In this chapter we use a combination of classifications of gastritis by four experts: Rubin,² Genta,⁴ Appelman,⁶ and Montgomery.⁷ The keystone of the mentioned classification is the fact that H. pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common causes of gastritis and reactive gastropathies (acute erosive gastritis), respectively. The chapter outline provides an etiology-based classification of gastritis and gastropathies.

CHRONIC GASTRITIS ⁷^–⁹

Most forms of chronic gastritis are clinically silent. Their importance relates to the fact that these gastritides are risk factors for other conditions such as peptic ulcer disease, gastric polyps, and benign and malignant gastric neoplasms.^8,⁹ Three types of chronic gastritis are recognized (Figs. 51-2 and 51-3).

Figure 51-2. Topographic patterns of chronic, nonspecific gastritis. The darkest areas in the schematics of autoimmune metaplastic atrophic gastritis and environmental metaplastic atrophic gastritis represent areas of focal atrophy and intestinal metaplasia.

Figure 51-3. Chronic nonspecific gastritides. A and B, Normal mucosal biopsy from the gastric body/fundus and antrum, respectively. C, Diffuse antral gastritis. The glands show an infiltrate of neutrophils, in addition to an increase in inflammatory cells in the lamina propria. This lesion is typically associated with Helicobacter pylori infection. D, Multifocal atrophic gastritis with intestinal metaplasia. Note several glands lined by goblet cells (arrow). The biopsy specimen is from the gastric body, and similar changes were present in the antrum. E, Diffuse corporal atrophic gastritis in a man with pernicious anemia. The gland in the lower left is lined by goblet cells. Nests of enterochromaffin-like cells are also visible (arrows).

Biopsies from the antrum and the incisura are useful for diagnosing H. pylori infection with its diffuse antral-predominant gastritis. However, biopsies from the gastric body mucosa may be more diagnostic for H. pylori infection in some patients treated with proton pump inhibitors. Environmental metaplastic atrophic gastritis (also called multifocal atrophic gastritis, or MAG) is patchy and involves the antrum and body mucosa and sometimes, but not always, is associated with H. pylori infection.⁷ The diagnosis of autoimmune metaplastic atrophic gastritis, also called diffuse corporal atrophic gastritis (DCAG) and type A gastritis, can be confirmed with multiple biopsies from the gastric body that show atrophy and biopsies from the antrum that do not show atrophy. In most cases biopsies are obtained at the time of endoscopy.

HELICOBACTER PYLORI GASTRITIS ^2,^6,^7,¹⁰^–¹⁹

H. pylori gastritis (HPG) is caused by infection of the antral mucosa with H. pylori.^2,^6,⁷ In the United States H. pylori gastritis is seen mainly in low socioeconomic and immigrant populations,⁷ and there is no increased risk of gastric cancer. Most patients with HPG are asymptomatic. In most cases the antrum appears normal to the endoscopist; some patients with active disease in the antrum may demonstrate red streaks. Radiographic differences between antral gastritis due to H. pylori and not due to H. pylori have been described; thickened gastric folds, especially in a polypoid configuration, and enlarged areae gastricae favor H. pylori as the cause, whereas antral erosions favor causes other than H. pylori.¹⁰

Histologically, a diffuse, chronic inflammatory infiltrate which includes numerous lymphocytes and plasma cells expands the lamina propria and epithelium (see Fig 51-3).⁷ The presence of acute inflammatory cells is best designated an active gastritis and not acute gastritis. Additional microscopic changes include injury to the surface and foveolar epithelium with loss of apical mucin and reactive nuclear changes and erosions.^6,¹¹ Lymphoid follicles with germinal centers are characteristic of an infection with H. pylori.^3,¹² H. pylori organisms lie in the superficial mucous layer along the mucosal surface and within the gastric pits. Although the organisms can be seen in routine hematoxylin and eosin–stained tissue when numerous organisms are present, special stains are useful when few organisms are present. Stains that may be used to highlight the organisms are Giemsa stain, Warthin-Starry silver stain, Gram stain, and immunocytochemical stains.¹³^–¹⁵ Helicobacter heilmannii spiral bacteria are a less frequent cause of active gastritis.¹⁶^–¹⁸ The organisms originally known as Gastrospirillum hominis are longer than H. pylori and have multiple spirals.^16,¹⁷ A topographic study of H. pylori density and distribution and the comparison of biopsy sites for the histopathologic diagnosis of H. pylori conclude that two antral biopsy specimens, one from the lesser and one from the greater curvature, have close to 100% sensitivity for detecting H. pylori infection (see Fig. 51-1).¹⁹ Biopsy specimens from the corpus increase the diagnostic yield if extensive intestinal metaplasia is present in the antrum.¹⁹

ENVIRONMENTAL METAPLASTIC ATROPHIC GASTRITIS ^4,^7,²⁰^–³²

Environmental metaplastic atrophic gastritis (EMAG), also called mutifocal atrophic gastritis (MAG), is characterized by the involvement of the antrum and body with mucosal atrophy and intestinal metaplasia.^4,^7,²⁰^–²² Atrophic gastritis involving the body may be associated with pseudopyloric metaplasia, in which the mucosa resembles antral mucosa but stains for pepsinogen I (PGI), a proenzyme expressed in body mucosa.²³ Gastroscopy may show a pale mucosa, shiny surface, and prominent submucosal vessels,²⁴ and magnifying endoscopy is much more sensitive in detecting atrophy.²⁵ The pathogenesis of EMAG is multifactorial. H. pylori plays an important role and has been identified in about 85% of patients with EMAG. EMAG can occur early in life in H. pylori–infected individuals living in developing countries.²³ Genetic and environmental factors, especially diet, are also important. Certain population groups are predisposed to EMAG including African Americans, Scandinavians, Asians, Hispanics, Central and South Americans, Japanese, and Chinese.

In patients with EMAG, intestinal metaplasia is a risk factor for dysplasia and gastric cancer, usually the intestinal type (see Chapter 54).^2,^4,^7,^22,²⁶^–³¹ Inflammation in EMAG destroys gastric epithelial cells, and eventually the atrophic glands are replaced by metaplastic epithelium.^4,^7,²² In some cases, especially in patients living in the Pacific basin, metaplastic gastric cells are ciliated, probably due to environmental factors that are more prominent in the Pacific than the Atlantic Ocean basins.³² Because criteria for gastric atrophy among pathologists are debated, intestinal metaplasia is the most reliable marker of atrophy. Intestinal metaplasia of the gastric mucosa can be classified into three types as described in Chapter 54, where their possible associations with the intestinal type of gastric cancer are discussed.

