Ulcers and More: The Beginning of an Era1
Brian E. Lacy2 and Justin Rosemore
Marvin M. Schuster Motility Center, Johns Hopkins Bayview Medical Center, Baltimore, MD 21224
2To whom correspondence should be addressed. E-mail: email@example.com.
KEY WORDS: • H. pylori • gastric cancer • peptic ulcer disease • nutrition • anemia
Many clinicians believe that H. pylori is a recent discovery. However, this bacterium was first described in pathology specimens in the 1890s and again in the 1930s, although these initial descriptions did not attract significant attention. In the early 1980s, Marshall and Warren (2) cultured H. pylori, proved its infectious nature, and described its clinical symptoms. Marshall fulfilled Koch’s postulates when he ingested approximately one billion bacteria in 1985 and subsequently developed H. pylori gastritis. This bacteria was originally described as a Campylobacter-like organism (hence the acronym CLO). Later it was renamed C. pyloridis to reflect its presence in the pylorus, then C. pylori, and finally it was renamed H. pylori in 1989.
In the U.S. the incidence of H. pylori infection in adults is 0.5–1.0% per year (3) . The major risk factors for the development of H. pylori include a low socioeconomic status, crowded living conditions (especially during childhood), poor sanitation, the absence of a hot water supply and poor hygiene. Most infections appear to occur early in life, and the rates of infection between men and women are similar. An oral-oral route of transmission is supported by studies demonstrating increased transmission in chronic care facilities and in institutionalized individuals (4) . However, some researchers believe that H. pylori may also spread by a fecal-oral route. The stomach is the natural habitat of this organism, although it has also been found in dental plaque and saliva (5) . At present, there are no known zoonotic reservoirs.
Bacteriology and pathogenicity.
H. pylori is a spiral shaped, gram-negative, microaerophilic rod with 4–7 flagella. The flagella aid in the colonization of the bacterium to the gastric mucosa. The bacteria is 3–5 µm long and 0.5 µm in diameter. H. pylori binds to normal gastric mucosa through one or more receptors and is often found near intercellular junctions. H. pylori prefers to bind to normal tissue rather than metaplastic tissue. This may explain the smaller number of organisms seen in the antrum of patients with chronic H. pylori gastritis, as the bacteria migrate to healthier tissue in the fundus. The organism resides on the surface of gastric epithelial cells, underneath a layer of mucous, and is thus protected from the acid environment of the stomach. Invasion into the cell may occur in vitro; however, this does not appear to be a major factor in the virulence of the organism in vivo. Although H. pylori produces many different chemicals and toxins, the most important is urease. Urease enables H. pylori to break urea down into ammonia and bicarbonate, the latter of which is then broken down into water and carbon dioxide. Ammonia alkalinizes the micro-environment that surrounds the bacteria—a protective device—as H. pylori does not like a highly acidic environment. However, H. pylori needs some acid in the environment to both grow and replicate, because these two processes are inhibited when the pH is >7.0.
H. pylori produces disease through a variety of processes. Although beyond the scope of this article, a brief mention is warranted. In the stomach, the bacteria colonizes the gastric mucosa by adhering to the cell surface (through expression of Lewis blood group antigens and lipopolysaccharide [LPS]), producing urease, cagA gene products, and antibacterial peptides (cecropins). H. pylori avoids host defenses by shedding bacterial proteins, by detoxifying reactive oxygen free radicals, and through the innately low biologic activity of H. pylori LPS. H. pylori can directly injure the host through the production of urease and the release of various hemolysins, cytotoxins (vac A) and LPS. Damage also occurs through the immune system as the host mounts an immune response with increased cytokine production and the subsequent migration and activation of mononuclear cells and phagocytes.
