Helicobacter pylori, a gram-negative bacterium found on the luminal surface of the gastric epithelium, was first isolated by Warren and Marshall in 1983, but the presence of spiral organisms in the stomach was noted on a number of occasions as early as in 1938. Within the human stomach, H. pylori can be found either free-living in the gastric mucus layer or attached to gastric epithelial cells.
H.pylori is able to survive in acidic milieu of stomach due to several adaptations. The enzyme urease hydrolyzes urea into carbon dioxide and ammonia which reduces acidity of gastric juice. Flagellae are essential for penetration into mucosal layer. Another adaptation is production of two main toxins of H.pylori, vacuolating toxin (VacA) and cytotoxic antigen (CagA). VacA is mainly secreted whereas CagA is injected by the bacteria into the host mucosal epithelial cells. VacA causes nutrient leakage via several mechanisms having as consequence release of urea. CagA interacts with intracellular signal transducers, deregulates their activities, and elicits pathobiological actions such as induced apoptosis, loss of gastric glands, and decreased gastric-acid secretion.
The infection usually starts from non–acid-secreting antral region of the stomach and stimulates the increased release of gastrin. The increased gastrin levels in turn stimulate excess acid secretion from the more proximal acid-secreting fundic mucosa which is relatively free of inflammation. The increased duodenal acid load damages the duodenal mucosa, causing ulceration. If infection progresses, stomach body is damaged, which could finally cause the development of gastric adenocarcinoma. This tumour is preceded by sequential pathological changes of gastric mucosa, from normal mucosa to superficial gastritis, atrophic gastritis, gastric ulcers and intestinal metaplasia. Main oncogenic factors are both nitrosating bacteria present in the lumen of hypochloric stomach, capable of generating potentially carcinogenic N-nitrosamines and reactive oxygen species, and H.pylori itself.
Duodenal or gastric ulcers are reported to develop in 1 to 10% of infected patients, gastric cancer- in 0.1 to 3%; at the same time, the great majority of patients with H. pylori remain asymptomatic carriers.
H. pylori is usually acquired in childhood. The bacteria are most likely spread through fecal-oral or oral-oral routes from person to person; additional transmission routes, such as water, may be important in developing countries.
H. pylori strains exhibit a high level of genetic diversity, and intraspecies genetic recombination occurs commonly. Despite microbe variability, reinfection with H. pylori after medical eradication is rare in developed countries. H. pylori strains are divided into cagA-positive and cagA-negative. The cagA-positive H. pylori strains are associated with higher grades of gastric inflammation, and are more virulent than the cagA-negative strains. Among cagA-positive strains, the grades of inflammation, activity of gastritis, and level of atrophy are significantly higher in patients who are infected with East-Asian cagA-positive strains than in patients infected with the Western cagA-positive strains.
Contrary to cagA, all strains of H. pylori contain the vacA gene. Strains of H. pylori that contain certain allelic forms of vacA are associated with an increased risk of symptomatic gastroduodenal disease.
Approximately two-thirds of the world’s population are infected with H. pylori. The overall prevalence of H. pylori infection is mostly correlated with socioeconomic conditions. The prevalence among middle-aged adults is over 80 percent in many developing countries, such as Brazil, Mexico, and China compared with 20 to 50 percent in industrialized countries. The prevalence levels are also high in Eastern Europe (Poland, Russia) and South-East Asia (Taiwan, Japan). Gastric carcinoma due to H.pylori is the second most common cause of cancer-related death worldwide.
Despite immune response, H. pylori infection in adults is usually chronic and requires specific therapy to be healed. IgG and IgA are reliable markers of disease; increased IgA seems to be a marker of infection with CagA-positive strain of H.pylori. On the contrary, IgM titres are not statistically different between infected and non-infected patients because a) IgM response is often absent, especially in children; b) IgM response is short-lived. IgM antibodies begin to appear about 2 weeks postinfection, are detectable in majority of patients 4 weeks postinfection, and disappear several months afterwards. IgG response begins to appear about 4 weeks postinfection and peaks 12 to 19 weeks postinfection. After eradication, IgG declines at a rate of 50%/year, but around 65% of patients remain seropositive for more than a year after treatment.
The main immunogenic proteins of H.pylori are chaperone HspB, urease B, CagA and VacA. Antigens associated with virulence such as CagA and VacA as well as H.pylori outer surface proteins show quite a high degree of inter-strain sequence variability. In addition, humoral immune response is highly variable, i.e. most immunogens are reactive only in relatively small proportion of sera. The factors mentioned above may explain the relatively insignificant role of recombinant proteins in the diagnostics of H.pylori infection.
In areas with high H. pylori prevalence, diagnosing of H.pylori presence may be unnecessary-empirical strategy is popular instead (treat without testing first). In most industrialized countries, endoscope-and-test strategy is used for patients with symptoms alarming for gastric cancer (anemia, gastrointestinal bleeding, or weight loss), as well as for patients older than 50 years. During endoscopy, biopsy specimens of the stomach and duodenum are obtained, and the diagnosis of H. pylori can be made by several methods:
• The biopsy urease test - a colorimetric test based on the ability of H. pylori to decompose urea; it provides rapid testing at the time of biopsy.
• Histologic identification of organisms - considered the gold standard of diagnostic tests.
• Culture of biopsy specimens for H. pylori - requires an experienced laboratory, and is necessary when microbial susceptibility testing is desired.
If no alarm symptoms are present, test-and-treat strategy should be used. This means that H.pylori infection is diagnosed by noninvasive methods which include the urea breath test, serologic tests, and stool antigen assays.
Diagnostics of H.pylori with subsequent eradication if positive is recommended if symptoms of dyspepsia are present, or gastritis/peptic ulcer are documented. In addition, European guidelines recommend diagnosing and eradicating H. pylori infection in following cases:
• in first-degree relatives of patients with gastric cancer;
• in patients with strong environmental risk factors for gastric cancer (heavy smoking, high exposure to dust, coal, quartz, cement and/or work in quarries);
• in patients with a fear of gastric cancer.