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Posted on June 8th, 2012, by

Helicobacter pylori is one of the widely spread bacteria which may be found in a half of human organisms inhabiting the planet. Despite the slow process of its development, the bacterium is characterized by the high level of motility and has a spiral shape. Potentially, this bacterium may be quite dangerous to human organism since it can provoke such infectious diseases as histologic hastritis, peptic ulcer disease, adenocarcinoma of the stomach and some others.

It should be said that the bacterium is quite strong and can overcome the resistance of the human immune system, especially if the latter is weakened, and may lead to a serious inflammatory process in human organism. At the same time, one of the major biochemical characteristics feature of H. pylori is the production of urease (Graham & Sung, 2006).

Epidemiology

As a rule, H. Pylori is particularly dangerous to children since their young organisms are the most susceptible to the negative impact of this bacterium and are more likely to get infected compared to adults. As an individual grows, the risk of the infection decreases. It is noteworthy that the population of both developed and developing countries are exposed to the risk of catching some diseases in the result of the impact of H. pylory.

Environmental and genetic factors

Traditionally, the major risk factors for acquiring H. pylori infection include: poor socio-economic conditions, poor family hygiene, and possible ethnic or genetic predisposition (Graham & Sung, 2006).

Pathophysiology

Basically, the infection is transmitted from individual to individual because this bacterium normally develops in human body and can be relatively easy transmitted from one person to another. At the same time, the modes of transmission may vary that indicates to the high level of risk of getting some infectious disease in the result of catching H. pylori. Among the most widely spread modes of transmission may be named oral-to-oral transmission because the bacterium may be transmitted along with saliva. Also there exist fecal-to-oral and gastro-oral modes of transmission but they are less widely spread and, as for the latter, this mode of transmission of H. pylori remains under-researched.

It should be said that the high ”˜effectiveness’ of H. pylori is, to a significant extent, closely related to the functioning of the immune gene polymorphisms which is supported by the gastric acid secretion. The mechanism of infection is quite simple since as H. pylori gets into the organism of a ”˜receiver’ that it gradually spreads and colonize gastric mucosal cells and starts damaging them producing a destructive effect on human organism. Specialists also emphasize that the development and spread of the bacteria may be supported  by the cytotoxin-associated gene pathogenicity island-encoded protein (CagA) and the vacuolating cytotoxin (VacA) help in the colonization (Kusters, van Vliet, Kuipers, 2006) and also triggers the host inflammatory response by activating the nuclear factor kappaB-dependent gene transcription (Zarrilli, Ricci, Romano, 1999).  “Urease and/or motility of the bacterium, presence of lipopolysaccharide (LPS) and various bacterial enzymes” are also known to affect the colonization (Lee, 2005.)

The healing of the gastric mucosa is also impaired “through inhibition of epidermal growth factor receptor-dependent signal transduction pathways and induction of apoptosis” (Zarrilli, Ricci, Romano, 1999).

At the same time, the bacterium may lead not only to the development of the new diseases but it can also substantially increase the risk of the progress of chronic disease such as gastritis and gastric adenocarcinoma. The “cag pathogenicity island (cagPAI), which encodes the type IV secretion system (TFSS) and its effector CagA, play an important role in the development of gastric carcinoma” (Hatakeyama & Brzozowski, 2006).  Some of the pathological mechanisms of gastric carcinoma due to H. pylori infection include: “morphologic alterations like atrophic gastritis, gastrointestinal metaplasia mediated by COX-2 overexpression, cancer cell invasion, and neo-angiogenesis via TLR2/TLR9 system and transcription factors (e.g., NF-kappaB) activation” (Hatakeyama & Brzozowski, 2006).

H. pylori can also contribute to the higher level of the expression and activity of adhesion molecules. This may lead to an increased “oxidative stress interacting with gastric production of appetite hormone ghrelin and nonsteroidal anti-inflammatory drugs” (Hatakeyama & Brzozowski, 2006).

