GASTRITIS AND GASTROPATHY
The term gastritis should be reserved for histologically documented inflammation of the gastric mucosa. Gastritis is not the mucosal erythema seen during endoscopy and is not interchangeable with “dyspepsia.” The etiologic factors leading to gastritis are broad and heterogeneous. Gastritis has been classified based on time course (acute vs. chronic), histologic features, and anatomical distribution or proposed pathogenic mechanism.
Classification of Gastritis
I. Acute gastritis
II. Chronic atrophic gastritis
A. Acute H. pylori infection
A. Type A: Autoimmune, body-predominant
B. Other acute infectious gastritides
B. Type B: H. pylori–related, antral-predominant
1. Bacterial (other than H. pylori)
2. Helicobacter helmanni
III. Uncommon Forms of Gastritis
C. Crohn's disease
E. Isolated granulomatous gastritis
The correlation between the histologic findings of gastritis, the clinical picture of abdominal pain or dyspepsia, and endoscopic findings noted on gross inspection of the gastric mucosa is poor. Therefore, there is no typical clinical manifestation of gastritis.
CLINICOPATHOLOGICAL APPROACH TO GASTRITIS
Gastritis, simply defined as the inflammation of the gastric mucosa, is a condition, not a disease. With rare exceptions (e.g., lymphocytic gastritis and the extremely rare phlegmonous gastritis), inflammation of the gastric mucosa per se does not produce signs or symptoms; its complications do. Thus, clinicians rarely search for gastritis. In dyspeptic patients with indications for endoscopy, biopsies from the stomach are often obtained to determine the patient’s Helicobacter pylori status. If an appropriate set of gastric mucosal specimens is collected and properly examined, valuable information in addition to the often implicit question “is there H.pylori?” may be obtained: the type, severity, and distribution of gastritis and perhaps other causes of the gastric inflammation. This chapter is a discussion of useful strategies gastroenterologists and pathologists can use to optimize the diagnosis of gastric diseases.
The discovery of H.pylori in 1982 coincided with a new trend in medicine: the birth of the expert group, whose task is to sift through the best available evidence (hence the term evidence-based medicine) and attempt to come to a consensus with regard to treatment strategies (clinical guidelines) or classifications of disease. Before the 1990 World Congress of Gastroenterology in Sydney, Australia, such a group of European gastroenterologists and pathologists set out to create a flexible matrix for the classification of gastritis. The resulting Sydney System had both endoscopic and histological divisions. The former was met with general indifference and faded into oblivion. The latter unleashed passions that were distributed largely along geocultural lines: enthusiasm in Europe, where the system was conceived; indignation in the Americas and Asia, where investigators felt excluded both politically (none were asked to participate in the expert group) and nosologically (the types of gastritis commonly seen in Asia and South America received limited attention). In spite of these operational shortcomings, the Sydney System described a framework useful to generate diagnoses and flexible enough to incorporate new ideas as they emerged. Four years after its introduction, the Sydney System was reapprised by a group of pathologists including a wider geographic and disease representation. This group established a terminology of gastritis and identified, defined, and attempted to resolve some of the problems associated with the original Sydney System. The Houston workshop resulted in what is known as the Updated Sydney System, which is currently the most widely used and cited method for the classification of gastritis.
To create a report as suggested by the Sydney System, appropriate biopsy specimens should be methodically evaluated and the findings synthesized. Whereas gastroenterologists in some institutions have made a habit of obtaining mapped specimens from each patient who undergoes gastroscopy, others continue to take few and often topographically unidentified specimens. These diagnostic guidelines can be best followed by those gastroenterologist-pathologist teams who work together and communicate effectively.
To obtain adequately representative samples for the classification of gastritis, the biopsy protocol is recommended. Biopsy specimens from the three compartments (antrum, incisura angularis, and corpus) should be separately identifiable when they are submitted to the laboratory. Proper orientation is indispensable for optimal histological evaluation; it may be accomplished either in the endoscopy suite when biopsy specimens are collected, or in the histopathology laboratory at the time of embedding. This latter option is generally preferable, unless endoscopy personnel are experienced and motivated to perform the precise and tedious work required to orientate minuscule fragments of fresh tissue properly.
To translate histopathological observations into well-defined topographic patterns, each feature is then graded using the standardized Visual Analogue Scale. The final diagnosis issued should synthesize all individual evaluations, for example, “H.pylori antrum-predominant gastritis” or “corpus-restricted atrophic gastritis without H.pylori infection, suggestive of autoimmune gastritis.”
The Updated Sydney System is also suitable for evaluating and diagnosing the special types of gastritis. A sample diagnosis might read “lymphocytic gastritis, corpus predominant, with H.pylori infection.” In the case of gastropathies, the Updated Sydney System is mainly useful for helping in the orderly assessment of the histopathological features of the mucosa. This applies even in the unlikely situation that the system’s recommended set of five biopsy specimens is obtained from a patient with portal hypertension or watermelon stomach. However, in most such cases, attempting to grade each specimen individually is neither recommended nor necessary.
Chronic gastritis and Helicobacter pylori organisms. A. H&E stain of gastric mucosa showing surface foveolar cells, adherent mucus, and scattered bacillary forms within the mucus. B. Steiner silver stain of superficial gastric mucosa, showing abundant darkly staining microorganisms layered over the apical portion of the surface epithelium. Note that there is no tissue invasion.
TOOLS TO DIAGNOSE AND CLASSIFY GASTRIC CONDITIONS
The different types of gastritides and gastropathies are characterized by various combinations of histological changes, many of which are expressions of immune, inflammatory, and adaptive responses common to several conditions. However, the presence, absence, and relative intensity of these responses provide important etiologic clues and are crucial in the categorization of the process. These histological changes can be viewed as the foundations for the terminology of gastritis, and some familiarity with them is indispensable to understand both the classification and the related manifestations of nonneoplastic gastric conditions.
Surface epithelial degeneration is a nonspecific response to injury seen in all forms of gastritis. It is most conspicuous in chemical gastritis and H.pylori gastritis. In H.pylori gastritis, the intimate contact of bacteria with the surface cell membrane makes epithelial degeneration particularly prominent. Cell injury and necrosis can lead to erosions, which are seen endoscopically either as flat superficial lesions or as elevated lesions whose chronic nature is suggested by polypoid regenerative mucosa at the margins. The former are often the result of acute damage caused by drugs, bile reflux, or ischemia, whereas the latter are almost always associated with H.pylori gastritis.
Elongation and increased tortuosity of gastric pits result from hyperplasia of the foveolar cells, a presumed adaptive response to increased cellular exfoliation from the surface epithelium. It can be viewed as a visual surrogate for increased epithelial cell turnover. Hyperplasia is accompanied by hyperchromatic nuclei and mitotic activity reaching an increased height of the pit and by other signs of cellular immaturity, such as mucin depletion and a high nucleocytoplasmic ratio. Marked foveolar hyperplasia is a prominent feature of chemical injury, but lesser degrees are commonly seen in H.pylori gastritis.
Hyperemia and Edema of the Lamina Propria
Mucosal hyperemia—often visible endoscopically—is considered to be an indicator of bile reflux gastritis, and a significant correlation has been found with the concentration of bilirubin in gastric juice. Histologically, marked edema of the lamina propria with minimal inflammation is a characteristic finding in bile gastritis.
The presence of neutrophils characterizes the “activity” in chronic gastritis. The cause is H.pylori in most cases, but other infectious and inflammatory conditions (e.g., syphilis and Crohn’s disease) may be responsible for the persistence of neutrophils, classically associated with “acute” inflammation. Neutrophils are found in virtually every patient with H.pylori infection. The intensity of neutrophil infiltration may help to distinguish among the acute phase of infectious gastritis, Helicobacter gastritis with a particularly active component, and acute hemorrhagic gastritis resulting from chemical injuries (e.g., nonsteroidal antiinflammatory drugs [NSAIDs] or alcohol), in which inflammation is a minor component. Neutrophils disappear rapidly after successful eradication therapy; their persistence is a highly sensitive indicator of therapeutic failure.
