AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1983, Warren (a biologist) and Marshall (a clinician) described Helicobacter pylori (HP). At first, they named the bacterium Campylobacter pyloridis. Later, it was named Campylobacter pylori. Since then, a large number of reports have been produced on H pylori and its pathogenetic potential. In fact, although peptic ulcer disease is the most studied disease related to H pylori infection, this bacterium is seemingly involved in the pathogenesis of several extragastric diseases, such as mucosa-associated lymphoid tissue lymphomas (MALTomas), coronaritis, gastroesophageal reflux disease, iron deficiency anemia, skin disease, and rheumatological conditions. However, at present, many of these associations remain largely uncertain, and the debate to confirm or refute causality related to these associations is still open.

The association of chronic H pylori infection with alterations in gastric mucosal cell proliferation is recognized worldwide. In addition, H pylori can produce and release several bioactive factors that may directly affect the stomach's parietal cells, which produce hydrochloric acid, and enterochromaffinlike (ECL) cells (ie, G cells and D cells), which produce gastrin and somatostatin, respectively. Evidence suggests that H pylori inhibits D cells and stimulates G cells. H pylori has some control mechanisms able to switch the transcription of different genes on or off when needed.

A strong association has been reported between H pylori infection and gastric lymphoma and adenocarcinoma of the body and antrum of the stomach. Some cofactors may play a key role in determining such diseases. Whether H pylori eradication can decrease the risk of cancer remains unknown.

H pylori infection occurs more frequently in developing countries than in industrialized countries. H pylori strains differ in their potential to cause diseases. Although anyone can develop a microscopic gastritis, only a minority of infected persons develop ulcers or other diseases.

Some Helicobacter-like organisms (HLOs) have been detected by specific polymerase chain reaction tests. The first of these HLOs was described in ferrets and is called Helicobacter mustelae. Helicobacter hepaticus has been described in Syrian hamsters. These HLOs are useful for researching H pylori infection modalities.

Pathophysiology

The most common route of H pylori infection is either oral-to-oral (stomach contents are transmitted from mouth to mouth) or fecal-to-oral (from stool to mouth) contact. Parents and siblings seem to play a primary role in transmission.

In a susceptible host, H pylori determines chronic active gastritis that may lead, in turn, to duodenal and gastric ulcer disease, gastric cancer, and MALTomas. H pylori infection causes chronic active gastritis, which is characterized by a striking infiltrate of the gastric epithelium and the underlying lamina propria by neutrophils, T and B lymphocytes, macrophages, and mast cells. Mast cells, usually responsible for the immune response balance, may be important effector cells in the pathogenesis of gastritis. However, H pylori does not seem to invade the gastric mucosa, although evidence suggests that the mucus creates a niche wherein the germ is protected from gastric secretions.

The release of host cytokines after direct contact of H pylori with epithelial cells of the gastric lining could recall the inflammatory cells in the infected area. One study demonstrated that the gastric epithelium, when infiltrated by neutrophils and macrophages in the lamina propria, highly expresses 2 neutrophil chemotactic factors: gro-alpha and interleukin-8. In addition, the interferon-gamma inducible protein–10 (IP-10) and the monokine induced by interferon-gamma (MIG), 2 selective chemotactic factors for T lymphocytes, are expressed by the endothelium and mononuclear cells of the gastric mucosa in patients with H pylori-related gastritis. According to the same study, gro-alpha and interleukin-8 may have a central role in neutrophils trafficking from the vessels to the mucosal epithelium, while IP-10 and MIG determine T lymphocyte recruitment into the mucosa.

Another hypothesis states that H pylori may recall immune cells from afar because of its own molecules, such as urea or lipopolysaccharide (LPS). Outer-membrane permeability is a function mediated by LPS. Despite the presence of bacterial LPS in biologically active quantities in the gastric mucosa, the mechanisms by which it may recall the immune cells are still unknown. According to one hypothesis, H pylori may induce the production of autoantibodies against the host's gastric lining.

The LPS of H pylori shows certain blood group antigens, such as Le^b, Le^x, Le^y, and H-type I. Such antigens are thought to represent important virulence factors involved in the adhesive process of the germ. Le^b constitutes an adhesin, and differences exist in the Le compositions of adherent and nonadherent bacteria. This, perhaps, accounts for a relationship between adhesion and Le expression. In addition, any Le antigen shows phase variation leading to the spontaneous and random switching on and off of the expression of these antigens. For example, the H-type I antigen seems to be the result of a reversible singular nucleotidic deletion/insertion in a tract of a glycosyl transferase gene. The LPS of the H pylori also seems to influence tumoral proliferation of ECL cells, stimulating the intracellular polyamine biosynthesis pathway and ornithine decarboxylase activity by the activation of a CD14 receptor on theECL cell.

