|A New Look at H. pylori: Understanding the Issues and Improving Treatment Options|
At an industry-sponsored symposium held in conjunction with the American College of Gastroenterologys 2002 Annual Scientific Meeting, a panel of experts reviewed the current issues on epidemiology and pathophysiology of Helicobacter pylori infections. The panel also discussed the relationship of H. pylori to gastrointestinal and other disorders and provided recent data on new paradigms for H. pylorii eradication.
This program was sponsored by Rush-Presbyterian-St. Lukes
Medical Center in Chicago, Illinois. This program was supported by an unrestricted
educational grant from Eisai, Inc., and Janssen Pharmaceutica.
This material represents a compilation from a series of industry-sponsored educational symposia presented October 1823, 2002 in conjunction with the Annual Meeting of the American College of Gastroenterology. This compilation is provided for information and critical scrutiny by physician readers, and is not intended to replace clinical judgment by the physician as to a specific patient.
The proceedings arise from industry-sponsored sessions, not from the official ACG program, and this synopsis/compilation of these sessions does not represent the official viewpoint of the American College of Gastroenterology.
Epidemiology and Pathophysiology
of Helicobacter pylori
The human host is the only known reservoir for Helicobacter
pylori, and transmission may occur via oral-oral or fecal-oral routes, reported
Mae F. Go, MD, Associate Professor of Medicine at the University of Utah School
of Medicine, in Salt Lake City, Utah.
H. pylori infection generally is acquired in childhood, resulting in acute gastritis, which usually progresses to chronic active gastritis (Figure 1). In industrialized nations, most infected patients develop antral-predominant gastritis, which increases their risk of duodenal ulcers as they age. Gastric MALT lymphoma may occur in a few patients. In developing regions, such as Asia and Latin America, patients are more likely to experience multifocal atrophic gastritis, which, combined with environmental factors, can lead to gastric ulcers. Less than 1% of these patients have a lifetime risk for gastric cancer. Some patients may develop gastric MALT lymphoma.
Risk Factors for H. pylori Infections
Risk factors for H. pylori infection include young age, being from a developing country, crowded living conditions, and low socio-economic status. Ethnicity affects susceptibility to some gastrointestinal manifestations. In one study, African American children were more susceptible to acquiring infections than were Caucasian children, as determined by seropositivity status. Further, 45% of all children aged 7-9 years had seroconverted, indicating that most H. pylori infections are acquired in childhood (Malaty HM, et al. Lancet. 2002; 359:931). An estimated 75% of Native Alaskans are infected with H. pylori (Parkinson AJ, et al. Clin Diag Lab Immunol. 2000;11:885), and the odds ratio risk for H. pylori infection among African American and Hispanic individuals in California are 3.1 and 4.1, respectively (Replogle ML, et al. Am J Epidemiol. 1995;142:856; Smoak BL, et al. Am J Epidemiol. 1994;139:513). Approximately 20% of H. pylori -infected individuals will develop a significant clinical outcome, such as peptic ulcer or gastric malignancy (Vaira D, et al. Gastroenterology. 2001;120:A128).
Global Prevalence of H. pylori
Prevalence of H. pylori infection is highest in developing nations, ranging from 22% in one region of South Korea to 94% in some areas of South Africa (Bardhan PK. Clin Infect Dis. 1997;25: 973). In the United States, prevalence is higher in some ethnic groups and among people living in close quarters, such as army recruits (Smoak BL, et al. Am J Epidemiol. 1994;139:513). Inter-estingly, migrating populations bring the prevalence of infection and the risks for various clinical manifestations with them from their country of origin (Kumar A, et al. Am J Gastroenterol. 1994;89: A1307).
Pathogenesis of H. pylori Infection
Both conserved and variable pathogenic factors affect disease outcome. Conserved factors are constitutively expressed in all microorganisms, such as urease and various adhesins. Urease is essential for initial colonization of the human host. Variable factors, such as the cytotoxin-associated gene A (cag-A), are associated with enhanced inflammation. Host factors that have been studied include cytokines and acid secretion.
Laboratory studies show that once the bacteria attach to the surface of host epithelial cells, bacterial cytoplasmic contents can be transferred into the host cell, leading to subsequent cellular proliferation or apoptosis. H. pylori infection can result in different outcomes. Superficial gastritis leads to chronic active gastritis, which can occur as antral predominant gastritis. This is associated with an increased risk for duodenal ulcers or pangastritis with atrophy and an increased risk for gastric ulcers. Individuals with chronic atrophic gastritis are at increased risk for gastric cancer, possibly via up-regulation of interleukin 1-beta expression (El-Omar E, et al. Nature. 2000; 404;398).
In one hypothetical pathway for gastric carcinogenesis, an individual infected with cag-A-positive strains is subject to chronic gastritis and up-regulation of cyclooxygenase-2 expression. The host develops atrophy and intestinal metaplasia, which can progress to dysplasia and ultimately to gastric cancer (van Rees BP, et al. J Pathol. 2002; 196:171).
Thus, concluded Dr. Go, the interaction between H. pylori and its human host involves host genetics and susceptibility factors, as well as H. pylori virulence factors, and these may be modified by environmental forces.
The Relationship of Helicobacter pylori to Gastrointestinal and Other Disorders
Pivotal US trials of regimens commonly used to treat Helicobacter
pylori infections have shown that only about
50%-70% of duodenal ulcers were associated with H. pylori, according to M. Brian Fennerty, MD, FACG, Professor of Medicine and Chief of the Section of Gastroenterology at the Oregon Health & Sciences University in Portland, Oregon. Further, even when the infection was eradicated, 20% of patients with ulcer disease experienced a relapse within 6 to 12 months, indicating that their ulcers probably were not related to H. pylori.