H. pylori may produce a destructive effect on the A-like cells which play an extremely important role in the formation of gastric ghrelin which is an essential peptide responsible for the appetite promotion. As a result, the bacterium, by means of gastric inflammation, destroys A-cells and decreases the level of gastric ghrelin secretion. It has also been found that patients with peptic ulcer had higher levels of plasma ghrelin than patients with gastritis without ulcer. Therefore, there is a “possible relationship between mucosal injury susceptibility and elevated fasting plasma ghrelin” (Suzuki et al., 2006).

There is a strong association between chronic H. pylori infection and the development of primary gastric B cell lymphoma of MALT-type.  However, the pathogenic mechanisms of lymphomagenesis are still unclear. It should be said that scientists still fail to find the precise way in which the destructive and dangerous transformation occur as well as it is still unclear the role of the immunoglobulin rearrangement which has been detected with the help of PCR.

There exist different explanations of the development of gastric B cell lymphoma. For instance, it may be developed from extranodal lymphoid tissue and than it is eventually formed by mucosa-associated lymphoid tissue. However, the paradox of this suggestion is that “there is no MALT in the gastric mucosa in normal individuals from which a primary lymphoma can arise” (Wotherspoon, 1998), although it has been shown that “organized lymphoid tissue with all the features of MALT can be acquired in the gastric mucosa” (Wotherspoon, 1998).

Nevertheless, it should be said that the role of H pylori infection is crucial in the development of gastric MALT lymphoma. To put it more precisely, studies have also shown that “there is an immunologically based drive to tumor cell proliferation in low-grade gastric MALT lymphomas associated with the presence of H. pylori” (Wotherspoon, 1998.)

Clinical features of H.Pylori infection

Basically, it is quite difficult to diagnose the infection and there exist a variety of symptoms and tests that can reveal the progressing destructive effect of H. pylori. In this respect, it should be said that acute infection is characterized by epigastric pain and nausea.  A histological examination reveals neutrophilic gastritis. Furthermore, it is possible to use a positive urea breathe test accompanied by negative IgG anti-H.pylori antibodies in order to reveal the presence of the bacteria and their negative influence on the organism. Chronic infection is characterized by a chronic active, non-atrophic, superficial gastritis. It is important to underline that, in this respect, it is extremely difficult to clearly diagnose the disease and find its cause since there are a few symptom that would definitely indicated to the growing health problem caused by the activity of H. pylori. Nevertheless, it is possible to name the following symptoms of H.Pylori infection: “upper abdominal fullness, early satiety, and bloating” (Ables, Simon, Melton, 2007).

Helicobacter pylori and gastric cancer.

The International Agency for Research on Cancer (IARC), which is a branch of the World Health Organization, has classified H. pylori as a group I carcinogen for gastric cancer. It should be said that the numerous researches dedicated to this problem have revealed the fact that H. pylori infection may be one of the major causes of gastric cancer.  The gastric mucosal atrophy and metaplasia caused by H. pylori infection can lead to “a 5-90-fold increased risk for cancer of the distal stomach, in particular of the intestinal type” (Kuipers, 1999). This is why it is possible to recommend eradicating of H. pylori. This measure may be quite effective in the decreasing of the negative consequences of H. pylori infection, including the risk of the gastric carcinoma.

Helicobacter pylori eradication to prevent gastric cancer

The latter measure can lead to a reduction in the gastritis and gastric epithelial cell proliferation.  However, this measure still can hardly be applied effectively because, till the present moment, the details of such therapy are still unclear. To put it more precisely, it is quite difficult to define what patients do really need such therapy and what the time may be needed for this therapy. Alternatively, many studies have considered the use of antibiotic therapy and/or dietary supplements.

The use of antibiotic therapy and/or dietary supplements with ascorbic acid and beta-carotene may be quite effective to minimize the risk of gastric dysplasia.  The recent study found an increased regression of “multifocal nonmetaplastic atrophy and/or intestinal metaplasia” with this intervention (Correa et al., 2000.)

At the same time, it should be said that the use of eradicating H. pylori infection may be quite effective since it may significantly reduce the risk of gastric cancer. All the currently available evidence suggests that although H. pylori eradication can be considered as a “primary chemo-preventive strategy in a subset of subjects” (Fuccio et al., 2007).

