Radiographic Imaging

No radiographic imaging study is accurate or reliable for diagnosing gastritis or ulcer disease. Clinical research studies performed prior to the routine use of endoscopy utilized barium upper gastrointestinal series to detect large ulcers with mucosal defects. With the advent of endoscopy, studies have shown that barium radiographic examinations have both poor sensitivity and specificity in detecting either gastric or duodenal ulcers when compared to endoscopy with biopsies.

Endoscopy

The role of endoscopy in the diagnosis of gastritis is to visualize the gastric mucosa for abnormalities, but more importantly to obtain tissue biopsies. Studies have shown that endoscopic visualization alone is not sufficient for diagnosing or excluding gastrointestinal diseases in children and that biopsies are recommended, even with unremarkable endoscopic findings. Another reason to obtain biopsies routinely during pediatric upper endoscopy, even in the absence of endoscopic abnormalities, is that the risk of repeat endoscopy with sedation in children outweighs the risk of complications from obtaining biopsies. When biopsies are done, the endoscopist must obtain sufficient tissue for the pathologist to provide accurate histologic diagnosis. Therefore, biopsy forceps appropriate for the size of the child should be used. In addition, biopsies must be obtained from appropriate locations. The Sydney system for the classification of gastritis combines topographic, morphologic, and etiologic information to provide a reproducible and accurate diagnosis. Although it has been applied to evaluate pediatric gastritis, the system is more widely used for chronic gastritis and H. pylori disease in adults. To best classify gastritis, the Sydney system recommends obtaining one biopsy from the lesser and greater curvature of the antrum, one biopsy from the lesser and greater curvature of the body, and one biopsy from the incisura, for a total of five biopsies ( Figure 26-2 ). Additional biopsies can also be obtained at the clinical discretion of the physician. During endoscopy, the duodenal bulb must be carefully evaluated for PUD and bleeding lesions, especially in patients with upper gastrointestinal bleeding. There are instances when a standard forward-viewing endoscope cannot fully visualize the entire bulb mucosa due to the bulb shape and orientation. The side-viewing duodenoscope can be useful in visualizing and treating duodenal bulb lesions that are in these difficult viewing angles.

Biopsy sites recommended by the Sydney system for classification of gastritis. Biopsy sites are indicated by the circled “X” and include the following: one biopsy each from the greater and lesser curvature of the antrum, both 2 to 3 cm from the pylorus; one biopsy from the lesser curvature of the body, approximately 4 cm from the incisura; one biopsy from the greater curvature, approximately 8 cm from the cardia; and one biopsy from the incisura.

Endoscopic appearance of gastritis may vary based on the severity and etiology of injury. The endoscopist should report the visual description of findings (e.g., erythema, erosion, nodularity) and not use terms such as “gastritis” or “duodenitis,” as these are histologic findings and terms. Dohil et al. proposed a pediatric gastritis classification based on endoscopic findings of whether gastritis was erosive/hemorrhagic or nonerosive. However, at this time there is no consensus for gastric endoscopic classification. There is accepted and commonly utilized terminology to describe endoscopic findings. Erythema or redness describes red discoloration of the mucosa and can be graded as mild, moderate, or marked. Erythema can be a result of capillary engorgement and mucus depletion, altering light reflection and producing a redder endoscopic appearance. Erosions are mucosa breaks that by definition do not breach the muscularis mucosa. Erosions are superficial and can be large or multiple. Therefore, even if an erosion were large, it should not be considered an ulcer unless the lesion penetrates to the submucosa. Endoscopically, it may be difficult to distinguish erosions from ulcers, unless the ulcer is deep and crater-like. In addition, erosions are more often multiple and appear flat and superficial. Granularity or nodularity describes the bumpy and nodular mucosa that can be commonly seen in H. pylori . Bleeding spots or hemorrhage is used to describe red petechial mucosal lesions due to capillary bleeding. Hyperrugosity refers to prominent or large gastric folds and fold atrophy refers to thin or absent gastric folds.

As stated previously, studies have shown that histologic pathology may be present even when endoscopic appearance is unremarkable. The finding of “non-specific chronic gastritis” is not uncommon and can be found on gastric biopsies in patients without clinical symptoms of dyspepsia and gastritis. Therefore, the physician should always consider the endoscopic and histologic findings within the clinical context of the patient’s history, physical examination, and laboratory findings.

Capsule endoscopy (CE) is an established modality to evaluate the esophagus, small bowel, and colon in adult patients. The small bowel capsule has regulatory approval in the United States for children. Although CE can purposely or incidentally detect gastric lesions not seen on gastroscopy examination, the modality is currently suboptimal as a primary test for evaluation of gastric lesions. Technology for the gastric capsule is under development and at this time not available for clinical application. The major drawback to CE technology is the inability to obtain tissue biopsy, which is required for the histologic diagnosis of gastritis and other diseases such as inflammatory bowel disease.