Rare, scattered eosinophils may be present in the gastric lamina propria of healthy persons, particularly in underprivileged populations. Prominent eosinophilic infiltration of the gastric wall either may be part of the rare eosinophilic gastroenteritis or may represent a process confined to the stomach. In either case, the cause, suspected to have an allergic basis, is not known. Eosinophils are a major component in the responses to anisakiasis and may be a constituent of the granulomata that sometimes form around fragments of the helminths remaining in the gastric wall. In adults with H.pylori gastritis, there are usually small numbers of eosinophils. In contrast, children have been reported to have a greater eosinophilic component in the H.pylori–infected gastric mucosa. After eradication of the pathogen, eosinophils may increase for some time and then decline in parallel with mononuclear cells.
Mononuclear Cell Inflammation
Infiltration of the lamina propria by lymphocytes, plasma cells, and small numbers of eosinophils and mast cells is a major feature of H.pylori gastritis, except in areas of severe atrophy and metaplasia, in which the infiltrate tends to be sparse. When lymphocytes are seen infiltrating the surface or glandular epithelium, the possibility of lymphocytic gastritis should be considered. In autoimmune gastritis, there is a diffuse infiltrate of mucosal plasma cells and lymphocytes. The latter are also present around and within oxyntic glands.
Lymphoid follicles are rare in the stomach of healthy, H.pylori–free adults. When an extensive biopsy protocol is used, lymphoid follicles or aggregates are found in virtually all patients with H.pylori gastritis. In infected children and young adults, these entities may produce a distinctive nodularity in the gastric antrum, known endoscopically as follicular gastritis. H.pylori infection is the major determinant of gastric acquired mucosa-associated lymphoid tissue (MALT) and, therefore, a crucial factor in the origin of primary gastric B-cell lymphomas (MALT lymphoma).
Gastric atrophy is defined as the loss of appropriate glands in a given gastric compartment; that is, glands that are expected to be present in the portion of gastric mucosa under examination (e.g., oxyntic glands in the mucosa of the corpus) have been replaced by tissues not normally found there. More recently, the narrower definition of loss of specialized cells has been proposed. Whenever the gastric mucosa is damaged, irrespective of the mechanism or cause, it may either regenerate or return to normal (restitutio ad integrum), or it may undergo adaptive reparative processes leading to the replacement of the native mucosa with other structures. Destroyed native glands may be replaced by fibroblasts and extracellular matrix, by glands of “pyloric” appearance ( pseudopyloric metaplasia), or by an intestinal-type epithelium ( intestinal metaplasia). During chronic H.pylori infection, all these types of repair occur, the respective proportion of each probably modulated by environmental, genetic, and bacterial factors. Widespread atrophy also occurs in autoimmune gastritis, as a consequence of the immune-mediated glandular destruction of the oxyntic mucosa. Atrophic foci found in stomachs with evidence of chemical gastropathy are probably the result of ulcer repair.
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 argyrophil histochemical 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.
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.
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 the decreased prevalence of the infection in the population.
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.
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 incisura angularis, 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 (vacuolating cytotoxin), 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.
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.
Histopathological examination of gastric biopsy specimens. Helicobacter spp. can be detected in histological preparations of gastric biopsy specimens stained with a variety of methods. Hematoxylin and eosin is a suboptimal choice of stains for the specific task of detecting H.pylori. Reliable special stains include the Warthin-Starry and the Steiner silver stains, the Giemsa, Diff-Quick, and Gimenez stains, and a triple stain, which, by combining modified Steiner staining, hematoxylin and eosin, and Alcian blue, allows the simultaneous visualization of the features of gastritis, including intestinal metaplasia, and the bacteria. Several modified versions of this stain have become available. Anti– H.pylori antibodies for the immunohistochemical detection of H.pylori in paraffin-embedded biopsy specimens have high sensitivity and specificity; some laboratories use them for routine clinical diagnosis.
In situ hybridization and polymerase chain reaction. In situ hybridization may be used for the detection of H.pylori in paraffin-embedded sections, but high cost and technical difficulties have relegated this procedure to the research laboratory. Polymerase chain reaction for the detection of H.pylori infection must also be considered a research tool because of its requirement for a sophisticated molecular biology laboratory, the availability of appropriate primers, and its high price.
Smear, brush, and touch preparations. Smears of gastric mucus and exfoliated epithelial cells, usually with Gram staining, may allow the detection of bacteria within minutes of the endoscopic procedure. Rapid urease tests have made cytologic assays obsolete.
Bacterial culture. H.pylori is best cultured in a microaerophilic and humid atmosphere on culture media requiring fresh horse or sheep blood and antibiotics to suppress contaminants. Cultures for H.pylori are technically more complicated than those performed by the usual clinical microbiology laboratory. Because many clinical facilities are not equipped to perform the time-consuming procedures necessary to culture H.pylori, several methods for transportation have been devised.
Rapid urease tests. These assays exploit the high content of urease of H.pylori. A fragment of gastric mucosa is placed into a broth or in agar containing various concentrations of urea. The urease produced by H.pylori hydrolyzes the urea and releases ammonia, which raises the pH of the broth or agar, and an appropriate indicator (e.g., phenol red) changes color as the pH increases. In the first commercially produced rapid urease test, the CLOtest, the original yellow gel capsule into which the specimen is placed becomes red within minutes to hours, depending on the quantity of bacteria present. Several rapid urease tests are now commercially available. Both their specificity and sensitivity, compared with histopathological examination, are extremely high, in most cases approaching 100%.
Serology. The development of new techniques has minimized the problems of cross-reactivity that plagued first-generation serologic tests. Currently available tests are highly reliable. The large numbers of studies aimed at the discovery of an optimal diagnostic test for H.pylori infection have also provided valuable information on the immune responses to this organism. For example, the selection of H.pylori strains as sources of antigen is critical to the specificity and sensitivity of a test, and it is imperative to evaluate specific tests in the population to which it would be applied before selection of a test for use in specific settings. This population specificity highlights the importance of the many different geographic strains that infect different world populations.
Simplified “in-office” immunoenzymatic tests. Several in-office devices have been developed for the rapid detection of IgG anti– H.pylori antibodies. Most of them consist of disposable kits that provide a yes/no answer within a few minutes of placing a drop of serum in a well that is preabsorbed with antigen and an immunoenzymatic detection system. Although some of these tests are accurate, results have been generally less than the minimum required sensitivity and specificity of 90%. Antibodies (mostly of the IgG class) against H.pylori have been detected in the saliva and the urine of infected patients. The specificity and sensitivity of urine tests have been found to be satisfactory in several studies, particularly in Japan.
Stool antigen assay. An enzymatic immunoassay (HpSA) that detects H.pylori antigens in stools (thus providing information on the presence of current infection) has become available for the diagnosis of H.pylori infection and for monitoring the response to therapy. The test is similar to an enzyme-linked immunosorbent assay, using polyclonal anti– H.pylori antibody absorbed to microwells. A large European multicenter study has yielded encouraging results.
