The term gastritis is often used somewhat loosely. Not infrequently, clinicians refer to a patient with epigastric pain or dyspepsia as having "gastritis," and radiologists sometimes diagnose "gastritis" on the basis of nonspecific radiographic changes, such as mucosal irregularity or swelling. However, gastritis is neither a clinical nor a radiologic diagnosis. Most often, it is a purely histologic diagnosis, made by the use of random or targeted endoscopic biopsies.
Although some conditions that injure the gastric mucosa may result in inflammation, others do not. Thus, "gastritis," as the suffix -itis implies, is characterized by the presence of inflammatory cells. In contrast, gastropathy is used to refer to conditions in which inflammation is not a prominent feature, although there may be epithelial damage and regeneration. In gastropathies, there are often abnormalities of the mucosa visible at endoscopy, with or without histologic changes. Sometimes the mucosal appearance at endoscopy is typical or diagnostic of a particular condition. Therefore, in the case of gastritis, the diagnosis is always based on biopsy, whereas gastropathies are sometimes diagnosed on endoscopy alone, sometimes histology alone, and sometimes both. (Strictly speaking, the word gastropathy refers to any and all disorders of the stomach, but in this article, we use its more recent application).
The categorization of entities into gastritides and gastropathies is an important concept and helps narrow the diagnostic possibilities in a given case. In this article, for the sake of simplicity, the term gastritis is often used generically to refer to both gastritides and gastropathies.
One purpose of this article is to propose an approach to and a classification of pediatric gastritis that is pertinent to practicing pediatric endoscopists. In so doing, we hope to focus attention on this little-studied area and to facilitate diagnosis of the various entities that comprise the classification. Further, by offering practical advice for endoscopists regarding endoscopic landmarks, terminology, and acquisition of biopsy specimens, we hope to facilitate consistency of communication among endoscopists and between endoscopists and pathologists. This, it is hoped, will lead to further work in pediatric gastritis and to improved diagnostic accuracy.
Once a child is scheduled for diagnostic upper gastrointestinal endoscopy, the endoscopist has an obligation to maximize the diagnostic potential of the procedure. Central to this must be the recognition that the ability to make a diagnosis based on macroscopic appearances alone is limited (1-5). For example, gastric mucosa that appears normal at endoscopy may harbor marked inflammation visible on microscopic analysis. The converse is also true-that is, a markedly red mucosa at endoscopy may be normal or may result from contact with the endoscope. Redness may reflect underlying microvascular congestion without the presence of inflammatory cells. Thus, there is often poor correlation between endoscopic and histologic findings. It follows, therefore, that multiple gastric biopsies must be an integral part of a proper examination of the gastric mucosa (1-5). In children, gastritis remains underrecognized and poorly characterized because of the flawed tendency to rely on macroscopic appearances at endoscopy, and an apparent reluctance to perform multiple gastric biopsies. In evaluating specimens obtained in such biopsies, collaboration with a pathologist with special expertise in gastrointestinal histopathology is of inestimable value.
A high yield of accurate diagnoses, including the definitive ruling out of mucosal disease, largely depends on the endoscopist's care and attention to detail in the following areas.
Endoscopic Landmarks and Histologic Zones
In reporting endoscopic appearances, the endoscopist is describing the gross pathologic appearance of disease. Gastric disorders often have a predilection for a particular area or zone of the stomach, and it is therefore important to identify endoscopic landmarks accurately. Inaccurate landmark identification may result in poorly targeted biopsies and erroneous or missed diagnoses.
The largest region of the stomach is the gastric body or corpus, characterized at endoscopy by thick mucosal folds or rugae. The body or corpus extends distally to the incisura or angulus on the lesser curvature. The fundus is the dome-shaped area immediately above the gastric body and abutting the diaphragm. Both corpus and fundus are comprised of oxyntic mucosa. The gastric antrum occupies the lower quarter or third of the stomach. When the stomach is distended with air to allow visualization, the antrum is seen to begin on the greater curvature where folds of the gastric body end. The antrum ends at the pylorus and consists of mucus glands. The gastric cardia comprises a short zone-in children, extending in length from a few millimeters to perhaps one centimeter from immediately below the Z-line-composed of mucus glands. Figure 1 shows anatomic landmarks of the stomach.
The different histologic zones of the stomach correspond to the different gross anatomic zones thereof, although not precisely, because there is always some over-lap and interdigitation of histologic zones at areas of transition. Therefore, the term transitional mucosa applies to these. Gastric landmarks and their histologic correlates are described in more detail elsewhere (6-8).
Although the number of inflammatory cells in the gastric mucosa of normal children has not been extensively studied, there are some published data, summarized elsewhere (8).
Use of nonstandardized terminology or interpretive terms results in poor interobserver reliability of findings and uninterpretable endoscopy reports. It is therefore more helpful to record endoscopic findings in factual, descriptive terms. The endoscopist should report only what he or she sees in terminology that is standard and unambiguous. Jargon, "-itis" terms, and interpretive terms should be avoided in the factual or objective part of the endoscopy report. For example, use of the term "gastritis" could mean anything from erythema to distinct erosions. If the mucosa is red, it should be documented as red or erythematous (mild, moderate, intense, or hemorrhagic) and not as antritis or gastritis, because inflammation may not be present (2). After all, the human eye is not a microscope.
An erosion is a mucosal break that does not penetrate the muscularis mucosae, whereas an ulcer extends through the muscularis into the submucosa. Endoscopists cannot accurately determine depth of lesions, but there are some clues. Erosions are often multiple and usually have white bases. Each erosion usually is surrounded by a ring of erythema. When erosions have recently bled, their bases may be black. Hemorrhage refers to a bright, shiny red appearance of the mucosa in patches, streaks, or discrete petechiae, not associated with a visible mucosal break. Although the term submucosal hemorrhage sometimes is used, endoscopists cannot see through the muscularis mucosae, and subepithelial hemorrhage is therefore preferable, to allow for varying depths of hemorrhage. Other confusing terms used for subepithelial hemorrhage (and best avoided) are acute gastritis, hemorrhagic gastritis (inflammation is usually absent from hemorrhagic lesions), or hemorrhagic erosion (usually, no is erosion present) (9).
