Last updated: 15-Jan-2007
Helicobacter Pylori
The bacterium Helicobacter pylori is able to invade and colonize the human stomach. There it can interact with gastric epithelial cells, leading to a number of tissue changes and disease conditions, including: inflammation, loss of mucosa
(i.e., an ulcer), and development of masses from benign polyps to full cancers.[1] The latter include gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Generally, the association between H. pylori and gastric cancer is well-accepted, though the debate is not completely concluded. As an example of supporting data, infected individuals appear to have a 6-fold increased risk of developing an adenocarcinoma compared to the uninfected population. Overall, it is proposed that about 70% of gastric cancers can be attributed to H. pylori.[2]
As noted in the table in the introduction of this report, H. pylori exists in up to 50% of the global population, making it the most common chronic bacterial infection in humans. In developing countries, the dominant means of transmission is consumption of sewage-contaminated water or food. Oral-to-oral transmission is also possible (e.g., by kissing), as well as via contaminated secretions (such as vomit). Generally, the bacterium is harder to contract in developed countries, but there, as in other parts of the world, transmission typically occurs in early childhood within a family context.[3],[4] Studies show, however, that mother-to-child transmission is rare, though it may occur through breastfeeding.[5]
It is known that only certain strains are highly pathogenic, so only a subset of the population carrying the bacteria actually experience disease. A larger proportion develops some sort of pre-neoplasias, but ultimately only 2% of infected people will get a malignancy. The infected pool is large, however, resulting in stomach cancer being the second most common cancer in the world. Of related significance is the survival rate, i.e., less than 20% after 5 years. In sum, this represents an enormous disease burden.
Smoking is an important co-factor; among patients carrying the most dangerous strain of bacteria, the risk of developing some form of cancer is almost three times higher in those who smoke.[6] Diet can hurt or help; excessive salt and (perhaps) alcohol are risk factors, whereas the antioxidants in regularly consumed vegetables and fruit are thought to decrease the risk of gastric cancer by up to a third.[7],[8],[9]
Two primary pathways are thought to be involved with gastric carcinogenesis: proliferation of epithelial cells in the gut and oxidative stress of stomach mucosa.[10] The precise molecular mechanisms at work in these processes are still being worked out, including the defences which protect the bacterium in unstable, often hostile microenvironment of the stomach.[11] Recently, a major advance occurred in our understanding of why certain patients develop serious disease; apparently, there can be a 90-fold difference in the risk of gastric cancer depending on particular mixtures of H. pylori virulence and host genetics.[12],[13]
The disease induced by H. pylori is not limited to the stomach. Infection with the bacteria has been linked to squamous cell cancer in the larynx,[14] and esophagus[15] (though it is actually thought to be protective against esophageal adenocarcinoma).[16]
Preventive Interventions
Given the ubiquity of the bacterium and its ease of transmission, it seems unlikely that early primary prevention will ever be the cornerstone of a public health strategy, at least not in the developed world. The measures promoted in developing countries do not really apply in North America.[17]
With the synergistically added risk represented by tobacco use, the one clear primary prevention method is smoking cessation (or encouragements to not take up the habit).[18] Controlling the intake of salted foods may also help.
