Table of contents:

1. Epidemiology
2. Pathomechanism of Helicobacter pylori infection
3. Association of Helicobacter pylori infection with risk of gastric cancer development

Epidemiology

Helicobacter p ylori is a Gram negative, spiral bacterium. As early as 1896 in Krakow, Poland, Walery Jaworski identified the presence of spiral bacteria in sludge from gastric contents, but the discovery of this pathogen for modern medicine was made by Warren and Marshall in 1983. Globally, it is estimated that at least 50% of people are infected, while the majority do not suffer any discomfort.

A major risk factor for infection is poor socioeconomic conditions during childhood. In developed countries, about 50% of children living in poor conditions are infected with Helicobacter pylori. In developing countries, up to 80% of children under 10 years of age are affected. Although about 60% of patients over 60 years of age are infected with Helicobacter pylori, adults become infected less frequently, with a seroconversion rate (spontaneous eradication) of 0.33-0.5% per person-year. The high prevalence of infection in adults is related to the so-called birth-cohort effect, when adults have already been infected in childhood.

The age at which infection is most common is still not precisely defined, but results from population-based studies indicate that it occurs under the age of five. It is possible that children who become infected for the first time carry multiple strains of Helicobacter pylori and by natural selection over the years one specific strain remains, which is detected in adulthood.

Pathomechanism of Helicobacter pylori infection

Helicobacter p ylori is a microaerophilic, Gram-negative, spiral bacillus possessing 4-7 flagella at one of its poles that allow it to move through the environment. The way in which Helicobacter pylori damages the gastric mucosa is related, among other things, to the bacterium's production of enzymes such as urease. Urease is a metalloenzyme that breaks down urea to ammonia and carbon dioxide. The ammonia formed from urea neutralises the acidic environment of the stomach and raises the pH locally on the surface of its cells in the immediate vicinity of the bacteria. This allows the bacteria to survive in the acidic environment of the stomach. In contrast, alkalinisation stimulates gastric G cells to produce gastrin to acidify the environment. This excessive gastrin production stimulates the secretion of hydrochloric acid and pepsin, which in turn is responsible for increasing the acidity of the contents passing into the intestine and is involved in the pathogenesis of duodenal ulcer disease.

The increased gastrin concentration and consequent change in acidity also appears to be the result of a bacterium-induced decrease in the number of somatostatin-producing cells and a consequent significant decrease in the amount of somatostatin. Urease also stimulates the migration of granulocytes and monocytes to the site of infection. Inflammatory reaction mediators (oxidative compounds and reactive nitrogen species) and chloride ions released as a result of the inflammatory process, which combine with ammonia to form toxic monochloramine, cause damage to epithelial cells and the development of gastritis.

Other proteins responsible for Helicobacter pylori virulence include flagellins, made up of the bacterial flagella, which enable movement in the viscous mucus layer, and adhesins, found on the surface of the bacteria and having an affinity for epithelial cell receptors, facilitating adhesion to the gastric mucosa. Helicobacter pylori produces a number of enzymes. One of these is ferritin, which binds iron ions and is probably responsible for the anaemia observed in children with this infection. Vacutainer cytotoxin A (VacA) can cause direct damage to gastric epithelial cells, swelling of the cells and lining, and is a stimulator of pepsinogen secretion, which directly alters acidity and is responsible for the inflammatory response, as well as duodenal ulcer disease. Due to the presence or absence of vacuolising cytotoxin, we distinguish between 2 strains of bacteria: the so-called Helicobacter pylori VacA (+) and VacA (-). VacA (+) strains are responsible for the development of peptic ulcer disease, while VacA (-) strains are only responsible for inflammatory changes in the gastric mucosa.

The Helicobacter pylori genome also encodes proteins associated with the VacA vacuolar cytotoxin, the so-called CagA and CagE. Again, it is possible to be infected with both CagA(+) and CagA(-) strains. Infection with both VacA (+) and CagA (+) strains of Helicobacter pylori is significantly more likely to lead to the development of chronic inflammation, which may eventually develop into gastric cancer, particularly in young patients.

In the paediatric population, approximately 70% of patients infected with Helicobacter pylori have the CagA (+) strain. Its presence correlates with a greater severity of inflammatory changes found on histopathology and a lower efficacy of eradication therapy for the bacterium. The severity of inflammation and its activity in children is also associated with high expression of IL-1b, IL-6.

CagE toxin may also be important in the pathogenesis of peptic ulcer disease. Recently, CagE-positive strains have been found to be most frequently isolated in children with duodenal ulcer disease, and are probably responsible for the most severe cases of the disease due to their high ability to induce the chemokine system.

Association of Helicobacter pylori infection with the risk of developing gastric cancer

The association of Helicobacter pylori infection with an increased risk of developing gastric cancer is now unequivocally proven, and in 1994 Helicobacter pylori infection was defined by the International Agency for Research on Cancer (IARC) as a class I gastric carcinogen. Only a small number of patients with this infection (approximately 1%) develop gastric cancer.

The process of carcinogenesis has several stages. It begins with chronic gastritis, followed by glandular atrophy, metaplasia and dysplasia. Atrophic gastritis and intestinal metaplasia are a consequence of Helicobacter pylori infection, while it is debatable whether eradication of the bacteria can reverse this process. Chronic gastritis destroys the gastric barrier and stimulates gastric cells to excessive proliferation, which, on the one hand, regenerates the gastric mucosa, but, on the other hand, can induce damage within the cell's DNA.

Helicobacter pylori directly inhibits apoptosis, while the mechanism of this process is not clear. Cytotoxic strains (vacA+, cagA+) play an important role in the pathogenesis of peptic ulcer disease and gastric cancer. Already reports from the late 1980s and early 1990s showed that neoplastic transformation of gastric mucosal cells requires multistep activation or, on the other hand, abnormal function of a number of component systems regulating cell cycle progression.

The first stage - 'preinitiation' - is the action of mutagenic agents on the gastric mucosa and the associated acquired, environmental damage to the cell's DNA. The initiation stage of carcinogenesis is the occurrence of a number of mutations in the cell, particularly within genes encoding DNA repair enzymes and oncosuppressor genes, and those of greatest significance are:

• activation of pathways that stimulate proliferation (e.g. mutations within K-ras),
• increased expression and release of gastrin, its receptors (_CCKB) and a number of other growth factors (_TGFa, EGF, EGF-R),
• mutations of oncosuppressor genes - e.g. p53,
• dysregulation of apoptosis - through, inter alia, increased expression of apoptosis-inhibiting genes such as bcl-2 and decreased expression of apoptosis-inducing genes such as bax,
• abnormal DNA repair.

Helicobacter pylori is not the only causative agent of carcinogenesis. The generally accepted model of gastric carcinogenesis is the Correa theory, published in 1992, which assumes that the development of cancer is due to the interaction of environmental and genetic factors such as high salt intake, deficiency of trace elements, vitamins or antioxidants, smoking and genetic susceptibility or autoimmune diseases.