If gastric rugae are large, accurate terms of description are thick folds or swollen folds, not edematous folds or hypertrophic folds, because edema and hypertrophy are histologic, not endoscopic, findings.
It is also important to describe nodules in the stomach accurately. For example, a nodule or patch of nodules may be seen occasionally, especially at the antrum-body junction; these may represent a prominent areae gastricae(10) and usually are unimpressive. In contrast, a continuous diffuse carpet of nodules spread throughout the antrum is characteristic of Helicobacter pylori infection, past or present (11,12) (Fig. 2A). These nodules are described further in the section on H. pylori. The nodules of chronic varioliform gastritis are again different. They are larger, discrete, more raised, often have an umbilicated central erosion or shallow ulcer, and predominate in the gastric fundus and body (13-15) (Fig. 3A). Large nodules, more like blebs, may occur in the proximal stomach with cytomegalovirus (CMV) gastritis (2). Similar nodules may occur in the antrum in eosinophilic gastritis. Thus, it is best for the endoscopist to describe accurately what is seen and to offer an interpretation or differential diagnosis only at the end of the endoscopy report, based on the factual findings.
Different disorders may have a predilection for one topographic zone or another of the stomach. Sometimes, the same agent causes different patterns of injury in different populations, (e.g., H. pylori) (16-19). Sometimes there is disease in more than one zone of the stomach, as in H. pylori infection, Crohn's disease, eosinophilic gastritis, atrophic gastritis, and CMV, as will be described. Thus, biopsy samples must be obtained from different topographic zones of the stomach (1,8,9,19).
Even with careful handling of biopsies by trained personnel, endoscopic biopsy specimens may sustain crush or other artifacts. Thus, when biopsy is indicated, at least two samples should be obtained from a particular lesion or zone of the stomach. Although the optimum number of biopsy samples has yet to be determined, when mucosa is normal-appearing, our practice is to take at least two samples from the prepyloric or midantrum and two from the greater curve of the midbody. Others take two from the antrum-body transition zone of the lesser curve (a zone in which inflammation and metaplasia occur in adults) (1). In addition, we and others obtain specimens of the gastric cardia, immediately below the Z-line, when H. pylori infection, Barrett's metaplasia, carditis (caused by gastroesophageal reflux or H. pylori) (19-23), or mucosa-associated lymphoid tissue (MALT) lymphoma (24) may be present. When endoscopic findings are puzzling, or a lesion is present, more specimens should be taken randomly and from the lesion or edge thereof.
The size of the biopsy specimens is also important. Samples obtained with "pediatric" forceps are often of little value, because they are tiny and difficult to mount. Thus, the quality and quantity of tissue are often insufficient. In most children more than 2 or 3 months of age, an endoscope with a 2.8-mm biopsy channel usually can be used (e.g., Model XQ20; Olympus, Tokyo, Japan) and samples obtained with these forceps often are adequate, if several are taken and care is taken with mounting and handling. In contrast, each specimen obtained with "jumbo" or large-cup forceps provides at least twice or three times the amount of mucosa for diagnosis, and these can often be used in older children.
We have previously described a grading system for pediatric gastritis (11), but to the best of our knowledge, other than an earlier pathologic description of pediatric gastritis from our group (8), there is no published classification of pediatric gastritis. Our purpose is to fill this void by proposing a classification geared to the needs of pediatric endoscopists. Further, by proposing a conceptual framework of gastritis and gastropathy and describing the specific entities encountered in the pediatric stomach and their differential diagnoses, we hope to make the process of accurate diagnosis easier for the clinician.
No classification of gastritis satisfies everyone, because the published classifications have different objectives. Some are a glossary of appearances (25); others list clinical disorders (2). The Sydney system is essentially a checklist to aid the pathologist in reviewing biopsy specimens and in uniformly reporting findings, by use of a visual analog scale (18). Thus it is aptly named a system rather than a classification (18,25-27). Its usefulness to pediatric endoscopists is limited, because its major focus is grading the severity of chronic gastritis, atrophy, and intestinal metaplasia, which are of concern more in adults than children. Furthermore, it does not integrate histopathology with endoscopic appearance, and it does not classify noninflammatory conditions (18).
We have chosen to classify mucosal disorders of the stomach in children primarily by their endoscopic appearances. In this system, gastritis is classified into two groups: erosive and/or hemorrhagic gastritis or gastropathy, and nonerosive gastritis or gastropathy (Table 1). Although some disorders can be either erosive or nonerosive, each is classified by its most common clinical manifestation. The disorders in each group are placed in approximate sequence of their prevalence in our practice. Each disorder is then described by cause and any distinctive clinical, endoscopic, and histologic features. We believe that the advantages of this approach are simplicity and ease of use for the practicing pediatric endoscopist. Based on this approach, a diagnosis or differential diagnosis may be made with some certainty at the time of endoscopy; however, for most disorders, confirmation of the initial impression, or definitive diagnosis is still dependent on biopsies, and therefore on an active dialogue and close collaboration with a pathologist.
Erosive and/or Hemorrhagic Gastritis or Gastropathy
Most of these entities are diagnosed endoscopically, usually in patients presenting with gastrointestinal bleeding. Because inflammation is not a feature of most hemorrhagic lesions, most conditions in this category are gastropathies. Biopsies are usually not required from erosive or hemorrhagic lesions, where the diagnosis is clear from the clinical context and endoscopic findings. However, there are gastritides not in the erosive or hemorrhagic category that may have erosions or hemorrhagic lesions, and in these cases, biopsies are essential for diagnosis (e.g., H. pylori, Crohn's disease, CMV, and allergic gastritis). Therefore, whenever there is the slightest doubt, biopsy samples should be taken.
This usually occurs within 24 hours of the onset of critical illness in which physiological stress is present, such as shock, hypoxemia, acidosis, sepsis, burns, major surgery, multiple organ system failure, or head injury. These stressors cause reduction of gastric blood flow with subsequent mucosal ischemia (28) and breakdown of mucosal defenses (29). Gastric acid is important in the pathogenesis of stress erosions, but actual hypersecretion is only seen in sepsis, and in trauma affecting the central nervous system. Risk factors for hemorrhage include gastric hypersecretion, mechanical ventilation, and use of high-dose corticosteroids (29,30).