AUTOIMMUNE METAPLASTIC ATROPHIC GASTRITIS ^6,^7,³³^–⁵⁵

Autoimmune metaplastic atrophic gastritis (AMAG), also called diffuse corporal atrophic gastritis (DCAG), is an autoimmune destruction of body/fundic glands. AMAG is relatively uncommon, accounting for less than 5% of all cases of chronic gastritis. Endoscopic features of AMAG include effacement of the gastric folds and a thin body/fundic mucosa. AMAG is the pathologic process in patients with pernicious anemia, an autoimmune disorder usually occurring in patients of northern European or Scandinavian background.³³ Patients with AMAG exhibit achlorhydria or hypochlorhydria, hypergastrinemia secondary to low or absent gastric acid with antral G-cell hyperplasia, and low serum PGI concentrations, and they often have circulating antibodies to parietal cell antigens and to intrinsic factor.^6,^7,³³ Incomplete (colonic) intestinal metaplasia (type III) may occur in AMAG and be a risk factor for gastric carcinoma in areas of the world that experience a higher incidence of gastric carcinoma than in the United States.³⁴ Metaplastic intestinal Paneth cells in AMAG appear to secrete an antibacterial peptide of the alpha-defensin family, human defensin 5 (HD-5), a peptide not produced in the normal stomach.³⁵ HD-5 could help the atrophic stomach against invasion by indigenous bacterial flora that overgrow in the anacidic stomach (see Chapter 49). Metaplastic pancreatic acinar cells are also a feature of autoimmune gastritis.³⁶

Atrophic glands with extensive intestinal metaplasia are confined to the body/fundic mucosa. Early in the course of this disease, atrophy may be focal and the preserved islands of relatively normal oxyntic mucosa may appear polypoid endoscopically or radiologically.³⁷ Rarely, AMAG progresses to diffuse (complete) atrophy. Hypergastrinemia, a consequence of achlorhydria, is associated with an increase in enterochromaffin-like cell hyperplasia and gastric carcinoid tumors. Cases of gastric carcinoids and simultaneous gastric cancer have been described.³⁸ Gastric carcinoid tumors are discussed further in Chapters 31 and 54.

In one study from Italy, half of 150 patients with AMAG had antibodies to H. pylori and another 25% had H. pylori in their oxyntic mucosa in addition to having antibodies against H. pylori.³⁹ Thus, H. pylori could have contributed to three quarters of the cases of AMAG. Recent studies suggest a role for H. pylori in the early pathogenesis of autoimmune gastritis; evidence of infection early in the course of the disease in individuals with parietal cell antibodies is frequent.⁴⁰ If gastric atrophy and achlorhydria develop, the incidence of H. pylori infection then decreases. Among 267 H. pylori–infected patients with dyspepsia, 65 had AMAG. Compared with the 202 patients without AMAG, the atrophics were older, more likely to have antibodies against cagA and vacA, more likely to consume alcohol and coffee, more likely to be taking sedative medicines, and less likely to have anxiety.⁴¹ Whether H. pylori results in AMAG thus appears to depend on length of infection, as well as bacterial, dietary, and emotional factors.

With regard to bacterial factors promoting atrophy, it appears that cagA+/vacA+ H. pylori are more likely to cause AMAG. These H. pylori are often the s1m1 vacA subtype that also express Lewis blood group antigens X and Y.⁴² Lewis antigens may help camouflage H. pylori because these antigens are also present on human gastric epithelial cells. It has been suggested that when antibodies to Lewis antigens from H. pylori develop, they cross-react with antigens on epithelial cells such as the H⁺,K⁺-ATPase on parietal cells, resulting in autoimmune chronic gastritis.⁴³ Based on uncontrolled studies from Tokyo,⁴⁴ eradication of H. pylori often leads to a decrease in the amount of gastric atrophy and intestinal metaplasia, whereas failed eradication attempts accomplish neither of these endpoints.

Antibodies to parietal cell antigens, most notably the proton pump (H⁺,K⁺-ATPase) are frequently present in autoimmune gastritis.⁴⁵ These antibodies are frequently detected in patients with various autoimmune diseases including type 1 diabetes mellitus⁴⁶ and thyroid diseases (Graves’, Hashimoto’s), explaining the association of these conditions with pernicious anemia. The risk of AMAG is increased three- to five-fold in type 1 diabetic individuals, and some authors have suggested screening type 1 diabetics with gastroscopy and mucosal biopsy.⁴⁷ One in eight patients with chronic hepatitis C treated with interferon-α develops antibodies to parietal cells and to thyroid tissue, and these antibodies recede after therapy is stopped⁴⁸; the clinical significance of these findings in the stomach is yet to be elucidated.

A proportion of the CD4⁺ lymphocytes present in the chronic inflammatory infiltrate within the gastric mucosa proliferate in response to H⁺,K⁺-ATPase, and most CD4⁺ cells secrete Th1 cytokines such as tumor necrosis factor-α (TNF-α); provide help for B cell immunoglobulin production; and enhance perforin-mediated cytotoxicity, as well as Fas ligand–mediated apoptosis.⁴⁵ These factors in combination may contribute to gland destruction in autoimmune gastritis. An interesting animal model of autoimmune gastritis has been developed in mice in which CD4⁺ T cells target the β subunit of the H⁺,K⁺-ATPase.⁴⁹

The risk of gastric adenocarcinoma in patients with AMAG is unclear. One recent study suggested a cancer risk of slightly more than 1% per year,⁵⁰ which would favor periodic endoscopic screening for individuals known to have AMAG. However, other investigators have found cancer much less often and have questioned the cost-effectiveness of cancer screening by endoscopy in AMAG.^51,⁵² The importance of incomplete intestinal metaplasia (type III) as a predictor of gastric cancer also has been questioned.⁵³ Thus, at what intervals AMAG patients should be screened, if at all, remains a matter of debate.⁵⁴

Molecular events involved in the sequence from AMAG to intestinal metaplasia are beginning to be clarified. For example, the expression of the intestinal transcription factor CDX2 precedes expression of other intestinal-specific genes such as CDX1, alkaline phosphatase, MUC2, HD-5, and sucrase-isomaltase ⁵⁵ and thus may be an early trigger of the metaplastic process that precedes dysplasia and carcinogenesis.