When choosing the appropriate test, it is important to consider the cost of the test, to determine if the patient has previously been treated for H. pylori, and to find out if the patient is on other medications that might influence test results (i.e., antibiotics, bismuth and proton pump inhibitors [PPIs]). Six methods are now routinely used to diagnose H. pylori infection. The first method is serology. Most laboratories now use an enzyme-linked immunosorbent assay (ELISA) to check for IgG antibodies. This test is inexpensive, and sensitivity and specificity are estimated to be 80–90%. This method cannot, however, differentiate between a current infection or previous exposure. After treatment and eradication, antibody levels remain positive for years, although titers may drop by 50% at 12 mo. The second method is pH indicator tests. These are performed at the time of upper endoscopy. The test strips (e.g., CLOtest, PyloriTek, Hpfast) check for the presence of urease. Sensitivity and specificity are high (95–98%). Recent antibiotic, bismuth, or PPI use (within 2 wk) may produce a false negative result. The urease tests themselves are inexpensive; however, they all require the additional expense of endoscopy. The third method is histology. At the time of endoscopy, biopsies are taken from the antrum and usually from the fundus as well. The presence of a chronic active gastritis strongly suggests infection, while the absence of chronic active gastritis virtually excludes infection. Various stains can be used (hemotoxylin and eosin, Giemsa, Warthin-Starry) to identify H. pylori. Sensitivity and specificity are high (95% range). Biopsy specimens are moderately expensive, although the cost of the endoscopy makes this an expensive test. The fourth method is tissue culture. This is reserved for those patients who have been treated for H. pylori infection in the past but have had a recurrence. Biopsy samples are submitted to the laboratory for culture and determination of antibiotic resistance. This is a cumbersome and expensive process. The fifth method is breath tests. These are now available and can be performed in the office. Patients are given a small amount of radioactively labeled carbon (13C or 14C) coupled to urea. The urease breaks down the urea, producing radioactive bicarbonate. This is absorbed through the gastric mucosa and then broken down into 13CO2 or 14CO2, which can be measured as the patient breathes into a bag. The dose of radioactivity is low—less than one-twentieth of a chest X-ray. The sensitivity and specificity are high (>95%), while the cost is moderate. This test is best used to determine H. pylori eradication after treatment. However, patients must be off all PPIs 7–14 d in advance of the test and need to be off bismuth products and antibiotics for at least 4 wk. The sixth method is stool antigen tests. These are new and became commercially available in the last year. They appear to be accurate (80 - 94% specificity and sensitivity) and reasonably priced. Antibiotics, bismuth products, and PPIs may all decrease sensitivity.
Over the past decade, hundreds of articles have been written about various strategies to eradicate H. pylori gastritis. Although it is beyond the scope of this article to review all of the strategies in detail, current recommendations for the treatment of H. pylori are that two different antibiotics be used in conjunction with a PPI for two continuous weeks. Eradication rates are generally in the 80–95% range, depending on the geographic area and the level of antibiotic resistance (6) . A novel therapy has recently been suggested by Zhang et al. (7) , who demonstrated that vitamin C inhibited the growth of H. pylori both in vivo and in vitro. Once eradicated, the risk for reinfection in the U.S. is 1% per year.
The strong association between H. pylori infection and the later development of duodenal ulcers is based on several lines of evidence. First, patients with duodenal ulcers who do not take nonsteroid anti-inflammatory agents (NSAIDs) are likely to be infected with H. pylori. Earlier studies found that >90% of duodenal ulcers were caused by H. pylori, although more recent carefully controlled studies have found that, in the absence of NSAIDs, H. pylori is the cause of duodenal ulcers in 70% of cases (8 ,9) . Second, patients with duodenal ulcers infected with H. pylori are unlikely to have recurrence of their disease if treated for H. pylori (10) . Patients with duodenal ulcers have nearly a 70% chance of recurrence if they are treated only with acid suppressants, while patients treated with acid suppressants and H. pylori eradication have a <10% chance of recurrence. Third, the natural history of H. pylori infection of the stomach involves a mechanism that predisposes one to duodenal inflammation and ulceration. This mechanism is as follows: when patients develop H. pylori infection, inflammation occurs predominantly within the antrum; the body of the stomach is relatively spared. The resultant gastritis leads to increased stimulation of G-cells, which release gastrin, a hormone that stimulates enterochromaffin-like cells to release histamine. When histamine is released, it binds to histamine–type 2 receptors on parietal cells, which then release acid. Over time, this constant stimulation leads to an increased acid load delivered to the duodenum, which results in mucosal irritation. If the infection is not eradicated, or if the acid load is not suppressed, duodenal ulceration can ensue.
