Intestinal Metaplasia

Intestinal metaplasia is the replacement of the mucous cells that line the normal gastric mucosa with an epithelium similar to that of the small intestine. The different types of intestinal metaplasia have been variously classified as follows: complete versus incomplete; types 1, 2a, and 2b; and types I, II, and III, based on their morphology and content in sulfomucins. In general, the greater the extension of metaplasia in a stomach, the greater the proportion of the incomplete types. Intestinal metaplasia is a virtually constant component of atrophic gastritis, and is found more frequently in the stomach of patients with H.pylori gastritis. Small antral foci of intestinal metaplasia are also frequently found in bile reflux gastropathy, both in postoperative and in intact stomachs.

Endocrine Cell Hyperplasia

Endocrine cell hyperplasia, a consequence of functional changes in chronic gastritis, is most prominent in autoimmune atrophic gastritis. In this condition, hypochlorhydria or achlorhydria lead to G-cell hyperplasia in the antral mucosa with an accompanying rise in serum gastrin levels. This, in turn, induces the histamine-producing enterochromaffin-like cells in the oxyntic glands to undergo hyperplasia. The type, number, and distribution of endocrine cells can now be established by using immunostaining techniques, which have replaced the less reliable classical argentaffin and argyrophilhistochemical stains. Gastric endocrine cell proliferations are commonly classified according to the criteria proposed by Solcia and colleagues, which distinguishes among hyperplasia, adenomatoid hyperplasia, dysplasia, and neoplasia.

Mild degrees of neuroendocrine proliferation may be seen, if they are searched for by immunoenzymatic methods, in many routine gastric biopsies: they represent an indirect and reversible effect of the widespread long-term use of proton pump inhibitors. In this condition, hypertrophy occurs almost exclusively in enterochromaffin-like cells, the most common type of endocrine cell in the oxyntic mucosa, and is believed to depend on the trophic effect of the concomitant hypergastrinemia.

Parietal Cell Alterations

Protrusions and pseudohypertrophy of oxyntic cells and glandular dilations are characteristic yet reversible responses to the long-term administration of proton pump inhibitors. These changes have also been described in patients with gastric ulcer disease, although the pathogenetic connection remains unclear.

HELICOBACTER PYLORI GASTRITIS

Chronic gastritis, one of the most common chronic conditions of humankind, is now known to be the result of specific and nonspecific responses mounted by the gastric mucosa against H.pylori infection. H.pylori infection is associated with most duodenal ulcer and gastric ulcers and with almost all primary gastric MALT lymphomas. In certain regions of the world, many infected persons develop metaplastic atrophic gastritis, a documented precursor of gastric carcinoma. Furthermore, certain extragastric conditions, including systemic autoimmune diseases, atherosclerosis, urticaria, and migraine, have been linked—albeit tenuously—to H.pylori infection. Thus, the importance of H.pylori extends into the realm of numerous major diseases that may have gastritis as their common denominator.

Clinical Manifestations

The initial phases of H.pylori infection elicit an acute mucosal inflammatory response whose clinical manifestations may include epigastric pain, nausea, and vomiting. Such symptoms are uncommon and are usually short-lived. Because patients rarely undergo endoscopic procedures in the early stages of H.pylori infection, information regarding clinical aspects is limited. However, well-documented case reports allowed a glimpse into the early aspects of the infection and of iatrogenic H.pylori infection resulting from the use of inadequately disinfected endoscopes. Most of these patients had multiple antral ulcers or erosions, whereas others had a predominance of hemorrhagic lesions; both their endoscopic and histopathological findings are virtually identical to those reported in subjects from human ingestion studies and in patients with epidemic gastritis and achlorhydria, a condition described before H.pylori was discovered and later found to be a manifestation of acute H.pylori infection.

In patients with uncomplicated chronic H.pylori gastritis, the prevalence of dyspepsia is probably no greater than in uninfected persons, and among patients with nonulcer dyspepsia, the prevalence of infected and noninfected persons is similar. Furthermore, cure of H.pylori in patients with nonulcer dyspepsia has not been shown conclusively to improve the dyspeptic symptoms, although the reasons for this apparent lack of effect continue to be debated. Even with its unclear relation to dyspepsia, H.pylori infection has been estimated to be responsible for approximately 5% of gastrointestinal ailments in the community, and patients with H.pylori gastritis are at increased risk of duodenal and gastric ulcer, gastric cancer, and lymphoma.

Epidemiology

In many developing countries, the prevalence of H.pylori in adults is close to 90%, with very high percentages of infected children, suggesting exposure to the bacteria early in life. In established industrialized countries (Western Europe, United States, Canada, and Australia), exposure occurs later, resulting in minimal percentages of infected children (<1% in Swedish and Danish schools in the year 2000) and low percentages of infected adults (~30% by age 50 years). Although the mechanisms of transmission remain poorly understood, improved socioeconomic conditions result in a decreased prevalence of H.pylori, as vividly illustrated by historical data from Finland, Sweden, and Japan. Furthermore, innumerable people receive amoxicillin, which, used alone, may cure approximately 10% of H.pylori infections, as well as other antibiotics for the treatment of respiratory and other infections. Among H.pylori–infected patients undergoing such therapies, a small but cumulatively significant percentage is cured. Finally, it is likely that targeted anti– H.pylori treatment in individual patients reduces transmission in the community and ultimately may contribute to thedecreased prevalence of the infection in the population.