CARDITIS ^56,⁵⁷

There has been recent attention to inflammation of the small rim of cardiac glands at the proximal portion of the stomach.⁵⁶ The pathogenesis of carditis is currently controversial.⁵⁷ Inflammation of this gland area has been attributed to H. pylori gastritis, EMAG, AMAG, gastroesophageal reflux disease, and other factors. Likewise, atrophy in this area, often accompanied by intestinal metaplasia, has been proposed to be a precursor of adenocarcinoma of the gastroesophageal junction (see Chapters 42 and 44). Der and associates⁵⁶ reported on 141 patients in whom the cardiac mucosa could be identified in endoscopic biopsies. In this endoscopy population, all biopsies exhibited acute and/or chronic carditis. Nearly 80% of them had no evidence of H. pylori infection on simultaneous biopsies from the gastric body and antrum. H. pylori was present in 20 patients, 17 of whom had pan-gastritis and 15 of whom had H. pylori carditis. The severity of chronic carditis was related directly to 24-hour acid exposure of the lower esophagus, whereas acute carditis was related to H. pylori infection.

INFECTIOUS GASTRITIDES ⁵⁸^–¹²³

VIRUSES

Cytomegalovirus⁶⁰^–⁶⁴

Cytomegalovirus (CMV) is a human herpesvirus that may affect the esophagus, stomach, small bowel, colon, rectum, anus, liver, and gallbladder. CMV infection may occur in an immunocompetent patient.⁵⁷ However, gastrointestinal CMV infection usually occurs in the immunocompromised patient. Eosinophilic gastroenteritis with cytomeglovirus infection has been reported in an immunocompetent child.⁶² Patients with malignant disease, immunosuppression (especially due to steroid therapy), transplants, and acquired immunodeficiency syndrome (AIDS) may experience life-threatening CMV infections.

Patients with CMV infection of the stomach may experience epigastric pain, fever, and atypical lymphocytosis. Upper gastrointestinal tract radiographic studies may reveal a rigid and narrowed gastric antrum suggestive of an infiltrating antral neoplasm. Endoscopic studies may reveal a congested and edematous mucosa of the gastric antrum, covered with multiple ulcerations, suggestive of gastric malignancy, submucosal antral mass, or gastric ulcer (Fig. 51-4). A hypertrophic and/or polypoid type of gastritis resembling Ménétrier’s disease with a similar type of protein-losing gastropathy has been described.^58,⁵⁹

Figure 51-4. Cytomegalovirus (CMV) gastritis. A, Low-power histopathology of CMV gastritis. An acute inflammatory infiltrate is present in the lamina propria. Glandular destruction and reactive glands are present. Cystic glands are also evident. B, High-power view of the cystic area deep in the mucosa shown in A. Several cytomegalic cells with the typical intranuclear and intracytoplasmic inclusions of cytomegalovirus are present.

Examination of biopsy specimens shows inflammatory debris, chronic active gastritis, and enlarged cells with CMV inclusion bodies indicative of an active infection (see Fig. 51-4). “Owl-eye” intranuclear inclusions are the hallmark of CMV infection in routine hematoxylin and eosin histologic preparations and may be found in vascular endothelial cells, mucosal epithelial cells, and connective tissue stromal cells. Multiple, granular, basophilic, cytoplasmic inclusions may also be present. Usual treatment with intravenous ganciclovir or foscarnet is of uncertain value (see Chapter 33).

Other Herpesviruses ⁶⁵^–⁷⁰

Gastric involvement with herpes simplex and varicella-zoster virus is rare. Infected individuals experience the infection at an early age, and the virus remains dormant until reactivation. Activation has been related to radiation therapy, chemotherapy, lymphoma, and cancer. The typical immunocompromised patient may experience nausea, vomiting, fever, chills, fatigue, cough, and weight loss. An acute abdomen caused by varicella-zoster virus–induced gastritis after autologous peripheral blood stem cell transplantation in a patient with non-Hodgkin’s lymphoma has been reported.⁶⁷ Barium-air double-contrast radiographs show a cobblestone pattern, shallow ulcerations with a ragged contour, and an interlacing network of crevices filled with barium that corresponds to areas of ulceration. Upper gastrointestinal endoscopy reveals multiple, small, raised, ulcerated plaques or linear, superficial ulcers in a crisscrossing pattern, giving the stomach a cobblestone appearance. Grossly, the ulcers are multiple, small, and of uniform size. Microscopically, cytologic smears and biopsy specimens show numerous single cells and clumps of cells, with ground-glass nuclei and eosinophilic intranuclear inclusion bodies surrounded by halos. Brush cytology and biopsies should be performed at the time of endoscopy. Brush cytology has the advantage of sampling a wider area of mucosa because biopsies may not be representative. Treatment with acyclovir is reasonable but of unproven value.

Human herpesvirus 7, a cause of roseola, is frequently present in the gastric mucosa but does not appear to cause gastritis.⁶⁸ Epstein-Barr virus (EBV) may cause an acute gastritis with lymphoid hyperplasia.⁶⁹ There is little evidence that EBV causes chronic gastritis.⁷⁰

Measles ⁷¹

Rare cases of morbilliform gastritis with giant cells of the Warthin-Finkeldey type have been described.⁷¹

Enterovirus ⁷²

Recently, it has been proposed that some patients with chronic fatigue syndrome are chronically infected with a noncytopathic, noncytolyic enterovirus that can be detected by immunostaining or by reverse transcriptase–polymerase chain reaction (PCR) techniques using gastric biopsy samples.⁷² Confirmatory studies are awaited.

BACTERIA

Helicobacter pylori (see earlier and Chapter 50)

Phlegmonous (Suppurative) and Emphysematous Gastritis ⁷³^–⁸²

Phlegmonous gastritis is a rare bacterial infection of the submucosa and muscularis propria of the stomach. Acute necrotizing gastritis (gangrene of the stomach) is a rare, often fatal disease that is now thought to be a variant of phlegmonous gastritis. It has been suggested that acute necrotizing gastritis begins as phlegmonous gastritis, producing primary necrosis and gangrene. Acute necrotizing gastritis and phlegmonous gastritis have been associated with a recent large intake of alcohol; upper respiratory tract infection; AIDS and other immunocompromised states; and an infected peritoneojugular venous shunt. Fulminant and fatal gas gangrene of the stomach in a healthy, live liver donor has been reported.⁷⁶ Patients typically present with acute upper abdominal pain, peritonitis, purulent ascitic fluid, fever, and hypotension. Preoperative diagnosis is possible with plain film, ultrasonography, or computed tomography (CT), and gastroscopy with or without biopsy and culture of gastric contents may establish the diagnosis. Grossly, the stomach wall appears thick and edematous with multiple perforations, and the mucosa may demonstrate a granular, green-black exudate. Microscopically, the edematous submucosa reveals an intense polymorphonuclear infiltrate and numerous gram-positive and gram-negative organisms, as well as vascular thrombosis. The mucosa may demonstrate extensive areas of necrosis.

