1. What is Helicobacter pylori?

   Helicobacter pylori, or H. pylori, is a spiral-shaped bacterium that is able to grow in the human stomach. Normally, the acidic stomach environment prevents the survival of viruses, bacteria, and other microorganisms. However, H. pylori has evolved to be uniquely suited to thrive in the harsh stomach environment. H. pylori bacteria secrete urease, a special enzyme that converts urea to ammonia. Ammonia reduces the acidity of the stomach, making it a more hospitable home for H. pylori.

   The ability to survive in the stomach provides H. pylori with a useful hiding place. White blood cells that would normally recognize and attack invading bacteria are unable to cross from blood vessels into the stomach lining. Instead, the ineffective white blood cells continue to respond to the site of infection, where they die and release nutrients that feed H. pylori.

   H. pylori has co-existed with humans for thousands of years. However, because scientists believed the stomach was a sterile organ, this bacterium was not discovered until the 1980s. Some other gut bacteria actually aid their human hosts in the absorption of nutrients and defense against other, more dangerous, microbes. Because H. pylori is relatively newly discovered, the complex interactions between this microbe and humans, including its risks and benefits, are still being discovered.

2. How was the association between H. pylori and disease established?

   In the 1980s, scientists began to notice the presence of curved bacteria, which later became known as H. pylori, in tissue samples taken from patients with ulcers of the stomach and upper small intestine. Believing that no bacteria could survive the harsh stomach environment, most scientists thought these mysterious bacteria were either due to contamination of tissue samples or just another harmless species of bacteria like many found in the gut. However, Australian researchers Barry J. Marshall, M.D., and J. Robin Warren, M.D., were convinced that the bacteria were actually the cause of ulcers. Marshall, frustrated with the lack of a good animal model of infection, infected himself with the curved bacteria. He became ill, developed inflammation of the stomach, and was able to culture the bacteria from his own ulcers, thereby proving the microbe to be the cause of stomach ulcers. For their discovery of H. pylori and its role in gastric ulcer formation, Marshall and Warren were awarded the 2005 Nobel Prize in Medicine.

3. What is the prevalence of infection with H. pylori?

   Human infection with H. pylori is common; the Centers for Disease Control and Prevention estimate that approximately two-thirds of the world's population harbors the bacterium, with infection rates much higher in developing nations than in Europe and North America.

   H. pylori is thought to be spread either through contaminated food and water or through direct mouth-to-mouth contact. In most populations, the bacterium is first acquired during childhood. Children living in crowded conditions and with a lower socioeconomic status are more likely to become infected.

   It has been estimated that between two percent to 20 percent of people infected with H. pylori will develop ulcers. Some evidence also links H. pylori infection to gastric cancer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and perhaps pancreatic cancer and cardiovascular disease. However, the majority of people infected with H. pylori will not become ill from the bacteria.

4. What is peptic ulcer disease?

   Peptic ulcers are holes in the lining of the stomach or upper small intestine (duodenum) that extend deep into the muscular layers of these organs. An ulcer forms when surface cells become inflamed, die, and are shed. The damage can be caused by mechanical abrasion, infection, or inflammation, which results from an overreaction of immune cells.

   Peptic ulcer disease (PUD) is responsible for over three million visits to the doctor per year in the United States (1). Stomach pain similar to heartburn or indigestion is the most prevalent symptom of a stomach ulcer. Other symptoms may include loss of appetite, weight loss, vomiting, blood in the stool, or anemia.

5. What is the relationship between H. pylori and peptic ulcer disease?

   Before the 1980s, due to its high acid content, scientists believed the stomach was sterile, and mistakenly attributed PUD to stress and spicy foods. Now, research has shown that bacterial toxins released by H. pylori and the inflammation that results from infection can damage the stomach lining and cause peptic ulcers. Although statistics vary depending on geographical region, H. pylori is responsible for the large majority of peptic ulcers.

6. What is gastric cancer?

   Gastric cancer, or cancer of the stomach, was once considered a single entity. Now, epidemiologists divide this cancer into two main classes: gastric cardia cancer (which is cancer of the top inch of the stomach, where it meets the esophagus) and non-cardia gastric cancer (cancer in all other areas of the stomach). This classification was adopted because these two types of stomach cancer have different risk factors and different patterns of occurrence. For example, H. pylori has been established as a strong risk factor for non-cardia gastric cancer, whereas its association with gastric cardia cancer is controversial.