In 1997, Tomb and coworkers completely sequenced the H pylori genome, and some differences were found in gene encoding factors that are likely to interact with the host, such as surface proteins.¹ Two of the most important genes of H pylori are VACA and CAGA. The VACA gene codes for the Vac-A cytotoxin, a vacuolizating toxin. Most H pylori strains (60%), by unexplained causes, do not produce this protein. The CAGA gene codes for the Cag-A protein, which seems to stimulate the production of chemotactic factors for the neutrophils by the gastric epithelium of the host. A certain portion of H pylori strains (40%), by unexplained causes, does not produce this protein.

After the exposure to CAGA-positive H pylori strains, an increase has been reported in catalase, glutathione peroxidase, and superoxide dismutase activity. This increase is associated with fewer DNA adducts and reduced susceptibility of the gastric cells to the irreversible injuries from reactive oxygen species (ROS) compared with exposure to CAGA-negative H pylori strains. Such alterations of the ROS scavenging enzymes may partly account for the increased risk of gastric cancer in individuals with H pylori infection.

A relationship among CAGA/Cag-A, VACA alleles, and the Le subtype of H pylori strains has been reported, as has a link between these and the redox status of the gastric mucosa. For example, H pylori is able to induce apoptosis in epithelial cells and T lymphocytes. The CAGA-positive strains of H pylori seem to be able to increase FASL expression in T lymphocytes (up-regulation of FASL on such cells is redox-sensitive), which facilitates a selective killing of the T lymphocytes. This molecular mechanism may have a key role in the persistence of CAGA-positive strains.

In addition, H pylori up-regulates caspases 3, 6, 8, and 9. Caspases 3 and 9 in epithelial cells are fundamental in inducing apoptosis. The expression of some bacterial genes is acid-regulated, as reported for the FILA gene (responsible for the H pylori motility) that codes for a sigma factor required for transcription of the flagellin gene FLAA. Flagella and urease are very important for the colonization of the gastric mucosa by the bacterium.

Frequency

United States

The frequency of H pylori infection may be linked to race. White persons account for 29% of cases, and Hispanic persons account for 60% of cases.

International

H pylori is a ubiquitous organism. At least half of all people are infected, but an exact determination is not available, mostly because exact data are not available from developing countries. H pylori may be detected in approximately 90% of individuals with peptic ulcer disease; however, less than 15% of infected persons may have this disease.

Mortality/Morbidity

The mortality rate related to H pylori infection is not precisely known, but it seems to be minimal (ie, approximately 2-4% of all infected people). Mortality is due to the complications of the infection, such as gastric ulcer perforation or MALTomas of the GI tract. Otherwise, the morbidity of H pylori infection can be very high.

Race

The pathogenetic role of H pylori may differ depending on geography and race. White persons are infected with H pylori less frequently than persons of other racial groups. The prevalence rate is approximately 20% in white persons, 54% in African American persons, and 60% in Hispanic persons.

Sex

No sex predilection is known; however, females have a higher incidence of reinfection (5-8%) than males.

Age

H pylori infection may be acquired at any age. According to some epidemiologic studies, this infection is acquired most frequently during childhood. Children and females have a higher incidence of reinfection (5-8%) than adult males.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

In the authors' opinion, no significant differences in the presence and frequency of symptoms, such as nausea, vomiting, pain, heartburn, or diarrhea, occur in patients who are infected with H pylori and patients who are not. No definite evidence demonstrates a clear relationship between the symptoms of the H pylori-associated gastritis and abdominal pain or dyspeptic symptoms from other conditions. Of patients, 30-35% have no symptoms.

• Adults and children differ in immune response to H pylori infection. This is probably due to a physiologic lower density of neutrophils and T lymphocytes during childhood, especially in children younger than 8 years.
• Although H pylori infection is not significantly related to recurrent abdominal pain, weekly pain is reported more often in children who are infected with H pylori compared with children who are not infected.

Physical

No specific clinical signs have been described in patients with H pylori infection.

• Patients may feel dyspepsia or abdominal discomfort, such as during gastritis or with epigastric pain (eg, duodenal ulcers).
• In some cases, patients may feel hungry in the morning and may have halitosis.