The mortality rate of phlegmonous gastritis is close to 70%, probably because it is so often misdiagnosed and because treatment is initiated too late. The definitive treatment is resection or drainage of the stomach, combined initially with large doses of systemic broad-spectrum antibiotics directed against the most common organisms such as streptococci, Escherichia coli, enterobacters, other gram-negative bacilli, and Staphylococcus aureus.

Emphysematous gastritis is a variant of phlegmonous gastritis in which the infection in the gastric wall is due to gas-forming organisms such as Clostridium welchii. Emphysematous gastritis associated with invasive gastric mucormycosis has been reported.⁷⁷ Predisposing factors are gastroduodenal surgery, ingestion of corrosive materials, gastroenteritis, or gastrointestinal infarction. Radiographic studies (plain films, CT) show gas bubbles conforming to the contour of the stomach, often in the form of cystic gas pockets.⁸²

Mycobacteria ⁸³^–⁸⁵

Gastric infection with Mycobacterium tuberculosis is a rare entity that usually occurs in association with pulmonary tuberculosis. Patients typically present with abdominal pain, nausea and vomiting, gastrointestinal bleeding, fever, and weight loss. Gastric tuberculosis associated with anemia has been reported.⁸⁵ Gastric tuberculosis may be associated with gastric outlet obstruction or with bleeding from a tuberculous gastric ulcer. Radiographic studies reveal an enlarged stomach with narrowed, deformed antrum with prepyloric ulcerations. Upper endoscopy demonstrates ulcers, masses, or gastric outlet obstruction. Grossly, the stomach may demonstrate multiple small mucosal erosions, ulcers, an infiltrating mass (hypertrophic) form, a sclerosing inflammatory form, acute miliary dissemination, and pyloric obstruction either by extension from peripyloric nodes or by invasion from other neighboring organs. Biopsies show necrotizing granulomas with the presence of acid-fast bacilli, best demonstrated with Kinyoun acid-fast stain. Treatment is discussed in Chapter 107.

Although Mycobacterium avium complex (MAC) is a common opportunistic bacterial infection among patients with AIDS, the stomach is rarely involved. Gastric MAC may be associated with a chronic gastric ulcer refractory to conventional antiulcer therapy. Patients may present with fever, night sweats, anorexia, weight loss, diarrhea, abdominal pain, chylous ascites, severe gastrointestinal hemorrhage, or chronic gastric ulcer. Serial CT scans of the abdomen may show mesenteric lymphadenopathy. Endoscopy may show a chronic gastric ulcer, a coarsely granular duodenal mucosa, or fine white duodenal nodules. Microscopically, the gastric mucosa demonstrates numerous foamy histiocytes containing many acid-fast bacilli. Treatment of MAC is difficult and is discussed in Chapter 33.

FUNGI

Candidiasis ^97,⁹⁸

Fungal contamination of gastric ulcers with Candida species is not uncommon. Data from some studies suggest that fungal colonization in patients with gastric ulcers and chronic gastritis have little clinical significance, whereas others suggest that fungal infection aggravates and perpetuates gastric ulceration. Endoscopically, gastric ulcers associated with Candida albicans tend to be larger in diameter and are more often suspected to be malignant than typical gastric ulcers. Diffuse superficial erosions may be noted.

Fungal colonization of the gastrointestinal tract is frequent in patients with underlying malignancy and in immunocompromised patients who have been treated with antibiotics or glucocorticoids but may occur also in immunocompetent patients. Symptoms are nonspecific. Massive growth of yeast organisms in the gastric lumen (yeast bezoar) is a potential complication of gastric surgical procedures, usually for peptic ulcer disease. Candida infection of the stomach may occur in alcoholic patients who ingest corrosive chemicals such as concentrated sulfuric acid and thiocyanates. Radiologic studies show tiny aphthoid erosions, which represent the earliest detectable radiographic change in gastric candidiasis. Aphthoid ulcers progress to deep linear ulcers.

Grossly, the gastric mucosa demonstrates tiny aphthous erosions; widespread punctate, linear ulcerations; or gastric ulcers. Microscopically, the layer of necrotic fibrinoid debris demonstrates yeasts or pseudohyphae. The organisms can be seen in the hematoxylin and eosin stain; however, special stains such as periodic acid–Schiff-diastase stain or Gomori methenamine silver stain may be required. Treatment is usually not necessary, but if symptomatic candidiasis is suspected, fluconazole is reasonable but of unproven efficacy.

Histoplasmosis ⁹⁹^–¹⁰¹

Progressive disseminated histoplasmosis is rare, occurring most frequently in the very young or the older adult or in those with immunodeficiency. Although disseminated histoplasmosis can involve any portion of the gastrointestinal tract, gastric involvement is rare. Hypertrophic gastric folds or a mass that mimics a gastric carcinoma may be associated with gastric histoplasmosis or disseminated histoplasmosis has been reported.¹⁰⁰ Radiographic studies may demonstrate an annular infiltrating lesion of the stomach, and endoscopy may demonstrate enlarged and reddened gastric folds. Biopsy specimens show an intensive infiltration of macrophages containing Histoplasma capsulatum. Gastric histoplasmosis has also been associated with a fatal hemorrhage from a gastric ulcer. Treatment with intravenous amphotericin B is appropriate.

Phycomycosis ¹⁰²^–¹⁰⁴

Gastric phycomycosis (also called zygomycosis or mucormycosis) is a rare and highly lethal fungal infection. Phycomycosis usually affects the paranasal sinuses, central nervous system, or lungs and is rarely confined to the gastrointestinal tract. Risk factors include malnutrition, immunosuppression, antibiotic therapy, and acidosis, usually diabetic ketoacidosis. A nosocomial outbreak of gastric mucormycosis due to contamination of wooden tongue depressors by Rhizopus microspores has been reported. Most patients presented with upper gastrointestinal bleeding.¹⁰³ Gastric phycomycosis can be classified as invasive or noninvasive (colonization). The former is characterized by deep invasion of the stomach wall and by blood vessel involvement with the fungus. Abdominal pain is the most frequent presenting complaint. In the noninvasive type, the fungus colonizes the superficial mucosa without causing an inflammatory response.