Pathologic Features of Gastritis

After endoscopic evaluation for gastric disease, the physician must correlate the clinical and endoscopic findings with the biopsy findings. Pathologic features of gastritis depend on the etiology, location, and duration of the insult ( Table 26-1 ). Neutrophil, mononuclear, and/or eosinophil infiltration can be seen in gastritis of various etiologies, whereas H. pylori gastritis can involve infiltration of all these cells. Chemical gastritis can demonstrate a pathologic picture of mucosal hyperemia, foveolar hyperplasia, and surface epithelium degeneration. Other pathologic features seen in gastritis include lymphoid follicles and surface erosions seen in H. pylori. Endocrine cell hyperplasia is seen in long-term proton pump inhibitor (PPI) use or autoimmune gastritis. Histology can also reveal gastric atrophy and atrophic gastritis, which are characterized by loss of gastric glands during regeneration from injury, largely seen in autoimmune and H. pylori gastritis. As stated previously, the Sydney system presents a guide to help standardize, grade, and classify gastritis. First, the location of the finding is noted (antrum only, corpus only, or pan-gastritis). The etiology (e.g., H. pylori ; chemical) is also noted in the diagnosis. Morphologic variables of chronic inflammation, activity of gastritis, intestinal metaplasia, atrophy, and presence of H. pylori are all graded as mild, moderate, or marked.

In acute gastritis, histopathology will show neutrophils in abnormal quantities in the lamina propria or in the epithelium, where neutrophils are not normally present. Other histologic features include lymphoid follicles seen predominantly in H. pylori gastritis and, in children, can lead to the typical nodular mucosa seen endoscopically. Eosinophilic infiltration can be seen in acute gastritis in children with eosinophilic gastroenteritis, parasitic infections, and H. pylori gastritis. Chronic gastritis will demonstrate mononuclear infiltration with lymphocytes and plasma cells. This is characteristic of chronic H. pylori gastritis and autoimmune gastritis. Normally, there are few mononuclear cells in the antral epithelium, and even fewer in the body mucosa. On the other hand, the number of mononuclear cells in the lamina propria varies, and several clusters of mononuclear cells are required for the diagnosis of gastritis. The term “active” is usually used in the context of “chronic active gastritis,” referring to the presence of neutrophils causing acute inflammation on a background of chronic inflammation ( Figure 26-3 ).

Gastric biopsy of a child with non– H. pylori gastritis. (A) 100× magnification demonstrates chronic active gastritis with increase in both neutrophils and lymphocytes in the lamina propria, and also necroinflammatory debris (arrow) indicating acute gastritis. (B) 400× magnification demonstrates increase in neutrophils (arrow), mononuclear cells (double arrows), and eosinophils (triple arrows) in the lamina propria.

Atrophy is characterized by the loss of gastric glands. Although atrophy is most commonly seen with H. pylori infection, it is present in many pathologic processes that damage the gastric mucosa, and is strongly associated with autoimmune gastritis. During repair, the mucosa can regenerate normal gastric glands, or replace the native glands with fibroblasts and extracellular matrix, leading to thinning of the mucosa. Lost glands can be replaced by pseudopyloric metaplasia that consists of mucus-secreting cells found in the antrum, or by intestinal metaplasia that consists of intestinal epithelial cells containing goblet cells and absorptive cells. Although intestinal metaplasia can occur independent of atrophy, the presence of antral intestinal metaplasia is a strong indicator of intestinal atrophy. Atrophy and intestinal metaplasia can be diffuse or multifocal; therefore, biopsy mapping is important not only to capture but also to identify correctly the locations of the abnormalities. Atrophy of the body or antrum with glandular replacement by intestinal metaplasia is associated with an increased risk of malignancy. This emphasizes the importance of accurately identifying the presence and site of gastric atrophy with intestinal metaplasia. There are instances when histologic appearance can be misleading. The presence of inflammatory cells interspersed between gastric glands gives an appearance of gastric atrophy where it does not really exist. Therefore, biopsy interpretation can be observer dependent, especially in the interpretation of gastric atrophy.

Helicobacter Pylori Gastritis

With its discovery by Drs. Marshall and Warren, H. pylori has been identified as the most common cause of gastritis in the world. After this discovery, treatment for H. pylori infection improved our ability to prevent the sequelae. H. pylori and its role in gastritis, peptic ulcer disease, gastric cancer, and lymphoma are discussed in a separate chapter.

Stress Gastropathy

Stress-related mucosal disease is a spectrum, from superficial mucosal injury (typically multiple erosions that are asymptomatic occurring within 24 hours of stress) to deep stress ulcers. Physiologic stresses such as shock, hypoxia, acidosis, sepsis, burns, surgery, or head injury lead to hypoperfusion followed by reperfusion injury, characterized by the breakdown of the mucosal barrier and increased susceptibility to injury. Hypoxic insult leads to oxidative stress and has been demonstrated in animal models to alter the transcription of various genes leading to injury. In the setting of physiologic stress, 1.5% to 2% of children present with overt upper gastrointestinal hemorrhage. Lesions begin in the fundus and proximal body, and spread distally to the antrum, resulting in a diffuse erosive and hemorrhagic appearance on endoscopy, and rarely mucosal inflammation. Because progression of gastropathy is proximal to distal, sole antral involvement is uncommon. Risk factors for stress gastropathy bleeding are respiratory failure requiring mechanical ventilation, coagulopathy, sepsis, hypotension, multiple trauma, severe burns, renal or liver failure, multiorgan failure, and use of corticosteroids. It is common practice for stressed patients to receive acid-suppressant therapies (H2-receptor antagonist or PPI ), as studies have shown that prophylaxis with acid-suppression medications prevents significant upper gastrointestinal bleeding; however, in systematic review of randomized control trials, prophylaxis has not been shown to improve survival.

