Helicobacter pylori

Biology of Helicobacter pylori

Helicobacter are Gram-negative, aerobic or microaerophilic, spiral-shaped bacilli that are motile by way of flagella at one end of the cell. Closely related to Helicobacter are species of the genera Aquaspirillum, Azospirillum, Spirillum, and Camplyobacter. The genetics of Helicobacter pylori are complex; there are many strains of H . pylori which are distinguished by the human disease with which they are associated. Once Helicobacter pylori colonizes its host, it lives in the interface between the surface of gastric epithelial cells and the overlying mucus gel layer, often clustering at the junctions of epithelial cells. In addition H. pylori can also be found on top of the gastric epithelium in the duodenum and esophagus. It was not until 1983 that H. pylori was recognized as having any medical importance. Now, it has been proven that H. pylori infection is the main cause of chronic superficial gastritis and it is associated with both gastric and duodenal ulcers.

Human Disease

Peptic ulcer disease is a common clinical ailment, once thought to be caused by oversecretion of acid and pepsin, an enzyme of the stomach that promotes digestion by breaking down proteins. Researchers have found, however, that although the injury caused by acid and pepsin is necessary for the formation of ulcers, acid secretion levels of the majority of patients with gastric or duodenal ulcers are normal. An ulcer is now known to be the result of an imbalance between aggressive and defensive mechanisms in the stomach and duodenum. Part of that imbalance can be attributed to infection by H. pylori.

Humans are the only known host of Helicobacter pylori. Its prevalence in healthy people increases with age to over 50% in people over the age of 60. Studies have shown that Blacks are more susceptible to infection than are Whites, and incidents of infection increase with decreasing socioeconomic status. Evidence of H. pylori infection in families, prisons, and nursing homes suggest that H. pylori is spread by close personal contact. However, the exact mechanism for transmission of the bacteria is not well understood.

Pathogenicity of Helicobacter pylori

Once acquired, Helicobacter pylori infection persists in its host indefinitely, apparently for life. Its persistence can be attributed to features that allow it to colonize the stomach. H. pylori is motile by polar flagella, allowing it to access susceptible areas. In addition, it is able to withstand the acidic environment of the stomach, because it produces urease, which increases the local pH.

Still, researchers are not sure how H. pylori escapes the bactericidal effects of gastric acid, or how it colonizes the gastric mucosa and damages the gastric epithelial cells. H. pylori produces urease, which leads to the formation of ammonia on the gastric mucosa, thereby increasing the pH of its environment. The organism also releases cytotoxins, toxic proteins, platelet activating factor, and lipopolysaccharide. the latter is overproduced in its outer membrane. Colonization of the stomach by H. pylori leads to an inflammatory response that is mediated by several of the bacterium's virulence determinants, which ultimately cause injury to the stomach tissues.

Diagnosis of H. pylori Infection

Several diagnostic tests are used to detect Helicobacter pylori infection (Table 1). These tests, including invasive and noninvasive techniques, have high sensitivity and specificity. The advantages of the various techniques are described below.

Invasive Techniques

Culture.Because of fastidious nature of H. pylori, culturing the bacterium is often tedious and is no more sensitive or specific than simple histologic analyses. Culturing H. pylori also involves the cost of endoscopy, making the method even less practical.

Histologic analysis of biopsy. Routine histologic analysis of biopsy samples is common and practical. This technique is helpful, because one can visualize the mucosa, permitting detection of histologic gastritis and lesions such as MALT-type lymphomas, which are tumors of lymphoid tissues. There are, however, clear drawbacks that should be considered. First, the organism may have a patchy distribution, especially at the base of the stomach, so more than two biopsy specimens are necessary for accurate results. Also, standard staining techniques (i.e., eosin staining) are usually unreliable for detection of H. pylori by microscopy. Adding to the impracticality of this method is that it requires endoscopy and diagnosis cannot be obtained until several days after the procedure.

Camplyobacter-like organism (CLO) test. This test is based on the fact that mucosal biopsy specimens can be inoculated into a medium containing urea and phenol red, a dye that turns pink in a pH of 6.0 or greater. The pH will rise above 6.0 when H. pylori, the Campylobacter-like organism, metabolizes urea to ammonia by way of its urease activity. This test is commercially available and therefore quite inexpensive. Only one-half hour is required for diagnosis of infection, and the test has shown 98% sensitivity and 100% specificity. These qualities have made the CLO test the invasive technique of choice for diagnosing H. pylori infection.

Noninvasive Techniques

Breath test. Although H. pylori itself can not be detected noninvasively, its urease activity can be detected by way of a breath test. In this test, urea that is radioactively labeled with carbon 13 and carbon 14 is ingested. Bacterial urease splits off labeled carbon dioxide, which can be detected in the breath. Accuracy is not a problem for either of these breath tests, since both elicit 100% sensitivity and specificity. The breath test technique reflects only current infection with H. pylori but can demonstrate very rapidly the existence of infection. A disadvantage of this technique is that it may involve a small amount of exposure to radiation. Although carbon 13 is a stable isotope and does not emit radiation, its detection requires a mass spectrometer, which may not readily available. The breath test is not yet commercially available.