Stress erosions typically are asymptomatic, multiple, and do not perforate, but when they produce symptoms, they do so with overt upper gastrointestinal hemorrhage. Newborns and infants appear to be more prone to perforations (31). Early stress lesions predominate in the fundus and proximal body, later spreading to the antrum to produce a diffuse erosive and hemorrhagic appearance. Antral involvement alone is uncommon.
In clinical practice, gastric mucosal disorders are seldom identified in the newborn, even in sick preterm infants. Perhaps this is in part because endoscopy is seldom indicated or because of a greater reluctance to perform endoscopy in infants. Nevertheless, a high prevalence of hemorrhagic gastropathy has been reported in sick neonates in an intensive care unit in whom no upper gastrointestinal symptoms or signs were present and who underwent endoscopy under a research protocol (32). Of note is that newborns with (33) and without (32) upper gastrointestinal symptoms seem to have a high prevalence of "esophagitis" associated with gastropathy. Hemorrhagic gastropathy has also been reported in otherwise healthy full-term infants (34) presenting with severe upper gastrointestinal hemorrhage-in one case, an antenatal hemorrhage (35).
An unusual gastropathy may occur in infants with congenital heart disease receiving prolonged infusions of prostaglandin E to maintain patency of the ductus arteriosus. This consists of antral mucosal thickening or a focal mass caused by foveolar cell hyperplasia, manifesting as gastric outlet obstruction (36). This entity has also been described in a 6-week-old infant, who received no medications (37).
Forceful retching or vomiting produces typical subepithelial hemorrhages in the fundus and proximal body of the stomach. It is caused by "knuckling" or trapping of the proximal stomach in the distal esophagus, resulting in vascular congestion, and is also known as prolapse gastropathy(38,39). Mallory-Weiss tears immediately above or below the gastroesophageal junction also may occur. Although prolapse gastropathy and tears tend to resolve quickly, they can result in significant blood loss. By a similar mechanism of trauma, linear erosions may occur in the herniated gastric mucosa of patients with large hiatal hernias, resulting in anemia from chronic blood loss (40). Suction through nasogastric tubes, ingestion of foreign bodies, and endoscopic procedures such as diathermy (41,42) are common causes of subepithelial hemorrhages and focal erosions.
Aspirin and Other Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs (NSAIDs) produce mucosal injury by local irritant and systemic effects (43,44). Although delayed-release and enteric-coated NSAIDs produce less acute, superficial mucosal damage, they still cause ulcers and the complications thereof. Even a single dose of aspirin may cause petechial hemorrhages in the stomach within a few hours and erosions within 24 hours (45). However, early lesions usually are of little clinical significance and are not predictive of clinically significant ulcer formation (43). Nevertheless, in severe erosive gastropathy caused by NSAIDs, ulcers may bleed and/or perforate. Lesions caused by NSAIDs are more commonly gastric than duodenal, occurring more typically in the gastric antrum than in the body. In children, hemorrhagic antral gastropathy and ulceration of the incisura are the typical NSAID lesions. Occasionally, more extensive gastric involvement occurs, as does duodenal ulceration. Bleeding from such lesions after ingestion of NSAIDs in children has been well documented (46-49). In one study, 75% of children with juvenile rheumatoid arthritis who had taken one or more NSAIDs for more than 2 months had endoscopic evidence of gastropathy, antral erosions, or ulcers (48). Of these, 64% had anemia and abdominal pain.
Although NSAID-induced gastropathy does not require the presence of H. pylori for its development (50), in adults taking NSAIDs, there are conflicting data regarding whether H. pylori eradication improves the rate of healing of peptic ulcers. Nevertheless, there seems to be agreement that H. pylori-infected people who have a history of peptic ulcer and who require NSAID therapy should have treatment directed at eradication of the organism (51).
Although many drugs may cause nonulcer dyspepsia, erosive or hemorrhagic gastropathies have been described with valproic acid, dexamethasone, chemotherapeutic agents, alcohol, and potassium chloride (52-60).
Portal Hypertensive Gastropathy
This congestive gastropathy occurs frequently in children with intrahepatic or extrahepatic causes of portal hypertension (61). The endoscopic findings in portal hypertensive gastropathy (PHG) vary from mild gastropathy with a mosaic pattern of 2- to 5-mm erythematous patches separated by a fine white lattice, to severe gastropathy typified by the presence of cherry red spots or even a confluent hemorrhagic appearance (62,63). The mosaic pattern is specific for PHG and was not found at endoscopy in any of 500 children without liver disease (61). In adults, congestive gastropathy is more frequently associated with large gastroesophageal varices than with esophageal varices alone (64), and previous sclerotherapy of esophageal varices may exacerbate PHG (64,65). The diagnosis of PHG is made at endoscopy. Biopsy is seldom indicated and is potentially dangerous. The histologic findings in PHG are ectasia of mucosal capillaries and venules, and submucosal venous dilatation (63).
In acute renal failure, gastropathy is caused by acute physiological stress, rather than renal failure itself. In adults with chronic renal failure receiving hemodialysis, gastroduodenal lesions occur in up to 67%, with the predominant lesion, antral gastropathy, in up to 50%. The presence and severity of gastroduodenal disease are not consistently related to the degree of hypergastrinemia, nor to that of chronic renal failure (66). Vascular ectasia in the stomach is an important cause of bleeding in chronic renal failure (67).
Chronic Varioliform Gastritis
Also known as chronic erosive gastritis, chronic varioliform gastritis is an uncommon disorder of unknown cause reported largely in middle-aged and elderly men (13). It has been reported in a few children (14,15,68,69), with variable combinations of upper gastrointestinal symptoms, anemia, protein-losing enteropathy, peripheral eosinophilia, and elevated serum immunoglobulin (Ig) E levels (68,69). Symptoms arise insidiously and often become subacute or chronic. Most striking endoscopically are the innumerable prominent nodules in the fundus and proximal body of the stomach (Fig. 3A). In children, the antrum is less often involved. Typically, the gastric rugae are irregularly thickened, with nodules located on the crests of the folds. The nodules sometimes have an umbilicated central crater or erosion; the lesions are said to resemble the skin lesions of chicken pox-therefore, the name. Histologic features include edema, foveolar hyperplasia, active chronic inflammation, and eosinophilic infiltrates. When present, focal superficial subepithelial collagen deposition may represent fibrosis at points of previous surface erosions (Fig. 3B). In some cases, there is an infiltrate of intraepithelial lymphocytes in the surface and foveolar epithelium, suggesting that chronic varioliform gastritis may be one cause of lymphocytic gastritis (70). We have observed variable degrees of collagen deposition with active inflammation and gland atrophy in three adolescents (see Collagenous Gastritis).
