Gastritis from NSAIDS to Helicobacter pylori

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1 Abdominal Imaging ª Springer Science+Business Media, Inc Published online: 30 December 2004 Abdom Imaging (2005) 30: DOI: /s Gastritis from NSAIDS to Helicobacter pylori S. E. Rubesin, 1 E. E. Furth, 2 M. S. Levine 1 1 Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA 2 Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA Abstract Gastritis is a histologic diagnosis. To understand gastritis, the radiologist must have some working knowledge of gastric histology and pathology. Therefore, this article first describes normal histologic and radiologic anatomy. The pathology of gastritis is then presented to give the radiologist a basis for understanding the radiologic findings. Finally, gastritis is discussed from a clinical and radiologic perspective. Normal anatomy Three distinct types of mucosa line the stomach: cardiac mucosa, body-type mucosa (also known as fundic- or oxyntic-type mucosa; Fig. 1) and antral-type mucosa (also known as pyloric-type mucosa; Fig. 2) [1 3]. These mucosal types can be distinguished by differences in their histologic architecture, the cells that form the glandular layer, and their location in the stomach. Gastric epithelium contains glands in its lower portion that empty into foveolae (also known as pits), which are conical depressions of the gastric surface. Undifferentiated stem cells responsible for mucosal proliferation and regeneration are located in a zone between the glands and foveolae, known as the mucous neck region (Fig. 3). In body-type mucosa, the glands are long, straight, and tightly packed. The glandular layer forms about 67% to 75% of the thickness of the body-type mucosa [4]. The glands of the body-type mucosa empty into foveolae that are relatively short, straight, and narrow. In contrast, the glandular layer of the antraltype mucosa is thinner, comprising about 50% of the thickness of the antral mucosa [4]. The antral glands are short, coiled, branching, and more loosely packed than Correspondence to: S. E. Rubesin; rubesin@oasis.rad.upenn.edu the body-type glands. The foveolae of antral type mucosa have a slightly villiform configuration. Tall, columnar mucus-secreting cells (the foveolar mucus cells) line the surface and foveolae (pits) of all portions of the stomach. These cells secrete a neutral mucin, in contrast to the surface cells of the small intestine and colon, which secrete acidic mucin. The glands of the gastric antrum are also lined primarily by foveolar mucus cells. The distinguishing feature of body-type mucosa is the presence of parietal (oxyntic) and chief (zymogenic) cells. Parietal cells produce hydrochloric acid, intrinsic factor, transforming growth factors, and cathepsins B and H [1]. Chief cells produce lipase and the proteolytic enzymes pepsinogen I and II. Chief cells are more numerous toward the cardia, and parietal cells are more numerous toward the antrum. Endocrine cells are widely distributed in the gastric glands and scattered in the lamina propria, but are not identifiable with routine histology. In antral-type mucosa, endocrine cells produce gastrin (G cells), serotonin (enterochromaffin cells), and somatostatin (D cells). In body-type mucosa, the predominant endocrine cell is the histamine-producing enterochromaffin-like cell (ECL cell). Gastrin stimulates acid and pepsinogen secretion and increases gastric motility. Gastrin also stimulates parietal cell and ECL cell proliferation. Somatostatin decreases secretion of gastric acid, gastrin, and intrinsic factor. Histamine produced by the ECL cells mediates gastrin-induced parietal cell secretion. The lamina propria of the mucosa contains capillaries, arterioles, nonmyelinated nerve fibers, rare endocrine cells, and fibers from the muscularis mucosae. The stomach is normally devoid of mucosa-associated lymphoid tissue (MALT). The lymphatics of the epithelium are located primarily in the deep portions of the lamina propria and within the muscularis mucosae. The location of cardiac-, body-, and antral-type mucosae do not completely correlate with traditional an-

2 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 143 Fig. 1. Normal oxyntic mucosa. The oxyntic mucosa is located in the body and fundus of the stomach. This mucosa is composed of neutral mucin-secreting cells at the surface and parietal and chief cells in the glands below. In general, the surface cells occupy approximately 25% of the total body mucosal height (upper double arrow). The gastric glands (lower double arrow) comprise about two-thirds to threefourths of the mucosal depth and contain the chief and parietal cells. ECL cells are present but are not distinguishable from other cells on routine staining hematoxylin and eosin. Gastrin stimulates the ECL cells to secrete histamine. The histamine, through histamine receptors on the parietal cells, stimulates parietal-cell HCl secretion. The parietal cells themselves also contain gastrin receptors, so gastrin may also directly stimulate parietal cell HCl secretion. Original magnification, 10 atomic and radiologic descriptions of the cardia, fundus, body, and antrum (Fig. 4). Cardiac-type mucosa usually lines a 1-cm long surface of stomach immediately distal to the esophagogastric junction. Oxyntic-type mucosa lines the gastric fundus (defined anatomically and radiologically as that portion of stomach superior to the gastric cardia) and most of the gastric body. Antral-type mucosa lines a larger percentage of the lesser curvature than of the greater curvature. The antral-type mucosa lines only the distal portion of the radiologic gastric antrum along the greater curvature. In younger people, antral-type mucosa extends to the incisura angularis on the lesser curvature. In elderly people, in particular women, antral-type mucosa extends farther up the lesser curvature into the radiologic gastric body. Fig. 2. Normal antral mucosa. The antral mucosa of the stomach is less than one-half the volume of the oxyntic mucosa that lines the fundus and body of the stomach. The antrum contains neutral mucin-secreting glands. G cells are neuroendocrine cells present only in antral mucosa but are not distinguishable from other cells with routine staining with hematoxylin and eosin. G cells secrete gastrin that stimulates acid secretion from the parietal cells located in the oxyntic mucosa. The lamina propria is the tissue between glands. The gastric lamina propria is devoid of MALT, unlike the lamina propria in the remainder of the luminal gastrointestinal tract. Original magnification, 10. Mucosal defense The gastric mucosa is continually exposed to damage by exogenous agents such as food and oral flora and endogenous agents such as hydrochloric acid, proteolytic enzymes, and bile salts. Mucosal defenses include the surface mucus layer, bicarbonate secretion, tight junctional complexes, rapid mucosal repair, and ion exchangers in the surface cell membranes [5]. The mucus layer on the gastric surface is the first layer of defense against these noxious agents. The surface foveolar cells secrete mucus, a viscous glycoprotein that continually replaces the mucus that has been degraded. Mucus production is stimulated by gastrin, histamine, and acetylcholine. Mucus secretion is stimulated by local prostaglandins. Bicarbonate is released into the mucus layer, creating a protective ph gradient. Bicarbonate is actively secreted by parietal cells at the base of the glands and transported to the epithelial surface by mucosal blood flow. Thus, bicarbonate secretion requires normal gastric blood flow. Damage to the surface epithelium is rapidly repaired. A mucoid cap composed of mucus, fibrin, and cellular debris forms a band-aid over damaged epithelium. The damaged cells are replaced from undifferentiated cells in the mucous neck region.

