or 5th line treatment – Useful if resistant to key antibiotics: amoxicillin, clarithromycin, metronidazole, ciprofloxacin, tetracycline 26
- 27. After Treatment • Post treatment course of PPI: – Not required for uncomplicated DU – Recommended for GU & complicated DU • Follow up testing: – Endoscopy + biopsy based tests for: GU, MALT lymphoma – Otherwise, non-invasive test recommended: UBT, SAT – Test > 4 weeks after end of treatment • HP recurrence – Defined as HP tests negative for 12 months, then positive – Developed countries < 1%; Developing countries > 10% 27
- 28. 28 Average Annual Recurrence in Developing Countries
- 29. Helicobacter & Gastric Cancer 29
- 32. 32 Pathogenesis
- 33. Cancer Risk in HP • HP is the most consistent risk factor for gastric cancer – HP increases risk > 20x – Other environmental factors are subordinate to HP effect: smoking, alcohol, nutritional factors, etc. • Cancer risk in HP patients based on prospective data: – Antrum predominant gastritis: 1x – Pangastritis: 15x – Corpus predominant gastritis: 34x – Severe atrophy: 5x – Intestinal metaplasia: 6x 33Uemura et al. NEJM 2001; 345: 784-9
- 34. Atrophic Gastritis • Atrophic corpus gastritis causes hypochlorhydria – Hypochlorhydria allows overgrowth of non HP organisms which produce carcinogenic metabolites • Progression to cancer 0-10%; annual incidence < 1% • Risk of progression to intestinal metaplasia (IM) & cancer increases with age; starts from 45yrs • Extent & severity of gastritis, atrophy & IM is positively associated with cancer 34
- 35. PPIs • Acid suppression affects gastritis pattern; may accelerate loss of specialize glands, leading to atrophic gastritis • In HP patients on PPI, inflammation increase in body & decreases in antrum, leading to atrophic gastritis • No evidence PPI accelerates progression to gastric cancer in humans 35
- 36. HP Eradication • Strong evidence that HP eradication reduces risk of gastric cancer – HP eradication abolishes the inflammatory response – May slow, arrest or reverse atrophy – May prevent progression of premalignant lesions to cancer • ‘Point of no return’ – Appears that by the time IM has become established, HP eradication cannot completely prevent cancer – HP eradication improves atrophic gastritis, but has no effect on IM 36
- 37. Who Gets HP Eradication? • 1st degree family history of gastric cancer • Previous gastric neoplasia already treated • Risk of gastritis: severe pangastritis, corpus predominant gastritis, atrophic gastritis • Chronic gastric acid inhibition > 1 year • Strong environmental risk factors: smoking, exposure to dust, coal, cement • Fear of gastric cancer 37
- 38. Endoscopic Surveillance • Consider for: – Pernicious anemia with histology proven type A autoimmune atrophic gastritis – Atrophic gastritis with hypo- or achlorhydria – Gastric adenoma with previous removal • Risk stratification of premalignant gastric conditions helps to manage patients according to cancer risk • Regular follow up – Moderate to severe atrophy & IM: 2-3 years – Dysplasia: 3-6 mths 38
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- 40. Final Words • Think about HP • Test for HP • Treat HP if present 40
- 41. Which of the following patients should have HP tested and eradicated? A. 70 year with IHD on long term ASA, with past history of PUD 5 years ago B. 60 year with newly diagnosed rheumatoid arthritis, now wants to start NSAIDs for pain C. 45 year with ankylosing spondylitis on long term NSAIDs, who now wants to increase NSAID dose D. 60 year with “gastritis” on OGD 6 months ago, mother had gastric cancer at 65 years E. 40 year patient, father just diagnosed with gastric cancer at 60 years, now worried about cancer 41