Neonatal Gastropathy

Gastritis or gastropathy in the neonate is usually stress gastropathy, as the sick neonate often has a variety of risk factors such as prematurity, hypoxia, prolonged ventilator support, acid–base imbalance, and sepsis. Exacerbating factors in these critically ill infants include traumatic suctioning, fetal distress, hypergastrinemia associated with maternal stress or antacid use, hyperpepsinogenemia, and cow’s-milk allergy. Hemorrhagic gastropathy has been reported in critically ill premature infants as well as in full-term infants. Although they may be asymptomatic, infants may also present with feeding difficulty, vomiting, upper gastrointestinal bleeding, poor weight gain, and even gastric perforation. Endoscopic evaluation is usually not required, as this gastropathy rapidly responds to acid suppressive treatment. In the presence of significant bleeding or persistence of symptoms despite medical therapy, endoscopic evaluation may be warranted.

Congenital heart defects and medications may also contribute to the development of gastric pathology. Gastropathy is commonly seen in neonates with ductal-dependent congenital heart lesions who are receiving prostaglandin E1. This medication promotes elongation and dilation of the gastric foveolae, leading to focal foveolar hyperplasia, which has been reported to cause gastric outlet obstruction requiring pyloromyotomy. After treatment of the obstruction and discontinuation of the medication, it takes several months for the gastric mucosa to normalize, although infants are usually asymptomatic during the recovery.

Trauma

Subepithelial hemorrhages in the fundus and proximal body of the stomach may result from forceful retching or vomiting. With these repetitive forces, the proximal stomach can become trapped in the distal esophagus, leading to vascular congestion known as prolapse gastropathy. Mallory-Weiss tears can also occur, involving injury proximal or distal to the gastroesophageal junction and result in variable degrees of bleeding. Although Mallory-Weiss tears are considered the more common of the two, a retrospective case series by Bishop et al. suggests that prolapse gastropathy is far more common in pediatrics. Prolapse gastropathy may also occur through a gastrostomy site and should be considered in the differential diagnosis, along with erosions or ulcerations from gastrostomy tube balloons, as a cause of gastrostomy site bleeding. Once gastric mucosa has prolapsed through the gastrostomy, surgical intervention is often required. Although both of the aforementioned entities tend to resolve quickly, they may result in significant blood loss. Diaphragmatic or hiatal hernia may result in mucosal trauma by similar pathophysiologic mechanisms. Other causes of trauma include the placement of nasogastric and gastrostomy tubes, and foreign body ingestions. Suctioning from a nasogastric tube may result in localized trauma, such as subepithelial hemorrhage, erosions, and even ulcers. Children who are anti-coagulated or have a bleeding diathesis are at particular risk.

Exercise-Induced Gastropathy

Exercise-induced gastropathy is a well-recognized phenomenon seen in long-distance runners. Because this form of exercise is becoming more popular, the number of individuals affected is increasing, with a reported incidence of 10% to 80%, depending on the type, duration, and intensity of exercise. Gastric ulcers, erosive gastritis, hemorrhagic gastritis, and anemia are not uncommon and can be presenting features of this disorder. These findings are usually attributed to reduced visceral blood flow, ischemia, and increased acid secretion. The use of acid suppressive therapy may be helpful in managing these patients.

Zollinger-Ellison Syndrome and Other Hypersecretory States

Zollinger-Ellison syndrome is caused by gastrin-secreting tumors. Although Zollinger-Ellison syndrome has been reported in children, it is rare. This condition is characterized by elevated plasma gastrin levels. Children receiving PPI therapy can have elevated gastrin levels; however, they are usually much lower than the levels seen with Zollinger-Ellison syndrome. Children with multiple endocrine neoplasia type 1 (MEN1) can also develop Zollinger-Ellison syndrome, and usually present at a younger age than those who have the sporadic form.

Children with sporadic Zollinger-Ellison syndrome develop this disorder secondary to gastrinomas, which usually arise in the pancreas but may also be seen in the stomach, duodenum, lymph nodes, kidneys, and liver. The clinical presentation is typically as multiple gastric ulcers that are recalcitrant to usual management. The ulcers can also be seen elsewhere in the gastrointestinal tract such as the jejunum. In addition to PUD symptoms, patients may have persistent diarrhea, weight loss, and gastrointestinal bleeding. Esophagogastroduodenoscopy commonly shows prominent gastric folds and may show strictures in the stomach, especially the pyloric area. Strictures in the esophagus or duodenum can also be seen. Treatment of this condition usually requires high doses of PPI therapy, and if possible, surgical resection of the gastrinoma.