Urea breath tests. The urea breath tests are among the most important and innovative methods to detect H.pylori infection. These tests rest on the ability of H.pylori to produce large quantities of urease. The ingestion of a solution containing urea is rapidly followed, in an infected patient, by the production of ammonia and carbon dioxide. The latter rapidly appears in the subject’s breath. If the ingested urea is labeled either with the radioactive isotope 14C or with the nonradioactive isotope 13C, then the exhaled carbon dioxide will also be labeled and, therefore, measurable by an appropriate detection method. When 14C-labeled urea is used, the general method consists of the ingestion of a solution or a capsule containing quantities between 0.5 and 10 µCi of the isotope-labeled urea. When 13C-labeled urea is used, test subjects are given a solution of 125 g of 99.9% labeled urea followed by a meal aimed at increasing its permanence in the stomach. After a period of time, the subject inflates a balloon, which is immediately sealed and sent to a laboratory for the detection of the isotope-labeled carbon dioxide. Both types of tests are now well standardized and are approved by regulatory agencies in Europe and North America. The urea breath tests are extremely sensitive and specific and, in contrast to serologic tests, detect current active infection (not evidence of past infection). Their widespread use has made them more affordable, and they have become the test of choice for a variety of populations, including children, pregnant women, and patients who cannot undergo an endoscopic procedure.
Helicobacter heilmannii Infection
More than 35 species of Helicobacter have been described, but only few other than H.pylori have been shown to cause gastritis in humans: H felis, H fennelliae, H cinaedi, and H heilmannii. Among these, H heilmannii (formerly known as Gastrospirillum hominis) is the most common, with an estimated prevalence of approximately 1% of all human Helicobacter infections. In some rural areas in Eastern Europe, this organism has been detected more commonly, leading to the hypothesis of zoonotic transmission. The bacterial morphology is characteristic: organisms measure 5 to 9 µm in length (twice as long as H.pylori) and have five to seven spirals clearly visible with a silver stain. Gastritis caused by H heilmannii is often milder and more patchily distributed than H.pylori gastritis. The inflammation tends to be more circumscribed and to affect mostly the antrum, although cases with severe corpus active inflammation are seen. Concurrent erosions and ulcers have been reported to be less common than in H.pylori gastritis. The diagnosis rests on the recognition of the bacterial morphology, although the distinction between H heilmannii and H felis is not possible by light microscopy.
Treatment of Helicobacter pylori Infection
At present, the only universally agreed on indications for treatment are H.pylori–related duodenal and gastric ulcers and low-grade, primary B-cell MALT lymphoma. H.pylori should be eradicated in patients with documented ulcer disease, whether or not the ulcers are currently active, to reduce the likelihood of relapse. Most clinical trials do not provide convincing data in support of the benefits of eradication of infection in patients with nonulcer dyspepsia, and there are no controlled studies showing that eradicating H.pylori from a population will reduce the incidence of gastric cancer. For various logistical and ethical reasons, it is unlikely that such trials will be ever carried out to the satisfaction of those who demand unequivocal evidence. The most pressing question then is whether we should hold back and wait for more data or act now based on current information. Today, there is ample epidemiologic and biologic evidence that whereas H.pylori gastritis may not be the only cause of the development of atrophy and intestinal metaplasia, it almost always provides the necessary background on which these lesions arise. By treating H.pylori gastritis, we can prevent the development of atrophy and metaplasia, and most likely we would also arrest the progress of these lesions in infected persons who have already developed them. As a result, we should be able to prevent millions of gastric cancers. The incidence of non–NSAID-induced peptic ulcers would also be greatly reduced, and primary gastric lymphomas would all but disappear. Thus, we ought to put aside the teleological questions on the ultimate significance of our immemorial amphibiotic relationship with H.pylori and its intriguing evolutionary and metaphysical implications and proceed to cure infected patients.
In vitro, H.pylori is susceptible to a wide range of antibiotics, but monotherapy has been disappointing in vivo, probably because of inadequate antibiotic delivery to the sites of colonization. Thus, several multidrug regimens have been developed, the most successful of which are triple and quadruple combinations that achieve H.pylori eradication rates of more than 90% in many trials and more than 75% in clinical practice. The most commonly used 7- and 14-day drug regimens consisting of a proton pump inhibitor and two or three antimicrobial agents. The major determinants of therapeutic failures are inadequate patient compliance and drug resistance, particularly to metronidazole and clarithromycin.
There are no established guidelines for posttreatment testing. When eradication therapy is given for gastric ulceration or MALT lymphoma, there is an opportunity to retest for H.pylori at repeat endoscopy, which is performed to evaluate healing or regression. For duodenal ulceration, a urea breath test, a stool antigen test, or an endoscopy with gastric biopsy should be performed 4 to 6 weeks after treatment. When therapy is administered to treat asymptomatic infections, posttreatment testing is generally not deemed necessary.
Evolution and Associations of Helicobacter pylori Gastritis
H.pylori gastritis is a life-long infection that can be viewed as a spectral disease. At the one end of the spectrum, inflammation remains mostly confined to the antrum and the cardia, the oxyntic mucosa is mildly affected, and atrophy is absent or minimal. At the other end, severe inflammatory changes involve the entire gastric mucosa and inflict progressive damage that results in loss of the normal gastric glands and their replacement by fibrous tissue and metaplastic epithelia. Although these are aspects of the same disease that can be placed on a continuous scale, the epidemiologic distribution and the associations of the two extremes are profoundly different. Gastritis confined to the antrum and without significant atrophy does not impair acid secretion, is commonly present in patients with duodenal ulcer, and has not been linked to increased cancer risk. Conversely, generalized gastritis with atrophy reduces acid secretion and is strongly associated with gastric adenocarcinoma. Thus, for the practical purposes of classification and prognostic evaluation, it has been expedient to divide gastritis into two phenotypes: nonatrophic antrum-predominant gastritis and multifocal atrophic gastritis.
Antrum-Predominant Gastritis This is the most common form of gastritis in the Western world. Its characteristics are as follows: a moderately to severely inflamed antrum; a mildly inflamed or normal corpus; minimal or absent atrophy or intestinal metaplasia, limited to the antrum; and normal or increased acid secretion. Most patients with this type of gastritis have neither symptoms nor complications. However, they have a risk of duodenal ulcer, estimated at 20% over their lifetime.
Atrophic Gastritis Also called multifocal atrophic gastritis, metaplastic atrophic gastritis, and atrophic pangastritis, this disorder is characterized by marked diffuse mucosal inflammation, often more severe in the oxyntic mucosa, by patches of atrophy and intestinal metaplasia in both antrum and corpus, and by variously reduced acid secretion. Atrophic gastritis is most prevalent in populations that are—or were, until a few decades ago—living in suboptimal sanitary conditions, including much of South and East Asia, Latin America, and parts of Central, Eastern, and Southern Europe. Socioeconomic factors may be a surrogate for other unknown agents that modulate the evolution of gastritis, because there are notable epidemiologic exceptions to this association. Japan, a country with high levels of sanitation and personal hygiene, has one of the world’s highest prevalences of atrophic gastritis and a high incidence of gastric adenocarcinoma. In contrast, Equatorial Africa, in spite of its precarious socioeconomic texture, inadequate sanitary standards, and a prevalence of H.pylori close to 90%, appears to have a low prevalence of atrophic gastritis and a low incidence of gastric adenocarcinoma. Several explanations have been proposed for this ‘African enigma,” ranging from diet, human and bacterial genetics, to unreliable statistics. Atrophic gastritis is a risk factor for gastric epithelial dysplasia, a precursor of the intestinal-type adenocarcinoma of the stomach. It also predisposes patients to gastric ulcer.
Peptic Ulcers, Carcinoma, and Lymphoma In addition to peptic ulcer disease and gastric carcinoma, H.pylori infection is also epidemiologically related to primary gastric MALT-lymphomas.
Extragastrointestinal Manifestations of Helicobacter pylori infection H.pylori infection has been proposed to be associated with an ever-growing number of extragastric manifestations of H.pylori infection, even if their causal relationship with H.pylori is far from conclusively demonstrated. Most of these associations are founded on epidemiologic data; however, both H.pylori infection and of some of the conditions allegedly associated with it (e.g., atherosclerosis) have a very high prevalence in many populations. Thus, biologic rather than epidemiologic data will be needed to prove causation. For one of these conditions, rosacea, there are several randomized trials that essentially disprove the association with H.pylori. Conversely, several clinical studies based on treatment results lend some support to the possibility of a pathogenetic involvement of H.pylori in iron deficiency anemia and autoimmune thrombocytopenic purpura. For most other conditions, data are insufficient to reach informed conclusions; however, the biologic plausibility in some of the proposed associations (e.g., with migraine) is so low that one must wonder whether attempts to prove causality are worth the effort.