Much of the evidence used to support the role of H. pylori in the development of duodenal ulcers also applies to gastric ulcers. That is, H. pylori is known to produce gastritis; eradication of H. pylori results in resolution of gastritis; and patients with H. pylori treated with antibiotics have significantly lower rates of gastric ulcer recurrence as opposed to those individuals who did not receive antibiotic therapy. In the absence of NSAID use, H. pylori is associated with gastric ulcers 60% of the time.
NUD is a heterogeneous condition, and researchers have attempted to categorize the symptoms into four separate classes: ulcer-like, reflux-like, dysmotility-like, and finally, nonspecific dyspepsia. The role of H. pylori infection in the pathogenesis of NUD is not entirely clear. The rate of H. pylori infection in patients with NUD is quite high—up to 87% in some studies (18) . A meta-analysis has shown that subjects with NUD are twice as likely to be infected with H. pylori as control subjects (19) . Several studies have demonstrated that H. pylori infection often precedes the development of symptoms (3) ; however, specific symptoms attributable to H. pylori in the NUD group have not been found.
Several theories have been proposed to account for the relation between H. pylori infection and NUD. These theories include the effects of H. pylori on gastric acid secretion, gastric motility and nociception. Acid secretion has been found to be higher in patients with NUD who are infected with H. pylori, as compared with those who are H. pylori negative. One study reported that patients with NUD who were H. pylori positive had delayed gastric emptying, which improved after eradication of H. pylori (20) . However, most studies have not demonstrated any consistent relationship between gastric emptying and H. pylori infection. Theoretically, H. pylori infection, acting through a generalized inflammatory response, may make patients with NUD more sensitive to normal gut stimuli.
Eradication of H. pylori in patients with NUD has provided mixed results. One meta-analysis found that 73% of patients with NUD who became H. pylori negative after treatment noted an improvement in symptoms, compared with only 45% of patients who remained H. pylori positive (21) . A second meta-analysis, however, found that eradication of H. pylori did not improve symptoms of NUD (22) . Treating H. pylori in patients with NUD has been shown to be cost-effective, however, and may reduce potentially unnecessary endoscopy (23) .
The recognition of symptoms and diseases attributable to H. pylori continue to increase with the development of biochemical methods able to detect minute quantities of the Helicobacter genome. A recent focus of research in the field of H. pylori has been on the role of Helicobacter species in the pathogenesis of biliary disease and/or primary liver cancer. Recent discoveries of H. canis in a dog with hepatitis (28) , H. hepaticus in the intestinal tract of mice with liver carcinoma (29) and H. bilis in both bile and the gallbladder of mice with chronic cholecystitis (30) have highlighted the opportunity to uncover new types of infectious agents in liver disease. Avenaud et al. (31) demonstrated the presence of Helicobacter genes in all patients with primary liver carcinoma, whereas only a small fraction of those without primary liver carcinoma had Helicobacter genes . Although only a part of a small study, these results raise the possibility that H. pylori may be a factor in primary liver cancer. Several studies have shown that H. pylori may play a role in the induction of hyperammonemia and the subsequent development of hepatic encephalopathy in patients with cirrhosis (32 ,33) . Although not confirmed by other studies, a putative mechanism is that elevated ammonia levels occur secondary to the effects of bacterial urease. Current research focuses on the role H. pylori may play in the formation of intrahepatic stones and the induction of biliary epithelial inflammation.