Other conditions that contribute to the development of a hypersecretory state include short bowel syndrome, hyperparathyroidism, cystic fibrosis, and systemic mastocytosis. Systemic mastocytosis is characterized by accumulation of mast cells in several areas of the body such as skin, liver, spleen, bone marrow, and gastrointestinal tract. Mast cells produce cytokines and histamine leading to gastric hypersecretion, and symptoms are similar to those seen in Zollinger-Ellison syndrome. The systemic form of the disease is characterized by a normal serum gastrin level, but the stomach and duodenum may have multiple ulcers and urticarial-like papules. Anesthesia can be associated with significant risks in this population, and therefore risks and benefits should be carefully considered before recommending procedures. Histamine receptor antagonists (H1 and H2) and acid suppression are usually effective in this condition.

Autoimmune Gastritis

Autoimmune gastritis is a chronic inflammatory process in which parietal cells are replaced by atrophic and potentially metaplastic tissue. It is often isolated to the fundus and body. Onset of gastric inflammation often occurs in adolescence, which precedes the later clinical presentation as either pernicious or iron-deficiency anemia. Years of gastric inflammation eventually lead to chronic atrophic gastritis and its subsequent manifestations. Serum biomarkers have been identified, namely parietal cell antibodies to gastric H ⁺ ,K ⁺ -ATPase, and have been shown to correlate with the presence of fundal gastritis. As atrophic gastritis develops, it is characterized by hypergastrinemia and hypochlorhydria, and eventually achlorhydria. Endoscopic findings reveal thin rugae or loss of rugae, and pathologic evaluation reveals gastric atrophy with loss of glands and parietal cells. Elevated gastrin levels have been used as a reliable marker of the presence of chronic atrophic gastritis and correlate well with gastric biopsies. Decrease in serum ghrelin level has shown greater sensitivity (97.3%) and specificity (100%) than gastrin levels in detecting gastric atrophy.

Pernicious anemia is the most common autoimmune disorder associated with autoimmune and atrophic gastritis, and is the result of intrinsic factor deficiency. Antibodies to intrinsic factor lead to malabsorption of vitamin B ₁₂ , achlorhydria, and subsequently to megaloblastic anemia. During early stages of the disease, anti-parietal cell antibodies are high, but begin to fall as atrophic gastritis becomes more severe with loss of gastric parietal cells. Anti-parietal cell antibodies are a sensitive, but not a specific, marker, as they are also seen in other autoimmune diseases, whereas anti-intrinsic factor antibodies are less sensitive but very specific to pernicious anemia. Left untreated, pernicious anemia will present with fatigue, weakness, and ataxia. A case series has described metaplastic changes independent of H. pylori infection in autoimmune and atrophic gastritis, suggesting the potential for malignant transformation.

Other autoimmune disorders that can be associated with autoimmune gastritis include thyroiditis, nongoitrous juvenile hypothyroidism, diabetes mellitus, and vitiligo, which may present with or without atrophy. Autoimmune gastritis can be independent of the severity of these autoimmune disorders, and should be investigated in the presence of iron-deficiency anemia, as its presence can suggest atrophic gastritis. Conversely, hypertrophic gastritis has been described in systemic lupus erythematosus.

Inflammatory Bowel Disease

Gastritis may be seen in both Crohn’s disease and ulcerative colitis. Endoscopic and histologic changes are typically seen in the body, but can also be seen in the antrum. These lesions are referred to as focally enhanced gastritis (FEG), which are inflammatory lesions with discrete inflammatory foci containing lymphocytes and histiocytes surrounding a small group of gastric glands with infiltrates of neutrophils. The specificity of FEG to Crohn’s disease is variable, as several studies have demonstrated that 24% of ulcerative colitis and 2% to 19% of non–inflammatory bowel disease (IBD) patients may have these lesions. The presence of FEG in a patient with clinical suspicion of IBD may more likely suggest Crohn’s disease over ulcerative colitis in the appropriate clinical setting, but does not exclude the diagnosis of ulcerative colitis. Crohn’s disease is more commonly associated with focal gastritis and is the most common cause of granulomas in the stomach, although granulomas are rarely isolated just to the stomach. Treatment of gastric manifestations of IBD is managed by targeting the underlying disorder, which may be responsive to corticosteroids, 6-mercaptopurine, and infliximab. Adult case reports of gastritis and ulcers in the stomach in patients with ulcerative colitis resolved with infliximab treatment.

Celiac Disease

Celiac disease is an autoimmune gluten-sensitive enteropathy characterized by duodenal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Although the gastric mucosa has a normal endoscopic appearance, lymphocytic gastritis may be present in untreated patients. Histologically, this is defined by more than 25 intraepithelial lymphocytes (predominantly T cells) per 100 surface and pit epithelial cells focally in the antrum. The lymphocytic changes are also associated with nonspecific chronic gastritis and mucin depletion. Patients may present with dyspeptic symptoms. Treatment with a gluten-free diet shows a significant decrease in the number of intraepithelial lymphocytes. Celiac disease has also been shown to be associated with varioliform gastritis, although its clinical significance is unclear.

