A. Introduction

1. Comma-shaped gram negative bacterium (baccillus classification)
2. Genome is 1.65 million base pairs, coding for 1500 proteins
3. Most strains of H. pylori are motile and flagellated (only motile strains colonize stomach)
4. Present in >90% of persons with gastric or duodenal (peptic) ulcer disease (PUD)
5. About 35% of people in developed countries are colonized with H. pylori
6. Most H. pylori infection occurs before age 10 years [2]

B. Disease Associations

1. About 90% of persons infected with H. pylori develop asymptomatic gastritis
2. Peptic Ulcer [5]
   1. Duodenal Ulcer
   2. Gastric Ulcer
   3. May lead to chronic upper gastrointestinal (GI) bleeding with consequent anemia
   4. Increases risk of NSAID induced ulcers ~2X [4]
3. Metaplastic (Multifocal) Atrophic Gastritis (see below)
4. Association with Non-Ulcer Dyspepsia [1]
   1. Probably not related to reflux esophagitis
   2. Eradication of H. pylori marginally improves symptoms of non-ulcer dyspepsia
   3. Eradication of H. pylori had no overall effect on heartburn or esophagitis [13]
5. Iron Deficiency Anemia [7]
   1. Gastritis related to Helicobacter pylori may be cause of Fe deficiency anemia
   2. Eradication of Helicobacter pylori in patients with gastritis can reverse anemia
6. Gastric Adenocarcinoma [8]
   1. Causes both intestinal type and diffuse type gastric cancers
   2. Severe gastric atrophy, corpus predominant gastritis, intestinal metaplasia are risk factors for adenocarcinoma
   3. H pylori eradication in China with 7.5 year followup showed no reduction in gastric cancer [3]
7. Lymphoproliferative Disease [1]
   1. Chronic Gastritis and inflammation
   2. Oligoclonal B cell expansion
   3. Mucosa associated lymphoid tissue (MALT) abnormalities
   4. Gastric MALT (non-Hodgkin type) Lymphoma (NHL) - see below
8. Hereditary Angioedema [10]
   1. Helicobacter pylori induced inflammation may provoke attacks
   2. 30% of patients with hereditary angioedema had anti-H. pylori Abs
   3. H. pylori induced inflammation may trigger humoral immune responses
   4. This inflammation could lead to C1-esterase inhibitor depletion triggering angioedema
   5. Eradication of H. pylori reduced angioedema attacks by ~80% in ~50% of patients

C. Pathogenesis of H. pylori Induced Disease [1]

1. Organism binds to gastric epithelium
   1. Receptors are the Lewis (a) and (b) blood group antigens
   2. Patients who are blood type O or nonsecretors of certain glycoproteins get disease
   3. Suited to live in highly acidic environment by neutralizing acid
   4. Organism produces large amounts of ammonia via enzyme called urease
   5. Urease cleaves urea into ammonia which can neutralize acid
2. Organism produces marked chronic gastric inflammation
   1. Highly inflammatory coat products and enzymes stimulate systemic and mucosal immunity
   2. Humoral (antibody responses) marked
   3. Ammonia production by H. pylori urease is very inflammatory
   4. Inflammation may be pathogenic in development of MALT lymphomas
   5. Various cytotoxins are produced as well (see below)
3. Inflammatory Response
   1. H. pylori induces increased endothelial integrin expression, increases leukocyte migration
   2. Neutrophils, T lymphocytes, plasma cells, macrophages accompany inflammation
   3. Anti-H. pylori antibodies (Abs) are produced vigorously
   4. Autoantibodies can be produced, including anti-H+/K+ ATPase Abs
   5. These Abs can destroy parietal cells and lead to atorphic gastritis (mainly in corpus)
4. Infected areas show high levels of various cytokines
   1. Interleukin (IL) 1ß - stimulates acute inflammation
   2. IL2 - stimulates T cells
   3. IL6 - stimulates acute phase response, B cells
   4. IL8 - likely central mediator of H. pylori inflammation; neutrophil chemotaxis, activation
   5. Tumor necrosis factor alpha (TNFa)
5. Organism-Specific Toxins (Virulence Factors)
   1. VacA - exotoxin causes vacuolated cytoplasm in epithelial cells
   2. CagA - 120kD protein, stimulates growth and cytokine production in infected areas
   3. Nearly all pathogenic strains of H. pylori produce both vacA and CagA proteins
   4. Degree of pathology induced correlates well with strain type
6. H. pylori initially increases acid production in stomach, which enhances mucosal damage

