Acid-Peptic Diseases of the Stomach and Duodenum Including Helicobacter pylori and NSAIDs Prof. Sheila Crowe

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1 Acid-Peptic Diseases of the Stomach and Duodenum Including Helicobacter pylori and NSAIDs 1 Division of Gastroenterology UC San Diego School of Medicine Clinical presentations of Helicobacter pylori infection Asymptomatic infection Dyspepsia Gastric Ulcer Duodenal Ulcer Gastric adenocarcinoma MALT lymphoma 2 Changing incidence of upper GI diseases and H. pylori infections 3 Blaser, J Infect Dis 1999; 173;

2 Microbiologic factors Gram negative Spiral shaped Microaerophilic Adheres to gastric epithelium Expresses urease 4 History Originated in Africa sixty thousand years ago 1 First isolated in 1982 Barry Marshall and Robin Warren won the Nobel Prize for this discovery in Using Koch s postulates to do so via self infection 5 1. Linz et. al; Nature; 445(7130); 915; 2007 Epidemiology Most common chronic bacterial infection in humans Usually contracted by children within the first 2 years of life 1 Prevalence of infection varies by area Increased prevalence in lower socioeconomic status and in poor living conditions An up to 80% prevalence in developing countries % prevalence in developed countries 2 Resides in gastric mucus layer and can be found in both the body and the antrum of the stomach 1. Cho and Blaser, Nature Review Genetics; Pounder; Aliment Pharmacol Ther; 9 (Supp 2:33);

3 Epidemiology/transmission Relation to consumption of salted foods 1 Increased in Hispanics and African-Americans in comparison to Caucasian in USA Evidence of genetic susceptibility? Method of transmission Oral-oral Fecal-oral Other? 7 1. Tsugane, Jpn J Cancer Res.; 85 (5); 474; 1994 Worldwide prevalence of H. pylori 8 Bauer et al; Ulcers; 2011; 4; 2011 Pathophysiologic factors Host inflammatory response Neutrophils, lymphocytes, plasma cells Bacterial virulence factors Adherence to gastric epithelium disrupted membrane integrity Host genetics Environmental factors Collectively these factors lead to gastric epithelial damage 9 3

4 Pathophysiology of gastritis Inflammation Migration of bacteria from antrum to body Loss of G and parietal cells 10 Intestinal metaplasia Decrease in acid secretion 11 H. pylori gastritis: Sydney classification Nonatrophic Helicobacter pylori Atrophic Autoimmune Multifocal Helicobacter pylori Dietary Other Chemical NSAIDs, bile Radiation, lymphocytic, noninfectious granulomatous, eosinophilic Dixon et al; Am J. Surg Pathol1996 Oct;20(10): H. pylori gastritis: Sydney classification (2) 12 Dixon et al; Am J Surg Pathol1996 Oct;20(10):

5 H. pylori gastritis: pathology findings Chronic inflammation with neutrophils, macrophages, lymphocytes, and plasma cells 13 Peptic ulcer disease (PUD) Helicobacter pylori infection NSAIDs Zollinger-Ellison syndrome (ZE) Alcohol and smoking increase susceptibility to ulcer formation Greater than 90% ulcers are attributable to H. pylori or NSAIDs 14 Pathophysiology of PUD H. pylori direct pathogenic mechanisms Not clearly established Disruption of mucosal integrity Acid hypersecretion Duodenal ulcer Low acid secretion Gastric ulcer NSAIDS indirect injury through disruption of mucosal defense mechanisms 15 5

6 16 Duodenal ulcer 80-95% of patients with duodenal ulcers were previously attributable to H. pylori 1 Other causes NSAIDs, ZE, Crohn disease, others Idiopathic? Gastric metaplasia Formation of gastric type epithelium in first segment of the duodenum Chronic inflammation, Brunner gland hyperplasia Weakened mucosa = increased susceptibility to acid injury 1. Moss et al; Gut 1992; 33; 289 Pathogenesis of duodenal ulcers Genetic predisposition Altered D cell and G cell function that arises from infection with H. pylori Increase in gastrin that drives acid production in the body of the stomach Duodenitis 17 Duodenal ulcer H. pylori Gastric ulcer Chronic infection leads to increased basal and stimulated acid secretion. Elevated gastrin levels; normalize after treatment within 1 year NSAIDS Due to COX-1 enzyme inhibition This leads to decreased prostaglandin production leading to disruption of mucosal barrier 18 6