Grossly, surgical specimens from affected patients reveal hemorrhagic necrosis involving the mucosa and gastric wall. Microscopically, nonseptate 10- to 20-µm hyphae branched at right angles are present in the tissue and they infiltrate into blood vessel walls. Treatment is resection of the affected necrotic portion of the stomach. Unfortunately, invasive gastric phycomycosis is almost always fatal.

Aspergillosis ¹⁰⁵^–¹⁰⁶

Acute aspergillus gastritis in a case of fatal aplastic anemia and a fatal case of pseudo-membranous gastritis due to this organism have been reported.

PARASITES (see also Chapters 109 and 110)

Cryptosporidiosis ¹⁰⁷^–¹¹⁰

Cryptosporidiosis may rarely involve the stomach. Gastric outlet obstruction and antral stricture due to cryptosporidiosis have been reported in patients with AIDS and diarrhea. A case of cryptosporidiosis-associated erosive gastritis in a patient with HIV infection also has been reported. Also, cryptosporidiosis associated with the immunocompromised state and small cell lung cancer has been reported.¹¹⁰

Strongyloidiasis ¹¹¹^–¹¹⁵

The stomach is rarely affected by Strongyloides stercoralis. However, the organisms may colonize the intact gastric mucosa and may be associated with a bleeding peptic ulcer. S. stercoralis hyperinfection has been associated with cimetidine therapy in an immunosuppressed patient and was diagnosed by endoscopic gastric biopsy. Diagnosis can be made by endoscopic biopsy, examination of stools, examination of duodenal aspirate, and examination of peripheral smear with elevated eosinophil count. A histologic diagnosis of strongyloidiasis must be taken into consideration when examining gastric and duodenal biopsies in immunocompromised patients.¹¹³ Disseminated strongyloidiasis can be rapidly fatal. Treatment is discussed in Chapter 110.

Anisakiasis ¹¹⁶^–¹²⁰

Invasive anisakiasis may occur after the ingestion of raw marine fish containing nematode larvae of the genus Anisakis. Hundreds of cases of anisakiasis have been diagnosed in Japan, and the number of reported cases in the United States has also increased. The parasite may migrate into the wall of the stomach, small intestine, or colon. Typically, patients present with sporadic epigastric pain or have no symptoms at all. Gastric perforation due to chronic gastric aniskiasis has been reported.¹²⁰ Misdiagnosis is common. Some patients may experience a mild peripheral eosinophilia. Endoscopy may show firm, yellowish submucosal masses with erosions.¹¹⁹ Radiographic studies may reveal notched-shadow defects suggestive of a gastric tumor.

Grossly, the stomach demonstrates multiple erosive foci with hemorrhage and small 5- to 10-mm gastric lesions in the stomach wall. Microscopically, sections of the stomach show a marked eosinophilic granulomatous inflammatory process with intramural abscesses and granulation tissue. The eosinophilic abscess may contain a small worm measuring 0.3 mm in diameter, which can be identified as the larval form. The diagnosis may be confirmed by a serodiagnostic test for human anisakiasis on the patient’s serum when the larvae may no longer be detectable by endoscopy.

Ascariasis ^121,¹²²

Although gastric ascariasis is rare, patients have experienced chronic, intermittent gastric outlet obstruction caused by roundworms (Ascaris lumbricoides) inhabiting the stomach. Gastric ascariasis has also been associated with upper gastrointestinal hemorrhage with endoscopic examination showing several Ascaris worms in the stomach and duodenum.

Hookworm ¹²³

Endoscopic discovery and capture of Necator americanus in the stomach has been reported.¹²³

GRANULOMATOUS GASTRITIDES

A variety of granulomatous diseases affect the stomach. Crohn’s disease is the most common (Fig. 51-6) and is discussed later and also in Chapter 111. The differential diagnosis of granulomatous gastritis also includes sarcoidosis, as well as rarer conditions such as xanthogranulomatous gastritis, foreign bodies,¹⁰⁵ lymphoma,¹⁰⁶ Whipple’s disease (see Chapter 106),¹⁰⁷ Langerhans cell histiocytosis (gastric eosinophilic granuloma),¹⁰⁸ granulomatous vasculitis¹⁰⁹ (Churg-Strauss syndrome), and chronic granulomatous disease of childhood.¹¹⁰ An isolated, idiopathic granulomatous gastritis also occurs.¹¹¹ Some of these latter cases may evolve to Crohn’s disease or sarcoidosis over time. Other cases of “idiopathic” granulomatous gastritis appear to be due to H. pylori infection and may resolve, albeit slowly, following appropriate antibiotic therapy.^112,¹¹³ Idiopathic granulomatous gastritis can be associated with gastric cancer.¹¹⁴

Figure 51-6. Histopathology of granulomatous gastritis in a patient with Crohn’s disease. A noncaseating granuloma is present within the lamina propria. (Hematoxylin and eosin, ×200.)

SARCOIDOSIS ¹²⁴^–¹³⁷

Gastrointestinal manifestations of sarcoidosis are uncommon (see Chapter 35). Sarcoidosis is a systemic disease, frequently involving the lungs, lymph nodes, skin, and eyes. Diagnosis of sarcoidosis of the stomach cannot be made with confidence in the absence of disease in other organs. The stomach (usually the antrum) is the most common part of the gastrointestinal tract affected in sarcoidosis, being involved in 10% of cases.¹³⁷

Affected patients, usually in the third to fifth decades of life, typically present with epigastric pain, nausea, vomiting, and weight loss. Occasionally they present with massive hemorrhage. Gastric sarcoidosis may cause pyloric outlet obstruction, achlorhydria, and pernicious anemia. Radiographically, gastric sarcoidosis may mimic the diffuse form of gastric carcinoma (“linitis plastica”) or Ménétrier’s disease.

Endoscopy may reveal a narrow distal half of the stomach with multiple prepyloric ulcers or erosions, atrophy, thick gastric folds with a diffuse cobblestone appearance, or normal mucosa associated with microscopic granulomas.

Surgical specimens of patients with gastric sarcoidosis show a thickened stomach wall with foci of erosions and ulcers. Microscopically, mucosal biopsies show multiple noncaseating granulomas. However, the presence of noncaseating granulomas in gastrointestinal tissue is a nonspecific finding and special stains should be performed to rule out infections, especially tuberculosis. In some cases it may be difficult to differentiate gastric sarcoidosis from gastric Crohn’s disease or from isolated, idiopathic granulomatous gastritis.