Eosinophilic and Allergic Gastritis

Eosinophilic gastrointestinal disease is often associated with allergies. Eosinophilic gastritis more commonly presents as part of an eosinophilic gastroenteritis rather than as an isolated entity. Eosinophilic gastritis is also associated with other disease processes such as IBD, collagen vascular disease, parasitic and bacterial infections (including H. pylori ), drug injury, and drug hypersensitivity. Although eosinophils may be seen in a variety of disease states, eosinophilia is more prominent in allergy and atopy. In patients with eosinophilic gastritis, the medical history may reveal seasonal allergies, food sensitivities, eczema, asthma, and atopy. The gastrointestinal manifestations are typically secondary to mixed immunoglobulin E (IgE) and non-IgE allergic reactions resulting in increased levels of interleukin 3 (IL-3), IL-5, and GM-CSF (granulocyte/monocyte–colony stimulating factor, all of which are proinflammatory cytokines.

Eosinophilic gastritis may be mucosal (most common subtype), muscular, serosal, or a combination of these. Mucosal eosinophilic gastritis symptoms are similar to other forms of gastritis. Cow’s milk, soymilk, egg, and wheat are the most frequently identified allergens in infants and children with allergic eosinophilic gastrointestinal disease, and the history reveals a temporal relationship between ingestion of the offending food and symptoms such as vomiting, hematemesis, irritability, and poor weight gain. Infants and younger children may present with failure to thrive or food refusal. In rare cases, eosinophilic gastroenteritis may present as gastric outlet obstruction due to swollen gastric folds as well as delayed gastric emptying. Anemia due to occult blood loss and hypoalbuminemia occurs commonly. If there is muscular and/or serosal involvement, abdominal pain and eosinophilic ascites may be present.

Endoscopic features are highly variable and nonspecific. There may be friability, erythema, erosions, ulcers, swollen mucosal folds, and scattered mucosal nodular lesions, or pseudopolyps, particularly in the antrum. These nonspecific findings emphasize the need for biopsies, which demonstrate eosinophilic infiltrates in the lamina propria with occasional lymphocytes, plasma cells, and neutrophils. Histologic criteria for diagnosis is greater than 50 eosinophils per high power field present in at least five high power fields in the absence of other disorders known to cause eosinophilia. Within the body, lesions are diffuse, while in the antrum, smaller focal lesions predominant. If deeper layers are involved, endoscopy with biopsy may not be diagnostic and endoscopic ultrasound or magnetic resonance imaging (MRI) may be utilized to demonstrate gastric wall thickening.

Although definitive diagnosis of food allergy requires formal allergy testing, the diagnosis is suspected based on the response to allergen elimination, and improvement of endoscopic and histologic findings. Reintroduction of the offending antigen is usually possible by 24 months of age or earlier, although allergies to peanuts, tree nuts, and seafood are likely to persist. Eosinophilic gastroenteritis is diagnosed according to criteria proposed by Klein et al., for which there needs to be “presence of gastrointestinal symptoms, biopsies showing eosinophilic infiltration of one or more areas in the gastro­intestinal tract from esophagus to colon, or characteristic radiologic findings with peripheral eosinophilia, and no evidence of parasitic or extraintestinal disease.” Only about 50% of patients with eosinophilic gastrointestinal disease will have a peripheral eosinophilia, which may be related to coexisting atopy and not to their gastrointestinal manifestations.

Treatment is targeted at eliminating the identified or presumed allergen, leukotriene receptor antagonists (montelukast), mast cell stabilizers (ketotifen), systemic corticosteroids, azathioprine, or elemental diet. Delivery of topical steroids to the gastric mucosa is challenging. Symptomatic relief may be provided with acid-suppressing medication such as a PPI. Some case reports have demonstrated partially responsive cases of eosinophilic gastritis due to prolonged eosinophil survival, in part due to elevated IL-5 levels. In severe or refractory cases, azathioprine and mycophenolate mofetil may be used and have been shown to induce and maintain remission in steroid-dependent cases. In infants, treatment consists of hydrolyzed protein or elemental formulas and results in symptom resolution as well as normalization of biochemical markers (anemia and hypoalbuminemia) and endoscopic changes.

Granulomatous Gastritis

Granulomatous gastritis is a rare type of chronic gastritis. The etiology of granulomatous gastritis varies. A primary cause of granulomatous gastritis is chronic granulomatous disease (CGD)—a rare inherited disorder affecting the phagocyte oxidative pathway resulting in increased risk of infections and granuloma formation. In a pediatric study of CGD patients with gastrointestinal involvement, all patients reported abdominal pain, and gastrointestinal symptoms were the primary symptom in one-third of patients. CGD gastritis can present with gastric obstruction, diarrhea, constipation, nausea, and vomiting. Endoscopic findings associated with CGD gastritis are usually nonspecific. Biopsies may reveal granulomas that are more sharply defined as opposed to the poorly defined granulomas more typical of Crohn’s disease. Topographically, granulomas are usually found in the antrum in both children and adults. Other gastric histologic findings may include microgranulomas, eosinophilia, and chronic and/or acute inflammation.