On the other hand, it is necessary to remember that it is not equally effective to all patients. For instance, patients who have advanced preneoplastic lesions are less likely to get a substantially positive effect in the result of eradication. This is why it is necessary to enhance the treatment with an endoscopic follow-up.

Helicobacter pylori and peptic ulcer disease

Statistically, about 70% of gastric ulcers are associated with H. pylori infection, and by nature, they correspond to the classical gastric ulcer. At the same time, a considerable part of the dangerous ulcers are developed in the result of the use of non steroidal anti-inflammatory drugs that are used during the treatment of H. pylori infection.

It is worthy of noting that the gastric corpus is the more likely location of the acute and severe chronic inflammation and epithelial degeneration. Basically, this is typical for all patients but those who have a chronic inflammation face a higher risk of the development of the disease. It is also important to underline that the type of H pylori colonization is crucial in the development of the inflammatory disease and it influences its severity. Potentially, it may considerably increase the risk of the development of the peptic ulcer disease.

However, there also exists the vacA s1/cagA-positive strains of H pylori. This strains can lead to a more negative consequences of the impact of the bacterium on human health and, what is more, it can increase the risk of peptic ulcer disease dramatically. At the same time it is necessary to underline that the problem of correlation of H pylori and gastric ulcer is still under-researched since the researches of this problem are obviously insufficient to make a definite conclusion concerning the correlation between the H. pylori infection and gastric ulcers.

Nevertheless, it is worthy of mention the study conducted by Mitani et al., 2004, followed-up 52 patients with H. pylori infection, and 34 patients without H. pylori infection by endoscopy, for a period of 52 months.  Biopsy specimens were obtained during each endoscopy from the antrum and the middle corpus, and examined histologically.  It was observed that 15% of patients with H. pylori infection developed gastric ulcers (Mitani et al., 2004)

 

Helicobacter pylori and gastric B cell lymphoma

As a rule, primary gastric lymphomas are of high-grade non-Hodgkin’s type, and others are low-grade B cell lymphomas.  Low-grade B cell lymphomas “have characteristic clinicopathological features that are different from those of their nodal counterparts” (Wotherspoon, 1998).

Gastric MALT lymphomas differ from nodal lymphomas since they differ in a substantial higher frequency of trisomy 3 as well as they are characterized by different clinical behavior that may be characterized as favorable. It is worthy of mention that a low grade MALT lymphoma is susceptible to changes and transformations. In this respect, it should be said that it can evolve into a high-grade lymphoma as the negative impact of H. pylori increases.

H. pylori has been shown to stimulate growth of tumor cells from low-grade gastric lymphomas in laboratory studies. It should be said that this effect is strain specific. Basically, it occurs under the impact of H. pylori-specific T cells which produce a contact-dependent influence on the functioning of bacteria and development of the disease.

Studies have also shown that eradication of H pylori  can cause regression of the tumor (mainly, the early lesions ) in 60 to 92% of cases (Wotherspoon, 1998).

Management of Helicobacter pylori Infection and Upper Gastrointestinal Symptoms

There are numerous guidelines for clinicians.  Some of the important recommendations are: use of nonendoscopic tests (like serologic or breath tests) unless endoscopy is clinically indicated, starting eradication therapy in those positive for H pylori infection, immediate endoscopy for patients with persistent vomiting, bleeding, weight loss, dysphagia, and anemia, and endoscopy for older patients (45-55 years) (Howden, Blume, de Lissovoy, 2007). Also it is possible to recommend screening and bacterial eradication which, being relatively under-researched, still may be potentially quite effective in the treatment and prevention of gastric cancer.

Diagnostic Tests for H. pylori

Basically, diagnostic tests for H. pylori may be divided into two major groups: 1) invasive tests-endoscopy with biopsy, histology, urease activity, and culture (Ables, Simon, Melton, 2007) and 2) noninvasive tests-serology for immunoglobulin G, urea breath test, and H. pylori stool antigen (Ables, Simon, Melton, 2007).