This is also known as alkaline gastropathy, or gastropathy caused by duodenogastric reflux. It has been well documented in the postoperative stomach (71) and in the intact stomach (72) in reports that are mainly in the adult literature. Typical endoscopic features include "beefy" redness or erythema and, occasionally, erosions. Despite this, there is very little cellular infiltrate in the lamina propria. The main histologic features are foveolar hyperplasia, occasionally with a corkscrew appearance; lamina propria edema; and venous congestion. These changes constitute the entity of so-called reactive gastropathy(9). After surgery, they are found more commonly in the stomach than at the stoma. Other features include stomal erosions, lipid islands, and mucosal cysts; the latter are sometimes grossly visible and are known as gastritis cystica profunda or polyposa. Some studies report a high prevalence of intestinal metaplasia, although this may reflect sampling from the stromal region, which normally reflects a mosaic of gastric and intestinal mucosa.
Although the postoperative syndrome of postprandial pain, nausea, and vomiting often is ascribed to duodenogastric reflux, there is poor correlation between symptoms and endoscopic and histologic findings. Intermittent reflux of bile may occur even in normal people (73), therefore, the mere presence of bile in the stomach at endoscopy does not carry clinical significance. Fortunately, currently there are hardly any indications for partial gastrectomy in children, and pyloroplasty in children (74) is seldom recognized to be attended by the described problems.
Endoscopy is seldom required for diagnosis of this condition, but when the diagnosis is uncertain, endoscopy may be helpful, showing a hemorrhagic and erosive picture typical of this disorder. In our experience and that of others (75,76) in children undergoing upper gastrointestinal endoscopy for symptoms including epigastric pain, hematemesis, and vomiting, the antral mucosa is erythematous and swollen with raised blebs 3 to 5 mm in diameter. On the blebs are punctate hemorrhages and, often, central erosions or ulcer with a yellow base. Similar lesions are often present in the duodenum. Although gastric mucosal specimens usually are too superficial to show typical histologic changes, they may show a leukocytoclastic vasculitis similar to that seen in the skin (75).
The most commonly ingested substances that injure the stomach are acids, iron, and strong alkalis. The latter predominantly involve the esophagus but occasionally involve the stomach. When gastric injury occurs, the prepyloric area is particularly vulnerable (77,78), probably because of pylorospasm and pooling of secretions. The presence of food may limit the degree of injury. Endoscopic findings run the gamut from mild friability and erythema to necrosis, ulcers, exudates, hemorrhage, and, rarely, perforation. Chronic cicatrization is relatively rare, and may take several months to become apparent. Iron poisoning, especially with ferrous sulphate, is common in children in some areas of the world and may cause corrosive gastropathy with stricture (79). Therapeutic administration of oral ferrous sulfate may cause mild endoscopic abnormalities in the stomach that are of uncertain clinical significance (80). Ingestion of pine oil cleaner may also cause cause gastric injury (81).
Exercise-Induced Gastropathy or Gastritis
This condition is well recognized in runners, usually presenting with blood loss anemia, with or without upper gastrointestinal symptoms. Erosive gastropathy has been described (82), as has nonerosive gastritis (83), the latter with acute inflammation on biopsy. Postulated mechanisms include splanchnic ischemia and repeated jarring of the organ.
This condition is rare but has been associated with massive abdominal irradiation in patients with malignancy, causing erosions or ulcers, particularly in the gastric antrum and prepyloric regions (84). Fibrosis and stricture formation may lead to gastric outlet obstruction.
Nonerosive Gastritis or Gastropathy
In nonerosive gastritis, there is usually a poor correlation between endoscopic appearance and histologic findings-that is to say, the diagnosis is almost always purely histologic. An exception is the nodular antrum of H. pylori-associated ulcer disease in children; however, nodularity persists even after eradication of H. pylori. Therefore, in this case the diagnosis is endoscopic and histologic. Furthermore, nodularity is not always present, and the diagnosis, again, ultimately depends on histology. Some of the entities in this section may also manifest endoscopically as an erosive gastropathy or gastritis but are included here because they more commonly occur without erosions.
Lymphocytic gastritis is a type of gastritis deserving of special mention. It may be seen in disorders as apparently diverse as celiac disease, CMV gastritis, Menetrier's disease, H. pylori infection, and chronic varioliform gastritis. Because ours is an endoscopic classification, lymphocytic gastritis is mentioned under each of those disease entities.
In our experience, a significant number of children have chronic gastritis for which no cause can be identified (8). In these cases, the inflammation is chronic, with lymphoid and plasma cells predominant, more focal than diffuse within the biopsy, and usually superficial. Although it appears to be more prevalent in the antrum than the corpus, this may reflect sampling bias.
Helicobacter pylori Gastritis
H. pylori causes active chronic gastritis both in adults and children (11,85,86) and is strongly associated with peptic ulcer disease and with atrophy, intestinal metaplasia, and gastric cancer in adults (87,88).
Virtually all people infected with H. pylori have gastritis, but there are considerable individual and geographic variations in intensity and distribution of inflammation and in the disease associations (19). In the Western world, most commonly, the inflammation is more marked in the antrum than in the corpus. This is "antral-predominant gastritis" or "diffuse antral gastritis," formerly known as "type B gastritis." It is largely asymptomatic and most often unassociated with any complications. However, duodenal ulcer disease develops in some 10% of such patients, probably in those with more intense antritis, minimally affected oxyntic mucosa, and a normal or high parietal cell mass (19,89). Although focal intestinal metaplasia may be present in 10% to 20% of adults with duodenal ulcer disease, it is much less extensive and severe than that in gastric ulcer and is limited to small, isolated foci in the antrum.