D. Peptic Ulcer Disease

1. Associated with >80% of non-NSAID peptic ulcers
2. Risk for ulceration in seropositive (H. pylori Ab) patients is ~4X general population
3. NSAIDS and H. pylori are synergistic for causing peptic ulcer [11,12]
4. Strongly associated with gastritis and gastric ulceration (and gastric cancer) as well
5. Apparent genetic predisposition to symptoms

E. Metaplastic Atrophic Gastritis

1. More than 75% of active gastritis associated with H. pylori
   1. Primarily related to autoantibody production due to chronic inflammation
   2. Autoantibodies directed against parietal cells (see above)
   3. Chronic inflammation + parietal cell atrophy leads to intestinal metaplasia
   4. This "protective" response can progress to dysplasia and frank cancer
2. Metaplastic Atrophic Gastritis (MAG) Syndrome Type B
   1. Environmental Factors appear to play major role, interacting with H. pylori
   2. Risk elevated in smokers and alcoholics
   3. Increased risk with chronic ingestion of smoked foods
   4. Atrophic gastritis is found in >80% of patients with gastric adenocarcinoma [14]
   5. Eradication of H. pylori improves histology of atrophic gastritis in ~60% of patients [15]

F. Gastric MALT Lymphomas [16]

1. These tumors are called mucosa-associated lymphoid tissue (MALT) lymphomas
   1. Gastric MALT lymphomas are caused by chronic Helicobacter pylori infection
   2. Chronic inflammation induced by H. pylori thought to promote lymphomagenesis
2. Lymphomas are often oligoclonal and have been shown to be present in early lesions
3. Chronic gastritis is therefore linked to gastric mucosal lymphomas through infection
4. H. pylori Eradication [16]
   1. Leads to regression or cures of tumors in ~75% of cases
   2. Multiple cycles of H. pylori eradication therapy are required for treatment of tumors
   3. Minimal residual low-grade MALT after H. pylori eradication does not require treatment with chemotherapy, but should be monitored closely [17]
5. Resistance of MALT NHL to H. pylori Eradication [18]
   1. associated with t(11;18) in neoplasm
   2. The t(11;18, q21;q21) translocation involves API2 and MLT genes
   3. This fusion is believed to provide a survival advantage to MALT NHL

G. Diagnosis of H. pylori [1]

1. About 30% of general (asymptomatic) population has serum anti-H. pylori antibodies
2. Serology is the preferred test in patients with no other obvious PUD risk factors
3. Urea breath test is considered an excellent non-invasive test for H. pylori
   1. This breath test (Meretek UBT®, about $300) uses 13C-labelled urea (non-radioactive)
   2. 13C-labelled carbon dioxide is produced and analyzed in breath sample
   3. Test shows that active infection (live organisms) is present
   4. Use of proton pump inhibitors can cause a false negative urea breath test [19]
   5. At least 2 weeks should elapse between stopping proton pump inhibitors and doing test
4. Stool based H. pylori detection assay is reliable, even in treated patients [20]
5. Endoscopy with mucosal biopsy and culture or biopsy urea test is gold standard
6. However, invasive testing is primarily related to research and resistant disease