INFECTIOUS GASTRITIS (EXCLUDING HELICOBACTER)
Because of the high acid content of the normal stomach, the gastric environment is inhospitable to most infectious agents. However, in patients with atrophic gastritis and decreased acid secretion, in patients with impaired immune responses, or as part of systemic infections, numerous viruses, bacteria, and parasites can infect the stomach. Although rare, some of these infectious gastritides have characteristic clinical and pathological features.
Enteric rotaviruses and caliciviruses probably infect the stomach during the course of gastroenteritis, but no pathological changes in the gastric mucosa have been documented in volunteer studies with these agents. Only cytomegalovirus (CMV) infection is known to have a distinct pathological appearance in the stomach. CMV gastritis is seen almost exclusively in young children and immunocompromised patients, and it is usually associated with concurrent CMV infection of other sites of the digestive tract. Endoscopically, the gastric mucosa may appear completely normal or may show erosions, shallow ulcers, or hemorrhagic gastritis. Rarely, the condition may present as grossly nodular mucosa that has been referred to as a pseudotumor. CMV inclusions may be abundant and thus easily detected using the routine hematoxylin and eosin stain, or they may be rare and impossible to demonstrate without using immunohistochemistry or in situ hybridization techniques. A characteristic manifestation of CMV infection in the stomach of young children is massive foveolar hyperplasia accompanied by edema and mild inflammation of the lamina propria. The resulting endoscopic appearance is that of a giant-fold hypertrophic gastropathy indistinguishable from Ménétrier disease.
The diagnosis of gastric CMV infection is made by demonstrating the characteristic nuclear or cytoplasmic viral inclusions. The only effective therapeutic agent is ganciclovir, a guanosine derivative that selectively inhibits CMV DNA polymerase. In patients with acquired immunodeficiency syndrome (AIDS) and CMV colitis, ganciclovir has a response rate of 70% to 90%.
Bacterial overgrowth may occur in stomachs that have become achlorhydric as a result of atrophy, complete antrectomy, or vagotomy or as a result of long-term use of histamine H 2-receptor antagonists or proton pump inhibitors. Patients with scleroderma and other severe motility impairments are also prone to bacterial overgrowth. In contrast to H.pylori, however, these bacteria colonize rather than infect the gastric mucosa, and they neither elicit inflammatory responses nor cause symptoms.
An extremely rare condition is acute suppurative gastritis, also known as phlegmonous gastritis. This life-threatening condition is caused by pyogenic bacteria (streptococci, staphylococci, Escherichia coli, Proteus, and Haemophilus spp.) and is characterized by large areas of purulent necrosis involving the full thickness of the gastric wall. When it is caused by gas-forming organisms, the term emphysematous gastritis has been used. Few cases have been reported, mostly in very young children, elderly persons, patients with alcoholism, and immunocompromised patients. Potential iatrogenic causes include polypectomy and mucosal injection with India ink. The diagnosis is made endoscopically or at surgery. Antibiotic treatment may have to be accompanied by surgical intervention.
Primary gastric tuberculosis is rare, particularly in industrialized countries. However, in patients with disseminated tuberculosis, necrotizing granulomata may be found in the gastric mucosa. Another Mycobacterium that has gained prominence with the spread of AIDS is Mycobacterium avium-intracellulare complex, but the stomach is rarely involved; when it is, typical lesions consist of accumulations of foamy histiocytes in the lamina propria, sometimes with formation of ill-defined granulomata without necrosis.
In the 1980s and early 1990s, increasing numbers of cases of gastric syphilis were reported in patients infected with human immunodeficiency virus. When associated with secondary syphilis, syphilitic gastritis is characterized by a prominent mixed inflammatory infiltrate consisting predominantly of plasma cells and with mucosal ulcerations. The infiltrate may be dense enough to cause the swelling of gastric folds, which may also undergo erosion and ulceration, sometimes mimicking the endoscopic appearance of lymphoma or infiltrating carcinoma. Symptoms include severe dyspepsia, nausea, vomiting, and anorexia, with rapid weight loss. The diagnosis is often delayed by a low index of suspicion. Although spirochetes may be seen in sections stained with appropriate silver stains (Dieterle, Steiner, or Warthin-Starry), the search may be painstaking and is usually beyond the reach of the nonspecialist pathologist. Standard treatment for secondary syphilis is rapidly effective.
Candida species, Histoplasma capsulatum, and Mucoraceae have been found in the stomach of immunocompromised patients, particularly those with AIDS, with disseminated infections, but none of these fungi have been reported as a primary cause of gastritis.
The stomach is not a preferred site for human parasitic infections, but Cryptosporidium spp. and Giardia intestinalis have been identified in the gastric mucosa. Strongyloides stercoralis has been found in the stomach of a few patients with widespread infections.
The only nematodes that invade the human gastric wall are those of the family collectively known as Anisakidae, or “sushi worms.” Anisakiasis is an important cause of morbidity in countries such as Japan, where large quantities of raw fish are consumed. The muscle of many species of edible fishes contain larvae of Anisakidae. In a small proportion of persons who eat infected fish, larvae penetrate the gastric wall and cause a sudden onset of epigastric pain. Because the worms can be easily removed endoscopically by an experienced operator and the disease is self-limited in any case, patients presenting with epigastric pain in high-prevalence countries should be asked routinely about ingestion of raw or undercooked fish within 12 hours before the onset of symptoms. This practice would help to avoid unnecessary surgery.
Autoimmune gastritis is a corpus-restricted chronic atrophic gastritis associated with circulating serum anti–parietal cell and anti–intrinsic factor antibodies and intrinsic factor deficiency, with or without pernicious anemia.
Most clinical manifestations of autoimmune gastritis become apparent only many years after the onset of the disease, when the parietal cell mass decreases beyond a critical point and the stomach becomes unable to produce sufficient amounts of acid, pepsinogens, pepsin, and intrinsic factor. Achlorhydria, the most direct result of the destruction of acid-producing oxyntic cells, typically occurs in the most advanced stages of the disease. Hypochlorhydria, however, may also occur in patients with moderate to large numbers of surviving parietal cells, suggesting that anti–proton pump antibodies or inhibitory lymphokines released by subsets of inflammatory cells may participate in the inhibition of acid secretion. Patients with corpus atrophy and achlorhydria have hypergastrinemia, which tends to correlate with the severity of the mucosal damage. Injury to chief cells leads to a reduction of pepsin activity in gastric juice and of pepsinogens in blood. A low serum pepsinogen I level (<20 ng/mL) is a sensitive and specific indication of corpus atrophy.
Many patients with autoimmune gastritis develop either iron deficiency or pernicious anemia. Hypochromic anemia is associated with corpus-restricted chronic atrophic gastritis in approximately 15% of patients. Achlorhydria seems to be the major contributor to the pathogenesis of iron deficiency anemia: gastric acid is important in the absorption of nonheme iron, which in Western diets supplies at least two thirds of nutritional iron needs. Pernicious anemia is usually preceded by corpus-restricted chronic atrophic gastritis and reduced acid secretion by approximately a decade, and it is generally associated with a histological pattern of end-stage atrophic gastritis. Pernicious anemia is a rarely diagnosed condition, with a reported prevalence of less than 1% even in elderly persons in high-incidence countries. Its true prevalence could be higher, but most patients are successfully treated by hematologists or general practitioners for their anemia and cobalamin (vitamin B 12) deficiency, and they are never referred to a gastroenterologist for the evaluation of atrophic gastritis, pepsinogens levels, or anti–parietal cell antibodies. Cobalamin deficiency affects the rapidly proliferating gastrointestinal epithelium, and patients with severe deficiency may complain of a sore tongue, which may be smooth and beefy red. Anorexia with moderate weight loss may also be evident, possibly accompanied by diarrhea and other gastrointestinal symptoms. Neurological manifestations include numbness and paresthesia in the extremities, weakness, and ataxia. There may be sphincter disturbances.
