Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits

Abstract

Helicobacter pylori infection contributes to the development of diverse gastric and extragastric diseases. The infection is necessary but not sufficient for the development of gastric adenocarcinoma. Its eradication would eliminate a major worldwide cause of cancer death, therefore there is much interest in identifying how, if, and when this can be accomplished. There are several mechanisms by which H pylori contributes to the development of gastric cancer. Gastric adenocarcinoma is one of many cancers associated with inflammation, which is induced by H pylori infection, yet the bacteria also cause genetic and epigenetic changes that lead to genetic instability in gastric epithelial cells. H pylori eradication reduces both. However, many factors must be considered in determining whether treating this bacterial infection will prevent cancer or only reduce its risk-these must be considered in designing reliable and effective eradication therapies. Furthermore, H pylori infection has been proposed to provide some benefits, such as reducing the risks of obesity or childhood asthma. When tested, these hypotheses have not been confirmed and are therefore most likely false.

Keywords: Bacteria; Barrett's Esophagus; Esophageal Adenocarcinoma; Prevention; Stomach Cancer.

Figure 1. Screening and Follow-up Approaches

The approach is based on initially identifying those with H pylori infections and assessing the health of the gastric mucosa using non-invasive testing with a locally or regionally validated IgG H pylori serology and serum pepsinogen tests. Those without H pylori infection or atrophic gastritis would require no further evaluation or follow up. All those with H pylori infections would undergo eradication therapy; eradication can be confirmed using non-invasive tests such as the urea breath or stool antigen assays. After H pylori eradication, those with non-atrophic gastritis would require no further follow up. Those with suspected atrophic gastritis (based on pepsinogen level) would undergo endoscopy for further risk stratification by a validated histologic staging system. Patients cured of H pylori infection and healed, non-atrophic gastritis would require no further follow up. Those with confirmed atrophic gastritis (e.g., OLGA stage III or IV) would enter a long-term endoscopic surveillance program. Because their cancer risk if likely to decrease with time, these patients might also be included in studies of surveillance intervals or to determine whether anti-inflammatory or anti-oxidant adjuvant therapies could further reduce the risk. There are not enough data available to make recommendations for patients who have undergone H pylori eradication therapy but still have mild atrophy (e.g., OLGA I and II scores). Further studies are needed to determine the best management strategies for these individuals.

Figure 2. Interactions Among Inflammation, Bacteria, and the Epithelium Leading to Gastric Cancer

We show the interaction of H pylori, environmental factors, and inflammation in the pathogenesis of gastric cancer. Each plays important roles leading to progressive chromosome instability. H pylori-induced inflammation leads to high gastric endothelial cell turnover and a microenvironment that is high in reactive oxygen and nitrogen species, increasing opportunities for DNA damage and somatic mutations. ROS = Reactive oxygen species. Adapted from references ^,

Figure 3. H pylori Infection Leads to Genetic Instability of Epithelial Cells

H pylori can induce methylation of multiple CpG islands and also acting through stimulation of NF B stimulates activation-induced cytidine deaminase (AID), which alters nucleotides. Furthermore, the interaction of H pylori with the cell can result in double-stranded breaks in DNA as well as alter the expression of microRNAs and impair DNA mismatch repair all of which serve to increase genetic instability. Adapted from reference , with permission

Figure 4. Relationship Between Coronary Artery Disease and H pylori Infection in the US

Data on coronary artery disease were collected from histologic analyses of autopsies performed on soldiers who died in the Korean, Vietnam, and Middle East wars ^-. They are compared with the prevalence of H pylori infection in the US population during the same time periods, based on the premise that infection at age 22 did not change during the lifetimes of this cohort .

Figure 5. Age-adjusted US Incidence Rates of Gastric and Esophageal Adenocarcinoma (2006–2010)

Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2013 Sub (1973-2011) National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2014, based on the November 2013 submission.

Figure 6. Incidence of Cancers in the US

Incidence values are based on data collected in 2011 by the Surveillance, Epidemiology, and End Results Program .