Peptic Ulcers and H. Pylori

Helicobacter pylori, or H. pylori, is a spiral-shaped bacterium that grows in the mucus layer that coats the inside of the human stomach.

To survive in the harsh, acidic environment of the stomach, H. pylori secretes an enzyme called urease, which converts the chemical urea to ammonia. The production of ammonia around H. pylori neutralizes the acidity of the stomach, making it more hospitable for the bacterium. In addition, the helical shape of H. pylori allows it to burrow into the mucus layer, which is less acidic than the inside space, or lumen, of the stomach. H. pylori can also attach to the cells that line the inner surface of the stomach.

Although immune cells that normally recognize and attack invading bacteria accumulate near sites of H. pylori infection, they are unable to reach the stomach lining. In addition, H. pylori has developed ways of interfering with local immune responses, making them ineffective in eliminating this bacterium (1, 2).

H. pylori has coexisted with humans for many thousands of years, and infection with this bacterium is common. The Centers for Disease Control and Prevention (CDC) estimates that approximately two-thirds of the world’s population harbors the bacterium, with infection rates much higher in developing countries than in developed nations.

Although H. pylori infection does not cause illness in most infected people, it is a major risk factor for peptic ulcer disease and is responsible for the majority of ulcers of the stomach and upper small intestine.

In 1994, the International Agency for Research on Cancer classified H. pylori as a carcinogen, or cancer-causing agent, in humans, despite conflicting results at the time. Since then, it has been increasingly accepted that colonization of the stomach with H. pylori is an important cause of gastric cancer and of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Infection with H. pylori is also associated with a reduced risk of esophageal adenocarcinoma.

H. pylori is thought to spread through contaminated food and water and through direct mouth-to-mouth contact. In most populations, the bacterium is first acquired during childhood. Infection is more likely in children living in poverty, in crowded conditions, and in areas with poor sanitation.

Epidemiologic studies have shown that individuals infected with H. pylori have an increased risk of gastric adenocarcinoma (1,2,8–12). The risk increase appears to be restricted to non-cardia gastric cancer. For example, a 2001 combined analysis of 12 case–control studies of H. pylori and gastric cancer estimated that the risk of non-cardia gastric cancer was nearly six times higher for H. pylori-infected people than for uninfected people (8).

Additional evidence for an association between H. pylori infection and the risk of non-cardia gastric cancer comes from prospective cohort studies such as the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study in Finland (13). Comparing subjects who developed non-cardia gastric cancer with cancer-free control subjects, the researchers found that H. pylori-infected individuals had a nearly eightfold increased risk for non-cardia gastric cancer (14).

Several studies have detected an inverse relationship between H. pylori infection and gastric cardia cancer (14–16), although the evidence is not entirely consistent (17, 18). The possibility of an inverse relationship between the bacterium and gastric cardia cancer is supported by the corresponding decrease in H. pylori infection rates in Western countries during the past century—the result of improved hygiene and widespread antibiotic use—and the increase in rates of gastric cardia cancer in these same regions.

Similar epidemiologic evidence suggests that H. pylori infection may be associated with a lower risk of esophageal adenocarcinoma. For example, a large case–control study in Sweden showed that the risk of esophageal adenocarcinoma in H. pylori-infected individuals was one-third that of uninfected individuals (15). A meta-analysis of 13 studies, including the Swedish study, found a 45 percent reduction in risk of esophageal adenocarcinoma with H. pylori infection (19). Moreover, as with gastric cardia cancer, dramatic increases in esophageal adenocarcinoma rates in several Western countries parallel the declines in H. pylori infection rates.

Although it is not known for certain how H. pylori infection increases the risk of non-cardia gastric cancer, some researchers speculate that the long-term presence of an inflammatory response predisposes cells in the stomach lining to become cancerous. This idea is supported by the finding that increased expression of a single cytokine (interleukin-1-beta) in the stomach of transgenic mice causes sporadic gastric inflammation and cancer (20). The increased cell turnover resulting from ongoing cellular damage could increase the likelihood that cells will develop harmful mutations.

One hypothesis that may explain reduced risks of gastric cardia cancer and esophageal adenocarcinoma in H. pylori-infected individuals relates to the decline in stomach acidity that is often seen after decades of H. pylori colonization. This decline would reduce acid reflux into the esophagus, a major risk factor for adenocarcinomas affecting the upper stomach and esophagus.

Some H. pylori bacteria use a needle-like appendage to inject a toxin produced by a gene called cytotoxin-associated gene A (cagA) into the junctions where cells of the stomach lining meet (21, 22). This toxin (known as CagA) alters the structure of stomach cells and allows the bacteria to attach to them more easily. Long-term exposure to the toxin causes chronic inflammation. However, not all strains of H. pylori carry the cagA gene; those that do are classified as cagA-positive.

Epidemiologic evidence suggests that infection with cagA-positive strains is especially associated with an increased risk of non-cardia gastric cancer and with reduced risks of gastric cardia cancer and esophageal adenocarcinoma. For example, a meta-analysis of 16 case–control studies conducted around the world showed that individuals infected with cagA-positive H. pylori had twice the risk of non-cardia gastric cancer than individuals infected with cagA-negative H. pylori (23). Conversely, a case–control study conducted in Sweden found that people infected with cagA-positive H. pylori had a statistically significantly reduced risk of esophageal adenocarcinoma (16). Similarly, another case–control study conducted in the United States found that infection with cagA-positive H. pylori was associated with a reduced risk of esophageal adenocarcinoma and gastric cardia cancer combined, but that infection with cagA-negative strains was not associated with risk (24).

Recent research has suggested a potential mechanism by which CagA could contribute to gastric carcinogenesis. In three studies, infection with CagA-positive H. pylori was associated with inactivation of tumor suppressor proteins, including p53 (25–27).

Gastric MALT lymphoma is a rare type of non-Hodgkin lymphoma that is characterized by the slow multiplication of B lymphocytes, a type of immune cell, in the stomach lining. This cancer represents approximately 12 percent of the extranodal (outside of lymph nodes) non-Hodgkin lymphoma that occurs among men and approximately 18 percent of extranodal non-Hodgkin lymphoma among women (28). During the period 1999–2003, the annual incidence of gastric MALT lymphoma in the United States was about one case for every 100,000 persons in the population.

Normally, the lining of the stomach lacks lymphoid (immune system) tissue, but development of this tissue is often stimulated in response to colonization of the lining by H. pylori (2). Only in rare cases does this tissue give rise to MALT lymphoma. However, nearly all patients with gastric MALT lymphoma show signs of H. pylori infection, and the risk of developing this tumor is more than six times higher in infected people than in uninfected people (29, 30).