From a practical standpoint, it seems reasonable that H. pylori might be involved in disorders of the skin, given that other infectious agents (viral hepatitis, tropherma whippeli and Enterotoxigenic E. coli) often have skin manifestations. Utas et al. (34) addressed the relationship between H. pylori and acne rosacea. They were able to show a significant improvement in the severity of rosacea after standard H. pylori treatment, although a statistical difference in seropositivity between patients with and without rosacea was not present. A high prevalence of H. pylori in patients with chronic urticaria has been suggested and supported by a small study (35) that showed seropositivity and a positive breath test in 62% of patients with chronic urticaria, as compared with 43% of patients without chronic urticaria. However, eradication of H. pylori in patients with chronic urticaria has not consistently improved symptoms. In addition, one case study has implicated H. pylori in the development of Sweet’s Syndrome, a dermatopathic process characterized by fever, leukocytosis and erythematous skin plaques (36) . Eradication of H. pylori in this case led to resolution of the skin lesions. Future research will likely focus on the major areas described above, with a greater emphasis on the design and size of the studies.
H. pylori has been suggested as a possible etiologic agent in the pathogenesis of atherosclerosis. Danesh et al. (37) showed a weak association between coronary artery disease (CAD) and H. pylori with 54% of coronary heart disease (CHD) patients seropositive for H. pylori, whereas 46% of control subjects were seropositive. The mechanism by which H. pylori would accelerate or initiate atheroma formation remains a mystery. Several theories that focus on the role H. pylori plays in the serum levels of lipids, coagulation factors and various inflammatory mediators exist. It has been proposed that H. pylori infection produces an inflammatory response that leads to elevated lipid levels and clotting factors, thereby facilitating clot formation and accelerating atherogenesis. However, this argument was weakened after two separate studies failed to show a definitive correlation between H. pylori seropositivity and blood lipids (38 ,39) . In addition, results from studies looking at coagulation factors in patients seropositive for H. pylori are mixed. Special interest has recently been paid to the possibility that different strains of H. pylori are more likely to induce CHD. Pasceri et al. (40) showed an almost fourfold increase risk of CHD in cagA-seropositive individuals. However, this was challenged by a larger study (41) that showed no significant increase in disease between cagA strains and other H. pylori strains. An alternative approach has involved examining atheromatous tissue for evidence of H. pylori DNA. This was performed in two studies (42 ,43) that failed to demonstrate significant evidence of H. pylori DNA by polymerase chain reaction in atheromatous tissue. Angiographically confirmed CAD has failed to correlate with H. pylori seropositivity as seen in the study by Tsai et al. (44) . In summary, no strong conclusions can be drawn from previously published data in regard to the role H. pylori plays in the pathogenesis of CAD.
Anemia and nutrition.
A recent case report indicates that H. pylori infection in children may be associated with iron deficiency anemia (45) . This was demonstrated by an inability to correct the iron deficiency anemia until H. pylori was eradicated. In a double-blind placebo-controlled trial in older children, a positive correlation between H. pylori infection and iron deficiency anemia was found (46) . This complements recent work by the same group, who showed subnormal growth in children with iron deficiency anemia and H. pylori infection (47) . Similar results were obtained by Annibale et al. (48) when 30 patients with iron deficiency anemia and H. pylori gastritis were treated for H. pylori, and the majority of patients recovered from their anemia.
Cobalamin deficiency and the subsequent development of megaloblastic anemia have also been suggested as a possible end result of H. pylori infection (49) . This is supported by data from Kaptan et al. (50) , who studied 138 patients with vitamin B-12 deficiency and identified those with H. pylori infection by upper endoscopy. A total of 77 of 138 patients were infected with H. pylori, and eradication was verified in 31 patients by repeat endoscopy. In all 31 patients successfully treated for H. pylori, vitamin B-12 levels increased and anemia improved without the need for supplements. This is fairly convincing evidence that patients with vitamin B-12–deficient anemia should be evaluated for H. pylori infection and, if positive, treated. The role of H. pylori in normocytic anemias, with concomitant vitamin B-12 and iron deficiency, has yet to be defined.
The mechanism of H. pylori involvement in subnormal growth is not clear, although various possibilities exist, including the development of iron deficiency anemia (see above) or a direct toxic effect by H. pylori infection. A large population-based survey conducted by Murray et al. (51) found a 0.85-cm decrease in the mean height of women infected with H. pylori, as compared with women who were H. pylori negative.