Often granulomatous gastritis is related to an underlying disease. In developed countries, granulomatous gastritis is usually secondary to immune disorders such as Crohn’s disease or sarcoidosis, whereas in nondeveloped countries infections such as those caused by Mycobacterium tuberculosis are usually the primary cause. H. pylori appears to be associated with granulomatous gastritis, but it does not appear to be causal. In two series of mostly adult patients from Belgium and the Cleveland Clinic (United States), Crohn’s disease followed by sarcoidosis was the most common etiology of granulomatous gastritis. Renault et al. reported on a series of 23 children with granulomatous gastritis from the United States in which Crohn’s disease was also the most common etiology. Other causes of granulomatous gastritis include parasitic infections, syphilis, Whipple disease, polyangiitis (Wegner disease) and other vasculitis-associated diseases, foreign body reactions, gastrointestinal carcinoma, and lymphoma. Although idiopathic isolated granulomatous gastritis is reported, it is rare and a diagnosis of exclusion.

Cytomegalovirus

Cytomegalovirus (CMV) is a ubiquitous virus that is more commonly symptomatic in immunosuppressed individuals such as patients with acquired immunodeficiency syndrome, solid organ or bone marrow transplantation, and premature infants. Immunocompetent hosts may be infected, and particularly in children, can present with Ménétrier’s disease. CMV tends to infect the stomach and colon, is most commonly implicated in colitis in immunosuppressed patients, and can affect both premature and full-term infants. If gastritis is present, symptoms are nonspecific and include epigastric pain, fever, nausea, and bleeding in the presence of ulcer disease. Endoscopic appearance can range from normal-appearing mucosa to wall thickening, diffuse erythema, nodules, pseudotumors, erosions, and ulcers that can bleed and perforate ( Figure 26-4 ). Although it can affect any part of the stomach, it is usually localized to the gastric fundus and body. Histologically, there may be evidence of acute and chronic inflammation with edema and necrosis. The hallmark of infection is intranuclear CMV inclusion bodies found in epithelial and endothelial cells in ulcer bases and mucosa adjacent to ulcers. CMV tends to penetrate the mucosa, resulting in panmucosal edema. Diagnostic yield is increased by viral culture of mucosal biopsies as well as immunohistochemical detection of CMV early antigen. Although spontaneous recovery occurs in 1 to 2 months, CMV may be treated with ganciclovir, which is particularly beneficial to immunosuppressed patients.

Endoscopy of a 3-year-old girl who presented with hematemesis. Multiple ulcers were visualized in the antrum. The patient was found to have cytomegalovirus (CMV) gastritis.

Other Viruses

A variety of viruses can infect the stomach. Most severe is influenza A virus, a rare cause of potentially fatal hemorrhagic stress gastropathy thought to be a manifestation of severe systemic illness, rather than the effects of direct virulence to the gastric mucosa. Epstein-Barr virus (EBV) has been associated with gastritis and diffuse lymphoid hyperplasia within the gastric mucosa. EBV has also been implicated in the development of gastric cancer, either directly through infection of epithelial cells, or indirectly by inflammation. Herpes simplex virus is a rare cause of gastritis and erosions in immunosuppressed patients, although typically limited to superficial infection. Biopsies show characteristic intranuclear inclusion bodies by which the diagnosis is established. The herpes zoster virus is a very rare cause of gastritis in both adults and children. There have been case reports demonstrating isolation of herpes zoster virus and resolution of symptoms with acyclovir treatment. Hepatitis C virus has been implicated in gastritis and associated with chronic lymphocytic cell infiltrates.

Parasites

Although Giardia lamblia is the most common parasite worldwide, and characteristically affects the duodenum, gastric colonization can occur. Patients present with dyspepsia, epigastric pain, and abdominal distension. Infection with this organism occurs in the presence of hypochlorhydria. It has been suggested that it may be a pathogen in the stomach in some individuals, and regurgitant contaminant from the duodenum in others. With endoscopy, one may see bile reflux through an open pylorus, patchy small cotton-like plaques, and visualization of the organism on biopsy. Gastric Giardia is associated with various patterns of gastritis, including reactive gastritis, chronic atrophic gastritis, and chronic active gastritis. Giardia infection should also be considered in the presence of gastric carcinoma, intestinal metaplasia, and atrophic gastritis. Another parasite, ascariasis, has been described in the literature with infant gastritis and massive gastrointestinal bleeding.

Fungi

Fungal infections of the stomach most commonly occur with Candida species. Critically ill neonates, malnourished children, burn patients, and patients with immunodeficiencies are most at risk. Intake of antacids and acid-suppressing medications facilitate overgrowth of Candida species in the stomach. Candidal infections may cause gastric ulcers and are more often reported in older patients. In the setting of immunodeficiency and gastric ulcer, fungal infection should be investigated and if present, treated in conjunction with peptic ulcer. It rarely recurs after treatment. Cryptosporidium is rarely found in the stomach, where it can cause PUD and erosive gastritis. Histoplasmosis is a rare infection of the gastrointestinal tract, usually seen in the setting of immunosuppression. It more commonly affects the colon and terminal ileum rather than the stomach.