It should be pointed out that serology for IgG is quite effective due to the high level of its sensitivity and specificity comparable to those of biopsy, but, on the other hand, serology for IgG cannot be always applicable. At least, its effectiveness is not always high. For instance, it can hardly be effective if it is used after antimicrobial therapy. The urea breath tests imply the use of urea which may be labeled as 13C or 14C. If urease is present in the stomach due to H. pylori infection, the labeled Co2 will be split off and absorbed into the circulation, where it’s presence can be detected by the analysis of expired breath. However, it is worthy of mention that this test is not very reliable because due to a small quantity of organisms it is quite difficult to provide a 100% precise results of the test, though, in general, this test is considered to be quite effective. At any rate, it is not recommended to fully rely on the result of this test while the use of other tests is highly recommended to get more accurate and reliable results.

Furthermore, it should be said that some category of patients are extremely sensitive to tests and it is important that the test were safe and non-traumatizing patients physical and psychological state. In this respect, children are the most susceptible to such risks. This is why it is possible to recommend using the urea breath test due to its noninvasive nature and high level of reliability.  Or else it is possible to use the monoclonal antibody-based stool antigen which is also quite friendly to patients’ state. However, it is worthy of mention that the latter test is not always applicable. To put it more precisely, it may be really effective and reliable in diagnosing the disease in patients who suffer from peptic ulcer before and after eradication of H. pylori, but it proves to be of little efficiency if it is applied to patients with bleeding peptic ulcer.

Treatment

Nowadays, there exist various ways of treatment that may be applied in different situations depending on the patient’s state and the development of the disease. Nevertheless, the treatment of the disease may be accompanied by numerous difficulties.

A. Non-ulcer dyspepsia

In a meta-analysis of 10 studies, eradication therapy did not show any symptomatic improvement (Ables, Simon, Melton, 2007). However, “an updated systematic review of 17 trials revealed a small but statistically significant benefit” (Ables, Simon, Melton, 2007). “An empiric trial of acid suppression with a proton pump inhibitor for four to eight weeks” (Ables, Simon, Melton, 2007) has been suggested by the American College of Gastroenterology for “initial treatment of dyspepsia in areas with a low prevalence of H. pylori infection (Ables, Simon, Melton, 2007).

B. GERD

Studies have shown that testing and treating for H. pylori has no improvement in the symptoms of GERD (Ables, Simon, Melton, 2007).

I. Selected Long-Duration Regimens for Helicobacter pylori Eradication

a. It is recommended to take 20 mg of Omeprazole, 20 mg twice daily. IN addition, it is necessary to take amoxicillin, 1 g twice daily and, finally, the treatment must be supported by clarithromycin, 500 mg of which should be taken twice daily. The period of treatment should last for 14 days at average.

It is worthy of mention that the positive effect of the treatment of H. pylori infection may be achieved when the combined therapy is used, i.e. when omeprazole, amoxicillin, and clarithromycin are used in a combination for a period of 1 week. However, recent meta-analysis have demonstrated that triple therapy with amoxicillin, clarithromycin, and a proton pump inhibitor has an eradication rate of only 74-76% and new therapeutic strategies may be necessary (De Bortoli et al., 2007).

The results of the study by De Bortoli et al., 2007, suggest that by adding bovine lactoferrin (bLf) and probiotics (Pbs), the standard eradication therapy for H. pylori infection would be more effective.  BLf helps by increasing the H. pylori eradication rate and Pbs helps by reducing the side effects of antibiotic therapy (De Bortoli et al., 2007).

b. Also it is possible to use Lansoprazole, 30 mg of which should be taken twice daily. It is necessary to take 1 g og amoxicillin, twice daily, and, finally, the treatment should include the use of 500 mg of clarithromycin, twice daily. The period of treatment should last from 10 days to two weeks.

c. Alternatively, it is possible to recommend taking 525 mg of Bismuth subsalicylate, four times daily in a combination with 250 mg metronidazole, four times daily. Also, it is necessary to take 500 mg of tetracycline, four times daily, and histamine H2 blocker, for the period of 14 days. This treatment is quite intensive and may be applied to difficult cases. At the same time, it is worthy of noting that the use of H2 blocker may be continued for 14 days more but it should be taken only once or twice daily without the use of other medicines.