H. Decision to Eradicate H. pylori [21]

1. Eradication therapy is strongly recommended in the following [1]:
   1. Any patient with PUD (whether or not H. pylori is present)
   2. Atrophic gastritis
   3. Recent resection of gastric cancer
   4. First degree relative of patient with gastric cancer
   5. H. pylori eradication clearly reduces risk of gastric cancer development
   6. Gastric MALT tumors should be treated with eradication therapy [23]
   7. Desire of patient after full consultation with physician
2. Cost Effectiveness of Empirical Treatment (for likely ulcer)
   1. If H. pylori serology is positive, drug treatment is cost effective
   2. Endoscopy in patients likely to have an ulcer is not cost effective
   3. Endoscopy is generally recommended in persons >45 years who have increased cancer risk
   4. Endoscopy provides no overall benefit beyond empiric therapy in <45 year olds [25,26]
   5. In <45 year olds with uncomplicated ulcer symptoms, recommend empiric treatment
3. Eradication Advised
   1. Functional dyspepsia (demonstration of ulcer not required) [33]
   2. Reflux esophagitis in patients receiving long term profound acid suppression
   3. Consider in patients on non-selective chronic NSAIDs [4]
4. Non-Ulcer Dyspepsia (NUD) [1]
   1. It is cost effective to treat H. pylori-seropositive patients with dyspepsia rather than to perform an endoscopy [27]
   2. About 20% of patients with H. pylori and NUD respond to H. pylori eradication [28,29]
   3. H. pylori eradication is recommended primarily due to other benefits
   4. Single day therapy may be as effective as 7-day eradication therapy (see below) [36]
5. Clarithromycin-metronidazole therapy for H. pylori can lead to long term persistence of resistant Eterococci [34]

I. H. pylori Eradication Therapy [1,21]

1. Recommended Treatment Regimens [1,7]
   1. Sequential 10 day therapy is superior to standard 7-10 day concomitant therapy [7]
   2. PPI therapy with two antibiotics (triple therapy) for 7 days as good as 10-14 days with 80-90% eradication [35]
   3. Sequential 10 day therapy is effective for H. pylori, including clarithromycin resistant strains, whereas standard 7 or 10 day regimen is not effective [24]
   4. Sequential 10 day regimen: 40mg pantroprazole, 1gm amoxicillin bid x 5 days, then 40mg pantoprazole, 500mg clarithromycin, 500mg tinidazole bid x 5 days [9]
   5. Omeprazole (Ome) 20mg bid + clarithromycin 500mg bid + amoxicillin 1gm bid
   6. Clarithromycin 500mg bid, amoxicillin 1gm bid, lansoprazole (Lan) 30mg bid [36]
   7. Esomeprazole 40mg qd + clarithromycin 500mg bid + amoxicillin 1gm bid
   8. Sequential rabeprazole (Rab) 20mg + Amox 1gm x all bid x 5 days followed by Rab 20mg + Clar 500mg + tinidazole 500mg all bid x 5 days is superior to 7-day triple therapy [22,24]
   9. In patients with reduced metablism of omeprazole due to CYP2C19 mutations, dual therapy with omeprazole 20mg/d and amoxicillin 2gm/day was 100% effective [30]
2. Single Day Eradication [36,37]
   1. May be as effective as 7 day therapy but not yet FDA approved
   2. Each of these is given over 1 day:
   3. 2 tablets 262mg bismuth subsalicylate 4 times
   4. Amoxicillin 2gm suspension 4 times
   5. Lan 30mg one tablet
   6. Not as effective as sequential 10-day treatment [9]
   7. Eradication rates of 20-95% reported
3. Resistant H. pylori [5,21,31]
   1. Metronidazole resistance is an increasing problem (may be >35%)
   2. Clarithromycin resistance has been reported (~10%)
   3. Resistance to tetracyclines or amoxicillin is very uncommon (<2%)
   4. Drug resistance testing should be considered with failed eradication
   5. Alternatively, high dose PPI + two antibiotics (which are active and for which the patient has not been exposed) may be used empirically in relapse or failed eradication [1]
   6. Sequential 10-day treatment (above) is effective in clarithromycin resistant strains [9]
   7. Ribabutin with amoxicillin and Pan for 10 days, provided 86% cure in refractory disease [1]
   8. Ome dose may need to be increased in ultrarapid metabolizers [30]
4. Quadruple Drug Therapy [31]
   1. Should only be used in cases of recurrence or known resistance
   2. Bismuth, tetracycline (TET), metronidazole and omeprazole for 7 days - 98% eradication
   3. Bismuth 120mg qid, TET 500mg qid, metronidazole 500mg tid, omeprazole 20mg bid
5. Multiple antibiotic + PPI eradication cycles can induce remission or cure of H. pylori positive gastric MALT non-Hodgkin's lymphomas [23]
6. Stool antigen test for H. pylori can be used after therapy to detect unsuccessful eradiction [32]

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