In other individuals, particularly in developing countries, a moderate to severe inflammatory process may involve the entire stomach (pangastritis). In some, the gastritis persists without complications ("nonulcer pangastritis"), but in many, atrophy and intestinal metaplasia develop. This is "multifocal atrophic gastritis," also known as "metaplastic atrophic gastritis," or "progressive intestinalizing pangastritis" (19). These patients are at risk for gastric ulcer and gastric adenocarcinoma of the intestinal type. However, only some adenocarcinomas are of the intestinal type, and the cause of these cancers is multifactorial, with H. pylori but one risk factor, and then only sometimes. For example, in two areas of China, both with a high prevalence of H. pylori infection, one area has a low prevalence of gastric cancer, the other a high prevalence (90,91). In addition, the presence of H. pylori-associated duodenal ulcer disease appears to protect against gastric cancer (19,87). Thus there appear to be many factors other than H. pylori that are important in the genesis of gastric carcinoma, such as environmental, and genetic factors. There are conflicting data regarding whether the age of acquisition of H. pylori is a marker for an increased risk of gastric carcinoma (91-93).
H. pylori is also a cofactor in the development of gastric B-cell lymphoma arising from MALT (94,95). Although most reports of H. pylori-associated gastric malignancy are in adults, cases have also been described in children, aged 11 to 16 years, with subsequent cure after H. pylori eradication in some (96-98).
In the pediatric literature, the most common types of H. pylori gastritis are diffuse antral gastritis and nonulcer pangastritis, but because pediatric reports seldom refer to corpus histology, this may simply reflect sampling bias. Occasionally in children, we have seen focal intestinal metaplasia in corpus and in antral specimens (Jevon G, Dimmick JE, Hassall E, Unpublished data). To our knowledge there are no published data on an association between H. pylori and intestinal metaplasia and gastric cancer in children.
The prevalence of H. pylori gastritis in children in the United States appears to be age dependent, with H. pylori accounting for few cases of gastritis in children less than 5 years of age, but increasing to become the most common identifiable cause of gastritis in teenagers (99). Our experience is similar.
The severity and depth of H. pylori gastritis are variable, but in general, inflammation is most intense in the antrum, then cardia, and least in the body (20). Our own highest diagnostic yields of H. pylori have come from antrum, cardia, and corpus, in that order (Jevon G, Dimmick JE, Hassall E, Unpublished data). Some authors have shown a correlation between the intensity of gastric colonization with H. pylori and the severity of gastritis both in children and adults (100,101). In our own patients antral gastritis scores were higher in those with H. pylori-associated duodenal ulcer than in those without ulcers, and antral gastritis was virtually absent in those with H. pylori-negative ulcer disease (11,102). Although normal gastric histology has been reported in children infected with H. pylori(103), "normal" and "gastritis" were not quantitatively defined, and few biopsy specimens were obtained in each patient for histology. Figure 2B shows typical H. pylori antral gastritis in a child.
Elimination of H. pylori is followed closely by the disappearance of neutrophils, which may be completely absent within 1 week of treatment. The chronic inflammation and the lymphoid hyperplasia subside more slowly, often taking longer than 1 year (104).
In H. pylori infection, endoscopy may show normal gastric mucosa, or reveal erythema, erosions, ulcers, and, especially in children, antral nodularity (11,85). This nodularity was first described in H. pylori disease in children, and subsequently in adults (12), although with lesser frequency. It has been our experience that when H. pylori gastritis is associated with duodenal ulcer in children, a striking diffuse nodularity of the antrum always is present; when H. pylori causes gastritis alone ("primary gastritis"), this nodularity being seen in only some 50% to 60% of cases (11). We have not seen this nodularity in cases of true non-H. pylori duodenal ulcer disease nor in any of the some 5000 upper gastrointestinal endoscopies in children at which neither ulcer disease nor H. pylori were present during the past 14 years. In our experience, approximately 20% of duodenal ulcer disease in children is non-H. pylori associated (102), and our recent unpublished data with much larger numbers of patients corroborate this proportion. Nodularity is sometimes not visible at first examination of the antrum, but once specimens have been taken, oozing blood acts as a vital stain, making visible a confluent carpet of nodules; we have coined the term "hematochromoendoscopy" for this (W. M. Weinstein, E. Hassall) (Fig 2A). Of note is that in 1977, i.e., in the "dark era" before the discovery of H. pylori, a report from South Africa described the radiologic and endoscopic appearances of diffuse antral nodularity with lymphoid follicles on biopsy in two teenagers (without ulcers). The authors called this "benign hyperplasia," noted it was strictly confined to the antrum, and likened it to the reactive lymphoid hyperplasia that may occur in the vicinity of peptic ulcers (105). In addition to the above findings, occasionally, thickened mucosal folds may occur in the body and antrum (106,107).
The absence of endoscopic abnormalities in some 50% of children with H. pylori infection (11), and the patchy nature of the infection and of gastric MALT lymphomas, emphasize the need to take biopsy samples from the gastric antrum, body, and cardia as an integral part of diagnostic endoscopy (20-22,24). Pediatric consensus guidelines for an approach to diagnosis and treatment of H. pylori are described elsewhere (108).
Gastroduodenal involvement is relatively common, and in children, Crohn's disease is the most common cause of granulomatous gastritis (8). The symptoms that may occur are similar to those of acid-peptic disease and of delayed gastric emptying, with hematemesis and melena occurring less frequently (109-112). Macroscopic and/or histologic abnormalities are present in the esophagus, stomach, or duodenum in up to 80% of children with Crohn's disease. However, some of these changes are nonspecific, and the incidence becomes 30% if features specific to Crohn's disease, such as giant cells and non-caseating granulomas, are considered (109). If focal deep gastritis is included, the incidence becomes approximately 50% (8,113). These figures largely depend on the number of biopsy specimens taken, and whether serial sections of those specimens are carefully examined. In the appropriate clinical context, the identification of non-caseating granuloma is diagnostic of Crohn's disease, but differentiation from other granulomatous gastritides (Table 2) is important (8). Endoscopic and/or histologic evidence of Crohn's disease of the stomach may occur in the absence of upper gastrointestinal symptoms and sometimes may precede diagnostic features in the colon. Not infrequently, gastroscopic and histologic findings result in a change of diagnosis from ulcerative colitis to Crohn's disease.