II. Short-Course Therapy for Eradication of Helicobacter pylori 

Short-course therapy may lead to “better compliance, fewer adverse drug effects, and reduced cost to the patient” (Ables, Simon, Melton, 2007), though this statement needs further researches and cannot be fully accepted as a totally correct. Nevertheless, it is possible to suggest several ways of treatment.

a. Basically, this treatment is based on the use of Bismuth subsalicylate, which has to be taken 524 mg four times a day. Also it is necessary to take 2 g of amoxicillin, four times a day and 500 mg of metronidazole, four times a day.

Finally, it is necessary to take 60 mg of lansoprazole, once. The treatment lasts for 1 day only.

b. This treatment implies the use of 500 mg of Clarithromycin, twice daily. Also, it is necessary to take 1 g of amoxicillin, twice daily, and, finally 30 mg of lansoprazole, twice daily, will accomplish the treatment which should last for 7 days.

c. Also it is possible to take 1 g of Amoxicillin, twice daily, along with 400 mg of metronidazole, twice daily.

Furthermore, it is necessary to take 250 mg of clarithromycin, twice dailyand 30 mg of lansoprazole, twice daily, in order to achieve the maximum positive effect of the treatment which should last for 5 days.

Naturally, there exist other treatments but the three mentioned above are the most widely spread and reliable ones.

Treatment in children

The treatment of children needs particular attention from the part of doctors. According to the North American Society for Pediatric Gastroenterology and Nutrition, eradication therapy in children is recommended for “endoscopically proven duodenal or gastric ulcer with H. pylori documented via histopathology” (Ables, Simon, Melton, 2007) and in children with “previous ulcer disease or iron deficiency anemia” (Ables, Simon, Melton, 2007).

Basically, it is necessary to avoid eradication therapy when children with gastritis are treated. The main reason for such a recommendation is the lack of research of the effects of such treatment that may be potentially dangerous to children’s health.

Traditionally, specialists recommend using various dosages of antibiotics, bismuth salts and proton pump inhibitors are used in regimens ranging from seven days to six weeks (Ables, Simon, Melton, 2007).

Follow-up

As a rule, the follow-up methods applied in the treatment of patients with H. pylori infection is based on the use of urea breath test and H. pylori stool antigen.

Recurrence

The recurrence of H. pylori infection may be revealed in the result of the tests used in the follow-up treatment, such as urea breath or stool antigen tests. As a rule, the positive results of the tests may be found after a period of half a year after the successful eradication therapy. In this respect, it is worthy of mention that there are some factors which increases the risk of recurrence considerably. Among these factors may be named “nonulcer dyspepsia, persistence of chronic gastritis after eradication therapy, female sex, intellectual disability, younger age, high rates of primary infection, and higher urea breath test values”(Ables, Simon, Melton, 2007). If a recurrence of H. pylori infection occurs an alternative regimen of treatment is applied.

Vaccines

A reduction of H. pylori load has been demonstrated in one trial, which used recombinant H. pylori urease co-administered with native Escherichia coli enterotoxin (LT) (Kabir S, 2007).  However, the outcomes of this study are not sufficient for the definite conclusion concerning its effectiveness. This is why the further researches are needed in order to fully prove its effectiveness.

Conclusion

Thus, taking into account all above mentioned, it is possible to conclude that Helicobacter pylori, is a Gram-negative bacterium infecting 50% of the world population, and is considered to be the one of the main cause of chronic gastritis, peptic ulcer disease, primary B cell gastric lymphoma and adenocarcinoma of the stomach   The bacterium induces a strong humoral and cellular immune responses in the host, but has the ability to persist in the body for decades.  H.pylori infection is typically acquired in childhood, and some of the major risk factors for acquiring H. pylori infection include poor socio-economic conditions, poor family hygiene, and possible ethnic or genetic predisposition.  An acute infection is characterized by epigastric pain and nausea.  Other features are upper abdominal fullness, early satiety, and bloating. Chronic infection causes a chronic active, non-atrophic, superficial gastritis, which is not symptomatic. Some of the diagnostic tests include: endoscopy with biopsy, histology, urease activity, and culture, serology for immunoglobulin G, urea breath test, and H. pylori stool antigen. Both long-term and short-course treatment with antibiotics, proton pump inhibitors, and bismuth are used.

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