Autoimmune gastritis is a risk factor for hyperplastic and adenomatous polyps, carcinomas, and endocrine tumors. Polyps are found in 20% to 40% of patients with pernicious anemia, and they are mostly sessile, smaller than 2 cm in diameter, and often multiple. Most polyps are hyperplastic, but up to 10% contain dysplastic foci. Gastric cancers associated with pernicious anemia are of the intestinal type and arise from intestinal metaplasia, a finding suggesting that the link between autoimmune gastritis and carcinoma may be intestinal metaplasia and its dysplastic transformation.
Autoimmune gastritis is substantially more common in patients with other diseases thought to be of immunologic origin (Graves disease, myxedema, thyroiditis, idiopathic adrenocortical insufficiency, vitiligo, and hypoparathyroidism) than in the healthy population. The high prevalence of specific familial histocompatibility haplotypes such as human leukocyte antigen (HLA)-B8 and HLA-DR3 in patients with corpus-restricted atrophic gastritis is another strong indicator of its autoimmune origin. The precipitating factors, however, remain unknown. The hypothesis that autoimmune gastritis could be initiated by H.pylori infection has received considerable attention. A high prevalence of antibodies with high specificity for gastric mucosa antigens has been reported in patients with H.pylori–associated gastritis; preabsorption of the serum from these patients with H.pylori removed most of these autoantibodies. Furthermore, 20% of these patients had autoantibodies that reacted with the secretory canalicular structures of parietal cells, which are among the major targets in autoimmune gastritis. In other studies, H.pylori–positive patients with and without previously demonstrated anticanalicular antibodies had a 30% to 50% prevalence of anti–H +,K +-ATPase antibodies, in contrast to a less than 3% prevalence in noninfected persons. It has also been demonstrated that H.pylori lipopolysaccharides express Lewis x and y blood group antigens, which are also expressed by either H +,K +-ATPase or gastric epithelial cells. Collectively, this information lends support to the concept that a cross-mimicking mechanism between H.pylori and gastric mucosa antigens participates in the pathogenesis of autoimmune gastritis. This correlation, however, remains unproven, and much stronger biologic, clinical, and epidemiologic evidence is needed before H.pylori can be viewed as the cause of autoimmune gastritis.
Atrophy causes a progressive thinning of the mucosa of the gastric corpus; this explains why few folds are left and why fine submucosal vessels are easily recognized on endoscopic examination, especially in advanced disease. The antral mucosa is endoscopically normal in the majority of cases. Polyps become common in the advanced stages of the disease; therefore, atrophic gastritis must be ruled out in patients in whom multiple hyperplastic gastric polyps are detected at endoscopy.
The main histopathological features of autoimmune gastritis are diffuse corpus-restricted chronic atrophic gastritis with mild to moderate intestinal metaplasia and, in the absence of concurrent H.pylori infection, a normal gastric antrum. This pattern is characteristic of the advanced stage of the disease and is found in patients with pernicious anemia. Persons with parietal cell antibodies and no pernicious anemia show a broad spectrum of atrophic changes, from minimal oxyntic gland loss to severe and diffuse atrophy of the oxyntic mucosa. In the early phases, one sees diffuse or multifocal, dense mononuclear cell infiltration of the lamina propria and lymphocytic infiltration of individual oxyntic glands. Later, marked atrophy of the oxyntic glands with diffuse mononuclear cell infiltration of the lamina propria develops. Pyloric metaplasia is extensive, whereas intestinal metaplasia tends to be still limited to few foci. The end stage is characterized by a great reduction in corpus mucosal thickness, foveolar hyperplasia, and replacement of oxyntic glands by pyloric, pseudopyloric, or intestinal metaplasia. The inflammatory infiltrate is minimal, although scattered lymphoid aggregates and follicles may be found.
In the majority of patients, the antral mucosa is either normal or shows only focal areas of mild chronic inflammation with intestinal metaplasia, similar in degree and extension to what is observed in the general asymptomatic population. Hyperplasia of gastrin cells secondary to achlorhydria is often seen. Enterochromaffin-like cell carcinoids may arise during the florid phase, but they are found more commonly in association with an end-stage histopathological pattern.
Autoimmune gastritis should be suspected in patients with megaloblastic anemia, with evidence of clinically significant cobalamin deficiency with values lower than 150 pg/mL, or with multiple gastric polyps. The diagnosis must be confirmed by the characteristic histopathological findings of corpus-restricted atrophic gastritis and by the presence of serum anti–intrinsic factor or anti–parietal cell antibodies.
The management of patients with autoimmune gastritis should address two aspects of the condition: the gastric lesions and the manifestations related to the cobalamin deficiency. Gastric mucosal atrophy is irreversible. Patients with extensive intestinal metaplasia and those with multiple polyps may be at increased risk of gastric cancer. Although there are no accepted guidelines, a surveillance gastroscopy every 1 or 2 years may represent a sensible empiric approach.
With cobalamin replacement, most abnormalities resulting from cobalamin deficiency undergo complete and lifelong correction, except for the neurological manifestations. Their improvement depends on the extent that irreversible changes in the nervous system may have occurred before treatment.
Lymphocytic gastritis is characterized by the presence of large numbers of mature lymphocytes infiltrating the surface and foveolar epithelium.
In his original report of this condition, Haot suggested that lymphocytic gastritis corresponded to the endoscopic entity previously known as varioliform gastritis. The histological features of lymphocytic gastritis may also be found in endoscopically normal stomachs and in patients with celiac disease, and the varioliform aspect (numerous thickened folds capped by small nodules that contain a central erosion or ulceration) can be found in H.pylori–infected stomachs.
Lymphocytic gastritis is rare, found in 1% to 3% of persons who undergo endoscopy with biopsy sampling. It is most commonly diagnosed in the sixth decade and appears to affect men and women equally.
In contrast to patients with chronic active gastritis, patients with the varioliform type of lymphocytic gastritis are often symptomatic; rapid weight loss and anorexia are reported in about half of affected patients, whereas epigastric pain is less common. Hypoproteinemia, hypoalbuminemia, and peripheral edema suggesting protein-losing gastroenteropathy have been documented in approximately 20% of patients. Lymphocytic gastritis is a chronic disease, but there have been few case reports of spontaneous resolution. When it is associated with gluten enteropathy, the signs, symptoms, and clinical course are those of celiac disease.
Both the etiology and the pathogenesis of most lymphocytic gastritides are unknown. Because virtually all intraepithelial lymphocytes are CD8 + suppressor T cells, the same cells that form the intraepithelial infiltrate in celiac disease, an allergic pathogenesis has been proposed. This hypothesis is supported by the increasingly apparent association between a subtype of lymphocytic gastritis and celiac disease. The relationship with H.pylori, initially enthusiastically embraced, then vigorously rejected, is now viewed with an agnostic attitude by most investigators.
Macroscopic and Endoscopic Appearance
Approximately 80% of patients in whom a histopathological diagnosis of lymphocytic gastritis is made have endoscopic lesions described as varioliform, aphthous, verrucous, or chronic erosive gastritis. The appearance is that of a complex pattern of enlarged folds, predominantly in the corpus, which are covered by thick mucus, are crossed by large erosions, and may be crested with clusters of elevated aphthoid nodules. Flat erosions may be found in the antrum. The remaining 20% of patients (including those with celiac disease and collagenous gastritis) have less dramatic lesions, with only scattered superficial erosions in the corpus or antrum. Some patients have an endoscopically normal stomach. This last group of patients with a normal-appearing stomach may have a pathogenetically distinct condition, even though the histopathological features are indistinguishable. Some authors have suspected a relationship between lymphocytic gastritis and Ménétrier disease.