Sound data regarding the outcomes in patients with dyspepsia and H. pylori infection are lacking, Dr. Fennerty noted. Indirect evidence, albeit inconclusive, suggests that H. pylori may contribute to dyspepsia in some populations (Moayyedi P, et al. Lancet. 2000;355: 1665). However, a recent US meta-analysis found that H. pylori eradication had a modest effect, if any, on non-ulcer dyspepsia (Laine L, et al. Ann Intern Med. 2001;134:361).
H. pylori and Gastric Neoplasia
Case-controlled and prospective (Uemura N, et al. N Engl J Med. 2001; 345:784) observational studies have demonstrated an increased risk and incidence of gastric cancer in patients with H. pylori (Figure 1), but eradication of H. pylori infection does not affect later cancer risk or have an impact on cancer outcome, believes Dr. Fennerty. The exception is MALT lymphoma: ample controlled data indicate that eradication of H. pylori in patients with MALT lymphoma clearly affects the phenotypic expression of this tumor.
Relationship Between H. pylori and Ulcers Related to Nonsteroidal Anti-inflammatory Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be a risk factor for peptic ulcer disease; however, the data regarding NSAID-related ulcers and H. pylori infections are conflicting and incomplete.
Various groups have shown that individuals who are beginning NSAID therapy and who also are infected with
H. pylori have a greater incidence of NSAID-related ulcers compared with individuals who are not infected. However, whether eradication of H. pylori affects the incidence of symptomatic ulcers, bleeds, or perforations remains unclear.
H. pylori and Reflux Disease
H. pylori causes atrophy and loss of acid secretory capacity in the otherwise healthy stomach. One hypothesis holds that patients with diseases related to gastric acid production, eg, reflux disease, might benefit from H. pylori infections. Data from Labenz et al (Labenz J, et al. Gastroenterology. 1997;112:1442) and others suggest that the presence of H. pylori, particularly cag-A-positive strains, is inversely related to the prevalence of reflux disease and its complications.
H. pylori and Non-gastrointestinal Diseases
Investigators have considered whether H. pylori can be implicated in various non-gastrointestinal diseases, including coronary artery disease (CAD), iron deficiency anemia, and pancreatic cancer. The Physicians Health Study has shown that no association exists between H. pylori and CAD (Ridker P, et al. Ann Intern Med. 2001;135:184), but a relationship between H. pylori and iron deficiency anemia has been reported in Native Alaskan children (Parkinson AJ, et al. Clin Diag Lab Immunol. 2000;11:885). One study maintains that the risk for pancreatic cancer increases two-fold in patients infected with H. pylori, but the underlying pathobiology of this association is not known (Stolenzenberg-Solomon RZ, et al. J Natl Cancer Inst. 2001;93:937).
New Paradigms for Helicobacter pylori Eradication
Alan F. Cutler, MD, FACG, of Digestive Health Associates, and Assistant Professor of Medicine at Wayne State University in Detroit, Michigan, reported that proton pump inhibitors (PPIs) reduce Helicobacter pylori density by causing bacterial lysis at a neutral pH in the presence of urea. By decreasing acid volumes, PPIs used in eradication therapies can increase concentrations of antibiotics in gastric juices. In addition, PPIs increase the permeability of gastric juices by decreasing their viscosity, and they reduce the degradation of acid-labile antibiotics in the stomach by increasing intragastric pH.
Comparison of Proton Pump Inhibitors in Eradication
The antibiotics amoxicillin, clarithro-mycin, and metronidazole are used for the eradication of H. pylori. Although metronidazole is unaffected by gastric pH, amoxicillin and clarithromycin require pH values of 3 and 4, respectively, for maximum effectiveness. Achieving and maintaining a pH of 4, therefore, is very important for successful eradication of H. pylori.
In H. pylori-negative individuals, rabeprazole achieved 88% of its maximal effect and a mean 24-hour intragastric pH value of 3.4 at day 1 of treatment (Pantoflickova D, et al. Gastroenterology. 2000;118:A1290). Thus, rabeprazole is able to rapidly achieve and maintain a pH>4. Although all PPIs are activated at low pH levels (pH = 0·5), some PPIs lose their activation as the pH increases. Rabeprazole, in contrast, maintains a short activation half-life at near-neutral pH levels.
Eradication Therapies with Proton Pump Inhibitors
Various US studies have found eradication rates of 75%-85% with 10-day regi-mens of omep-razole/ amoxicillin/clarithro-mycin (OAC) or lansoprazole/ amoxicillin/clarithromycin. Although 7-day regimens had not been as successful as 10- or 14-day therapies, the short-term treatments were associated with greater compliance.
A randomized, controlled, prospective study of eradication rates with 3-, 7-, and 10-day treatments with rabeprazole/amoxicillin/clarithromycin (RAC) found that a 3-day treatment was ineffective, but 7-day and 10-day RAC therapies were as effective as a 10-day regimen of OAC (Figure 1) (Vakil NB, et al. Gastroenterology. 2002;122: A551). This trial, which included patients with ulcers and non-ulcer dyspepsia, also demonstrated that the presence of an ulcer did not affect eradication of H. pylori.
Rabeprazole significantly reduces acid secretion and elevates intragastric pH, resulting in increased antibacterial concentrations in the gastric juices. Moreover, one study has indicated that rabeprazole achieves higher eradication rates with shorter duration of therapy. Dr. Cutler believes that 7-day and 10-day regimens, compared with 14-day treatments, will improve compliance and may reduce costs by up to 50%.
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