Endoscopic Appearance

Chronic H.pylori gastritis has no distinct endoscopic pattern. Depending on the stage or distribution of gastritis, hyperemia, erosions, ulcerations, hypertrophy, and atrophy may coexist in various combinations in the same stomach, juxtaposed to one another and to apparently normal areas. Yet, none of these features is useful for predicting the presence or absence of chronic H.pylori. Therefore, the diagnosis of H.pylori gastritis requires histopathological analysis.

Histopathology

H.pylori organisms are found in greatest numbers in the gastric mucous gel and attached to surface mucous cells. Bacteria are also present in the intercellular spaces and, particularly in patients receiving long-term antisecretory therapy with proton pump inhibitors, within the canaliculi of parietal cells. The difficulty of visualizing bacteria in these latter locations before the development of polyvalent staining techniques may explain the misconception that H.pylori is a strict gastric surface dweller.

Antral, oxyntic, and cardiac mucosae are equally susceptible to infection and are colonized with similar frequencies. In patients with extensive antral intestinal metaplasia, a type of epithelium to which H.pylori rarely adheres, the infection is virtually confined to the nonmetaplastic areas of the corpus. This is also the case in many patients who regularly use proton pump inhibitors.

Infiltration of the gastric epithelium by polymorphonuclear neutrophils is the most distinctive feature of the gastric mucosa infected by H.pylori: neutrophils are generally more abundant in the antrum and the cardia than in the corpus, where they may be rare or even completely absent in spite of visible bacterial colonization. This distribution of inflammation characterizes antrum-predominant gastritis, the most common type of gastritis in Western populations. Neutrophils are usually the only inflammatory cells that infiltrate the gastric epithelium in H.pylori infection, but in the lamina propria they are almost always mixed with lymphocytes, plasma cells, and variable amounts of eosinophils. Inflammation tends to be most intense in the superficial portions of the lamina propria, hence the term superficial gastritis, still occasionally used as a synonym for nonatrophic gastritis.

Lymphoid follicles are virtually always found in infected stomachs, and their presence is a reliable indication of active or recently treated H.pylori gastritis. Their greatest density is in the region of the incisuraangularis, and the lowest density is in the proximal greater curvature.

“Disease-Specific” Virulence Factors

Since the discovery of the H.pylori toxins VacA and CagA, which were linked to certain types of damage to the gastric mucosa, there have been continuous attempts to correlate them and other virulence factors with a specific manifestation or complication of H.pylori gastritis. Although some of these factors can affect the intensity of inflammation and, perhaps through this mechanism, may ultimately influence the outcome of gastritis, the virulence of H.pylori seems to be largely host dependent, and none of these factors are disease specific. Thus, at present, there is no clinical application for tests that purport to determine the potential pathogenicity of an individual patient’s H.pylori strain. The best studied putative virulence factor is the cytotoxin-associated gene product (Cag) A, the product of one of the genes in the cag pathogenicity island. Subjects infected with H.pylori with a functional cag pathogenicity island have elevated mucosal levels of interleukin-8, marked neutrophilic infiltration into the gastric mucosa, and an increased risk of developing a symptomatic outcome such as peptic ulcer or gastric cancer. However, the relationship between the presence of the cag pathogenicity island and outcome is not consistent in different geographic regions, especially in East Asia, where more than 90% of isolates possess the cag pathogenicity island. In Western countries, where H.pylori strains lacking the cag pathogenicity island are found in a higher percentage than in Asian countries, the increased likelihood of a symptomatic outcome can be seen. However, the presence of a functional cag pathogenicity island has no value in predicting current or future clinical presentation in individual patients.

Other putative pathogenicity factors include the following: IceA (induced by contact with epithelium), a bacterial restriction enzyme for which no biologic or epidemiologic evidence as a virulence factor in H.pylori–related disease has been confirmed; and VacA (vacuolatingcytotoxin), which has been subtyped into an s1 genotype (presumably associated with duodenal ulcer disease) and an s2 genotype with reportedly low ulcerogenic potential. A compilation of studies involving approximately 1500 isolates from Europe, the United States, and Asia has shown overwhelming that VacA genotyping is not useful to predict degree of inflammation, symptoms, presentation, or response to therapy.

The blood group antigen binding adhesin (BabA) is an outer membrane protein that appears to be involved in the adherence of H.pylori to Lewis-b (Le b) blood group antigens on gastric epithelial cells. A small study suggested that infection with strains with the babA2 gene, cagA +, and vacA s1 (triple-positive strains) may be correlated with duodenal ulcer, but a larger multinational study did not confirm the association.

Diagnosis

The diagnosis of H.pylori gastritis rests on the identification of H.pylori in the gastric mucosa. When the search for H.pylori relied exclusively on the availability of gastric biopsy specimens (for histopathology, rapid urease tests, or culture), only patients who required an endoscopic examination were tested. The development of increasingly accurate noninvasive tests allows the accurate diagnosis of H.pylori gastritis based on indirect methods, that is, without necessarily visually identifying or culturing the organism. Furthermore, the availability and popularization of new, simple, and inexpensive tests have expanded the indications to a greater variety of patients and settings, including self-referring patients in the general practitioners’ office.

Significant progress has been made also in our knowledge of factors that may influence the interpretation of the results and may interfere with the accuracy of each test. The prevalence of a condition in the population studied influences both the positive and negative predictive value of tests, even if a test’s sensitivity and specificity are independent values inherent to the test itself. Therefore, clinicians should be familiar not only with the performance parameters of the tests they use, but also with their potential interpretative pitfalls as well as with the prevalence of H.pylori in their patient population.