3 144 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 3. Neck region of oxyntic mucosa. The arrow indicates the junction of the surface neutral mucin-secreting cells and the underlying parietal and chief cells. This neck region houses the stem cells of the stomach and thus is the place where mitotic figures may be seen. Original magnification, 20. Tight junctional complexes between epithelial cells help prevent noxious agents from entering between epithelial junctions. Sodium hydrogen ion and chloride bicarbonate exchangers on the cell membrane help maintain intracellular ph. Gastritis and gastropathy from clinical and histologic perspectives Chemical and ischemic gastropathy Many different conditions result in acute mucosal ischemia and stress-induced acute hemorrhagic gastropathy [4, 6]. These conditions include cardiac dysfunction, shock, sepsis, acute brain injury, and burns. In patients with acute stress or ischemic gastropathy, erosions initially develop in the gastric fundus and spread distally [7]. True ulcers may develop, termed Curling ulcers, in burn patients, and Cushing ulcers in patients with brain trauma or increased intracranial pressure. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause acute and chronic gastric injury by direct toxic breakdown of the mucosal barrier and by inducing mucosal hypoxia [8]. NSAIDs inhibit prostaglandin synthesis, leading to diminished mucin secretion and diminished blood flow, resulting in decreased delivery of Fig. 4. Spot radiograph from a double-contrast upper gastrointestinal series demonstrates a line of transition (black arrows) from a smooth surface in the gastric antrum to areae gastricae in the gastric body. This corresponds to the line of transition between the antral-type and body-type mucosae. The transition zone is relatively high on the lesser curvature and distal on the greater curvature. Rugal folds (white arrow) are composed of mucosa and submucosa. bicarbonate to the mucus layer [7]. The end result consists of many areas of focal necrosis of surface epithelium, with a paucity of inflammation. Vascular dilatation and hemorrhage are found in the lamina propria. Given the relative lack of neutrophilic or chronic inflammatory infiltrates, the term gastropathy is favored by some researchers over the term gastritis (Table 1) [9]. Macroscopically, multiple petechial hemorrhages or erosions are found in the gastric antrum. Erosions are small (about 5 mm) areas of superficial epithelial necrosis, with discrete, raised edges. A mild neutrophilic infiltrate may be seen in the gastric foveolae and glandular lumina. An exudate of debris, proteinaceous fluid, neutrophils, and red blood cells may overlie the erosions [1]. With long-term NSAID exposure, the reparative response includes foveolar hyperplasia: the foveolae lengthen and become tortuous. Increased smooth muscle fibers are seen in the lamina propria. Reflux of bile salts and pancreatic enzymes into the stomach induces a chemical gastropathy similar to longterm NSAID exposure. Bile (alkaline) reflux gastropathy has been found in patients with malfunctioning pyloric sphincters or abnormal duodenal motility and after gastroduodenostomy and gastrojejunostomy (Billroth I and II procedures). The foveolae are hyperplastic, some with a villiform cytoarchitecture. The glands are tortuous and elongated (Fig. 5). Inflammation is minimal. Other forms of gastropathy include damage by alcohol, chemotherapeutic agents, cocaine use, uremia, and

4 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 145 Table 1. Simplified classification of gastritis and gastropathy Infectious Bacterial Helicobacter pylori gastritis a Mycobacteria Syphilis Viral Parasitic Fungal Chemical gastropathy Nonsteroidal anti-inflammatory drugs a Bile reflux Alcohol a Atrophic gastritis Autoimmune Environmental a Stress. hypovolemia a Other Crohn disease Sarcoidosis Isolated granulomatous gastritis Lymphocytic Menetrier disease Zollinger-Ellison syndrome a These entries indicate a common form Fig. 6. Helicobacter pylori (arrow). This spiral bacterium infects the surface of the stomach, predominantly in the antrum. Helicobacter pylori is not invasive but incites cellular damage, in part by the generation of cytotoxins such as Cag A. Thiazine; original magnification, 100. endarteritis, and fibrosis. True ulceration may appear within 1 to 2 months of radiation or months to years after the stomach is included in the radiation portal. Fig. 5. Chemical gastropathy. The antral gastric mucosa in response to chemical injuries such as those due to bile and NSAIDS becomes highly reactive and proliferative without much of an inflammatory response. The antral glands take on a typical cork screw contour. Original magnification, 20. radiation therapy. Ethanol directly damages epithelial cells and impairs mucus synthesis. Ethanol use may result in petechial hemorrhage and erosion formation. Cocaine use may cause intense vasoconstriction and focal ischemia, even perforation. Chronic uremia increases parietal cell mass and diminishes mucus production by surface mucus cells. Gastric irradiation causes acute mucosal necrosis. The long-term effects of gastric irradiation include variable amounts of mucosal atrophy, Helicobacter pylori gastritis Helicobacter pylori is a curved or spiral-shaped gramnegative bacterium (Fig. 6). It is a motile organism with sheathed flagella [9 11]. Helicobacter pylori colonizes the mucus adjacent to the surface and in the lumen of the gastric pits. It attaches to the membrane of surface foveolar cells and may also penetrate intercellular spaces [4]. Although H. pylori may be found throughout the stomach, it most frequently infects the gastric antrum [12]. Helicobacter pylori damages gastric epithelium in part by production of cytotoxins such as Cag A. Helicobacter pylori is the most common cause of gastritis in adults [13]. This organism is found in more than 50% of Americans older than 60 years [14]. Helicobacter pylori causes acute and chronic gastritis. In the acute form of H. pylori gastritis, patients experience acute epigastric pain, nausea, and vomiting. An intense neutrophilic infiltrate is seen near the gastric pits. The mucus neck cells proliferate to replace the dying surface foveolar cells. This acute form quickly evolves into a form of chronic gastritis. A lymphocytic and plasma cell infiltrate is seen primarily in the upper portion of the gastric mucosa. Neutrophils may be scattered in the foveolar epithelium and lamina propria (Fig. 7). The inflammatory infiltrate may also contain eosinophils, basophils, macrophages, and mast cells. Aggregates of lymphocytes and other lymphoid cells form lymph follicles (Fig. 8), a finding