Glucocorticoid therapy is the cornerstone of treatment for gastric sarcoidosis. Subtotal gastric resection is reserved for patients with obstruction and severe hemorrhage.

XANTHOGRANULOMATOUS GASTRITIS ¹³⁸^–¹³⁹

Xanthogranulomatous gastritis is characterized by inflammation of the gastric wall by foamy histiocytes, inflammatory cells, multinucleated giant cells, and fibrosis. The destructive inflammatory process may extend into adjacent organs and simulate a neoplasm. Xanthogranulomatous gastritis has been associated with xanthogranulomatous cholecystitis. Xanthogranulomatous gastritis with pseudosarcomatous changes mimicking a neoplasm has been reported.¹³⁹

DISTINCTIVE GASTRITIDES

COLLAGENOUS GASTRITIS ¹⁴⁰^–¹⁴⁸

Subepithelial fibrosis has been reported in the colon (collagenous colitis), small bowel (collagenous sprue), and stomach (collagenous gastritis). Collagenous gastritis is a rare form of gastritis, and fewer than 20 cases have been reported in the literature. Collagenous gastritis may be associated with collagenous colitis, lymphocytic colitis, and celiac disease.

Patients may experience intermittent epigastric abdominal pain, hematemesis, hematochezia, anemia, diarrhea, hypotension, or weight loss. Collagenous gastritis in a Korean child who had been receiving treatment for refractory iron deficiency anemia has been reported.¹⁴⁴ Upper gastrointestinal barium radiography may demonstrate an abnormal mucosal surface with a mosaic-like pattern in the body of the stomach, corresponding to mucosal nodularity. Endoscopy may reveal multiple diffusely scattered, discrete submucosal hemorrhages; erosions; and nodularity of the body of the stomach along the greater curvature.

Biopsy specimens from the body and antrum of the stomach reveal a patchy, chronic, superficial gastritis, focal atrophy, and focal deposition of collagen in the subepithelial region of the lamina propria, which measures from 20 to 75 mm thick (Fig. 51-7). Tiny erosions of the surface epithelium are present, and the inflammatory infiltrate consists of mainly plasma cells, intraepithelial lymphocytes and eosinophils, together with marked hypertrophy of muscularis mucosae.¹⁴⁴ Little is known about the etiology, natural history, and proper treatment of this rare condition.

Figure 51-7. Histopathology of collagenous gastritis (top, Hematoxylin and eosin, ×200; bottom, Masson trichrome, ×400). The subepithelial thickening of the collagen band is apparent.

(From Wang HL, Shah AG, Yerian LM, et al. Collagenous gastritis: An unusual association with profound weight loss. Arch Pathol Lab Med 2004; 128:229.)

LYMPHOCYTIC GASTRITIS ¹⁴⁹^–¹⁵⁷

Lymphocytic gastritis is characterized by a dense lymphocytic infiltration of surface and pit gastric epithelium (Fig. 51-8A). Lymphocytic gastritis is related to an endoscopic form of gastropathy known as varioliform gastritis. Lymphocytic gastritis is also seen in H. pylori infection and in celiac disease. Recent findings provide compelling evidence that lymphocytic gastritis may occur as a manifestation of celiac disease, and thus the lymphocytic infiltration of celiac disease may affect gastric epithelial mucous cells. Lymphocytic gastritis in untreated celiac disease may be associated with functional changes such as increased permeability. Gastric biopsies from 10 of 22 patients with diarrhea or malabsorption and small bowel changes characteristic of celiac disease showed striking lymphocytic gastritis. Following institution of a gluten-free diet, lymphocytic gastritis resolves after approximately two years.

Figure 51-8. Histopathologic examples of two distinctive forms of gastritis: lymphocytic gastritis (A) and eosinophilic gastritis (B). A, High-power view of the antral mucosa shows numerous dark-staining mononuclear cells with striking intraepithelial lymphocytosis. B, Numerous eosinophils are noted within the lamina propria and within the walls and lumina of the gastric glands. The patient also had peripheral blood eosinophilia. (Hematoxylin and eosin.)

(Courtesy Pamela Jensen, MD, Dallas, Tex.)

Lymphocytic gastritis has also been attributed to an atypical host immune response to H. pylori. H. pylori eradication treatment in patients with lymphocytic gastritis causes significant improvement in the gastric intraepithelial lymphocytic infiltrate, corpus inflammation, and dyspeptic symptoms. H. pylori may be the cause of some cases of protein-losing hypertrophic lymphocytic gastritis. The disease may resolve clinically, endoscopically, and pathologically with therapeutic eradication of H. pylori in some patients. The relationship between lymphocytic gastritis and gastric lymphoid hyperplasia, which also is associated with H. pylori, is not yet clear.¹⁵⁴

Patients with gastric lymphoma have a significantly increased prevalence of lymphocytic gastritis due to H. pylori. Because intraepithelial lymphocytes are speculated to have a role in the regulation of normal mucosal inflammatory reaction, they may also participate in the pathogenesis of mucosal lymphoma. In a 10-year follow-up study of lymphocytic gastritis, the patients with lymphocytic gastritis also appeared to have a significant increase in the grade of intestinal metaplasia in the corpus mucosa. In another study, lymphocytic gastritis was more prevalent in patients with gastric adenocarcinoma (16 of 30 cases [12.3%]) than in unselected patients undergoing endoscopy (0.8% to 2.5%). Lymphocytic gastritis with anasarca and venous thrombosis at the confluence of the splenic and mesenteric veins has been reported.¹⁵³

Endoscopy in lymphocytic gastritis shows thick mucosal folds, nodularity, and aphthous erosion, historically known as varioliform gastritis. Gastric biopsies show expansion of the lamina propria by an infiltrate of plasma cells, lymphocytes, and rare neutrophils. These findings may be seen in the antral mucosa only, body mucosa only, or in antral as well as body mucosa. The surface and superficial pit epithelium shows a marked intraepithelial infiltrate with T lymphocytes, with flattening of the epithelium and loss of apical mucin secretion. Quantification of epithelial lymphocytes revealed 46.5 lymphocytes per 100 epithelial cells in lymphocytic gastritis, compared with 3.5 lymphocytes per 100 cells in normal controls and 5.1 lymphocytes per 100 cells in disease controls including patients with H. pylori gastritis. The immunohistochemistry profile of lymphocytic gastritis in celiac disease and H. pylori infection and the interplay between infection and inflammation has been reported. Only intraepithelial lymphocytes positive for CD3 and CD8 were increased significantly in celiac disease patients with or without H. pylori infection.¹⁵⁵