3 Abbreviations used: CAD, coronary artery disease; CHD, coronary heart disease; GERD, gastroesophageal reflux disease; LPS, lipopolysaccharide; MALT, mucosal-associated lymphoid tumor; NSAID, nonsteroid anti-inflammatory agent; NUD, nonulcer dyspepsia; PPI, proton pump inhibitor.
2. Marshall B. J. & Warren J .R. (1984) Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1:1311-1315.[Medline]
3. Parsonnet J., Blaser M. J., Perez-Perez G. I., Hargrett-Bean N. & Tauxe R. V. (1992) Symptoms and risk factors of Helicobacter pylori infection in a cohort of epidemiologists. Gastroenterology 102:41-46.[Medline]
4. Lambert J .R, Lin S. K., Sievert W., Nicholson L., Schembri M. & Guest C. (1995) High prevalence of Helicobacter pylori antibodies in an institutionalized population: Evidence for person-to-person transmission. Am. J. Gastroenterol. 90:2167-2171.[Medline]
5. Nguyen A. M., El-Zaatari F. A. & Graham D. Y. (1995) Helicobacter pylori. in the oral cavity. A critical review of the literature. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod 79:705-709.[Medline]
6. Walsh J. H. & Peterson W. L. (1995) The treatment of Helicobacter pylori infection in the management of peptic ulcer disease. New Engl. J. Med. 333:984-990.[Free Full Text]
7. Zhang H. M., Wakisaka N., Maeda O. & Yamamoto T. (1997) Vitamin C inhibits the growth of a bacterial risk factor for gastric carcinoma: Helicobacter pylori. Cancer 80:1897-1903.[Medline]
8. Hosking S. W., Ling T. K., Yung M. Y., Cheng A., Chung S. C., Leung J. W. & Li A. K. (1992) Randomized controlled trial of short term treatment to eradicate Helicobacter pylori in patients with duodenal ulcer. B.M.J. 305:502-504.
9. Jensen D. M., You S. & Pelayo E. (1992) The prevalence of Helicobacter pylori and NSAID use in patients with severe UGI hemorrhage and their potential role in recurrence of ulcer bleeding. Gastroenterology 102:A90.
10. Hentschel E., Brandstatter G., Dragosics B., Hirschl A. M., Nemec H., Schutze K., Taufer M. & Wurzer H. (1993) Effects of ranitidine and axomicillin plus metronidazole on the eradication of Helicobacter pylori and the recurrence of duodenal ulcer. New Engl. J. Med. 328:308-312.[Abstract/Free Full Text]
11. Bayerdorffer E., Neubauer A., Rudolph B., Thiede C., Lehn N., Eidt S. & Stolte M. (1995) Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet 345:1591-1594.[Medline]
12. Wotherspoon A. C., Ortiz-Hidalgo C., Falzon M. R. & Isaacson P .G. (1991) Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet 338:1175-1176.[Medline]
13. Stolte M. (1992) Helicobacter pylori and gastric MALT lymphoma. Lancet 339:745-746.[Medline]
14. Morgnier A., Bayerdorffer E., Neubauer A. & Stolte M. (2000) Malignant tumors of the stomach. Gastroenterology Clin. N.A. 29:593-607.
15. Parkin D. M., Laara E. & Muir C. S. (1988) Estimates of the worldwide frequency of sixteen major cancers in 1980. Int. J. Cancer. 41:184-197.[Medline]
16. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N. & Sibley R. K. (1991) Helicobacter pylori infection and the risk of gastric carcinoma. New Engl. J. Med. 325:1127-1131.[Abstract]
17. Watanabe T., Tada M., Nagai H., Sasaki S. & Nakao M. (1998) Helicobacter pylori infection induces gastric cancer in Mongolian gerbils. Gastroenterol 115:642-648.[Medline]
18. Buckley M. J., Scanlon C. & McGurgan P. (1995) A validated dyspepsia symptom score. Ital. J. Gastroenterol. 29:495-500.
19. Armstrong D. (1996) Helicobacter pylori infection and dyspepsia. Scand. J. Gastroenterol. 31:38-45.[Medline]
20. Murakami K., Fujioka F., Spiotu K., Ito A., Fujiyama K., Kodama R., Kawasaki Y., Kubota T. & Nasu M. (1995) Influence of Helicobacter pylori infection and the effects of eradication on gastric emptying in patients with non-ulcer dyspepsia. Eur. J. Gastroenterol. Hepatol. 1:593-598.