In our own experience, 67 (29%) of 229 patients with Crohn's disease who underwent upper gastrointestinal endoscopy had histologic evidence of gastritis (8). Only one-third of these had endoscopic features of loss of vascular pattern, mucosal swelling, aphthous ulcers, or luminal narrowing. We have also seen deep ulceration in the duodenum that can mimic peptic ulcer disease. Histologic features range from focal chronic active inflammation to more typical nonnecrotizing granulomas. For both the endoscopic and histologic findings, the antrum is the most common repository of disease, but we have found granulomas also in the corpus and the cardia. In our experience, gastric Crohn's disease is second overall to H. pylori as a specific, identifiable cause of gastritis in children.
This is the gastric component of allergic gastroenteritis. Although allergic gastritis and eosinophilic gastritis (described later) have some features in common, in allergic gastroenteritis the disease is always mucosal and not deeper, the endoscopic changes are milder, and it is a more benign disease, of limited duration. In addition, it is usually associated with a specific allergen. In children, cow's milk protein or soy milk protein is the most frequently identified antigen, usually causing symptoms within the first 6 to 12 months of life (114). Reintroduction of the antigen is almost always possible by 24 months of age, often earlier. The histologic features include an eosinophilic infiltrate in the lamina propria and the surface and foveolar epithelium, and, occasionally, lymphocytes, plasma cells, and neutrophils are present. Endoscopy may show normal mucosa, or changes similar to those of eosinophilic gastritis, but usually not as marked. However, erosions have been described in children (115).
Proton Pump Inhibitor Gastropathy
Long-term or high-dose proton pump inhibitor (PPI) therapy often causes characteristic hyperplasia of parietal cells, with a thickened parietal cell zone, and lingular pseudohypertrophy of individual parietal cells. Cystic changes often occur in the glands. In some cases there is a co-occurrence of benign fundic gland polyps. The parietal cell changes return to normal some weeks after cessation of acid-suppression therapy (116-120). This gastropathy is benign and not specific to any particular PPI.
Lymphocytic gastritis has been described relatively recently in celiac disease (121-125). In celiac disease and in H. pylori infection, it usually occurs in the presence of a normal-appearing mucosa at gastroscopy. The gastritis in celiac disease is characterized by the intraepithelial location of the lymphocytic infiltrate.
In one study, this gastritis was present in 10 (45%) of 22 adults with celiac sprue (123). It was characterized by a striking mononuclear infiltrate (primarily T cells), mainly in the surface and pit epithelium of the antrum and body, with sparing of the deeper glandular epithelium. The lamina propria was expanded by an infiltrate of plasma cells, lymphocytes, and rare neutrophils. Children and adults with celiac gastritis have a mean of some 40 to 46 lymphocytes per 100 epithelial cells, compared with means of 3 to 5 in normal control subjects or in those with the lymphocytic form of H. pylori gastritis (8,123-125). In the latter, the infiltrate is predominantly in the lamina propria (122). Milder lymphocytic gastritis was seen in another pediatric study (125). The pattern of gastric lymphocytic inflammation in celiac disease resembles that seen in the small bowel and in the colon in that disease. This gastritis is associated with increased gastric permeability (126) and resolves in some patients after treatment of celiac disease.
In one pediatric study (124), 15 of 25 children with celiac disease had chronic gastritis; 9 of these had lymphocytic gastritis and 6 had mild nonspecific inflammation. Dyspeptic symptoms, such as epigastric pain and vomiting, were significantly more frequent in those celiac-affected children with lymphocytic gastritis than in those without (124). In our experience with celiac gastritis (125), we found no clear correlation between the presence of gastritis and dyspeptic symptoms. We have seen one case of celiac disease with multiple duodenal erosions, and a case of severe bleeding from multiple gastric ulcers has been described in an adult with celiac disease and lymphocytic gastritis (127).
Chronic Granulomatous Disease
This is a rare X-linked recessive immune deficiency disorder occurring in boys, in which granulomatous gastric wall involvement is common. When present, symptoms are those of delayed gastric emptying, and a narrowed, poorly mobile antrum is present on contrast radiography (128,129). There are no specific endoscopic findings, but often, the antral mucosa is pale, lusterless, and swollen. Histologic findings include focal, chronic, active inflammation in the antrum, with granulomata or multinuclear giant cells. In our own experience of six cases, the diagnostic lipochrome-pigmented histiocytes were absent in gastric specimens but were found in the lower gastrointestinal tract (8).
On those rare occasions when CMV infection occurs in immune-competent children, it manifests as Menetrier's disease (described later). It is so rare in apparently immune-competent adults (130) that its finding suggests an occult malignancy or early immune deficiency (131). Conversely, CMV infection is so common in immune-suppressed patients (such as those with AIDS, or those who have undergone solid organ or bone marrow transplant) that in some cases it is difficult to know whether it is a pathogen or a commensal. In such patients, this compounds the diagnostic difficulty in distinguishing between gross or histologic lesions caused by infection, graft-versus-host disease, physiologic stress, or chemotherapy (59,60). However, if the highly distinctive pattern of injury is present, it is more likely that CMV is the cause. The infection tends to occur in the gastric fundus and body and may cause wall thickening, ulceration, hemorrhage, and perforation (132,133). Histologic findings include active acute and chronic inflammation with edema, necrosis, and cytomegalic inclusion bodies in epithelial and endothelial cells, as well as in ulcer bases and mucosa adjacent to ulcers (134). In contrast to herpes virus infection, which tends to be superficial, CMV usually affects deeper portions of the mucosa, and the active inflammation may be focal or panmucosal. The diagnostic yield is increased by viral culture of mucosal specimens and by immunohistochemical detection of CMV early antigen. Treatment with ganciclovir may be beneficial in immune-suppressed patients; otherwise, spontaneous recovery usually occurs within 1 to 2 months.