Histopathology and Diagnosis
Because the endoscopic appearance of varioliform gastritis may result from either H.pylori infection or lymphocytic gastritis, the diagnosis can be suspected clinically, but it can be confirmed only by histopathologists. In biopsy specimens from these patients, a substantial increase in intraepithelial lymphocytes, particularly in the corpus, is associated with a histopathological spectrum ranging from marked chronic inflammatory cell infiltration of the lamina propria, activity, and focal erosions to a minor increase in chronic inflammatory cells with no activity. In most cases, the histological picture can be readily distinguished from that of chronic H.pylori gastritis, in which few intraepithelial lymphocytes are present (rarely more that 5 or 6 per 100 epithelial cells). The diagnostic threshold for lymphocytic gastritis is generally accepted as more than 25 intraepithelial lymphocytes per 100 epithelial cells, but in most cases the counts are much greater, between 25 and 50 lymphocytes. If H.pylori infection is present, immunohistochemistry to detect CD8 + T cells may be helpful: in pure lymphocytic gastritis, most intraepithelial lymphocytes are CD8 +, whereas a heterogeneous infiltrate characterizes H.pylori gastritis.
When concurrent H.pylori infection is present, eradication of the infection may resolve the inflammation and is therefore recommended. Patients with gluten enteropathy will benefit from the standard dietary limitations recommended to restore the small intestinal integrity. For patients with “pure” lymphocytic gastritis and severe gastric mucosal lesions, there are no consistently effective therapies. The use of proton pump inhibitors has resulted in healing of the ulcers and erosions in some patients. Therapy with glucocorticosteroids or sodium cromoglycate, often successfully used for the treatment of eosinophilic gastroenteritis, has obtained unclear results.
Rather than a clinical entity, granulomatous gastritis can be viewed as a histopathological category to which stomachs bearing granulomata are temporarily assigned while the condition responsible for their development is identified. In most cases the morphologic appearance of granulomata does not provide useful clues as to their cause, except when foreign materials, acid-fast bacilli, or fungal forms are found. Thus, a specific diagnosis can be made only by integrating histopathological data with clinical and laboratory information.
Clinical Manifestations and Pathogenesis
Because granulomata can be found in the gastric mucosa of patients with infectious, inflammatory, and neoplastic diseases, as well as in otherwise healthy persons, neither clinical manifestations nor endoscopic appearances are useful to predict the presence of gastric granulomata. Thus, the stomach may be completely normal or may exhibit characteristics of the associated conditions.
Mycobacterium tuberculosis and Histoplasma capsulatum Infection Tuberculosis is the most common cause of granulomatous disease of the gastrointestinal tract, but the stomach is rarely affected, even in the presence of severe ileocecal involvement. Primary gastric tuberculosis has been reported mostly from developing countries with a high prevalence of Mycobacterium tuberculosis infection. In almost all such cases, gastric tuberculosis was diagnosed because of the presence of a large, nonhealing gastric ulcer. A few cases of primary infection of the stomach by the dimorphic fungus Histoplasma capsulatum have been reported. As in patients with gastric tuberculosis, these patients presented with signs and symptoms that led to the discovery of a large gastric ulcer initially interpreted clinically as malignant.
Helicobacter pylori Infection Unexplained granulomata have been found in patients with H.pylori gastritis, but this finding is extremely rare, on the order of less than 1 in 1000 infected patients. Although a role for H.pylori in the causation of granulomata has been postulated, there is no evidence to support this hypothesis.
Anisakiasis Early lesions of anisakiasis range from interstitial edema with a loose, eosinophilic inflammatory infiltrate to eosinophilic abscesses, in which well-preserved larvae are often detected. In later lesions, the most common finding is the presence of foreign body granulomata, sometimes associated with fragments of helminthic cuticles.
Foreign Bodies A common cause of gastric foreign body granulomata is suture material in patients who have undergone a partial gastrectomy. In patients with gastric ulcer, food particles may become engulfed in the ulcer crater and may cause a foreign body reaction. When such granulomata are found in biopsy specimens obtained from active ulcers, their origin is readily apparent; diagnostic difficulties may arise when granulomata are found in specimens from healed ulcers and the pathologist is unaware of the relevant clinical information.
Tumors Rarely, adenocarcinomas (particularly mucin-secreting tumors) may induce the formation of foreign body granulomata in the gastric mucosa or perigastric lymph nodes. Granulomata have also been noted in the gastric mucosa of few patients with gastric non-MALT lymphoma.
Other Unusual Causes In rare instances, granulomatous gastritis may be part of an immune-mediated vasculitis syndrome or Wegener granulomatosis. Sometimes, it may assume a form akin to xanthogranulomatous cholecystitis.
Granulomatous Gastritis in Sarcoidosis and Crohn’s Disease
Granulomata detected in the gastric mucosa of a patient with established sarcoidosis or Crohn’s disease can be assumed to be part of the systemic process, and no further investigation is required. Because the finding of gastric mucosal granulomata may precede the discovery of the disease in other organs, the careful interpretation of gastric biopsy findings together with appropriate suggestions for further tests may lead to the prompt diagnosis of a condition that could otherwise remain obscure for a long time.
In sarcoidosis, involvement of the gastrointestinal tract is found occasionally at autopsy, but only rarely has it clinical importance. However, severe gastric disease with outlet obstruction or bleeding has been reported. Endoscopic findings may include nodularity, polypoid changes, erosions, ulcers, and segmental, usually distal, rigidity resembling linitis plastica. These gross changes reflect the presence of numerous mucosal granulomata and severe fibrosis.
Studies have challenged the perception that gastric involvement is rare in Crohn’s disease, and they found a prevalence of gastric granulomata of approximately 10% to 15% and a prevalence of “focally enhanced” H.pylori–negative active gastritis of between 30% and 70%. In these patients, focal gastritis was almost twice as frequent in the corpus as in the antrum, and epithelioid granulomata were twice as prevalent in the antrum.
Isolated Granulomatous Gastritis
Isolated granulomatous gastritis is a “holding category,” applied as a temporary diagnostic label to cases of granulomatous gastric inflammation for which no cause has yet been determined. Support for this approach derives from studies showing that most gastric granulomata are an expression of either concurrent or incipient Crohn’s disease or systemic sarcoidosis. Even after careful evaluation, some gastric granulomata will remain unexplained. These lesions are usually asymptomatic, there is no information on their natural history or evolution, and, therefore, no treatment can be recommended.
CHEMICAL (REACTIVE) GASTROPATHY
An association between the presence of bile in the stomach and gastric mucosal damage ( duodenogastric reflux) was first postulated by William Beaumont in 1859, and several subsequent clinical observations led to the development of surgical techniques to prevent or minimize the regurgitation of duodenal contents into the stomach. In 1983, Dewar, Dixon, and Johnston systematically described the histopathological changes associated with bile reflux in the stomachs of patients who had undergone gastrectomy as well as patients with duodenal or gastric ulcer. The original term bile reflux was later replaced by chemical gastritis, to include the recently discovered NSAID-induced changes in the gastric mucosa. The terms reactive gastritis, type C gastritis, and chemical gastropathy have also been used. Chemical gastropathy is now defined as the constellation of endoscopic and histological changes caused by chemical injury to the gastric mucosa. This is an implicit admission that this diagnosis can be made only when converging clinical and histopathological evidence is present. Radiation gastritis, which results from a physical agent rather than a chemical one.