21. Laheij R. J., Jansen J. B., van de Lisdonk K., Severens J. L. & Verbeek A. L. (1996) Symptom improvement through eradication of Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment. Pharmacol. Ther. 10:843-853.[Medline]
22. Laine L., Schoenfeld P. & Fennerty M. B. (2001) Therapy for Helicobacter pylori in patients with nonulcer dyspepsia. Ann. Int. Med. 134:361-369.[Abstract/Free Full Text]
23. Ofman J. J., Etchason J., Fullerton S., Kahn K. L. & Soll A. H. (1997) Management strategies for Helicobacter pylori-seropositive patients with dyspepsia: clinical and economic consequences. Ann. Int. Med. 126:280-291.[Abstract/Free Full Text]
24. Mihara M., Haruma K. & Kamada K. (1996) Low prevalence of H. pylori infection in patients with reflux oesophagitis. Gut 39(Suppl. 2):A94.
25. Sacca N., De Medici A. & Rodino S. (1996) Reflux oesophagitis: A complication of Helicobacter pylori eradication therapy?. Gut 39(Suppl. 2):A91.
26. Labenz J., Blum A. L., Bayerdorffer E., Meining A., Stolte M. & Borsch G. (1997) Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterol 112:1442-1447.[Medline]
27. Schenck B. E., Kuipers E. J., Klinkenberg-Knol E. C., Eskes S. A. & Meuwissen S.G.M. (1999) Helicobacter pylori and the efficacy of omeprazole therapy for gastro-esophageal reflux disease. Am. J. Gastroenterol. 94:884-887.[Medline]
28. Stanley J., Linton D., Burens A. P., Dewhirst F. E. & Owen R. J. (1993) Helicobacter canis sp. nov., a new species from dogs an integrated study of phenotype and genotype. J. Gen. Microbiol 139:2495-2504.[Medline]
29. Fox J. G., Dewhirst F. E., Tully J. G., Paster B. J., Yan L., Taylor N. S., Collins M. J., Gorelick P. L. & Ward J. M. (1994) Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. J. Clin. Microbiol. 32:1238-1245.[Abstract/Free Full Text]
30. Fox J. G., Yan L. L., Dewhirst F. E., Paster B .J., Shames B., Murphy J. C., Hayward A., Belcher J. C. & Mendes E. N. (1995) Helicobacter bilis sp. nov., a novel Helicobacter species isolated from bile, livers, and intestines of aged, inbred mice. J. Clin. Microbiol. 33:445-454.[Abstract]
31. Avenaud P., Marais A., Monteiro L., Le Bail B., Sage P .B., Balabaud C. & Megraud F. (2000) Detection of Helicobacter species in the liver of patients with and without primary liver carcinoma. Cancer 89:1431-1439.[Medline]
32. Quero J. C., Hartmann I.J.C., de Rooij F., Wilson J.H.P. & Schalm S. W. (1995) Hyperammonaemia and Helicobacter pylori. Lancet 346:713-714.[Medline]
33. Miyagi H., Ito S., Azuma T., Ito Y., Yamazaki Y., Ohtaki Y., Sato F., Hirai M., Kuriyama M. & Kohli Y. (1997) Effects of Helicobacter pylori eradication therapy on hyperammonemia in patients with liver cirrhosis. Gut 40:726-730.[Medline]
34. Utas S., Ozbakir O., Turasan A. & Utas C. (1999) Helicobacter pylori eradication treatment reduces the severity of rosacea. J. Am. Acad. Dermatol. 40:433-435.[Medline]
35. Valsecchi R. & Pigatto P. (1998) Chronic urticaria and Helicobacter pylori. Acta Derm. Venereol. 78:440-442.[Medline]
36. Kurkcuoglu N. & Aksoy F. (1997) Sweet’s Syndrome associated with Helicobacter pylori infection. J. Am. Acad. Dermatol. 37:123-124.[Medline]
37. Danesh J., Wong Y., Ward M. & Muir J. (1999) Chronic infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus: population based study of coronary heart disease. Heart 81:245-247.[Abstract/Free Full Text]