Both endoscopic biopsies and non-invasive tests are used to establish whether a gastric disease process has begun, but neither of these approaches are considered cost-effective at a population level.[19] However, the potential benefits of surveillance may propel this approach onto the high priority list in the next few years.[20]
When disease is detected, combination therapies involving a proton-pump inhibitor[21] and two to three antibiotics are effective in eradicating H. pylori, with good tolerance by the patient; a one-week regimen is curative in 80 to 90% of cases.[22] This type of treatment has been shown to accomplish regression of precancerous lesions and low-grade MALT lymphomas.[23],[24] Supplementation with ascorbic acid or beta-carotene also has resulted in a smaller but still significant likelihood of regression in at least one study.[25] However, the Cochrane review of antioxidants in the prevention of gastric cancer cast grave doubts on their effectiveness.[26] Anti-inflammatories are also being investigated as a means to slow disease progression.[27] When disease is not detected and / or conservative therapies fail, then surgery is the best solution for any early cancer that develops. The techniques for resection increase in levels of invasiveness: endoscopic, laparocscopic and, finally, open surgery.[28]
The Cochrane review of H. pylori eradication methods is still at the protocol stage. The reality is that there has been little recent advance in therapies for H. pylori, though many long term intervention trials (with gastric cancer as the end-point) are now underway in the US and Europe.[29] Many compounds can kill the bacterium in vitro, but reproducing such effects in live bodies is more elusive. Animal models are helping in the development of vaccines; there has been some success, but no clear strategy has emerged.[30],[31] One cost-effectiveness analysis suggested that resource allocation for vaccine development and implementation only made sense in developed countries.[32]
At this point, anti-H. pylori therapies remain the best option, one that is recommended for all symptomatic infected individuals according to recent professional consensus statements.[33] Using such an approach with the entire infected population would hardly seem to be feasible.[34] Nonetheless, one modeling study demonstrated that a program of universal screening (plus treatment for those who test positive) would generate an incremental cost of only US$26 per case.[35] Many uncertainties remain, including the effect of total eradication of H. pylori on gastric cancer risk, and the fact that infection actually seems to be protective against certain cancers.[36],[37] One Canadian review has called for a major demonstration project to help answer some of the scientific and pragmatic questions.[38]
[1] de Luca A, Iaquinto G. Helicobacter pylori and gastric diseases: a dangerous association. Cancer Letters. 2004; 213(1): 1-10.
[2] McLoughlin RM, Sebastian SS, O'Connor HJ et al. Review article: test and treat or test and scope for Helicobacter pylori infection. Any change in gastric cancer prevention? Alimentary Pharmacology & Therapeutics. 2003; 17 Suppl 2: 82-8.
[3] Herrera AG. Helicobacter pylori and food products: a public health problem. Methods in Molecular Biology. 2004; 268: 297-301.
[4] Moss SF, Sood S. Helicobacter pylori. Current Opinions in Infectious Diseases. 2003; 16(5): 445-51.
[5] Kitagawa M, Natori M, Katoh M et al. Maternal transmission of Helicobacter pylori in the perinatal period. Journal of Obstetrics & Gynaecology Research. 2001; 27(4): 225-30.
[6] Brenner H, Arndt V, Bode G et al. Risk of gastric cancer among smokers infected with Helicobacter pylori. International Journal of Cancer. 2002; 98(3): 446-9.
[7] Tsugane S. Salt, salted food intake, and risk of gastric cancer: epidemiologic evidence. Cancer Science. 2005; 96(1): 1-6.
[8] Correa P. Helicobacter pylori infection and gastric cancer. Cancer Epidemiology, Biomarkers & Prevention. 2003; 12(3): 238s-41s.
[9] Lunet N, Barros H. Helicobacter pylori infection and gastric cancer: facing the enigmas. International Journal of Cancer. 2003; 106(6): 953-60.
[10] Mucosa refers to the moist tissue that lines some organs and body cavities (such as the nose, mouth, lungs and stomach).
[11] de Luca A, Iaquinto G. Helicobacter pylori and gastric diseases: a dangerous association. Cancer Letters. 2004; 213(1): 1-10.
[12] Figueiredo C, Machado JC, Pharoah P et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. Journal of the National Cancer Institute. 2002; 94(22): 1680-7.
[13] Rad R, Prinz C, Neu B et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. Journal of Infectious Diseases. 2003; 188(2): 272-81.
[14] Aygenc E, Selcuk A, Celikkanat S et al. The role of Helicobacter pylori infection in the cause of squamous cell carcinoma of the larynx. Otolaryngology - Head & Neck Surgery. 2001; 125(5): 520-1.
[15] Ye W, Held M, Lagergren J et al. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. Journal of the National Cancer Institute. 2004; 96(5): 388-96.
[16] de Martel C, Llosa AE, Farr SM et al. Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma. Journal of Infectious Diseases. 2005; 191(5): 761-7.