5 146 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 7. Chronic active gastritis. In this image, neutrophils infiltrate the lamina propria and glands. The term activity refers to the influx of neutrophils into the lamina propria and/or glands. If neutrophils are the only inflammatory cells present, the term acute gastritis is used. If the neutrophils are accompanied by a chronic inflammatory component, the term chronic gastritis with activity is used. Helicobacter pylori is by far the most common cause of chronic gastritis with activity. Original magnification, 40. Fig. 8. Chronic gastritis and lymphoid aggregate. Chronic gastritis is a histologic diagnosis requiring the influx of lymphocytes and/or plasma cells into the lamina propria of the stomach. In addition, over time, lymphoid aggregates (arrows) may form. Original magnification, 10. rarely seen except in adult patients infected by H. pylori [15, 16]. Helicobacter pylori gastritis is found in approximately 80% of patients with gastric ulcers [17]. The role of H. pylori in causing ulceration is not established. Ulcers are found most frequently in areas of intestinal metaplasia (Fig. 9) and mucosal atrophy and in the transition zone between antral- and body-type mucosae. Helicobacter pylori is one of the causes of atrophic gastritis and is associated with development of gastric adenocarcinoma [18, 19]. Prolonged antigenic stimulation by H. pylori may predispose patients to the development of low-grade gastric MALT lymphoma (Fig. 10) [20, 21]. In MALT lymphomas associated with H. pylori, the malignant lymphocytes infiltrate the gastric glands and surround the reactive lymphoid follicles. Atrophic gastritis Metaplasia is the change of one epithelial type to another (Fig. 9). Atrophic gastritis is a nonspecific term, reflecting the loss of gastric glands, often associated with varying forms of metaplasia. Pyloric (or pseudopyloric) metaplasia refers to replacement of parietal and chief Fig. 9. Intestinal metaplasia. Metaplasia refers to the replacement of one cell type by another type. Intestinal metaplasia may develop in the stomach as a consequence of chronic injury. This image demonstrates numerous intestinaltype goblet cells that secrete acidic mucin. Importantly, H. pylori cannot infect this type of metaplastic mucosa. Original magnification, 20.

6 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 147 Fig. 11. Autoimmune gastritis. In autoimmune gastritis, antibodies and T cells are directed to destroy parietal cells. The lamina propria is expanded by chronic inflammatory cells. Glands lined by parietal cells may show severe distortion and cellular atypia (arrow). Original magnification, 40. Fig. 10. MALT lymphoma (MALToma). Extranodal marginal cell B-cell lymphoma (MALT lymphoma, MALToma) in the stomach is almost always associated with prior H. pylori infection. In this image, a lymphomatous infiltrate is present in the mucosa and submucosa. Grossly, MALT lymphomas are manifested as focal nodularity or mass- or plaque-like lesions. Original magnification, 5. cells in the gastric glands by mucus-secreting cells similar to those found in antral- or pyloric-type mucosa [1]. These metaplastic mucus cells arise from the mucus neck cells or stem cells in the damaged glands. Pyloric metaplasia first occurs near the transition zone between antral- and body-type mucosae. Intestinal metaplasia refers to replacement of the mucus cells of the foveolae or surface of the stomach or the cells of the glandular portions of body- or antral-type mucosa by intestinal epithelial cells (absorptive cells, goblet cells, and Paneth cells). Intestinal metaplasia also begins at the transition zone between antral- and bodytype mucosae, most frequently on the lesser curvature. Pancreatic-type metaplasia may also occur [1]. Nests and lobules of pancreatic-type cells may be found in the gastric glands and in the cardia. Atrophic gastritis has many causes but has been subdivided into an autoimmune and environmental or multifactorial basis. Autoimmune atrophic gastritis is an autosomal dominantly passed immune response directed at parietal cells (Fig. 11). This condition is most frequently seen in Scandinavia and Northern Europe. Glandular atrophy and inflammatory reaction are confined to body-type mucosa. Pyloric or intestinal metaplasia may be seen. The parietal cell loss results in hypochlorhydria and loss of intrinsic factor. This intrinsic factor loss results in inadequate B12 absorption, cobalamin deficiency, and megaloblastic anemia. Antibodies to parietal cells and intrinsic factor are found in the serum. Immune disorders such as Hashimoto thyroiditis, dermatitis herpetiformis, and vitiligo are associated with autoimmune atrophic gastritis. In patients with autoimmune atrophic gastris, hyperplasia of G cells in the gastric antrum is a response to diminished acid output. Overproduction of gastrin leads to hyperplasia of ECL cells in the gastric body. Hyperplasia of these endocrine cells results in microcarcinoid tumors (Fig. 12) and occasional transformation into macro-carcinoid tumors (Fig. 13). With intestinal metaplasia, there is also about a threefold risk of developing gastric adenocarcinoma [22]. Intestinal-type adenocarcinoma arises in areas of intestinal metaplasia in the gastric body. Many cases of multifactorial atrophic gastritis are due to chronic infection by H. pylori. Other possible causes of environmental atrophic gastritis include ingestion of salts or nitrates. It is not known whether infection by H. pylori alone causes atrophic gastritis or H. pylori infection renders the mucosa more vulnerable to the effects of environmental factors. This form of gastritis is seen most frequently in China and Japan and less frequently in Europe, the United States, and urban portions of South America. Environmental atrophic gastritis begins in antral-type mucosa near the transition zone with body-type mucosa. In late-stage disease, antral- and