Detection of IgG antibody. When a host recognizes H. pylori an immune response immediately stimulates IgG and secretory antibody IgA. Therefore, serologic testing for antibodies to H. pylori using the enzyme-linked immunosorbent assay (ELISA) has become a widely accepted diagnostic test. The test is simple, inexpensive, and readily available. ELISA detects IgG with a sensitivity of up to 99% and is 100% specific. Since spontaneous clearing of H. pylori by lgG or IgA is rare, an elevated antibody titer indicates current infection. This test also detects the decline in antibody titer after removal of the organism; however, the rate of decline of IgG after eradication is still not known. This technique, although useful and accurate, still has certain limitations. In order to determine a clear decline in antibody titer, the patient must be monitored for at least six months, and the cutoff for a significant decline is unclear. In addition, in order to control the inherent variability of the test, the base and follow-up titer must be measured simultaneously. Still, the outstanding accuracy and low cost makes this test an attractive choice for detecting H. pylori infection.

In current practice, endoscopy is still required for diagnosis of infection by Helicobacter pylori. The full range of noninvasive techniques is expected to be more readily available soon, with the antibody tests ideal for assessing current infection, and the carbon 13-urea breath test the method of choice for determining the response to infection.

Table 1. Diagnostic Tests for Helicobacter pylori

Treatment of Peptic Ulcer Disease

Many excellent treatments for peptic ulcer disease exist. In the case of duodenal ulcers and gastric ulcers, histamine H2-receptors can be blocked to cause healing in about 90% of cases within 8 weeks. However, both duodenal and gastric ulcers rapidly recur after successful anti-secretory therapy. Relapses can be prevented by long-term low-dose therapy with any histamine H2-receptor blockers. The National Institute of Health recommends that all patients infected with H. pylori be treated with an antibiotic. However, although the bacterium is sensitive to most antimicrobial therapy in vitro, in vivo results have been disappointing. Researchers have attributed this discrepancy to the locale of H. pylori infection, under the mucus gel layer in the stomach. Environments which are this acidic often decrease the antimicrobial activity of most antibiotics.

Triple Therapy

Eradication of Helicobacter pylori is defined as the absence of the organism four or more weeks after eradication therapy. Since the eradication rate for single-drug therapy is only 19% and that for double-drug therapy is still only 48%, researchers have found that combining three antibiotics offers a better chance for eliminating the bacterium. The highest eradication rate, 82%, was achieved by combining bismuth, metronidazole, and tetracycline. There are obvious drawbacks to this type of treatment. First of all, it is inconvenient for the patient, so it is difficult for doctors to convince their patients to comply with the therapy. Second, such multidrug therapy is almost always associated with many adverse side effects, namely diarrhea, nausea, and vomiting, which occur in approximately 20% of all patients.

Figure 1. Recurrence rate of gastric ulcers and duodenal ulcers after successful healing with triple antimicrobial therapy

Immune Response

The human immune response to H. pylori involves the activation of neutrophils, monocytes and macrophages, and the production of serum antibody IgG and secretory antibody IgA. In addition, T cells proliferate as in a cell mediated response. However, as stated earlier, Helicobacter pylori infection, once acquired, persists indefinitely. Therefore, although there is a definite and immediate immune response to H. pylori, the host is still unable to eliminate the parasite.

The intensity of the host immune responses can culminate in one of several ways:

1. The most common result is chronic superficial gastritis, which is an inflammation of the stomach lining due to the infiltration of lymphocytes, plasma cells, eosinophils, and monocytes into the mucosal lining of the stomach, which causes injury to the gastric glands.

2. The immune response can actually benefit H. pylori by releasing nutrients locally for the organism.

3. The host could be harmed by the immune response due to the direct damage of epithelial cells, which affects their function and vitality. The host, in order to avoid this type of cell damage, will often down-regulate its immune response, making it even more difficult to completely eliminate H. pylori from the affected area.

4. The immune response can also cause inflammation of the duodenum, leading to duodenal ulcers.

5. Atrophic gastritis,which is a nonspecific inflammation of the entire lining of the stomach, may be the result of the infiltration of lymphocytes into the stomach.

6. MALT-type and other lymphomas, which are tumors of the mucosal and lymphoid tissues, can also result from H. pylori infection.

The effects of infection by Helicobacter pylori represent a delicate equilibrium between the host's inability to remove the organism and its ability to contain the damage caused by the pathogen. It is the integrity of this equilibrium that allows H. pylori to persist in most cases for a lifetime in their hosts.