Helicobacter pylori

Colorized electron micrograph of H. pylori bacteria. Source: NIH.

Other Names

• H. pylori

Effect on Humans

Role in disease

Prior to the discovery of H. pylori in 1982, stomach ulcers were thought to be caused by eating spicy food, increased stomach acid production, stress, and lifestyle choices. With the discovery of H. pylori in the mucous layer of people with gastric and duodenal ulcers, this organism was found to be a major contributor to ulcer disease.^[3]

H. pylori weakens the protective mucous coating of the stomach and duodenum, which allows acid that is normally in the stomach to get through to the lining beneath. Both the acid and the bacteria irritate the lining and cause a sore, or ulcer.^[4]

H. pylori is able to survive in stomach acid because it secretes enzymes to neutralize the acid. This mechanism allows H. pylori to make its way to the stomach's protective mucous coating. Once there, the bacteria's spiral shape helps it burrow through the mucous layer.

H. pylori and cancer

H. pylori has been associated with some types of cancer affecting the stomach and possibly pancreatic cancer.

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 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.

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. In 1994, the International Agency for Research on Cancer (IARC) classified H. pylori as a carcinogen, or cancer-causing agent.^[5]

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 when H. pylori infects the stomach.^[6] MALT lymphomas account for approximately four percent of all cases of 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. Furthermore, up to 80% of patients with gastric MALT lymphoma achieve complete remission of their tumors after treatment with antibiotics that kill H. pylori.^[7]

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.

Very little is known about what causes pancreatic cancer or how to prevent it.^[8] 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. 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.^[9] Another study conducted in Finland found a positive association between infection with H. pylori as measured by the presence of antibodies and the risk for pancreatic cancer in 121 patients.^[10] More research needs to be done in this area since the link between H. pylori and pancreatic cancer is still in doubt.^[8]

Microbiology

Identification and diagnosis

Instruments used in an endoscopy. Source: National Cancer Institute

H. pylori is diagnosed through blood, breath, stool, and tissue tests. Blood tests are most common. These tests detect antibodies to H. pylori bacteria.

Another diagnostic method is the breath test. In this test, the patient is given either 13C- or 14C-labeled urea to drink. H. pylori, if present, metabolizes the urea rapidly, and the labeled carbon is absorbed. This labeled carbon can then be measured as CO2 in the patient's breath to determine whether H. pylori is present. Urea breath tests are an effective diagnostic method for H. pylori. They are also used after treatment to see whether the treatment worked. The breath test is 96 percent accurate.

A stool test may be used to detect H. pylori in the patient's stool. This test is called the Helicobacter pylori stool antigen (HpSA) test.

Tissue tests are usually done using the biopsy sample that is removed during an endoscopy. There are three types of tissue tests as follows:

• The rapid urease test detects the enzyme urease, which is produced by H. pylori.
• A histology test allows the doctor to find and examine the actual bacteria.
• A culture test involves allowing H. pylori to grow in the tissue sample in the laboratory.

In diagnosing H. pylori, blood, breath, and stool tests are often done before tissue tests because they are less invasive. However, blood tests are not used to detect H. pylori following treatment because a patient's blood can show positive results even after H. pylori has been eliminated.

Treatment

H. pylori peptic ulcers are treated with antibiotics and drugs which reduce stomach acid production and protect the stomach lining. The two classes of drugs aimed at reducing acid production are H2 blockers and proton pump inhibitors (PPIs). H2 blockers work by blocking histamine (or antihistamines) which stimulates acid secretion. Proton pump inhibitors suppress acid production by halting the mechanism that pumps the acid into the stomach.

The standard regimen in the United States and Europe used to treat ulcers caused by H. pylori is a combination of two antibiotics, used to kill the bacterium, taken along with either an H2 blocker or a proton pump inhibitor. One regimen that can be used is the following:

• proton pump inhibitor such as omeprazole or rabeprazole plus
• two antibiotics such as amoxicillin and clarithromycin, taken for 14 days.

Recently, however, it has been found that the standard regimen fails to get rid of H. pylori in up to 25% of people with ulcer disease.^[11] Another regimen that uses a sequence of medications may be more effective.^[12] One such regimen uses the following:

• proton pump inhibitor plus amoxicillin taken for five days, followed by
• proton pump inhibitor plus clarithromycin plus tinidazole taken for another five days.