   In 2006, there will be an estimated 22,280 new cases of gastric cancer and approximately 11,430 deaths due to the disease in the U.S. Gastric cancer is the second most common cause of cancer-related deaths in the world, killing approximately 700,000 people in 2002. Gastric cancer is more common in developing countries than in the U.S.

   Overall gastric cancer incidence rates are decreasing. However, this decline is mainly in non-cardia gastric cancer rates. In contrast, gastric cardia cancer rates are increasing, particularly in Western countries, such as the U.S. and many parts of Europe. Gastric cardia cancer, which was once very uncommon, now constitutes nearly half of all stomach cancers in white males in the U.S.

   Infection with H. pylori is the most important risk factor for gastric cancer. Other risk factors include chronic gastritis (inflammation of the stomach); older age; being male; a diet high in salted, smoked, or poorly preserved foods and low in fruits and vegetables; certain types of anemia; smoking cigarettes; and a family history of stomach cancers.

7. What is pancreatic cancer?

   Pancreatic cancer is cancer of the pancreas, a six-inch gland shaped like a thin pear. The pancreas is found behind the stomach and in front of the spine. It produces juices that help digest food as well as hormones, such as insulin, which help control blood sugar levels. The digestive juices are produced by exocrine pancreas cells and the hormones are produced by endocrine pancreas cells. About 95 percent of pancreatic cancers begin in exocrine cells.

   It is estimated that 32,180 new cases of pancreatic cancer will be diagnosed in the United States in 2006. Only 20 percent of patients survive one year after diagnosis; an estimated 31,800 people will die from the disease in 2006, making it the fifth leading cause of cancer deaths in the United States.

   Very little is known about what causes pancreatic cancer or how to prevent it. Long-term diabetes, obesity, and certain inherited genetic conditions are considered risk factors. In addition, smokers are twice as likely as nonsmokers to be diagnosed with pancreatic cancer.

8. What is gastric MALT lymphoma?

   Cancer affecting the mucosa-associated lymphoid tissue (MALT) in the stomach, or gastric MALT lymphoma, is a rare type of non-Hodgkin lymphoma characterized by B lymphocytes, a type of immune cell, that slowly multiply in the stomach lining. The lining of the stomach normally lacks lymphoid (immune system) tissue, but this tissue nearly always appears in response to colonization of the lining by H. pylori bacteria (2). MALT lymphomas account for approximately four percent of all cases of lymphoma.

9. Is there evidence that shows that H. pylori infection increases the risk of gastric cancer?

   Many studies have demonstrated a link between H. pylori infection and gastric cancers (3–7). In 1994, the International Agency for Research on Cancer (IARC) classified H. pylori as a carcinogen, or cancer-causing agent, despite conflicting results at the time.

   Since then, colonization of the stomach with H. pylori has been increasingly accepted as an important risk factor for gastric cancers. However, this association varies by region of the stomach. In 2001, a combined analysis of 12 H. pylori and gastric cancer studies estimated that the risk of non-cardia gastric cancer was nearly six times higher for H. pylori-infected people than for uninfected people (3). Data show that infection with H. pylori plays an important role in the development of non-cardia gastric cancer, but its association with gastric cardia cancer is less clear.

10. What evidence shows that H. pylori infection increases the risk of pancreatic cancer?

    Observational findings show that many people who had surgery to treat peptic ulcers developed pancreatic cancer up to 20 years later. In addition, one study found that out of 92 pancreatic cancer patients, 65 percent tested positive for H. pylori, while only 45 percent of non-cancer control participants tested positive. Although the study group was small and patients were not tested for H. pylori until after they were diagnosed with cancer, this study concluded that a positive association exists between H. pylori and pancreatic cancer (8).

11. What evidence shows that H. pylori infection increases the risk of MALT lymphoma?

    Nearly all patients with gastric MALT lymphoma are infected with H. pylori, and the risk of developing this tumor is over six times higher in infected people than in uninfected people (9). Furthermore, up to 80 percent of patients with gastric MALT lymphoma achieve complete remission of their tumors after treatment with H. pylori-eradicating antibiotic therapy (2).

    The exact incidence of gastric MALT lymphoma in H. pylori-infected persons is unknown, but these tumors occur in less than one percent of infected individuals.