Three categories of patients may exhibit the endoscopic and histological changes of chemical gastropathy: patients with alkaline reflux after partial gastrectomy, patients with duodenogastric bile reflux as part of a poorly understood dysmotility syndrome, and patients who take NSAIDs.
Postgastrectomy alkaline reflux may present with a syndrome characterized by burning midepigastric pain unresponsive to antacids and aggravated by eating and recumbency. Bilious vomiting, anemia, and weight loss may occur. Endoscopic confirmation of bile reflux and documentation of the characteristic histopathological findings support the diagnosis, and corrective surgery (e.g., creation of a 40- to 50-cm Roux-en-Y gastrojejunostomy) is successful in about half of all cases.
Duodenogastric bile reflux secondary to gastroduodenal dysmotility or to cholecystectomy is a controversial condition, rarely considered in the differential diagnosis of dyspepsia in patients with an intact stomach. Thus, the frequency of endoscopic or histological changes of chemical gastropathy in these patients is unknown.
Millions of persons take daily doses of NSAIDs for indefinite periods, in many cases for life, to control pain caused by osteoarthritis, rheumatoid arthritis, or other chronic conditions. Unknown numbers of these NSAID users experience epigastric pain; approximately 10% per year develop erosions or ulcers, and 1% to 2% per year have a major gastric bleeding episode. Reactive gastropathy has been documented histopathologically in 10% to 45% of long-term users of NSAIDs, but no relationship could be established between the appearance of the mucosa and dyspeptic symptoms.
Duodenogastric reflux (with alkaline pancreaticoduodenal secretions as well as acids, bile salts, and lysolecithin) disrupts the mucous barrier and directly damages the gastric surface epithelium. This combined injury leads to accelerated exfoliation of surface epithelial cells and a histamine-mediated vascular response that manifests as edema and hyperemia. Persistent epithelial damage may lead to the release of other proinflammatory agents, such as platelet-derived growth factor, which among its many actions stimulates smooth muscle and, later on, fibroblastic proliferation. Epithelial injury after exposure to NSAIDs appears to be mediated by reduced prostaglandin synthesis. Prostaglandins are important cytoprotective agents in the gastric mucosa and exert their effects by maintaining mucosal blood flow, by increasing secretion of mucus and bicarbonate ions, and by augmenting epithelial defense against cytotoxic injury. Thus, NSAID-inflicted injury can be partially prevented by simultaneous administration of prostaglandin analogs such as misoprostol and by suppression of gastric acid production with proton pump inhibitors. Newer selective cyclooxygenase 2 inhibitors (inhibitors, second-generation NSAIDs, or selective NSAIDs) are reportedly better tolerated by the gastric mucosa. Whether the initial encouraging results will hold true when these drugs become widely used, remains to be evaluated.
In patients who have undergone a Billroth II gastrectomy, the gastric mucosa at the anastomotic site may have a polypoid appearance with congestion, edema, and friability. Superficial erosions may be present in more proximal areas of the gastric stump, but they are not specific, because they can be caused by a variety of injuries. In patients with nonoperated stomachs and possible duodenogastric bile reflux, the mucosa may exhibit congestion, edema, and erosions. In long-term NSAID users, the mucosa may be normal or may show congestion, erosions, or ulcers.
Although some histological features are more frequently found in regular NSAID users, the histopathological diagnosis of chemical gastropathy remains a challenging problem. The histopathological changes that have been associated with reactive gastropathy include evidence of epithelial regeneration, foveolar hyperplasia, edema of the lamina propria, and expansion of the smooth muscle fibers into the upper third of the mucosa, an area in which they are not normally found. Both the specificity and the predictive value of these features are low because of several potential confounding factors. Surreptitious use of NSAIDs, other substances in the diet (e.g., alcohol, spices, salt) that may cause similar mucosal changes, and clinically silent bile reflux can rarely be excluded; furthermore, the difficulty of obtaining a perfect control population cannot be overemphasized. H.pylori infection induces some of the features traditionally considered characteristic of chemical gastropathy: mucosal hyperemia and edema, superficial erosions, foveolar hyperplasia, and regenerative changes. Therefore, the pathologist can suspect chemical gastropathy and communicate this suspicion to the clinician, but a firm histopathological diagnosis can be made only when supportive clinical data are available and H.pylori infection is absent.
Partial Gastrectomy and Carcinoma
The polypoid appearance of the distal portions of the gastric stump in patients who have undergone gastrectomy has been referred to as gastritis cystica polyposa. Several studies, mostly conducted in Europe and Asia, have reported a high prevalence of low-grade dysplasia in these polypoid areas, as well as an increased incidence of gastric adenocarcinoma 2 to 3 decades after gastrectomy. The implications of these findings, potentially important because of the suggestion that patients who undergo partial gastrectomy may need endoscopic surveillance, seem less urgent in the present era, when partial gastrectomy for peptic ulcer disease has become an exceedingly rare operation.
Hemorrhagic gastropathy (hemorrhagic gastritis) refers to a group of conditions characterized by subepithelial hemorrhages and erosions. These mucosal lesions do not cause major bleeding unless ulcers develop. Three major factors are involved in the pathogenesis of hemorrhagic gastropathy: use of NSAIDs, ingestion of large quantities of alcohol, and severe physical stress.
Aspirin and other NSAIDs may induce mucosal edema, hyperemia, and multiple erosions and ulcerations. Such lesions may occur suddenly, without warning symptoms such as pain or discomfort, in first-time NSAID users and in patients who have taken NSAIDs regularly for years. Except for generic risk factors such as older age, female sex, and previous episodes, there is no known trait to identify NSAID users prospectively who may be susceptible to severe gastric injury.
Similar mucosal lesions, although usually less severe and only rarely evolving to ulcerations, can be caused by ingestion of large quantities of alcohol. Because alcohol and aspirin may act synergistically to break down mucosal defenses, one wonders how many hemorrhagic gastropathies have been caused by attempts to prevent hangovers by taking aspirin after an alcoholic binge.
The most severe degrees of hemorrhagic gastropathy are those induced by stress. Originally described in 1842 by Thomas Curling, stress-induced gastroduodenal mucosal breakdowns (known as Curling ulcers) can be found in most patients admitted to an intensive care unit; approximately 20% are a source of overt bleeding, and 2% to 5% of these ulcers cause life-threatening hemorrhage.
The pathogenesis of stress-induced hemorrhagic gastritis is not known, but lumenal acid seems to be essential. Acid exerts its deleterious effects when the mucosal defense mechanisms (e.g., the mucous-bicarbonate barrier and the epithelial layer) lose their integrity. Vascular disturbances—in association with stasis, vasoconstriction, and increased vascular permeability—may further contribute to mucosal vulnerability. Aspirin and NSAIDs act by interfering with prostaglandin synthesis, as noted earlier. Alcohol causes direct damage to the gastric mucosa; at a concentration of 12.5% (that of table wine), it induces hyperemia and petechiae, and concentrations greater than 40% (“hard liquors”) cause necrosis of the surface epithelium and capillaries and subsequent interstitial hemorrhage.
Acute hemorrhagic gastritis is characterized by a hyperemic edematous mucosa with erosions and various degrees of active bleeding. The clinical history (e.g., shock, burns, recent alcohol binge, ingestion of aspirin), rather than the widely overlapping nature of the lesions, will help the endoscopist to determine the precipitating factors. Because the diagnosis is often clear from the clinical context, gastric biopsies are rarely obtained from critically ill patients who undergo endoscopy because of upper gastrointestinal hemorrhage.