Causes

• H pylori infection causes atrophic and even metaplastic changes in the stomach.
• The bacterial adhesion appears to result in tyrosin phosphorylation and is specific for gastric cells.
• The adhesion of H pylori to the gastric cells causes a direct decrease in mucosal levels of glutathione, a fundamental molecule in the maintenance of the cellular redox status and in the molecular regulation of host immune responses. However, the LPS of H pylori may induce the production of autoantibodies that are able to worsen atrophy in the corpus mucosa and cause a concomitant increase in parietal cell antibodies. Such events are accompanied by a decrease in anti-H pylori immunoglobulin titers. This process leads to a scenario of severe atrophy without bacterial colonization combined with high levels of autoantibodies against gastric parietal cells.
• A number of reports show the close association between H pylori infection and low-grade gastric MALTomas.
• Giannakis and colleagues demonstrated that H pylori may adapt to gastric stem cells, influencing their biology and contributing to tumorigenesis of the stomach.²

DIFFERENTIALS

Section 4 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• H pylori fecal antigen test 
• • This novel rapid test is based on monoclonal antibody immunochromatography of stool samples. The test has been reported to be very specific (98%) and sensitive (94%).
  • The results are positive in the initial stages of infection and can be used to detect eradication after treatment.
  • Although the H pylori fecal antigen test is an interesting tool, information about the cost of the test is pending.
• Carbon 13 urea breath test  
• • The carbon 13 urea breath test (UBT) is based on the detection of the products created when urea is split by the organism.
  • Patients are asked to drink urea (usually with a beverage) labeled with a carbon isotope (carbon 13 or carbon 14). After a certain duration, the concentration of the labeled carbon is measured in the breath. The concentration is high only when urease is present in the stomach. Because the human stomach does not produce urease, such a reaction is possible only with H pylori infection.
  • The breath test is expensive but is becoming increasingly more available.
  • Other problems include false-negative results due to infection with coccoid forms of H pylori that do not produce as much urease or intake of antibiotics, bismuth, histamine 2 (H2) blockers, or proton pump inhibitors.
• H pylori serology  
• • The serology test has a high (>90%) specificity and sensitivity. It is currently based on the quantitation of immunoglobulin G antibodies against H pylori by the means of an enzyme-linked immunosorbent assay.
  • It is useful for detecting a newly infected patient, but it is not a good test for follow-up of treated patients because the results do not indicate present infection with H pylori. The antibody titer may remain elevated for a long time after H pylori eradication. The number of false-positive results is age related and increases with age.
• Antibiogram  
• • In geographic areas with a high resistance rate against metronidazole and clarithromycin, culture for antibiotic susceptibility testing (antibiogram) seems to be useful.
  • Alternatively, metronidazole and clarithromycin should not be recommended as first-line drugs in such areas.

Imaging Studies

• Imaging studies are not helpful in the diagnosis of H pylori infection. Otherwise, they may be useful in patients with complicated disease (eg, ulcer disease, gastric cancer, MALToma).

Other Tests

• Esophagogastroduodenoscopy  
• • An esophagogastroduodenoscopy (EGD) is often necessary in patients with symptoms of peptic ulcer disease in order to view the condition of the mucosal lining of the stomach and duodenum and to obtain biopsy specimens from the gastric antrum.
  • An echography associated with an EGD is mandatory in patients with biopsy results that are positive for gastric MALTomas in order to allow a more precise staging of the disease.
• Peptic ulcer disease and gastric cancer may manifest with the same symptoms, and the only way to differentiate them is to view the lesion and to perform a histologic examination on biopsy specimens.

Procedures

• Patients with new peptic ulcer disease should have a UBT, they should be tested for antibody titers, or they may require an investigation for stool antigens.
• In patients with prior peptic ulcer disease, an EGD with biopsy and histological studies may be performed. Also, a UBT is helpful in these patients.

Histologic Findings

H pylori is a gram-negative bacterium. It produces urease, has a spirallike conformation, and is microaerophilic and motile because of the flagella. Flagella and urease are very important for its colonization of the gastric mucosa. Urease neutralizes gastric acidity, converting the gastric urea to ammonium ions, and flagella help the bacterium pass from the acidic gastric lumen into the mucus of the stomach. Two of the most important genes of H pylori are VACA and CAGA. The VACA gene codes the Vac-A cytotoxin, a vacuolizating toxin, and the CAGA gene codes for Cag-A protein, which seems to stimulate the production of chemotactic factors for the neutrophils by the gastric epithelium of the host.