EOSINOPHILIC GASTRITIS ¹⁵⁸^–¹⁶⁴

Eosinophilic gastrointestinal disorders are characterized by marked tissue eosinophilia in the absence of known causes for eosinophilia or other gastrointestinal disorders. These disorders include eosinophilic esophagitis, eosinophilic gastritis, eosinophilic enteritis, and eosinophilic colitis. Eosinophilic gastroenteritis is a rare condition of unknown etiology characterized by peripheral eosinophilia, eosinophilic infiltration of the gastrointestinal tract, and gastrointestinal symptomatology. It is discussed in detail in Chapter 27. The gastric mucosa is frequently involved, and thus eosinophilic gastritis is one of the manifestations of eosinophilic gastroenteritis. Eosinophilic gastroenteritis is classified according to the layer of gastrointestinal tract involved (i.e., mucosal layer disease, muscle layer disease, and subserosal disease). Mucosal involvement may result in abdominal pain, nausea, vomiting, diarrhea, weight loss, anemia, protein-losing enteropathy, intestinal perforation, and iron deficiency anemia secondary to gastrointestinal blood loss. Patients with muscular layer disease generally have obstructive symptoms, and patients with subserosal eosinophilic infiltration develop eosinophilic ascites. Patients with gastric involvement frequently present with pyloric obstruction. Radiographic studies may demonstrate thickened mucosal folds, nodularity, or ulcerations. Endoscopy may reveal normal-appearing mucosa or hyperemic edematous mucosa with surface erosions or prominent gastric folds. Eosinophilic gastritis simulating gastric carcinoma has been reported.¹⁶¹

Gastric mucosal biopsies are critical to the diagnosis and show marked eosinophilic infiltration, eosinophilic pit abscesses, necrosis with numerous neutrophils, and epithelial regeneration (see Fig. 51-8B). Abnormal eosinophilic infiltration is defined as at least 20 eosinophils per high-power field either diffusely or multifocally. A full-thickness surgical biopsy is necessary for the diagnosis of muscle layer disease.

As discussed in Chapter 27, patients with disabling symptoms can be effectively treated with glucocorticoids (after other systemic disorders associated with peripheral eosinophilia have been excluded) or possibly with oral sodium cromoglycate. Surgical intervention may be required in patients with obstructive complications or refractory disease. Collagenous colitis associated with eosinophilic gastritis in a four-year-old girl has been reported.

MISCELLANEOUS FORMS OF GASTRITIS

GASTRITIS IN INFLAMMATORY BOWEL DISEASE (CROHN’S AND ULCERATIVE COLITIS)¹⁶⁵^–¹⁷⁷

Crohn’s disease is the most common disease associated with granulomatous gastritis.¹¹¹ Crohn’s disease involving the stomach is uncommon, however, and almost always occurs together with lower intestinal disease (see Chapter 111). Cases may be isolated to the stomach or the stomach and duodenum. The diagnosis of isolated Crohn’s disease of the stomach should be made with caution,¹⁶⁵ and close follow-up is indicated for the subsequent development of Crohn’s disease elsewhere in the gastrointestinal tract or of other granulomatous diseases such as sarcoidosis.

Symptoms are nonspecific and include nausea and vomiting, epigastric pain, anorexia, and weight loss. Radiologic studies show antral fold thickening, antral narrowing, shallow ulcers (aphthae), or deeper ulcers. Involvement of the stomach from adjacent ileal or colonic disease segments is best visualized by radiologic examination. Endoscopy allows better visualization of mucosal defects and is characterized by reddened mucosa, irregularly shaped ulcers, and erosions in a disrupted mucosal pattern. Nodular lesions occur and often reveal the presence of erosions on the top of nodules. An atypical cobblestone pattern may be associated with the nodules surrounded by fissure-like ulceration. In contrast with peptic ulcers, the ulcerations and erosions of Crohn’s disease are frequently serpiginous or longitudinal, rarely round or oval. Ulcerations or erosions associated with Crohn’s disease of the stomach typically are most commonly located in the antrum and the prepyloric region.

The microscopic features of surgical specimens of gastric Crohn’s disease can be, but are not always, similar to those in the ileum or colon (see Chapter 111). They include granulomas, transmural chronic inflammation, ulcers, and marked submucosal fibrosis (see Fig. 51-6). Granulomas may be present in endoscopically normal antral mucosa.

In the past few years it has been recognized that although Crohn’s patients may have granulomatous gastritis, H. pylori–associated gastritis (HAG) or focal active antral gastritis is even more common.¹⁶⁶^–¹⁷⁵ The majority of pediatric inflammatory bowel disease (IBD) patients (Crohn’s or ulcerative colitis [UC]) have HAG and/or focal active gastritis, although the latter is more prevalent in Crohn’s patients than in UC patients.¹⁷⁴ The focal active gastritis is not due to H. pylori and is accompanied by macrophages in the center of the focal lesion and mast cells at its periphery.¹⁶⁹ It is as yet unclear whether the type of gastritis identified in pediatric IBD patients can reliably distinguish Crohn’s colitis from UC (except for granulomatous gastritis, which favors Crohn’s)¹⁶⁸ and even less is certain in adult IBD patients.

Therapy of gastritis in Crohn’s disease should be driven by gastric symptoms and not solely by demonstration of gastritis on mucosal biopsy. Double-blinded, randomized, controlled clinical trials of pharmacologic agents are lacking in gastric and gastroduodenal Crohn’s disease. Proton pump inhibitors should be the first therapy for symptomatic patients.^176,¹⁷⁷ The effectiveness of glucocorticoids, immunosuppressive medications, and anti–TNF-α drugs such as infliximab has not been clearly demonstrated. Gastric outlet obstruction refractory to medical therapy can be treated by gastroenterostomy, ideally laparoscopically. Treatment of Crohn’s disease is discussed in more detail in Chapter 111.