38. Patel P., Mendall M. A., Carrington D., Strachan D. P., Leatham E., Molineaux N., Levy J., Blakeston C., Seymour C. A., Camm A. J. & Northfield T. C. (1995) Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. BMJ 311:711-714.[Abstract/Free Full Text]
39. Murray L. J., Bamford K. B., O’Reilly D.P.J., McCrum E. E. & Evans A. E. (1995) Helicobacter pylroi. infection: relation with cardiovascular risk factors, ischemic heart disease, and social class. Br. Heart J. 74:497-501.[Medline]
40. Pasceri V., Cammarota G., Patti G., Cuoco L., Gasbarrini A., Grillo R. L., Fedeli G., Gasbarrini G. & Maseri A. (1998) Association of virulent Helicobacter pylori strains with ischemic heart disease. Circulation 97:1675-1679.[Medline]
41. Whincup P., Danesh J., Walker M., Lennon L., Thomson A., Appleby P., Hawkey C. & Atherton J. (2000) Prospective study of potentially virulent strains of Helicobacter pylori and coronary heart disease in middle-aged men. Circulation 101:1647-1652.[Medline]
42. Blasi F., Denti F., Erba M., Cosentini R., Raccanelli R., Rinaldi A., Fagetti L., Esposito G., Ruberti U. & Allegra L. (1996) Detection of Chlamydia pneumoniae but not Helicobacter pylori in atherosclerotic plaques of aortic aneurysms. J. Clin. Microbiol. 34:2766-2769.[Abstract]
43. Danesh J., Koreth J., Youngman L., Collins R., Arnold J., Balarajan Y., McGee J. & Roskell D. (1999) Is Helicobacter pylori a factor in coronary atherosclerosis?. J. Clin. Microbiol. 37:1651-1659.[Free Full Text]
44. Tsai C. & Huang T. (2000) Relation of Helicobacter pylori infection and angiographically demonstrated coronary artery disease. Dig. Dis. Sci. 45:1227-1231.[Medline]
45. Dufour C., Brisigotti M., Fabretti G., Luxardo P., Mori P.G. & Barabino A. (1993) Helicobacter pylori gastric infection and sideropenic refractory anemia. J. Pediatr. Gastroenterol. Nutr. 17:225-227.[Medline]
46. Choe Y. H., Kim S. K., Son B. K., Lee D. H., Hong Y.C. & Pai S. H. (1999) Randomized placebo-controlled trial of Helicobacter pylori eradication for iron-deficiency anemia in preadolescent children and adolescents. Helicobacter 4:135-139.[Medline]
47. Choe Y. H., Kim S. K. & Hong Y. C. (2000) Helicobacter pylori infection with iron deficiency anaemia and subnormal growth at puberty. Arch. Dis. Child. 82:136-140.[Abstract/Free Full Text]
48. Annibale B., Marignani M., Monarca B., Antonelli G., Marcheggiano A., Martino G., Mandelli F., Caprilli R. & Delle Fave G. (1999) Reversal of iron deficiency anemia after Helicobacter pylori eradication in patients with asymptomatic gastritis. Ann. Intern. Med. 131:668-672.[Abstract/Free Full Text]
49. De Luca V. A. Jr (1992) Helicobacter pylori gastric atrophy and pernicious anemia. Gastroenterology 102:744-745.[Medline]
50. Kaptan K., Beyan C., Ugur Ural A., Cetin T., Avcu F., Gulsen M., Finci R. & Yalcin A. (2000) Helicobacter pylori: is it a novel causative agent in vitamin B12 deficiency?. Arch. Intern. Med. 160:1349-1353.[Abstract/Free Full Text]
51. Murray L. J., McCrum E. E., Evans A. E. & Bamford K. B. (1997) Epidemiology of Helicobacter pylori infection among 4742 randomly selected subjects from Northern Ireland. Int. J. Epidem. 26:880-887.[Abstract/Free Full Text]