Antimicrobial resistance

The effectiveness of the standard treatment regimen to get rid of H. pylori infections and associated ulcer disease has been decreasing in recent years. This is likely due to the development of H. pylori resistance to clarithromycin and other macrolide antibiotics used in the standard regimen.^{[11] [13]} Newer antibiotic regimens are being studied that may be more effective than the standard regimen.^[12]

Research

Since the discovery of H. pylori and the use of antimicrobials to treat peptic ulcers, researchers have also found that the eradication of H. pylori decreases gastric cancer risk. The link between H. pylori and gastric cancer is still being researched. However, only a small percentage of colonized persons ever develop disease. The use of genomics has identified certain host and H. pylori genotypes that increase the risk for gastric cancer. This is an important step that may permit physicians to focus diagnostic and eradication strategies in high-risk populations.

Recently, the National Commission on Digestive Diseases, a commission set up by the National Institutes of Health, produced a draft report on the priorities in research on digestive diseases.^[14] Their report recommends the following: "H. pylori has been categorized as a Class 1 carcinogen for stomach cancer and is a major risk factor for PUD. Several important issues remain unresolved, and there have been reports that H. pylori is inversely related to other diseases, such as esophageal disease and asthma. Research now must be directed towards obtaining a better understanding of the cellular and molecular basis of H. pylori-associated diseases, particularly in defining the role of chronic mucosal inflammation. Knowledge of the pathogenesis of H. pylori will enable the rational development and testing of novel therapeutics and optimization of existing treatments. Importantly, with the falling prevalence of H. pylori, the proportion of idiopathic ulcers is likely to increase; the cause of this significant minority of ulcers is a new focus of investigation."

The report lists several objectives for future H. pylori research:

• Profile the microbial, molecular, cellular, and epidemiological features of H. pylori-induced gastric carcinogenesis and pelvic ulcer disease to identify diagnostic, prognostic, predictive, preventive, and therapeutic targets.
• Define the relationship between H. pylori and GERD complications and assess prolonged proton-pump inhibitor use.
• Develop noninvasive technologies to screen for H. pylori-induced pre-malignant lesions.
• Develop prevention strategies based on mechanisms of H. pylori/host interactions that lead to pre-malignant/malignant lesions and evaluate their effectiveness in at-risk populations.

History

H. pylori was first isolated from humans in 1982. Its role in the development of ulcer disease and gastritis was questioned by many in the medical community. ^{[15] [16] [17]} The work of Marshall and Warren helped to establish the causative role of H. pylori in stomach ulcers.^{[18] [19]} Further research into H. pylori has firmly established its role in ulcer disease and helped to refine treatment regimens.^{[2] [3] [20]}

Interesting Facts

Before 1983, ulcers were thought to be caused by stress and/or spicy food. In the early 1980s, two Australian researchers, Robin Warren and Barry Marshall isolated and cultured a helical bacterium from human mucosal specimens. Their contention that most stomach ulcers and gastritis were caused by infection with this bacterium was not greeted with universal acceptance, however. Marshall, to prove his theory, drank a Petri dish of H. pylori, developed gastritis, and the bacteria were recovered from his stomach lining, thereby satisfying three out of four of Koch's postulates. The fourth was satisfied after a second endoscopy, performed ten days after inoculation, revealed signs of gastritis and revealed the presence of H. pylori. Marshall was then able to treat himself with bismuth salts and metronidazole taken for fourteen days. Marshall and Warren went on to show that antibiotics are effective in the treatment of many cases of gastritis.^[21] In 2005, Warren and Marshall were awarded the Nobel Prize in Medicine for their work on H. pylori.^[22]

Famous people

Barry Marshall's Helicobacter Foundation has a list of famous people with helicobacter, including Ayatollah Khomeini, James Joyce, George Bush, and Imelda Marcos.