Biopsy specimens from EGD, stained with Giemsa stain, usually demonstrate a variable number of H pylori organisms adhering to the gastric epithelium, both coating the gastric wall and lining the gastric glands. The mucous film appears decreased. A large inflammatory infiltrate is present, with lymphocytes, neutrophils, and a variable number of mast cells that seem to play an important role in the pathogenesis of the gastric injury of persons infected with H pylori. Other stains are Genta, Warthin-Starry silver, and the classic hematoxylin and eosin. A rapid urease test may demonstrate the presence of the H pylori in the gastric mucosa via histochemistry results. Bacterial culture is very difficult. It is not used for diagnosis; it is used for experimental purposes only.

Staging

Although a staging system for the H pylori infection does not exist, some steps of the disease are well described. The first step is chronic gastritis, followed after a time by the second step, atrophic gastritis. The third step is intestinal metaplasia, which may evolve into dysplasia. The last step in this process is gastric adenocarcinoma. This process is very slow and may stop at any step because gastric cancers undoubtedly require several other factors to develop, not only an H pylori infection. As reported above, ultrasound and EGD should be considered in patients with gastric MALTomas in order to allow a more precise staging of the disease.

TREATMENT

Section 6 of 11  

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Medical Care

Only treat patients who have a test result positive for H pylori infection. Carefully educate patients regarding the importance of completing the prescription and about the potential adverse effects of the medication. Importantly, consider possible antibiotic resistance when selecting the treatment regimen.

• The US Food and Drug Administration has approved some regimens, which are now accepted internationally, for the treatment of H pylori infection in patients with peptic ulcer disease, both gastric and duodenal.  
• • These regimens are also known as triple therapies and have reported cure rates from 85-90%.
  • Administer triple therapies for 10-14 days. The treatment regimens are omeprazole, amoxicillin, and clarithromycin (OAC) for 10 days; bismuth subsalicylate, metronidazole, and tetracycline (BMT) for 14 days; and lansoprazole, amoxicillin, and clarithromycin (LAC), which has been approved for either 10 days or 14 days of treatment.
  • Macrolide resistance in patients with H pylori infection is an important problem. Although the molecular mechanisms of nitroimidazole resistance are very complex and still unclear, resistance has been shown to be due to a single point mutation (usually in the RDXA gene, although other genes may be involved, eg, FRDXA) in 1 of 4 positions of the bacterial 23S rDNA. Such mutations also determine cross-resistance to other macrolides.
  • An emerging and increasing problem in many Western countries is the fact that some H pylori strains in children are resistant to the antibiotic clarithromycin. The causes are not known.
• All the eradication treatments have a high incidence of certain adverse effects (eg, nausea, metallic taste). If skin rash, vomiting, or diarrhea occurs, discontinue treatment.
• The links between H pylori and nonulcer dyspepsia are debated; however, some patients with nonulcer dyspepsia benefit from eradication. Patients with symptoms have a higher eradication rate than patients with nonulcer dyspepsia disease. Eradication of H pylori in patients without peptic ulcer disease has resolved the dyspepsia in a few cases.
• See related CME at American College of Gastroenterology Issues Guidelines for Treatment of Helicobacter pylori Infection.

Surgical Care

Surgery is not required for patients with H pylori infection, but it may be considered in patients with severe complications, such as cancer.

Diet

No dietary restrictions are usually needed.

Activity

No limitations of physical activity are needed if patients do not have complications.

MEDICATION

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The goals of pharmacotherapy are to eradicate the microorganism, to prevent complications, and to reduce morbidity. Triple therapies are used. Worldwide, accepted treatment regimens are BMT, LAC, and OAC. BMT regimen is based on the administration of bismuth subsalicylate, metronidazole, and tetracycline. Add an H2-receptor antagonist for an additional 4 weeks. LAC regimen is based on the administration of lansoprazole, amoxicillin, and clarithromycin. OAC regimen is based on the administration of omeprazole, amoxicillin, and clarithromycin.

Drug Category: Antidiarrheals

The approved antidiarrheal for this infection is bismuth subsalicylate. It has both antisecretory and antimicrobial activity.

Drug Category: Antibiotics

Use agents known to be effective against H pylori.

Drug Category: Proton pump inhibitors

Bind to proton pump of parietal cell, inhibiting secretion of hydrogen ions into gastric lumen. Relieve pain and heal peptic ulcers more rapidly than H2 antagonists.