7 NSAIDs and ulcer formation NSAIDs inhibit cyclo-oxygenase (COX) enzymes. Major effects secondary to inhibition of prostaglandin synthesis Increased gastric acid production Decreased bicarbonate, glutathione production Mucosal integrity Mucosal vascular flow 19 Jick et al; Arch Intern Med 1981; 141; H. pylori (Hp) treatment and ulcer eradication 27 RCT compared Hp eradication treatment in 2509 patients after DU healing RR of relapse 0.2 (CI= ) NNT to prevent one ulcer relapse = 2 11 RCT compared Hp eradication treatment to no treatment in 1104 patients after GU healing RR of relapse 0.29 (CI= ) NNT to prevent one ulcer relapse = 2.6 Studies show economic benefit too Ford et al., Cochrane Database Systematic Review4; 2004 Sonnenberg et al., Arch Intern Med, 158; 852, 1998 Non-ulcer dyspepsia and H. pylori (Hp) treatment Cochrane systemic review on effect of eradicating H. pylori in non-ulcer dyspepsia 17 RCT compared Hp eradication treatment in 3566 patients and the effects on non-ulcer dyspepsia NNT to cure one case of dyspepsia = 14 Clinical significance unknown 21 Moayyedi et al., Cochrane Database Systematic Review 2;

8 Antrum-predominant gastritis and gastroesophageal acid reflux H. pylori elevates levels of gastrin leading to acid hypersecretion Affects somatostatin producing D cells Leads to decreased feedback inhibition on G cells Eradication of infection leads to normalization of gastrin levels, subsequent reduced acid secretion and less heartburn 22 Corpus-predominant gastritis and gastroesophageal acid reflux Increased gastrin levels due to decreased acid secretion arising from atrophy of the gastric glands and effects of inflammatory cytokines Eradication of H. pylori eventually leads to increased gastric acid production, sometimes leading to GERD symptoms 23 Gastric adenocarcinoma 24 Risk factors: Helicobacter pylori infection High intake of salt and salt-preserved foods Nitroso compounds Obesity Smoking The incidence of gastric cancer varies regionally despite similar prevalence. Incidence of gastric cancer is decreased in those with duodenal ulcers. 8

9 25 Gastric cancer and H. pylori The majority of gastric adenocarcinoma cases are associated with H. pylori infection 1. Only a minority of infections will progress to cancer. Sequence of change: Gastric atrophy intestinal metaplasia dysplasia carcinoma Intestinal metaplasia (IM) Replacement of glandular epithelium in the gastric mucosa with intestinal type epithelium. Goblet cells are the hallmark of this metaplastic change. Increased rate of gastric adenocarcinoma associated with IM 1. Uemura; NEJM 2001; 345: Gastric adenocarcinoma: treatment and prognosis Treatment options: Endoscopic mucosal resection Based on tumor size and histology Gastrectomy Subtotal vs. total based on tumor location Role for chemotherapy and radiation unclear Prognosis: 5 year survival rate with treatment Nearly 100 % for mucosal tumors 80 90% for submucosal tumors Maehara et al; Br J Surg 1992; 79 (3); 245 Everett et al; Gut 1997; 41(2); 1 Gastric lymphoma Mucosa associated lymphoid tissue Normal stomach has very little to no lymphoid tissue H. pylori inflammation leads to hyperproliferation of lymphoid follicles Remission of tumor once H. pylori eradicated 27 9

10 28 Gastric lymphoma: staging and treatment Luango staging system Stage I confined to GI tract Stage II tumor extends into the abdomen 1,2, E subcategories based on nodes and serosa involvement No stage III Stage IV disseminated extranodal involvement Treatment Stage I/II H. pylori eradication Stage IV H. pylori eradication +/- immunotherapy and or chemotherapy Rohatiner et al; Ann Oncol 1994; 5; 397 When and whom to test for H. pylori infection? Test only if you intend to treat Must offer treatment if positive results Peptic ulcer disease MALT lymphoma Early gastric cancer Dyspepsia? Other indications? 29 ACG criteria for testing Active gastric/duodenal ulcer or history of active gastric/duodenal ulcer not previously treated for H. pylori Gastric MALT lymphoma History of endoscopic resection of early gastric cancer Uninvestigated dyspepsia 30 McColl; N Engl J Med 2010; 362;

11 Maastricht III & IV criteria for testing Same as ACG criteria with additional criteria: Gastric cancer in first-degree relative Atrophic gastritis Unexplained iron-deficiency anemia Chronic idiopathic thrombocytopenic purpura McColl; N Engl J Med 2010; 362; Malfertheiner, P et al., Gut, 56:772; Direct tests require tissue biopsy Histochemical Culture Rapid urease Indirect tests Serology Urea breath test Stool antigen test Diagnostic tests 32 Biopsy-based tests Antral biopsies Numerous stains can be used H& E Giemsa Immunohistology with antibodies to H. pylori Warthin-Starry silver 90-95% sensitive and % specific All biopsy based tests can be falsely negative if recent GI bleeding or recent/current PPI use. 33 McColl; N Engl J Med 2010; 362;