12. What is the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study?

    From 1985 to 1993, the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study in Finland studied a group of 29,133 male smokers between the ages of 50 and 69 years to determine whether daily supplementation with alpha-tocopherol, beta-carotene, or both, would reduce the number of lung or other cancers (10). After the original trial period ended, researchers continued to follow the participants.

13. What is the link between H. pylori and gastric cancer, according to the ATBC follow-up study?

    Through April 1999, the Finnish Cancer Registry diagnosed 234 participants of the ATBC study with gastric cancer. Each of these participants was randomly matched by age with a cancer-free control participant. H. pylori infection status was determined from blood samples initially obtained from each study participant at the time of enrollment in the study. Comparing cancer subjects with non-cancer controls, the ATBC gastric cancer follow-up study concluded that infection with H. pylori was a strong risk factor for non-cardia gastric cancer and increased risk for the disease nearly eight-fold. In contrast, the study found that presence of the bacteria decreased the risk of cardia gastric cancer by about two-thirds (11).

    There is little debate that H. pylori increases risk of non-cardia gastric cancer. However, the inverse association between H. pylori and gastric cardia cancer is relatively new. Only one study other than the ATBC has demonstrated statistically significant data to support the association of H. pylori and decreased risk of gastric cardia cancer (13), while others have reported conflicting results. Time trends of gastric cancer rates support the ATBC study results. In recent years, the number of H. pylori infections in developed countries has decreased, most likely due to changes in diet, refrigeration, better hygiene, and increased antibiotic use. The decline in H. pylori infection in developed countries has coincided with a decline in rates of non-cardia gastric cancer, but a rise in rates of gastric cardia cancer and certain types of esophageal cancer.

    The ATBC Study has the advantage of examining blood samples collected years before cancer diagnosis. H. pylori bacteria prefer to grow on normal stomach cells rather than pre-cancerous cells, meaning that the development of advanced gastric cancer may result in lower numbers of the bacteria present in the stomach. By determining H. pylori status only after diagnosis of cancer, some previous studies may have underestimated the infection rate in participants with gastric cancer.

14. What is the link between H. pylori and pancreatic cancer, according to the ATBC follow-up study?

    Similar to the ATBC follow-up study for gastric cancer, a pancreatic cancer follow-up study identified all cases of pancreatic cancer diagnosed through December 1995.

    This follow-up study compared the levels of antibodies to H. pylori from blood samples taken at the start of the study (before the cancer was diagnosed). Researchers examined a group of 121 men who developed pancreatic cancer and compared them to a subgroup of 226 men who did not develop cancer but were similar in age and other characteristics. ATBC study participants infected with H. pylori were approximately twice as likely to develop pancreatic cancer as those without the bacteria (12).

15. How can H. pylori infection decrease the risk of some cancers while increasing the risk of others?

    H. pylori infection is associated with a reduced risk of gastric cardia cancer. It is not clear why this bacterium could be inversely related to risk of cardia gastric cancer. One hypothesis is that the H. pylori urease enzyme reduces acid production in the stomach during colonization, thereby decreasing acid reflux into the esophagus, a major risk for cancers affecting regions of the upper stomach and esophagus.

16. What role do antibiotics play in gastric cancer rates?

    The results of the ATBC gastric cancer study (11) and others (14, 15) suggest that caution might be needed in wide-spread H. pylori eradication programs. The possibility of an inverse relationship between the bacterium and cardia gastric cancer is supported by correlating the decrease in H. pylori infection rates in Western countries during the past century, the result of improved hygiene and widespread antibiotic use, to lower rates of non-cardia cancer and higher rates of cardia cancer in these same regions.

17. What is CagA-positive H. pylori and how does it affect risk of cancer?

    H. pylori bacteria use a needle-like appendage to inject CagA, a toxin produced by cytotoxin-associated gene A, into the junctions where two stomach lining cells meet. Not all strains of H. pylori carry the CagA gene; those that do are classified as CagA-positive. This toxin alters the structure of stomach cells and allows the bacteria to attach themselves more easily. Long-term exposure to CagA causes chronic inflammation.