[17] Plummer M, Franceschi S, Munoz N. Epidemiology of gastric cancer. IARC Scientific Publications. 2004; (157): 311-26.
[18] Brenner H, Arndt V, Bode G et al. Risk of gastric cancer among smokers infected with Helicobacter pylori. International Journal of Cancer. 2002; 98(3): 446-9.
[19] Correa P. Helicobacter pylori infection and gastric cancer. Cancer Epidemiology, Biomarkers & Prevention. 2003; 12(3): 238s-41s.
[20] Whiting JL, Sigurdsson A, Rowlands DC et al. The long term results of endoscopic surveillance of premalignant gastric lesions. Gut. 2002; 50(3): 378-81.
[21] A proton pump inhibitor is a drug that reduces the amount of gastric acid produced by stomach cells.
[22] Axon A. Review article: gastric cancer and Helicobacter pylori. Alimentary Pharmacology & Therapeutics. 2002; 16 Suppl 4: 83-8.
[23] Correa P. Helicobacter pylori infection and gastric cancer. Cancer Epidemiology, Biomarkers & Prevention. 2003; 12(3): 238s-41s.
[24] Moss SF, Sood S. Helicobacter pylori. Current Opinions in Infectious Diseases. 2003; 16(5): 445-51.
[25] Correa P, Fontham ET, Bravo JC et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. Journal of the National Cancer Institute. 2000; 92(23): 1881-8.
[26] Bjelakovic G, Nikolova D, Simonetti et al. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Hepato-Biliary Group. Cochrane Database of Systematic Reviews. 2004.
[27] Juhasz M, Herszenyi L, Tulassay Z et al. Helicobacter pylori and molecular mechanisms of gastric carcinogenesis: targets for prevention and therapy. Expert Review of Anticancer Therapy. 2004; 4(1): 97-103.
[28] Kitajima M. Strategies for gastric cancer treatment in the twenty-first century: minimally invasive and tailored approaches integrating basic science and clinical medicine. Gastric Cancer. 2005; 8(2): 55-8.
[29] Hasham-Jiwa N, Kasakura Y, Ajani JA. Brief review of advances in the treatment of gastric carcinoma in North America and Europe, 1995-2001. International Journal of Clinical Oncology. 2002; 7(4): 219-24.
[30] Moss SF, Sood S. Helicobacter pylori. Current Opinions in Infectious Diseases. 2003; 16(5): 445-51.
[31] Moran AP, Svennerholm AM, Penn CW. Pathogenesis and host response of Helicobacter pylori. Trends in Microbiology. 2002; 10(12): 545-7.
[32] Rupnow MF, Owens DK, Shachter R et al. Helicobacter pylori vaccine development and use: a cost-effectiveness analysis using the Institute of Medicine Methodology. Helicobacter. 1999; 4(4): 272-80.
[33] Coelho LG, Leon-Barua R, Quigley EM. Latin-American Consensus Conference on Helicobacter pylori infection. Latin-American National Gastroenterological Societies affiliated with the Inter-American Association of Gastroenterology (AIGE). American Journal of Gastroenterology. 2000; 95(10): 2688-91.
[34] Li H, Stoicov C, Cai X et al. Helicobacter and gastric cancer disease mechanisms: host response and disease susceptibility. Current Gastroenterology Reports. 2003; 5(6): 459-67.
[35] Leivo T, Salomaa A, Kosunen TU et al. Cost-benefit analysis of Helicobacter pylori screening. Health Policy. 2004; 70(1): 85-96.
[36] Roderick P, Davies R, Raftery J et al. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model. Health Technology Assessment. 2003; 7(6): 1-86.
[37] Fendrick AM, Chernew ME, Hirth RA et al. Clinical and economic effects of population-based Helicobacter pylori screening to prevent gastric cancer. Archives of Internal Medicine. 1999; 159(2): 142-8.
[38] Sullivan T, Ashbury FD, Fallone CA et al. Helicobacter pylori and the prevention of gastric cancer. Canadian Journal of Gastroenterology. 2004; 18(5): 295-302.