Drug Category: H2 receptor blockers

Reversible competitive blockers of histamine at H2 receptors, particularly those in gastric parietal cells, wherein they inhibit acid secretion. H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents. Proton pump inhibitors are usually preferred.

FOLLOW-UP

Section 8 of 11  

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• Medication
• Follow-up
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• Multimedia
• References

Further Outpatient Care

• Consider performing a UBT 4-12 weeks after the end of treatment.
• EGD with biopsy and a urease test also may be useful, but, importantly, remember that this test does have a significant rate of false-negative results.

Deterrence/Prevention

• Risk is increased for patients who have an H pylori infection and whose first-degree relatives have a history of gastric cancer, even if they are asymptomatic.
• Persons emigrating from geographic areas with a high incidence of gastric cancer have an increased risk.
• Consider any patient with precancerous lesions of the stomach (ie, intestinal metaplasia) for treatment of H pylori infection.
• See related CME at Eradicating H pylori Reduces Risk for Gastric Cancer Recurrence.

Complications

• Gastric adenocarcinoma is the most severe consequence of an H pylori infection.
• Gastric MALToma may be treated with H pylori eradication therapy and has a better prognosis than gastric adenocarcinoma.  
• • A significant difference exists between the therapeutic response of MALTomas restricted to the mucosa and other, more infiltrating lesions.
  • The only predictive factor for disease regression seems to be the absence of nodal involvement.
• H pylori infection is associated with squamous cell esophageal cancer.
• H pylori may play an important role in idiopathic thrombocytopenic purpura. This is due to anti-CagA antibodies that cross-react with platelet antigens.
• According to some reports, H pylori eradication may cause peptic esophagitis, probably due to a protective action of the bacteria on the cardia area.

Prognosis

• The prognosis is usually excellent, even in patients with complications, such as gastric MALToma. However, the prognosis becomes poor for patients who develop squamous cell esophageal cancer or gastric carcinoma.
• The rate of reinfection is very low (1-2%); however, children and females have a higher incidence of reinfection (5-8%).

Patient Education

• Educate patients with a high risk for gastric cancer about clinical control methods and, if H pylori-positive, to begin eradication therapy. However, patients must be educated about the adverse effects of the therapy in order to impress upon them the importance of compliance with the full regimen in order to prevent antibiotic resistance and relapse.
• For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center and Heartburn/GERD/Reflux Center. Also, see eMedicine's patient education articles Gastritis, Peptic Ulcers, Heartburn, Understanding Heartburn/GERD Medications, and Abdominal Pain in Adults.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Consider performing an EGD before prescribing a treatment for peptic ulcer disease. Peptic ulcer disease and gastric cancer may manifest with the same symptoms, and a correct diagnosis is mandatory to avoid legal claims. Also consider that in a small number of cases (2%), peptic ulcer disease and gastric carcinoma, even ulcerated, may coexist.

Special Concerns

• If H pylori infection occurs during pregnancy, delay the treatment until after delivery because of the adverse teratogenous effects of some drugs used in the therapeutic protocols for H pylori eradication. In addition, delaying a new pregnancy for at least 1 month after the end of treatment may be advisable.
• H pylori has been associated with conjunctival MALT lymphoma, particularly with the vacA s1 virulent strain.³

MULTIMEDIA

Section 10 of 11  

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Media file 1:  An antral gland of the stomach with a large Giemsa-stained colony of Helicobacter pylori in the lumen (arrow) at 250X power. Courtesy of Pantaleo Bufo, University of Foggia, Italy.
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Media file 2:  Helicobacter pylori infection. Lamina propria of the stomach is shown with 2 mast cells overlapping each other. Note the upper part the degranulating process with the release of granules of inflammation mediators (Giemsa staining, 250X). Courtesy of Pantaleo Bufo, University of Foggia, Italy.
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Media file 3:  Helicobacter pylori infection. A transverse section of the gastric lamina propria is shown. In the lower part, an antral gland of the stomach is present with some Helicobacter pylori in the lumen (red-blue arrow). In the upper part, a mast cell (yellow arrow) is present (Giemsa staining, 250X). Courtesy of Pantaleo Bufo, University of Foggia, Italy.
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Media type:  Photo

Media file 4:  An antral gland of the stomach is shown with a large colony of Helicobacter pylori in the lumen (Giemsa staining, 425X). Courtesy of Pantaleo Bufo, University of Foggia, Italy.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Introduction
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• Differentials
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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: Aug 14, 2008