Global Impact

Approximately two-thirds of the world's population is infected with H. pylori. In the United States, H. pylori is more prevalent among older adults, African Americans, Hispanics, and lower socioeconomic groups. Approximately 25 million Americans suffer from peptic ulcer disease at some point in their lifetime. Each year there are 500,000 to 850,000 new cases of peptic ulcer disease and more than one million ulcer-related hospitalizations.^[23]

References

1. ↑ Price AB. Histological aspects of Campylobacter pylori colonisation and infection of gastric and duodenal mucosa. Scand J Gastroenterol Suppl. 1988;142:21-4.Abstract
2. ↑ ^{2.0 2.1} Blaser MJ, Perez-Perez GI, Lindenbaum J, et al. Association of infection due to Helicobacter pylori with specific upper gastrointestinal pathology. Rev Infect Dis. 1991 Jul-Aug;13 Suppl 8:S704-8. Abstract
3. ↑ ^{3.0 3.1 3.2} Nomura A, Stemmermann GN, Chyou PH, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and the risk for duodenal and gastric ulceration. Ann Intern Med. 1994 Jun 15;120(12):977-81. Abstract | Full Text
4. ↑ Sidebotham RL, Batten JJ, Karim QN, Spencer J, Baron JH. Breakdown of gastric mucus in presence of Helicobacter pylori. J Clin Pathol. 1991 Jan;44(1):52-7. Abstract | PDF
5. ↑ H. pylori and Cancer: Fact Sheet
6. ↑ H. pylori and Cancer: Fact Sheet
7. ↑ Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews 2006;19:449-90.
8. ↑ ^{8.0 8.1} Risch HA. Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity. J Natl Cancer Inst. 2003 Jul 2;95(13):948-60. Abstract | Full Text | PDF
9. ↑ Raderer M, Wrba F, Kornek G, et al. Association between Helicobacter pylori infection and pancreatic cancer. Oncology. 1998 Jan-Feb;55(1):16-9. Abstract
10. ↑ Stolzenberg-Solomon RZ, Blaser MJ, Limburg PJ, et al. Helicobacter pylori seropositivity as a risk factor for pancreatic cancer. J Natl Cancer Inst. 2001 Jun 20;93(12):937-41. Abstract | Full Text | PDF
11. ↑ ^{11.0 11.1} Fuccio L, Minardi ME, Zagari RM, Grilli D, Magrini N, Bazzoli F. Meta-analysis: duration of first-line proton-pump inhibitor based triple therapy for Helicobacter pylori eradication. Ann Intern Med. 2007 Oct 16;147(8):553-62. Abstract
12. ↑ ^{12.0 12.1} Jafri NS, Hornung CA, Howden CW. Meta-analysis: sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naive to treatment. Ann Intern Med. 2008 Jun 17;148(12):923-31. Abstract | PDF
13. ↑ Egan BJ, Katicic M, O'Connor HJ, O'Morain CA. Treatment of Helicobacter pylori. Helicobacter. 2007 Oct;12 Suppl 1:31-7. Abstract
14. ↑ NIDDK. Opportunities and challenges in digestive diseases research: Recommendations of the National Commission on Digestive Diseases. PDF
15. ↑ Blaser MJ. Helicobacter pylori and the pathogenesis of gastroduodenal inflammation. J Infect Dis. 1990 Apr;161(4):626-33. Abstract
16. ↑ Carrick J. Problems with clinical trials on Campylobacter pylori. J Clin Gastroenterol. 1988 Jun;10(3):247-8. Abstract
17. ↑ Rabeneck L, Ransohoff DF. Is Helicobacter pylori a cause of duodenal ulcer? A methodologic critique of current evidence. Am J Med. 1991 Dec;91(6):566-72. Abstract
18. ↑ Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984 Jun 16;1(8390):1311-5. Abstract
19. ↑ Forbes GM, Glaser ME, Cullen DJ, et al. Duodenal ulcer treated with Helicobacter pylori eradication: seven-year follow-up.Lancet. 1994 Jan 29;343(8892):258-60. Abstract
20. ↑ Wyle FA. Helicobacter pylori: current perspectives. J Clin Gastroenterol. 1991;13 Suppl 1:S114-24. Abstract
21. ↑ Helicobacter pylori in peptic ulcer disease. NIH Consensus Statement Online Jan 7–9;12(1):1-23}}
22. ↑ The Nobel Prize in Physiology or Medicine 2005 awarded to Barry J. Marshall and J. Robin Warren "for their discovery of the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease".
23. ↑ CDC Ulcer Factsheet

External Links

The Helicobacter Foundation

Microbe Wiki:Helicobacter

American Gastroenterological Association (AGA)

H. pylori and Cancer: Fact Sheet