This is the gastric component of eosinophilic gastroenteritis. In this disorder, the term "gastroenteritis" is somewhat misleading, because in addition to the stomach and small bowel, the colon and esophagus also may be involved. This is a chronic, severe disease, of unknown origin, characterized by the presence of upper gastrointestinal symptoms and signs, as well as poor growth, gastrointestinal bleeding, and often, diarrhea. Iron-deficiency anemia and hypoproteinemia with protein-losing enteropathy commonly are present (135-137). In most but not all patients, serum IgE is elevated, and peripheral eosinophilia is present (136). All layers of the gastric wall may be involved. The eosinophilic infiltrate may be patchy, and there may be selective predominance of eosinophilic infiltrates in the mucosa, muscle layer, or subserosa (135). Therefore, diagnosis by endoscopy with biopsies may not always be possible; sometimes, surgical full-thickness biopsy is necessary. When present, gastroscopic features are nonspecific and include friability and erythema, erosions, swollen mucosal folds, and scattered mucosal blebs or nodular lesions, particularly in the gastric antrum. When present, these nodules differ from those associated with H. pylori gastritis, in that they are scattered, few in number, and not of uniform size. Even when the mucosa is normal at endoscopy, analysis of biopsy specimens often reveals a striking eosinophilic infiltrate through the lamina propria into the epithelium. Occasionally, small numbers of lymphocytes and plasma cells are present. Eosinophilic gastritis has also been described as a manifestation of collagen vascular diseases (138), and of parasitic infection of the stomach by the fish parasite Anisaka simplex (see below under Other Infectious Gastritides).
This uncommon entity is characterized by subepithelial collagen deposition and associated gastritis. It probably does not comprise a stand-alone disorder or a distinct disorder in itself. Rather, it appears to occur as a consequence of inflammation or a local immune response in the stomach (15,139) or as one histologic feature of a more diffuse disease process. For example, it has been described in association with the histologically similar conditions of collagenous sprue and collagenous colitis (140,141). It has also been described as a prominent histologic feature in some children with the typical endoscopic features of chronic varioliform gastritis (15,139,142) (Fig. 3A). The pattern of mucosal fibrosis in collagenous gastritis (Fig. 3B), collagenous colitis, and collagenous sprue is quite different from the much deeper (usually circular muscle) involvement seen in scleroderma (143).
Acute graft-versus-host disease (GVHD) is defined as beginning 3 to 4 weeks after transplantation, with mucositis, dermatitis, enteritis, and hepatic dysfunction (59). Upper gastrointestinal symptoms also often occur. More recently, the stomach has been shown to be an important area for the histologic diagnosis of gastrointestinal GVHD, even when diarrhea is the main symptom, and the small bowel is more damaged (144,145). Endoscopy with biopsies is not routinely required for the diagnosis of GVHD, but when performed for investigation of abdominal pain, bleeding, or to exclude opportunistic infection, the findings vary considerably. These range from normal or subtle changes, even when most or all of the epithelium is lost, to patchy erythema with erosions, to extensive mucosal sloughing. The early biopsy findings are unique to GVHD, consisting of crypt epithelial cell apoptosis and drop-out. In more severe cases, whole crypts may drop out. There is variable lymphocytic infiltration of the epithelium and lamina propria. In advanced cases, there may be ulceration, edema, fibrosis, and perforation. When acute GVHD is suspected, biopsies should be performed in the duodenum and esophagus and in the proximal and distal stomach, with recognition that duodenal biopsy carries higher risk in these patients (144,145). Chronic GVHD rarely involves the stomach.
The typical childhood form of this rare disorder follows a viral prodrome, and includes upper gastrointestinal symptoms, edema, hypoproteinemia, and, in some, raised IgE levels (146). In the past, many children underwent diagnostic full-thickness gastric biopsy at laparotomy or even partial gastric resection, but surgery for diagnosis became obsolete with the advent of pediatric endoscopy. The combination of endoscopic and histologic findings is diagnostic. Endoscopy shows swollen convoluted rugae sometimes with a polypoid or nodular configuration. The histology typically shows elongated, tortuous foveolae, with reduction of chief and parietal cell glands and often with cystic dilatations that may extend into muscularis mucosae and submucosa. The lamina propria is edematous with increased eosinophils, lymphocytes, and round cells, and the muscularis mucosa may be hyperplastic with extensions into the mucosa. Pediatric Menetrier's disease has been strongly associated with CMV infection (146,147). The cause of adult Menetrier's disease is unknown, although a genetic predisposition is suggested in a report of three affected generations in one family (148), and cure of H. pylori infection has resulted in resolution of adult Menetrier's disease (149). Although this condition is reported from the neonatal period onward (150), the mean age of onset is 4.7 years (151). In children, the natural history is of self-resolution within weeks or months (146,150,151). In contrast, the adult disease is usually chronic, and, occasionally, partial gastrectomy has been required to alleviate persistent abdominal symptoms, hypoproteinemia, and blood loss. Lymphocytic gastritis has been described in the adult form of Menetrier's disease (152).
In adults, pernicious anemia (PA) is caused by an autoimmune process with autoantibodies to parietal cell components, including the proton pump and intrinsic factor. This results in absolute achlorhydria and megaloblastic anemia caused by vitamin B12 deficiency. At endoscopy, rugae of the gastric corpus are seen to be thin, sometimes with blood vessels visible through the mucosa. Histology shows severe atrophic fundic gland gastritis with absence of parietal cells. This "classic" or "adult form" of PA occurs in children with autoimmune thyroid disease, diabetes mellitus, and collagen vascular disease (153). However, there are other forms of PA in childhood. In PA caused by absence of vitamin B12 in the diet, gastric atrophy or achlorhydria are not present (154). A separate entity entirely is so-called juvenile PA (JPA). This is a heterogeneous group of disorders in which there is no gastric atrophy, but megaloblastic anemia and hypochlorhydria or achlorhydria are present (155). Recently, secretion of abnormal intrinsic factor (IF), or abnormalities of secretion of IF have been found as the cause of JPA (156). A congenital anomaly of B12 metabolism (cobalamin C disease) occurs very rarely. It is accompanied by striking cystic dysplastic changes in gastric mucosa and total absence of parietal and chief cells (157). Although the adult or classic form of PA may occur in patients more than 10 years of age, the other (metabolic) forms of PA usually present under the age of 2 years.
Gastritis Associated With Autoimmune Diseases
Gastritis has been reported in association with several autoimmune conditions. In children and adults with connective tissue diseases, mast cell gastritis and combination mast cell and eosinophilic gastritis have been described (136,158). We have seen atrophic gastritis in a teenage girl with scleroderma.
In a large group of children with insulin-dependent diabetes mellitus, 7% had upper gastrointestinal symptoms for which endoscopy was performed (159); 48% of these had evidence of erosions and ulcers, and 35% had old food in the stomach. Histologic gastritis was reported in 25 of 27 children in whom biopsies were performed; all were negative for H. pylori.