12 Stains for detecting H. pylori Giemsa stain of H. pylori Wartharin Starry silver stain of H. pylori Serology Noninvasive testing ELISA technology to detect IgM, IgA, IgG antibodies IgM early responder; acute infection IgA intermediate responder; transition from acute to chronic infection IgG late responder; chronic infection or protective antibody from resolved infection; IgG most commonly used Secondary testing and treatment highly dependent on pretest probability Urea breath test Hydrolysis of urea = CO 2 and ammonia C13, C14 labeled urea converted to labeled CO % sensitivity; % specificity Vaira et al; Gut 2001; 48: H. pylori fecal antigen Noninvasive testing (2) Monoclonal or polyclonal antibodies Monoclonal are more accurate For both the breath and urea tests must be off PPI and antibiotics for at least 4 wks, H 2 blockers for 24 hr Otherwise suppression of infection reduces sensitivity Other tests Antibodies in urine, saliva but typically not used 36 McColl, N Engl J Med 2010; 362;

13 Treatment No one medication is effective by itself Classical triple therapy: Bismuth 525 mg four times a day Tetracycline 250 mg four times a day Metronidazole 500 mg three to four times a day 37 McColl, N Engl J Med 2010; 362; Treatment (2) Due to difficulties taking classical triple therapy new regimens developed: PPI triple therapy: 7 14 days Proton pump inhibitor twice a day Amoxicillin 1 g twice a day Clarithromycin 500 mg twice a day 38 McColl, N Engl J Med 2010; 362; Treatment (3) Quadruple therapy: days Proton pump inhibitor twice a day Bismuth 525 mg four times a day Metronidazole 250 mg three to four times a day Tetracycline 500 mg four times a day Proven to have higher rates of eradication than triple therapy 39 McColl, N Engl J Med 2010; 362;

14 Sequential therapy Recently sequential treatment has been studied with good eradication rates. 10-day total regimen PPI + amoxicillin for 5 days, followed by PPI + clarithromycin and tinidazole for 5 more days 93% eradication rate for sequential vs. 77% eradication for standard triple therapy Jafri et al; Ann Intern Med 2008; 148: Treatment issues 20 percent of initial attempts result in failure For both triple and quadruple therapy, retreatment result in 70-75% eradication Side effects of therapy Increasing rates of antimicrobial resistance 1 Mastricht III and IV guidelines no longer recommend using PPI-based triple therapy In the USA limited availability of testing H. pylori for antimicrobial resistance 1 Probiotics are not a substitute for standard regimens but in combination can increase eradication and decrease adverse effects. 1. Graham, DY, Shiotani, A, Gastroenterol, 143: 10; 2012 Confirmation of eradication: who? 2007 ACG recommendations: H. pylori associated ulcer Persistent dyspepsia after test-and-treat MALT lymphoma Resection of early gastric cancer Maastricht III and IV recommendations: All individuals documented to be infected and treated should have eradication confirmed. 42 Chey et al., Am J Gastroenterol2007 Aug; 102(8):

15 Confirmation of eradication: how? Urea breath test or fecal antigen test 4 weeks or longer after treatment is completed Must avoid PPI for 4 weeks before confirmation of eradication can be performed Eradication can also be confirmed by repeat endoscopy in those patients who already underwent endoscopy during initial diagnosis and need a repeat endoscopy (e.g., for healing of a gastric ulcer). 43 McColl, N Engl J Med 2010; 362; Management of treatment failure: who? Further treatment indicated in those with confirmed ulcer, MALT lymphoma, or early resection of gastric adenocarcinoma Unclear for uninvestigated dyspepsia decision should be individualized in these cases 44 McColl, N Engl J Med 2010; 362; Management of treatment failure: how? Alternate regimen of triple or quadruple using a different combination of antibiotics for 14 days Many antibiotics have been used and proposed with varying success as rescue therapy Tetracycline Levofloxacin Rifabutin 45 Malfertheiner et al; Baillieres Best Pract Res Clin Gastroenterol. 2000; 14(1):

16 Antibiotic resistance in the treatment of H. pylori infection Naturally resistant to multiple antibiotics Vancomycin, sulfamethoxazole/trimethoprim Increasing resistance to clarithromycin and metronidazole Patients with refractory infection may be candidates for culture and sensitivity testing to determine if resistance is a factor H. pylori vaccination Large area of research in the past three decades with limited success in humans Oral vaccination development has been challenging for various reasons H. pylori s noninvasive nature Difficulty producing effective mucosal immunity Challenges with finding suitable adjuvants Results in mouse models are not translatable to humans Intranasal and rectal vaccination also explored Issues with safety and side effects less likely to lead to an eventual route of vaccination Arora et al; Cancer Epidemiol Biomarkers Prev August ; Summary Helicobacter pylori infection is a global issue leading to gastrointestinal ulcers, gastric malignancies, and dyspepsia. There are various methods and strategies to test for Helicobacter pylori. Multidrug treatment regimens are the mainstay of Helicobacter pylori eradication. Increasing bacterial resistance to antibiotics Helicobacter pylori vaccination is a goal and potential target for future research. 16

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