Acute hemorrhagic gastritis, irrespective of its cause, is characterized by dilation and congestion of the capillaries, edema, and various degrees of interstitial hemorrhage in the lamina propria. Epithelial erosions are generally small; aggregates of fibrin and polymorphonuclear cells replace the eroded epithelium and may project above the surface to form small, elevated clumps of necrotic debris. In the absence of concurrent H.pylori infection, there is no significant inflammation in the unaffected areas of the stomach. Therefore, a diagnosis of erosive hemorrhagic gastritis can usually be made, and possible etiologic agents may be listed (e.g., alcohol or NSAID ingestion). If H.pylori gastritis is present, widespread active inflammation often obscures or worsens the changes caused by other agents, and a separate diagnosis of the diverse causes of the changes is usually impossible.
The suppression of acid with H 2-receptor antagonists or proton pump inhibitors helps to reduce the severity of the mucosal damage and facilitates healing. Sucralfate, although less commonly used, is also effective.
Gastric vascular gastropathies comprise a heterogeneous group of conditions characterized by alterations in the gastric circulation and their effects on the gastric mucosa. The best-defined conditions, from morphologic and pathogenetic viewpoints, are the watermelon stomach, which is described, and portal hypertensive gastropathy.
Portal Hypertensive Gastropathy
Clinical Manifestations and Pathogenesis Portal hypertensive gastropathy is a dilation of the mucosal vessels, more prominent in the proximal stomach, that occurs in a proportion of patients with cirrhosis of the liver; its prevalence parallels the severity of portal hypertension. Bleeding from this lesion is relatively uncommon and rarely severe; in general, patients with the most severe portal hypertension have diffuse lesions and higher rates of gastric bleeding.
Endoscopic Appearance The endoscopic appearance of portal hypertensive gastropathy is nonspecific and does not correlate well with the degree of portal hypertension. The endoscopic patterns have been variously described as snake skin, scarlatina rash, cherry-red spots, and mosaic. The mosaic pattern was found by a consensus conference to be the most reliable indicator of mild portal hypertensive gastropathy with a low risk of hemorrhage. Red marks suggest a more severe degree of hypertension and a greater risk of hemorrhage.
Histopathology Dilation and tortuosity of small arteries and veins, with occasional thickening of the walls, are among the pathological changes of portal hypertensive gastropathy. The changes are more prominent in the corpus and are more apparent in submucosal vessels than in mucosal capillaries. Because of the location of these changes and the understandable reluctance of most gastroenterologists to obtain large and deep biopsy samples from patients who may have an increased risk of bleeding, the diagnosis of portal hypertensive gastropathy is not commonly reached by evaluating mucosal biopsies. In patients with concurrent H.pylori gastritis, it is difficult, if not impossible, to separate the respective contribution of infection and congestion to the resulting complex of changes observed in the mucosa.
Management Because bleeding is relatively uncommon, most patients do no require specific therapy. Sclerotherapy of esophageal varices does not seem to influence the natural history of this condition. In severe cases, portal decompression surgery, but not transjugular intrahepatic portosystemic shunting, is effective in reducing the risk of hemorrhage.
In numerous inflammatory and noninflammatory conditions, the mucosal folds ( rugae) that confer a rugged appearance to the normal gastric corpus may become extremely enlarged and may give the mucosa an appearance that has been compared to that of the cerebral cortex (cerebriform). Based on this macroscopic morphologic characteristic, shared in various degrees by all of them, certain etiologically heterogeneous conditions have been categorized as hypertrophic gastritis, hypertrophic gastropathy, or, more recently, giant-fold gastropathies. To complicate our understanding of these diverse conditions further, many authors have used indiscriminately the term Ménétrier disease, after the condition described in 1888 by the French gastroenterologist who initially called it polyadenomes en nappe (polyps in layers).
In 1973, Ming introduced the term hyperplastic gastropathies and proposed a classification that recognizes three main histological types:
1. Foveolar hyperplasia, with normal or atrophic oxyntic glands and corresponding to Ménétrier’s description
2. Hyperplasia of oxyntic glands, with a largely unaffected mucous component and corresponding to Zollinger-Ellison syndrome
3. A mixed type, in which both mucous and oxyntic glands show variable degrees of hyperplasia; it incorporates various conditions that may cause mixed glandular hyperplasia, including infections ( H.pylori infection, CMV infection in children, syphilis, and histoplasmosis) and other diseases of uncertain origin (lymphocytic gastritis, eosinophilic gastroenteritis, sarcoidosis, and Cronkhite-Canada syndrome).
Ménétrier, in his original description, included patients with multiple hyperplastic polyps and patients with giant folds and focused his observations on the increased gastric cancer risk of these patients. Today, the condition associated with his eponym is defined as an idiopathic diffuse enlargement of the gastric folds in the antrum. Histologically, glands show massive foveolar cell hyperplasia with normal or slightly reduced numbers of parietal and chief cells. Neither significant inflammatory infiltrates in the lamina propria nor epithelial lesions (erosions, intestinal metaplasia, or cellular atypia) are present. If chronic active inflammation or lymphocytic infiltration of the epithelium is seen, the large-fold type of H.pylori gastritis or lymphocytic gastritis should be considered. In children, giant folds are almost always associated with CMV infection. This association has rarely been reported in adults. The hyperplastic foveolar cells secrete large amounts of mucus and fluid resulting in protein-losing enteropathy (found in almost all patients) and hypoacidity (in part from dilution of the acid produced by oxyntic cells).
Pure Ménétrier disease is a rare condition, with an estimated prevalence of no more than 300 or 400 persons worldwide. Patients are more often men in their fifth or sixth decade who present with dramatic weight loss, epigastric and abdominal pain, nausea, and vomiting. Later in the course of the disease, usually protracted for several years and even decades, virtually all patients develop hypoalbuminemia as a consequence of the protein-losing enteropathy. The pathogenesis is unknown, but an interesting hypothesis has been put forward. Transforming growth factor-a (TGF-a), a critical mediator of gastric mucosal homeostasis normally produced by the gastric mucosa, inhibits acid secretion, stimulates mucosal repair, cell migration, and proliferation, and augments gastric mucin levels Overproduction of TGF-a could explain several of the disturbances occurring in Ménétrier disease. Support for this hypothesis is further lent by the successful treatment of some patients by a monoclonal antibody against the TGF-a receptor (the epidermal growth factor receptor). Other forms of treatment, including antacids, anticholinergic drugs, corticosteroids, H 2-receptor antagonists, and proton pump inhibitors, have been proven consistently ineffective. Eradication of H.pylori has been reported to have successfully cured patients with Ménétrier disease. One of the possible pathological aspects of H.pylori gastritis is the development of large, edematous folds, and this variant may have been interpreted as a type of H.pylori–induced Ménétrier disease. Not surprisingly, it regresses after the eradication of H.pylori infection.
Since the 1970s, a rise in the incidence of adenocarcinoma of the cardia has occurred in the very populations in which the incidence of gastric cancer has been decreasing. Thus, there has been an emerging interest in exploring the pathology of this relatively ill-defined area of the stomach. Virtually all patients who have H.pylori gastritis in other regions of the stomach also have bacteria and inflammation in the region immediately distal to the gastroesophageal junction. Some patients, including those without H.pylori infection and patients with and without gastroesophageal reflux disease, have a localized inflammation of the cardia, commonly referred to as carditis. Intestinal metaplasia is found in the cardia of approximately 20% of patients with a variety of gastric disorders, even in the absence of H.pylori infection, and apparently also in healthy persons. The relationship between intestinal metaplasia in this location and adenocarcinoma of the junction remains unclear, but it is important to differentiate the intestinal metaplasia of the cardia from Barrett specialized epithelium. Cytokeratin and immunoreactive patterns may help to distinguish between intestinal metaplasia in long-segment Barrett esophagus and junctional metaplasia; conversely, the epithelium of short-segment Barrett esophagus may be impossible to separate from metaplasia originating in the cardia. Until the implications of such findings are clarified, it is advisable to collect as much specific information as possible carefully from each patient with changes at the gastroesophageal junction. Lesions of uncertain prognostic value today could acquire clinical significance when new knowledge is acquired.