7 148 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 13. Macro-carcinoid formation in autoimmune atrophic gastritis. There is decreased mucosal thickness with loss of parietal and chief cells. The arrow demonstrates a carcinoid tumor visible during endoscopy, and thus the term macrocarcinoid is applied. Original magnification, 10. Fig. 12. Micro-carcinoid formation in autoimmune atrophic gastritis. When loss of parietal cells and acid production occurs in autoimmune gastritis, hypergastrinemia ensues. The ECL cells of the oxyntic mucosa survive and may proliferate, creating micro-carcinoids (arrow). The term micro-carcinoid is used for endocrine cell proliferations seen only with microscopy. Original magnification, 40. body-type mucosae are involved, but the greatest changes are present in the antrum. The transition zone between antral- and body-type mucosae migrates proximally. There are patchy areas of chronic inflammation, glandular atrophy, and intestinal metaplasia. In contrast to autoimmune atrophic gastritis, there are no antibodies to parietal cells or intrinsic factor, hypochlorhydria is not severe, and serum gastrin levels are not elevated. Atrophy of the parietal cell mass may also be seen in patients who have had an antrectomy. With antrectomy, G cells are lost, leading to diminished gastrin secretion and loss of parietal cells and even occasional vitamin B12 deficiency. This form of gastritis is often associated with bile-reflux gastritis. Infectious gastritis other than H. pylori Infectious agents other than H. pylori can infect the stomach. Helicobacter heilmannii is a spirochete-like organism related to H. pylori [9]. This organism may be acquired from pets or domestic animals. M. tuberculosis causes ulcers and hypertrophic nodular lesions in the gastric antrum. Gastritis may be present in secondary and tertiary syphilis. This infection results in erosive antral gastritis, occasional ulceration, and thickened rugal folds. A massive plasma cell infiltrate involves the mucosa and submucosa. Vasculitis may be seen. Cytomegalovirus causes gastritis in debilitated or immunodeficient patients, in particular patients with transplants or acquired immunodeficient syndrome (AIDS). Intranuclear inclusions are seen in the epithelial cells of the glands, macrophages, and endothelial cells. Phlegmonous gastritis is a severe, acute inflammatory gastritis often associated with mucosal necrosis. This gastritis is seen in alcoholics, the elderly, and patients with pancreatitis or AIDS. A transmural neutrophilic infiltrate is present. Patchy mucosal necrosis and pneumatosis may be present. Bacteria such as Streptococci, Escherichia coli, staphylococci, and Haemophilus are causative organisms in phlegmonous gastritis [23]. Anisakis is the most common helminth to infect the stomach and is related to ingestion of Anisakis larvae contained in raw or undercooked fish [24]. This parasitic gastritis occurs most frequently in Japan and the Netherlands. The larvae penetrate gastric, small intestinal, or colonic mucosa, resulting in an intense inflammatory response, including neutrophils and eosinophils. Bowel wall perforation may occur. Eosinophilic gastritis Any segment of the gastrointestinal tract may be involved by eosinophilic gastroenteritis [25, 26]. The full spectrum of this disorder includes asthma, eczema, food sensitivity, peripheral blood eosinophilia, and elevated serum immunoglobulin E. An eosinophilic infiltrate may involve any layer of the gastrointestinal tract, including

8 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 149 the mucosa, muscularis propria, or subserosa. In the stomach, the antrum is usually involved. An intense eosinophilic infiltrate may involve the lamina propria and extend into superficial and pit epithelia. The diagnosis of eosinophilic gastritis must be made with caution because eosinophils may be a prominent component of the inflammatory response in H. pylori gastritis, parasitic infections, foreign body reactions, drug reactions, or Crohn disease [9]. Granulomatous gastritis A granulomatous reaction may be seen in many infectious forms of gastritis, including infections such as tuberculosis, syphilis, H. pylori, Whipple disease, histoplasmosis, South American blastomycosis, and anisakiasis. Granulomas are also found in the stomach of patients with sarcoidosis and Wegener granulomatosis. A granulomatous reaction to foreign material may also occur. Many patients with Crohn disease have histologic gastritis. An acute and chronic infiltrate with focal, noncaseating epithelioid granulomas may be found in the gastric antrum. Fig. 14. Lymphocytic gastritis. The lamina propria is diffusely infiltrated by small, benign lymphocytes. These lymphocytes also infiltrate the glands but do not destroy the mucosa. Lymphocytic gastritis, especially affecting the gastric antrum, is associated with gluten sensitive enteropathy (celiac disease). Original magnification, 10. Lymphocytic gastritis An intense T-cell lymphocytic infiltration of the surface and foveolar epithelia is an uncommon form of gastritis. This form of gastritis mimics the changes found in gluten-sensitive or gluten-resistant sprue. Some patients with gluten-sensitive sprue (celiac disease) have antral lymphocytic gastritis (Figs. 14, 15). Hyperplastic gastropathies: Menetrier disease and Zollinger-Ellison syndrome Hyperplasia, meaning increased cell number, is a term appropriate for Menetrier disease and Zollinger-Ellison syndrome. Hypertrophy is a less-specific term, meaning increased cellular or organ mass from any cause. Menetrier disease Massive hyperplasia of the foveolar mucus cells is seen in Menetrier disease (Fig. 16). The foveolae are tortuous, elongated, and occasionally cystic. The underlying glands may be secondarily atrophic. There is little edema or inflammatory reaction. Leakage of albumin into the gastric lumen results in hypoalbuminemia. Hypochlorhydria resulting from parietal cell atrophy results in mild elevation of serum gastrin. Pathologic diagnosis requires at minimum a full-thickness mucosal biopsy. Radiologists should be aware that there is frequent uncertainty in the diagnosis of Menetrier disease, even in published cases. Fig. 15. Lymphocytic gastritis. The lymphocytes invade but do not destroy the glands. This feature distinguishes this specific, rare type of gastritis from usual chronic gastritis, in which only the neutrophils involve the glands. The lack of gland destruction also distinguishes this entity from MALT lymphoma. Original magnification, 40.

