Gastritis, Gastropathy, and Ulcer Disease

Anatomy, Histology, and Pathophysiology

To understand gastritis, appreciation of normal anatomy and mucosal histology at the different parts of the stomach is necessary. The layers of the stomach consist of the mucosa, submucosa, muscularis propria, and serosa. In ulcerating disease, the injury usually penetrates to the submucosa and possibly to the muscularis propria. The gastric mucosa is divided into two levels: the superficial foveolar cells that line the mucosa and the pits and the deeper glandular compartment that contains gastric glands.

The most proximal gastric region is the cardia, composed of mucous glands without parietal cells. The fundus and body of the stomach, where the rugae are most prominent, contain chief cells that secrete pepsinogen and parietal cells that secrete acid. The antrum is where most of the endocrine cells exist, although endocrine cells are also found less prominently in the fundus and body. These include the enterochromaffin-like cells that secrete histamine and serotonin, G-cells that secrete gastrin, and D-cells that secrete somatostatin.

Alteration in the balance of acid secretions of the previously mentioned cells contributes to the mechanism of gastritis and ulcerations. Several pathways regulate acid secretion, including the neuroendocrine, endocrine, and paracrine pathways. Increased acid production is associated with duodenal ulcers, whereas decreased acid production and gastropathy are associated with gastric ulcers. The gastric pH in patients with gastric ulcers has been shown to be higher than in patients without ulcer disease at certain times of the day and consistently higher compared with patients with duodenal ulcer disease.

Disturbances in the bicarbonate-mucous barrier that lines the gastroduodenal epithelium can expose the gastric lining to hydrochloric acid and pepsin. Oxidative stress, the innate immune system, and mucin secretion all affect the integrity of the mucous barrier. Inhibition of bicarbonate secretion seen in NSAID use decreases the ability of the gastric mucosa to buffer acid. Once gastritis and duodenitis are established, the intestinal epithelium is compromised, exposing the lining to acid and thus contributing to the progression of more severe disease, such as PUD. The severe end of the spectrum of these insults can lead to defects of the gastric or duodenal lining through the muscularis mucosa and into the submucosa or the muscularis propria, resulting in ulcer disease ( Fig. 26.1 ).

Genetic and environmental factors also contribute to the pathophysiology of gastritis and PUD. Ascertainment of genetic influences in the pathogenesis of gastritis and PUD can be difficult, given the familial aggregation of H. pylori gastritis and PUD. Yet studies have shown that familial aggregates of PUD are likely not solely caused by the presence of H. pylori . Polymorphisms in tumor necrosis factor α (TNFα) have been associated with synergistic effects with H. pylori in duodenal ulcers in children. In addition, twin studies have suggested genetic predisposition to PUD independent of the presence of H. pylori . ^,

Environmental factors that can predispose patients to gastritis and PUD include smoking, alcohol ingestion, and psychological and physical stress. Smoking is thought to affect gastric epithelium’s protective factors by decreasing gastric prostaglandin production and mucus secretion, decreasing duodenal bicarbonate secretion, and stimulating pepsin secretion. ^, Diet has not been shown to contribute to PUD but is related to symptoms of dyspepsia. Intake of certain food such as coffee and milk can stimulate gastric acid secretion, but studies have not shown that these or other foods are independently associated with gastritis or PUD. Alcohol ingestion in high concentrations may cause mucosal hemorrhage and increase acid secretion, but modest alcohol consumption has not been linked to gastritis. However, alcohol abuse, especially in the setting of psychiatric disorders, has been associated with increased PUD. ^, Epidemiologic studies have also implicated psychological and work-related stress as an independent risk factor for PUD.

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 with 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 ( Fig. 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.

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 are 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 “nonspecific 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 suboptimal as a primary test for evaluation of gastric lesions. Technology for the gastric capsule including magnetic-assisted CE 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 ( Fig. 26.3 ).

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 independently of atrophy, the presence of antral intestinal metaplasia is a strong indicator of gastric 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, PUD, 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 and occur 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 a systematic review of randomized controlled 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 resulting 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. Gastric volvulus may also lead to gastropathy with abdominal pain, vomiting, and hematemesis due to mucosal tears and ischemic injury ^,

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 anticoagulated or have a bleeding diathesis are particularly at 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. Gastrin levels greater than 1000 pg/mL in the setting of gastric pH less than 2 or an increase of at least 200 pg/mL (95 pM) over basal serum gastrin concentration with secretin stimulation can be diagnostic of 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 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 the 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 urticaria-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 the 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. ^, Serum ghrelin of less than 188 pmol/L has shown greater sensitivity (97.3%) and specificity (100%) than gastrin levels in detecting gastric atrophy in adults, though this can be normal in postpubertal children. ^,

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, antiparietal cell antibodies are high but begin to fall as atrophic gastritis becomes more severe with loss of gastric parietal cells. Antiparietal cell antibodies are a sensitive, but not a specific, marker, as they are also seen in other autoimmune diseases, whereas antiintrinsic 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 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) and 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 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 disease over ulcerative colitis in the appropriate clinical setting but does not exclude the diagnosis of ulcerative colitis. Crohn 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, immunomodulators, or biologic medications. Adult case reports of gastritis and ulcers in the stomach in patients with IBD resolved with infliximab treatment. ^,