Gastritis with and without atrophy has been seen in children with autoimmune thyroiditis and nongoitrous juvenile hypothyroidism, some with achlorhydria and gastric parietal cell antibodies (153). Autoimmune atrophic gastritis has also been described in 15% of adults with vitiligo (160).
Other Granulomatous Gastritides
These disorders are rare, and the differential diagnosis includes foreign body reaction and tuberculosis, among other disorders (161,162) (Table 2).
Idiopathic isolated granulomatous gastritis is a rare condition of a chronic granulomatous reaction limited to the stomach, and a diagnosis of exclusion. Primarily reported in adults, it also has been reported in a 14-year-old patient who responded to steroids (161). However, in most cases of apparent "idiopathic granulomatous gastritis," a diagnosis of Crohn's disease or sarcoidosis can be established (162).
Langerhans' cell histiocytosis (histiocytosis X), a rare condition in which organs are infiltrated by proliferating histiocytes, can cause granulomatous gastritis (163) and gastric polyps (164). Sarcoidosis is very rarely encountered in the gastrointestinal tract, and reported cases are confined to the adult literature (165-167).
Phlegmonous gastritis is a rare, life-threatening condition in which a rapidly progressive bacterial inflammation of the gastric submucosa results in necrosis and gangrene (168). Most cases are caused by α-hemolytic streptococci, Staphylococcus aureus, Escherichia coli, or Clostridium welchii (perfringens), but other organisms may be involved. Patients may have infections elsewhere in the body or may be immune-compromised.
Acute emphysematous gastritis is a complication of phlegmonous gastritis in which gastric wall infection is caused by gas-forming bacteria (169-172). This often fatal condition is characterized by severe abdominal pain and systemic toxicity, with radiologic evidence of gas bubbles and thickening of the gastric wall. Predisposing factors include ingestion of caustic agents and abdominal surgery. It has also been reported in a child with leukemia (171), a child with a phytobezoar (169), and a patient who ingested large volumes of a carbonated beverage (172). Emphysematous gastritis must be distinguished from two other nondisease entities that cause gas to be present in the gastric wall, gastric emphysema and cystic pneumatosis. These usually follow instrumentation or gastric outlet obstruction and in of themselves are not clinically significant (170-172).
Other Infectious Gastritides
Helicobacter heilmanii (previously Gastrospirillum hominis), is probably transmitted from cats and dogs (173,174) and may cause chronic active gastritis similar to that of H. pylori but with less severe inflammation (175,176). Gastric ulceration has been reported in one teenager, and antral nodularity in another (173,174). However, as yet, a definite association between H. heilmanii infection and ulcer disease has not been established.
Herpes simplex is a rare cause of gastritis and erosions in immunosuppressed patients, with intranuclear inclusion bodies on biopsy (177,178). In one study evidence of herpes simplex virus type 1 was identified in 4 of 22 gastric or duodenal ulcers, using immunohistochemistry and molecular probes (178). The herpes zoster-varicella virus is a very rare cause of gastritis in adults and possibly in children (179,180).
Influenza A is a rare cause of bleeding from hemorrhagic gastropathy in children and is sometimes fatal (181). Serology has been positive in all cases, but gastric specimens were negative for virus. This may have been a stress gastropathy caused by a severe systemic illness, rather than directly due to the virus.
Gastropathy with hypertrophic gastric folds and protein-losing enteropathy has been described in a 3-year-old with a rising titer of IgM to Mycoplasma pneumoniae and no evidence of recent CMV infection (182).
Mycobacterium tuberculosis involvement of the stomach is very rare and is usually associated with tuberculosis elsewhere or with immune deficiency (183-185). Syphilis involving the stomach is very rare (186).
Fungal infections of the stomach, such as Candida albicans, histoplasmosis, and mucormycosis may occur, especially in sick neonates, malnourished children, and those with burns or immune deficiencies (187-192). If gastric ulceration is seen in immune-deficient patients, fungal infection should be sought and treatment should be initiated along with peptic ulcer therapy.
Infection with fungi of the Mucoraceae family (Rhizopus, Mucor, and Absidia), can cause the systemic disease mucormycosis, which is fatal in malnourished or immune-suppressed children and preterm neonates (193,194). Mucoraceae are ubiquitous organisms occurring in bread, fruit, and decaying material. Bleeding, gastric ulcers and perforation may occur in the rare involvement of the stomach.
Fungal infection of the stomach with histoplasmosis and aspergillosis or the parasite Strongyloides stercoralis occurs rarely (9,195,196). Acute gastric anisakiasis occurs with some frequency in Japan, Spain, and other areas of high consumption of sushi, sashimi, or raw fish in other forms (197,198). With the increasing consumption of raw fish in North America and Europe, the incidence of anisakiasis may be increasing. The disorder is probably under-recognized, as it may present in many guises. Typically, it presents with acute upper gastrointestinal symptoms as few hous after ingestion of contaminated raw fish; occasionally, symptoms are so severe that a surgical condition is suspected. However, it may also present with acute, severe urticaria or angioedema, and mistakenly be diagnosed as an idiopathic allergic reaction, or as a "food allergy" (199,200). It often causes an eosinophilic gastritis with peripheral eosinophilia, which mistakenly may be assumed to be idiopathic (201). Although the acute infection may self-resolve in some cases, the advisable approach is early endoscopy that allows for accurate diagnosis and relief of symptoms by removal of the worm with endoscopic forceps (197-201). When eosinophilic gastritis occurs in the absence of a parasite at endoscopy, serology may aid in diagnosis of anisakiasis (201).
Gastric colonization with Giardia lamblia has been reported in 0.37% of analyses of more than 15,000 gastric specimens. Those with Giardia had atrophic gastritis, usually with intestinal metaplasia and H. pylori infection. Given this, it is not possible to implicate Giardia as a gastric pathogen (201).
Acknowledgment: Dr. Hassall is most grateful to Dr. Wilfred Weinstein (Division of Gastroenterology, Department of Medicine, University of California, Los Angeles), whose infectious enthusiasm initiated and fostered his interest and education in gastric mucosal pathology over some 15 years-an interest that provided the inspiration to write this manuscript.
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