9 150 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 17. Portal hypertensive gastropathy. The veins (arrows) become dilated and proliferate in response to portal hypertension. This vascular response occurs at the surface of the mucosa in the antrum and fundus. The lamina propria lacks inflammatory cells but may become somewhat fibrotic. Original magnification, 20. Fig. 16. Menetrier disease. Marked expansion of the foveolar surface compartment (F) by neutral mucin-secreting cells is seen. The oxyntic glands (G) now comprise less than 20% of the mucosal thickness. Zollinger-Ellison syndrome Zollinger-Ellison syndrome is a severe peptic diathesis related to parietal cell hyperplasia in the body and fundus of the stomach, most frequently due to a sporadic gastrin-secreting tumor. Most gastrinomas (>80%) are found in the gastrinoma triangle involving the second part of the duodenum and the head and body of the pancreas. Other sites of gastrinomas include the stomach, bones, ovaries, heart, and lymph nodes. Multiple tumors or metastases are found in 30% to 55% of patients [27]. About 25% of gastrinoma patients have multiple endocrine neoplasia syndrome I, an autosomal dominant disorder associated with tumors of the parathyroid glands (87%), pancreas (81%), and pituitary gland (65%) [28]. Hypercalcemia from a parathyroid adenoma stimulates gastrin release. About 20% of patients with multiple endocrine neoplasia syndrome I have gastric antral carcinoids. The markedly elevated serum gastrin stimulates gastric acid secretion by parietal cells and stimulates parietal cell growth. Ulcers are detected in the first part of the duodenum in 75% of patients. About 15% of patients have ulcers in the second to fourth portions of the duodenum, and about 10% have ulcers in the jejunum. Portal hypertensive gastropathy Chronic portal hypertension may cause areas of erythema, petechiae, or vascular ectasia in the mucosa of the stomach [29]. Histologically, subepithelial hemorrhages and edema are seen, with little inflammatory infiltrate. The veins in the mucosa dilate and proliferate (Fig. 17). These mucosal changes may result in acute or chronic gastrointestinal bleeding from the stomach, even in the absence of gastric varices. Gastritis from clinical and radiologic perspectives This part of our review focuses on the radiographic findings of gastritis that the radiologist encounters when performing an upper gastrointestinal series, in particular erosive gastritis, abnormal mucosal patterns, and thickened gastric folds. The radiographic findings of gastritis include erosions, abnormal areae gastricae, antral striae, mucosal nodularity, a hypertrophied antral pyloric fold, enlarged rugal folds, and absent mucosal folds [30 32]. Erosive gastritis An erosion is a focal area of mucosal destruction that does not extend through the muscularis mucosae into the

10 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 151 Fig. 18. Erosive gastritis due to aspirin. Spot radiograph of the gastric antrum from a double-contrast upper gastrointestinal series shows numerous punctate and linear barium collections, most surrounded by radiolucent halos (representative erosions are identified by solid arrows). The depth of one erosion is demonstrated when viewed in profile (open arrow). Fig. 19. Spot radiograph of the gastric antrum from a double-contrast upper gastrointestinal series demonstrates three linear erosions (arrows) lying on the crest of a scalloped fold. This was erosive gastritis due to aspirin use. submucosa. Radiographically, an erosion is a 1- to 5-mm punctate, linear, or stellate collection of barium, frequently surrounded by a radiolucent halo (Fig. 18) [33]. The collection represents barium filling a tiny crater or barium adhering to an area of focal necrosis. The halo represents a slightly elevated area of mucosal edema surrounding the erosion or an edematous area to which barium does not adhere. Because neither a radiologist nor an endoscopist can determine the location of the muscularis mucosae, the examiner arbitrarily relies on the size of the barium-filled niche to distinguish an erosion from a small ulcer. Erosions are often seen on the crests of gastric folds (Fig. 19) [34], particularly when the radiologist flows the barium across the mucosal surface of the dependent gastric wall. These folds are focally enlarged with a scalloped contour. Thus, when scalloped antral folds are detected, erosions are present but unfilled with barium or the erosions have healed, leaving mildly scalloped folds as the sequela of erosive gastritis. Incomplete erosions are punctate collections of barium that are not associated with radiolucent halos. It is very difficult to determine whether punctate dots or slits of barium are true erosions, barium trapped within areae gastricae, or small droplets of flocculated barium. Aspirin and other NSAIDs are by far the most common cause of gastric erosions. NSAIDs most frequently produce punctate erosions, often along the greater curvature of the distal gastric body and proximal gastric antrum. However, NSAIDs not infrequently produce linear or small, serpentine erosions (Fig. 18). In one study of patients with erosions and a history of NSAID use, linear erosions were seen in 40% of patients and punctate erosions in 60% [35]. Linear or serpentine erosions are virtually pathognomonic for NSAID-induced erosive gastritis [36]. Flattening and deformity of the greater curvature of the gastric antrum are also seen in patients with longstanding NSAID use, related to chronic scarring [37]. Because most cases of erosive gastritis are related to NSAID use, the radiologist must aggressively question the patient concerning medication ingestion, including over-the-counter medications for headaches, arthritis, and menstrual cramps. Many patients do not realize that they are taking a medication containing aspirin or pay little attention to ingestion of a small dose of NSAIDs. However, as few as two aspirin tablets can cause erosive gastritis within 24 h [38, 39]. At the same time, the significance of erosive gastritis is problematic because this