Bacteria

H. pylo ri is the most commonly known bacterial cause of gastritis. Other members of the Helicobacter genus may colonize the stomach such as Helicobacter heilmannii , transmitted from cats. It causes a chronic gastritis similar to H. pylori , but with less severe inflammation, and is restricted to the antrum without ulcer disease. Several Helicobacter species are associated with gastric carcinomas in animal models. Other bacterial causes of gastritis include infection caused by Mycobacterium tuberculosis , which endoscopically demonstrates ulceration and mucosal hypertrophy, and resolves upon treatment. Mycoplasma pneumoniae is another organism reported to be associated with protein-losing hypertrophic gastropathy.

Phlegmonous Gastritis and Emphysematous Gastritis

Phlegmonous gastritis is a rare fatal condition caused by bacterial inflammation, necrosis, and gangrene of the stomach. The offending organism can be Staphylococcus aureus , β-hemolytic streptococci Escherichia coli , or Clostridium welchii . The condition can occur if the immune system is compromised. Peritonitis and gastric perforation can be presenting symptoms.

Emphysematous gastritis can occur as a complication of phlegmonous gastritis when the infection is caused by anaerobic gas–forming bacteria such as Clostridium perfringens , especially after caustic ingestion or with abdominal surgery. This leads to severe abdominal pain and systemic toxicity with radiographic signs of gas in the gastric wall. The condition has been reported in immunocompromised children, patients with liver cirrhosis, and in association with caustic ingestion or phytobezoar.

NSAIDs

Gastric complications caused by NSAIDs occur due to their direct effect on the mucosa and pharmacologic mechanism of action. Inhibition of cyclooxygenase (COX)–catalyzed conversion of arachidonic acid to prostaglandins reduces prostaglandin synthesis, and is responsible for the analgesic, antipyretic, and anti-inflammatory effects of these medications by reducing the pro-inflammatory prostaglandins. Unfortunately, their use is limited by their very well-described adverse effects on the gastrointestinal tract, ranging from superficial mucosal damage to frank ulcerations resulting in life-threatening gastrointestinal bleeding. These effects are related to the chemical composition of the medication that allows direct uptake of NSAIDs into the cell interior. Upon ingestion, there may be subepithelial hemorrhage and erosions, regardless of dose. These effects are rapid, within 15 to 30 minutes of ingestion and primarily affect the antrum. Fortunately, these early superficial mucosal changes are often asymptomatic.

In children, thickened folds and ulceration of the incisura presenting with gastrointestinal bleeding is typical and may occur with both short-term and chronic use. Microscopically, there is reactive gastropathy featuring epithelial hyperplasia, mucin depletion, enlarged nuclei, fibromuscular hyperplasia, vascular ectasia, and edema. Reactive gastritis may also be seen. Although the effects are more commonly recognized in the stomach, there can be changes throughout the gastrointestinal tract, including the esophagus, small intestine, and colon.

With long-term use, upper gastrointestinal bleeding is of significant concern and has been reported in up to one-third of children using NSAIDs. Children with prolonged NSAID use, for greater than 2 months, have been shown to develop evidence of gastropathy, antral erosions, or ulcers, accompanied by anemia and abdominal pain. Other factors that increase the risk for NSAID-related gastrointestinal ulcers are concomitant use of another NSAID or corticosteroids, higher NSAID dose, previous history of ulcer disease, use of an anticoagulant, and H. pylori infection.

To reduce the adverse effects of NSAIDs on the gastrointestinal tract, concomitant use with PPIs or misoprostol (a prostaglandin analog) may be beneficial. In patients treated for gastrointestinal bleeding who require an NSAID, a PPI with a COX-2 inhibitor may reduce rebleeding. H2-receptor antagonists do not effectively prevent NSAID-induced gastric ulcers; therefore, PPIs are the preferred acid-suppression medication.

Corticosteroids

Dexamethasone has been described to cause gastritis and even perforation in premature infants. In animal models, it stimulates basal gastric acid secretion, resulting in gastritis. Pathologic findings are not limited to the gastric mucosa, but include duodenal ulcers, for which prophylaxis is recommended.

Proton Pump Inhibitor Gastritis

PPIs have been associated with gastropathy and abnormalities including atrophy, nodules, and gastric polyps ( Figure 26-5 ). These lesions are benign and resolve with medication discontinuation. High-dose PPIs resulting in gastric acid suppression induce hypergastrinemia. In animal models, this leads to the development of neuroendocrine tumors, and also enterochromaffin-like cell hyperplasia, gastric atrophy, metaplasia, and adenocarcinoma. However, in humans, these changes have not been documented. Because many patients are taking PPIs long term, it is important to consider the neuroendocrine changes induced by these medications.

Gastric gland polyps in an 8-year-old boy with prolonged proton pump inhibitor use.

Other Medications

Gastric erythema, erosions, and subepithelial hemorrhages have been seen with several medications such as valproic acid, chemotherapeutic agents, alcohol, potassium, chloride, iron, cysteamine, long-term fluoride use, and aspirin. Use of enteric-coated low-dose aspirin has not reduced gastrointestinal toxicity.