    Scientists may not be able to definitively attribute CagA alone to increased development of cancer because CagA-positive and CagA-negative strains also have other genetic differences. While results are conflicting, recent research suggests that infection with CagA-positive strains of H. pylori further increases the risk of gastric cancer above the risk associated with CagA-negative strains. Laboratory studies show that CagA-induced cellular changes can lead to accumulation of genetic mutations involved in the development of malignancies (16). This link is supported by a combined analysis of 16 studies that found a two-fold increase in the risk of non-cardia gastric cancer associated with CagA-positive H. pylori as compared to CagA-negative H. pylori (17).

    The ATBC study determined H. pylori infection status at the time of study enrollment between 1985 and 1988 by the presence of antibodies directed against either the whole bacteria or the CagA toxin. The gastric cancer follow-up study reported that CagA-positive H. pylori strains had a stronger association with risk of non-cardia gastric cancer, as compared with Cag-A negative strains, although this difference was not statistically significant (11). In the ATBC pancreatic cancer study, infection with CagA-positive H. pylori strains were associated with an approximately two-fold increase in risk for the disease over people in the study who were not infected (12).

18. Where can I find more information?

    • NCI Publications: What You Need To Know About™ Stomach Cancer
    • Centers for Disease Control and Prevention: H. pylori and peptic ulcer disease
    • NIH Library: UpToDate®

Selected References

1. Vakil N and Fennerty B. The economics of eradicating Helicobacter pylori infection in duodenal ulcer disease. American Journal of Medicine 1996;100:60S–63S.
2. Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews 2006;19:449–90.
3. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49:347–53.
4. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. New England Journal of Medicine 1991;325:1127–31.
5. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114:1169–79.
6. Eslick GD, Lim LL, Byles JE, Xia HH, Talley NJ. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. American Journal of Gastroenterology 1999;94:2373–9.
7. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. New England Journal of Medicine 2001;345:784–9.
8. Raderer M, Wrba F, Kornek G, Maca T, Koller DY, Weinlaender G, Hejna M, Scheithauer W. Association between Helicobacter pylori infection and pancreatic cancer. Oncology 1998;55:16–19.
9. Parsonnet, J, Hansen S, Rodriguez L, Gelb AB, Warnke RA, Jellum E, Orentreich N, Vogelman JH, and Friedman GD. 1994. Helicobacter pylori infection and gastric lymphoma. New England Journal of Medicine 1994;330:1267–71.
10. The ATBC Cancer Prevention Study Group. The alpha-tocopherol, betacarotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Annals of Epidemiology 1994;4:1–10.
11. Kamangar F, Dawsey SM, Blaser MJ, Perez-Perez GI, Pirjo Pietinen, Newschaffer CJ, Abnet CC, Albanes D, Virtamo J, Taylor PR. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. Journal of the National Cancer Institute. 2006;98:1445–52.
12. Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, Perez-Perez G, Taylor PR, Virtamo J, Albanes D. Helicobacter pylori Seropositivity as a risk factor for pancreatic cancer. Journal of the National Cancer Institute 2001;93:937–41.
13. Hansen S, Melby KK, Aase S, Jellum E, Vollset SE. Helicobacter pylori infection and risk of cardia cancer and non-cardia gastric cancer. A nested case-control study. Scandinavian Journal of Gastroenterology 1999;34:353–60.
14. Ramakrishna BS. Helicobacter pylori infection in India: the case against eradication. Indian Journal of Gastroenterology 2006;25:25–28.
15. Rothenbacher D, Blaser MJ, Bode G, Brenner H. Inverse relationship between gastric colonization of Helicobacter pylori and diarrheal illnesses in children: Results of a population-based cross-sectional study. Journal of Infectious Diseases 2000;182:1446–9.
16. Bagnoli F, Buti L, Tompkins L, Covacci A, Amieva MR. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proceedings of the National Academy of Science USA 2005;102:16339–44.
17. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology 2003;125:1636–44.

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Related NCI materials and Web pages:

• Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study
  (http://dceg.cancer.gov/atbcstudy/)
• Pancreatic Cancer Home Page
  (http://www.cancer.gov/cancertopics/types/pancreatic)
• Stomach (Gastric) Cancer Home Page
  (http://www.cancer.gov/cancertopics/types/stomach)
• What You Need To Know About™ Cancer of the Pancreas
  (http://www.cancer.gov/cancertopics/wyntk/pancreas)
• What You Need To Know About™ Stomach Cancer
  (http://www.cancer.gov/cancertopics/wyntk/stomach)

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