11 152 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 20. Aphthoid ulcers in Crohn disease. Spot radiograph of the gastric antrum from a double-contrast upper gastrointestinal series shows innumerable punctate collections of barium surrounded by radiolucent halos. form of gastritis correlates poorly with symptoms [38]. Further, gastrointestinal bleeding should not be attributed to gastric erosions until larger structural abnormalities have been excluded. Other causes of erosions include Crohn disease, alcohol ingestion, viral infections, iatrogenic injury, hemorrhagic gastritis, and H. pylori gastritis. Aphthoid ulcers are detected in about 20% of patients with Crohn disease on double-contrast barium studies (Fig. 20) [40, 41]. Severe scarring with luminal narrowing occurs in only about 4% of patients with Crohn disease involving the distal gastric antrum and duodenum [42]. Opportunistic infection by cytomegalovirus, particularly in patients with AIDs, may be manifested by erosive gastritis [43]. Erosions may also be seen with iatrogenic injuries such as nasogastric intubation or heater-probe coagulation [44]. Helicobacter pylori is an uncommon cause of erosions. In one study, only 5% of patients with biopsy-proven H. pylori had erosions detected on double-contrast examinations [35]. Erosions are much more frequently encountered in H. pylori negative patients. Abnormal surface patterns Areae gastricae Each form of columnar epithelium lining the stomach, small intestine, and colon is divided into tuft and groove Fig. 21. Areae gastricae. Spot radiograph of the gastric antrum from a double-contrast upper gastrointestinal series shows innumerable, 2- to 3-mm, sharply edged, polygonal radiolucencies outlined by barium in grooves between the tufts. The tufts do not have rounded contours. patterns. In the stomach, the tufts are termed the areae gastricae. Double contrast examinations demonstrate the areae gastricae pattern (Fig. 21) in about 60% to 70% of patients [45]. The areae gastricae are more likely to become visible with advancing patient age [46] and with a barium suspension of proper viscosity [45]. Visualization of prominent areae gastricae is relatively easy on doublecontrast studies; determination of whether this finding is abnormal is more problematic. It is difficult to measure the size of the areae gastricae or a difference in distribution. Normal areae gastricae in pigs measure 2 to 3 mm in the gastric antrum and 3 to 5 mm in the gastric body [47]. They have sharp, polygonal borders and are relatively flat [48]. Disruption of the normal areae gastricae pattern of the stomach is seen in about 33% of patients with H. pylori gastritis [35]. It is has been postulated that the areae gastricae are more visible in the elderly or patients with H. pylori gastritis because the mucus layer is thinner in these individuals, so barium more easily fills the grooves between mucosal tufts [46]. Thus, the tufts are more prominent, although not necessarily larger. There are conflicting data in the radiologic literature concerning assessment of the areae gastricae. Keto et al. found no correlation between the size of the areae gastricae and the presence or absence of superficial or

12 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 153 Fig. 22. Development of MALT lymphoma over a 7-year period. A Spot radiograph of midstomach from a double-contrast upper gastrointestinal series shows a prominent areae gastricae pattern. The tufts are polygonally shaped. B Spot radiograph from a doublecontrast upper gastrointestinal series performed 7 years later shows a focal area of enlarged (5 to 7 mm), rounded nodules (arrows). This proved to be a MALT lymphoma in a patient with H. pylori gastritis. atrophic gastritis [49]. In contrast, other investigators have found the areae gastricae to be enlarged in hypersecretory states or in the presence of duodenal ulcers [50, 51]. In patients with atrophic gastritis severe enough to cause pernicious anemia, Levine et al. found that many patients had small or absent areae gastricae in the region of body-type mucosa [52]. If there is focal disruption of the areae gastricae pattern and the areae gastricae lose their polygonal contours by becoming rounded and nodular, the radiologist should consider the possibility of MALT lymphoma (Fig. 22) [53, 54]. In summary, the presence of prominent areae gastricae, especially in the gastric antrum, suggests the possibility of H. pylori gastritis. Focal replacement of the sharply angulated areae gastricae by small three to five round or ovoid nodules, however, suggests the possibility of MALT lymphoma. Gastric striae Thin, barium-etched striations traversing the lumen of the gastric antrum are termed gastric striae (Fig. 23). These striations are seen when the antral lumen is diminished in caliber, in particular during gastric peristalsis. The striae are radiologically analogous to the thin transverse striations seen in the feline esophagus. Most patients with gastric striae have antral gastritis [55]. Lymphoid hyperplasia The development of lymph follicles in the stomach is virtually pathognomonic for H. pylori gastritis [16]. Lymphoid hyperplasia is detected histologically in 50% Fig. 23. Gastric striae. Spot radiograph from double-contrast upper gastrointestinal series shows numerous, thin, barium-filled lines perpendicular to the longitudinal axis of the gastric antrum. This patient had chronic superficial gastritis on biopsy. to 100% of patients with H. pylori gastritis [15, 56]. Therefore, when a radiologist or endoscopist detects lymphoid hyperplasia, H. pylori gastritis should be suspected [57, 58]. Unfortunately, a radiologist detects only the extreme cases of lymphoid hyperplasia of the stomach. Numerous, small (1 to 3 mm), uniform, round nodules carpet the mucosa and disrupt the areae gastricae pattern, most frequently in the gastric antrum or