Portal Hypertensive Gastropathy

Portal hypertensive gastropathy can be present in both cirrhotic and noncirrhotic patients; however, it requires the presence of portal hypertension, which is most commonly due to cirrhosis. An association of portal pressure with portal hypertensive gastropathy has been demonstrated. Portal hypertensive gastropathy resolves after transjugular intrahepatic portosystemic shunt (TIPS) with improvement of portal pressures. It has been suggested that increased gastric blood flow and impaired gastric mucosal defense mechanisms contribute to the pathogenesis in portal hypertensive gastropathy. The pattern of portal hypertensive gastropathy is variable, ranging from mild gastropathy with a “mosaic pattern” of small erythematous patches diffusely and homogenously scattered throughout the stomach to severe disease with hemorrhagic gastritis. When bleeding occurs, it may appear as black-brown spots. The diagnosis is often made endoscopically without the need for biopsies, which may result in bleeding. Histologically, there is a mosaic or “snakeskin” pattern, flat or bulging erythema that resembles ectasias without a significant inflammatory component commonly identified in the fundus and body. If biopsies are obtained, it is often to differentiate portal hypertensive gastropathy from gastric antral vascular ectasia (GAVE), which may be seen in patients with and without cirrhosis or portal hypertension. This distinction is important as management differs.

Treatment is targeted at reducing venous pressure and gastric mucosal blood flow, as bleeding may occur. A prospective study demonstrated that portal hypertensive gastropathy developed less in patients with cirrhosis and fundal varices; however, it worsened after obliteration of esophageal varices. Recent studies in adults have shown effectiveness of losartan, an angiotensin II receptor antagonist, in reducing portal pressure and reducing the risk of portal hypertensive gastropathy bleeding. Endoscopic control of bleeding is a consideration; however, it is difficult because the bleeding is diffuse, unlike in esophageal variceal bleeding or GAVE, which respond to banding or ablative techniques.

Gastric Antral Vascular Ectasia

Gastric antral vascular ectasia is an uncommon cause of upper gastrointestinal bleeding. As with portal hypertensive gastropathy, it is associated with cirrhosis or portal hypertension. Although more commonly seen in adults, the finding has been reported in children with bone marrow transplants and erosive gastritis. Patients usually present with nonvariceal upper gastrointestinal bleeding, and gastric outlet obstruction has also been reported. The typical endoscopic description of GAVE is a “watermelon stomach,” which is caused by irregular red stripes in the antrum resembling the stripes on watermelon. The histologic findings include hyperplasia of the surface epithelium and the lamina propria with dilation and congestion of the submucosal venous channels. Treatment of the bleeding lesions is achieved endoscopically with thermal coagulation methods such as argon plasma coagulation.

Lymphocytic Gastritis

Lymphocytic gastritis is not a cause but rather a distinct type of gastritis characterized by 25 or more intraepithelial lymphocytes per 100 surface epithelium in the gastric foveolar and surface epithelium. It can be seen in patients with celiac disease, H. pylori infection, and varioliform gastritis. Distribution of lymphocytosis may vary, depending on the etiology, with greater intraepithelial lymphocytes in the antrum than the body in celiac disease, whereas the opposite distribution can be seen in H. pylori and varioliform gastritis. Case reports have described hypoproteinemia with lymphocytic gastritis secondary to leakage of plasma proteins into the gastric lumen. Endoscopically the gastric mucosa may appear normal or with mucosal erosions and large folds.

Graft versus Host Disease

Graft-versus-host disease (GvHD) gastritis is most often seen in patients who have received an allogeneic bone marrow transplant rather than a solid organ transplant. Acute GvHD occurs within the first 100 days after bone marrow transplantation and may manifest with a spectrum of symptoms affecting the skin, liver, and gastrointestinal tract. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, hematochezia, and/or diarrhea. Endoscopic evaluation is usually required to confirm GvHD when evaluation for other etiologies such infection and medication toxicity are unremarkable. The endoscopic appearance of GvHD gastritis may range from mild erythema to sloughing of the mucosa. When endoscopy is performed, biopsies should be obtained to confirm the diagnosis, as endoscopic appearance may appear normal or underestimate the severity in GvHD. Care must be taken when obtaining duodenal biopsies, as patients with bone marrow transplant may have coagulopathy with higher risk of hemorrhage and duodenal hematomas. GvHD may be present only on upper gastrointestinal biopsies, even when patients have lower gastrointestinal symptoms. However, some studies report biopsies obtained during colonoscopy or flexible sigmoidoscopy have a higher yield. Pediatric studies also vary as to which biopsy location (upper gastrointestinal vs. rectosigmoid) is most sensitive for identifying GvHD. Therefore, there is no consensus regarding the endoscopic approach to patients with GvHD symptoms. A survey of several bone marrow transplantation (BMT) centers in Europe revealed most centers performing lower gastrointestinal endoscopy with some performing both upper and lower gastrointestinal endoscopy. Histologically, GvHD will consist of crypt epithelial cell apoptosis ( Figure 26-6 ) and crypt loss with higher grades of GvHD, and may also consist of neutrophil and mononuclear cell infiltration of the lamina propria. GvHD histology may resemble CMV infection, adenovirus, mycophenolate mofetil colitis, human immunodeficiency virus, and primary immunodeficiencies. Chronic GvHD usually does not involve the stomach or small bowel.

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