13 154 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 24. Lymphoid hyperplasia in H. pylori gastritis. Spot radiograph of gastric antrum from double-contrast upper gastrointestinal series shows numerous, 1- to 2-mm, round, uniform radiolucent nodules. The barium-filled grooves between nodules are thicker than the grooves between areae gastricae. Some of the lymph follicles have central umbilications (representative umbilicated lymph follicles identified by arrows). Fig. 25. The rugal fold pattern. Spot radiograph from double-contrast upper gastrointestinal series shows that the rugal folds (arrow) are most prominent along the greater curvature. Slight undulation of a thin rugal fold is normal. The gastric antrum is devoid of rugal folds. antrum and distal gastric body (Fig. 24) [58, 59]. The lymph nodules may be umbilicated. These tiny, round, uniform lymphoid follicles must be distinguished from polygonal areae gastricae, from the nonuniform and slightly larger nodules of MALT lymphoma, and from the slightly larger aphthoid ulcers of Crohn disease. Abnormal gastric folds The folds of the stomach are composed of the mucosa, including muscularis mucosae, and a portion of the submucosa. The rugal folds of the stomach are located primarily in body-type mucosa (Fig. 25). The gastric antrum is usually devoid of folds, especially when distended. The rugal folds are relatively straight on the lesser curvature. The folds of the greater curvature of the gastric body and fundus are larger and more undulating, especially when the stomach is relatively collapsed. Rugal folds become straighter and thinner when the stomach is distended. Theoretically, rugal folds should disappear in a fully distended stomach. The presence of redundant mucosa in the rugal folds allows the stomach to distend to accommodate food, liquid, and swallowed gas. Hypertrophied antral pyloric fold A hypertrophied antral pyloric fold is a single, thickened fold seen radiographically on the lesser curvature of the Fig. 26. Hypertrophied antral pyloric fold. Spot radiograph from double-contrast upper gastrointestinal series demonstrates a smooth-surfaced submucosal appearing protrusion (arrows) into the lumen of the distal lesser curvature of the pre-pyloric gastric antrum. distal gastric antrum in about 2% of patients with antral gastritis (Fig. 26) [60, 61]. The fold has an average length of 2.5 cm, with a smooth or slightly lobulated contour, appearing on barium studies as a submucosal or plaquelike fold. The fold extends to the pylorus or, in some patients, through the pylorus into the base of the duodenal bulb. Most patients have associated findings of antral gastritis. It is not known whether a hypertrophied antral pyloric fold is specific for H. pylori or other form

14 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 155 of gastritis. In any case, this fold should not be confused with a small, polypoid, or plaque-like tumor in the distal gastric antrum. Enlarged rugal folds Rugal folds change size and shape with different degrees of luminal distention and can disappear when the stomach is fully distended. In a less than fully distended stomach, the rugal folds are thicker on the greater curvature. Therefore, there are no fixed radiographic criteria for enlarged folds because a normal fold size is extremely variable. Normal folds are thicker in the more proximal portions of the stomach, have a smooth contour in profile, and taper distally. Therefore, the following findings are more important than fold size for determination of abnormal rugal folds: nodular or scalloped folds; folds that are larger distally than proximally; folds that are larger on the lesser curvature than on the greater curvature, and focal enlargement of a fold or folds. The presence of any folds in a well-distended gastric antrum should also be considered a suspicious finding. By far the most common cause of enlarged rugal folds is H. pylori gastritis. Thickened folds are detected in the gastric antrum in about 90% of patients with this infection [35]. Fold enlargement can also involve the gastric body and fundus in some patients with H. pylori gastritis [62]. The fold enlargement in most patients with H. pylori gastritis is mild to moderate. However, with severe H. pylori gastritis, markedly thickened (>1 cm), lobulated folds may be detected in the gastric antrum, mimicking the polypoid folds of a gastric tumor (Fig. 27) [35]. The term hypertrophic gastritis should be eliminated because most cases of hypertrophic gastritis in the literature were published in an era before H. pylori gastritis was discovered. Patients with hypertrophic gastritis frequently had associated duodenal or gastric ulcers, now known to be strongly related to H. pylori infection. Enlarged rugal folds due to hyperplasia of the parietal cell mass or the foveolar cells should be relegated to more specific entities, Zollinger-Ellison syndrome or Menetrier disease, respectively. In Zollinger-Ellison syndrome, markedly thickened folds are found in the body and fundus of the stomach (Fig. 28), correlating with parietal cell hyperplasia in body-type mucosa. A large volume of fluid is seen in the gastric lumen related to parietal cell hypersecretion. Duodenal and proximal jejunal folds may be enlarged as a response to increased acid entering the proximal small bowel. About 75% of ulcers in Zollinger-Ellison syndrome are located in the stomach and duodenal bulb; only 25% are located in the postbulbar duodenum and proximal jejunum [63]. Radiographic clues to the diagnosis of Zollinger-Ellison syndrome in a patient with thickened rugal folds include the presence of postbulbar ulcers, multiple ulcers, and increased intraluminal fluid. Fig. 27. Large rugal folds in H. pylori gastritis. Spot radiograph from double-contrast upper gastrointestinal series shows large, lobulated folds throughout the gastric body (representative folds etched by barium are identified by white arrows; enlarged folds in the barium pool are identified by black arrows). Repeated biopsies showed only H. pylori gastritis. This type of fold enlargement on a barium study requires biopsy to exclude malignancy. Fig. 28. Zollinger-Ellison syndrome. Spot radiograph of the upper gastric body from a double-contrast upper gastrointestinal series shows thickened rugal folds. Poor barium coating is probably secondary to increased acid and fluid in the stomach. A representative enlarged fold is identified by arrows. The foveolar mucus cells are hyperplastic in Menetrier disease, so gastric folds should be enlarged in any portion of the stomach. For this reason, Menetrier dis-

15 156 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori Fig. 29. Menetrier disease. Spot radiograph of the gastric fundus and body from a double-contrast upper gastrointestinal series shows marked, diffuse fold enlargement resulting in diffuse narrowing of the stomach. The diagnosis of Menetrier disease was made by intraoperative full-thickness biopsy. ease is no longer thought to spare the gastric antrum [64]. The gastric folds are extremely large, lobulated, and mass-like on barium studies (Fig. 29) and computed tomography (CT). The folds of the gastric fundus and body may be mildly enlarged in patients with portal hypertension, termed portal hypertensive gastropathy [65]. This fold enlargement is distinctive from the smooth, round, submucosa-appearing nodules or serpentine gastric folds seen in patients with gastric fundal varices. In summary, the following points are important for considering enlarged, lobulated folds on barium studies or CT. When no previous gastric surgery has been performed, most mild to moderately thickened, lobulated folds are due to H. pylori gastritis. Whereas folds may be enlarged in NSAID-related gastritis, gastric erosions are usually detected on barium studies. However, markedly enlarged (>1 cm), thickened, lobulated folds cannot be ascribed only to H. pylori gastritis; lymphoma, adenocarcinoma, and various gastropathies should be considered. Menetrier disease and Zollinger-Ellison syndrome are uncommon. Clues for the diagnosis of Zollinger- Ellison syndrome include the presence of a large amount of intraluminal fluid, gastric fold enlargement confined to body-type mucosa, multiple ulcers, and thickened folds or ulcers in the postbulbar duodenum or proximal jejunum. Clinical clues for the diagnosis of Menetrier disease are hypoalbuminemia and hypochlorhydria. Fold enlargement in gastric lymphoma is often relatively focal and mass-like but may involve large portions of the stomach (Fig. 30). Local or diffuse lymphadenopathy may be detected on CT. Rarely, adenocarcinoma of the Fig. 30. Lymphoma. Spot radiograph of the gastric fundus from a double-contrast upper gastrointestinal series shows lobulated folds in the barium pool (white arrows) and en face (small black arrow). This type of distorted fold enlargement should not be attributed to gastritis. Biopsy diagnosis must be performed. A clue to the diagnosis is the presence of a large ulcer (large black arrow) protruding from the greater curvature. stomach may also be manifested as enlarged, lobulated folds that are difficult to distinguish from the enlarged folds of marked H. pylori gastritis if there is no luminal narrowing to indicate the infiltrating nature of the tumor. Gastric varices may appear as smooth, serpentine, lobulated, and, occasionally, mass-like folds confined to the cardia and gastric fundus (Fig. 31). Evidence of portal hypertension or isolated splenic vein occlusion or pancreatic disease should be present on CT. The folds in portal hypertensive gastropathy are only mildly enlarged and should be confused only with H. pylori gastritis. In summary, mild, relatively uniform fold enlargement is usually due to H. pylori gastritis. Marked, lobulated fold enlargement needs histologic investigation because it may be due to lymphoma, adenocarcinoma, or Menetrier disease. Polypoid antral folds Relatively smoothly surfaced, enlarged lobulated, polypoid -appearing folds may be seen in the gastric antrum in patients with H. pylori gastritis (Fig. 32) [35]. In some patients, the folds may be so lobulated that the findings are indistinguishable from those of an infiltrating carcinoma or lymphoma [35]. If there is any concern

16 S. E. Rubesin et al.: Gastritis from NSAIDS to H. pylori 157 Fig. 31. Gastric varices. Spot radiograph of the gastric fundus from a double-contrast upper gastrointestinal series demonstrates smooth-surface, large, undulating folds of relatively uniform thickness (arrows). Fig. 33. Atrophic gastritis complicated by adenocarcinoma. Spot radiograph of the upper stomach from a double-contrast upper gastrointestinal series does not demonstrate a normal rugal fold pattern. No rugal folds are seen. Barium etches a plaque-like mass (arrows) that disrupts the normal contour of the high lesser curvature. Because the rugal folds are composed of mucosa and submucosa, the rugal folds of the gastric body and fundus become thin and, in severe disease, are virtually absent. The end result is that the stomach is narrowed and devoid of rugal folds (Fig. 33). Thus, in about 80% of patients with pernicious anemia, the stomach is smoothly narrowed with a tubular contour (<8 cm in width at the level of the cardia), has thin or absent rugal folds, and small areae gastricae [52]. However, these findings are not specific for atrophic gastritis because they are also seen in about 10% of patients without this condition. Fig. 32. Polypoid antral gastritis. Spot radiograph of the gastric antrum from a double-contrast upper gastrointestinal series shows enlarged, smooth, lobulated folds (arrow). Biopsy demonstrated H. pylori gastritis. about the possibility of malignant tumor, endoscopic biopsy specimens should be obtained. Absent rugal folds In the autoimmune form of atrophic gastritis, loss of parietal cell mass leads to loss of body-type mucosa. Questions concerning the diagnosis of gastritis The endoscopic or radiologic diagnosis of gastritis is problematic. Neither radiology nor endoscopy without biopsy is particularly accurate for the diagnosis of gastritis [66]. In one study of antral gastritis, nearly 50% of patients with normal findings on biopsy had endoscopically diagnosed antral gastritis [35]. Conversely, in patients with biopsy-proven antral gastritis, endoscopy was also normal in nearly 50% of patients. Thus, there is poor correlation between the endoscopic findings and the histologic diagnosis of gastritis [66]. In contrast, findings of gastritis were present in on double-contrast studies in