GASTRITIS CYSTICA PROFUNDA ¹⁷⁸^–¹⁸²

Gastritis cystica profunda is a rare complication of partial gastrectomy with gastrojejunostomy for benign peptic ulcer disease and typically occurs at the site of the gastroenterostomy. Gastritis cystica profunda may also develop in the unoperated stomach, and chronic atrophic gastritis may be a risk factor for it. Radiography and endoscopy typically demonstrate multiple exophytic gastric masses that simulate a malignancy. Endoscopic ultrasound may assist in the diagnosis. Grossly, the gastric mucosal surface demonstrates multiple nodules and exophytic masses. On section, the gastric wall is thick and multiple cysts are present. Microscopically, the mucosa is characterized by foveolar hyperplasia, and cystic glands extend through a disrupted muscularis mucosae into the submucosa and, rarely, the muscularis propria (Fig. 51-9). Gastritis cystica profunda may be associated with gastric stump adenocarcinoma.

Figure 51-9. Gastritis cystica profunda. Note the cystic dilatation of numerous gastric glands that extend through the muscularis mucosae (arrow), simulating a gastric carcinoma.

Removal of this lesion by snare polypectomy after submucosal injection to elevate the lesion has been reported.¹⁷⁹ The disease may also coexist with gastric inverted hyperplastic polyp, and the latter may in fact be a variant of gastritis cystica profunda.¹⁸² Gastritis cystica profunda, if present, should lead to a thorough examination for a synchronous or metachronous gastric cancer, although exact recommendations for surveillance interval are not clear.

GASTRIC GRAFT-VERSUS-HOST DISEASE ¹⁸³^–¹⁸⁷ (see also Chapter 34)

Graft-versus-host disease (GVHD) may affect any portion of the gastrointestinal tract; therefore, upper as well as lower gastrointestinal tract biopsies may provide diagnostic information not evidenced in biopsy from a single site. GVHD most often occurs after allogeneic bone marrow transplantation and rarely after solid transplantation. GVHD occurs in an acute and chronic form. Acute GVHD occurs between post-transplant days 21 and 100, whereas chronic GVHD occurs after day 100. The gastrointestinal tract is commonly affected in acute GVHD, especially the small and large intestines, and to a lesser extent the stomach and esophagus. Gastric GVHD is characterized by nausea, vomiting, and upper abdominal pain without diarrhea. Stomach biopsies may be necessary to diagnose GVHD in patients with upper gastrointestinal symptoms but no diarrhea and normal rectal biopsy specimens. The basic pathologic lesion consists of necrosis of single cells (apoptotic bodies) in the crypts of the large and small intestinal mucosa and in the neck region of the gastric mucosa. The necrosis consists of an intraepithelial vacuole filled with karyorrhectic debris and fragments of cytoplasm.

ALLERGIC GASTRITIS ¹⁸⁸^–¹⁹⁰

Whether allergies to certain foods can lead to gastritis and whether the gastritis correlates with upper gastrointestinal symptoms are unclear (see Chapter 9). Children with food allergy as diagnosed by an open elimination challenge test have no higher incidence of gastritis than children without food allergy.¹⁸⁸ An exception may be infants who are allergic to cow’s milk protein, in whom hematemesis and endoscopic signs of gastritis are common.¹⁸⁹

REACTIVE GASTROPATHIES (ACUTE EROSIVE GASTRITIS)

The gastric mucosa may be damaged by a variety of agents or factors that do not produce a significant inflammatory infiltrate. Because of the paucity of inflammatory cells, the mentioned lesions are best referred to as reactive gastropathies, as opposed to acute erosive gastritis.

The gastric mucosa in patients who experience a reactive gastropathy demonstrates a spectrum of hemorrhages, erosions, and ulcers. Erosions and ulcers are frequently multiple, and the base of these lesions often stains dark brown owing to exposure to acid.

Grossly, most erosions and acute ulcers appear as well-defined hemorrhagic lesions 1 to 2 mm in diameter. If the insult is severe, the mucosa between the lesions is intensely hemorrhagic. Microscopically, an erosion demonstrates superficial lamina propria necrosis. An acute ulcer is an area of necrosis that extends to the muscularis mucosa. Foveolar hyperplasia, the reactive epithelial changes secondary to regeneration of the mucosa (Fig. 51-10), is often associated with glands with atypical nuclei that can be misdiagnosed as dysplasia or carcinoma. The diagnosis of neoplasia in a background of necrosis, cellular debris, and granulation tissue should be made with utmost caution. The biopsy procedure itself may induce tissue hemorrhage; thus, subepithelial hemorrhage should involve more than one fourth of a biopsy specimen to be considered significant.¹⁷

Figure 51-10. Histopathology of foveolar hyperplasia. The gastric pits show an elongated, corkscrew appearance.

MEDICATIONS AND TOXINS ¹⁹¹^–²⁰¹

Aspirin (even in low daily or less-than-daily doses) and NSAIDs (including cyclooxygenase [COX]-2 selective inhibitors) are the most common causes of reactive gastropathy (see Chapter 52). Oral iron therapy may rarely cause mild endoscopic abnormalities consisting of erythema, small areas of subepithelial hemorrhage, and erosions.¹⁹¹ Oral potassium chloride may also be associated with endoscopic erosions.¹⁹² Endoscopic petechiae, erosions, and erythema have been associated with long-term fluoride ingestion.¹⁹⁵ Bisphosphonates for osteoporosis or Paget’s disease can also cause gastric erosions, although their clinical significance is uncertain.^196,¹⁹⁷ These drugs exacerbate gastric damage from NSAIDs such as naproxen as well. Various intensive cancer chemotherapy drugs given to children with leukemia, lymphoma, or solid tumors are associated with a hemorrhagic or erosive gastropathy and histologic evidence of inflammation, but cause and effect have not been clearly established in these ill individuals.¹⁹⁸

Reactive gastric epithelial atypia and gastric ulceration may be associated with hepatic arterial infusion chemotherapy for metastatic disease to the liver.^199,²⁰⁰ The marked epithelial atypia that results may erroneously be interpreted as carcinoma and lead to unnecessary surgery.

Toxin ingestion of heavy metals such as mercury sulfate poisoning may cause an erosive or ulcerative gastropathy with hematemesis.²⁰¹ Corrosive gastric injuries are discussed in Chapter 25.

ALCOHOL ²⁰²^–²⁰⁹

After acute alcohol ingestion, subepithelial hemorrhages are seen frequently at endoscopy, typically without prominent mucosal inflammation on biopsy specimens (Fig. 51-11).²⁰² Gastric biopsy specimens obtained from patients with chronic alcoholism have shown a higher prevalence of chronic antral gastritis due to H. pylori, with almost complete normalization of histologic findings after treatment.^203,²⁰⁴

Figure 51-11. Histopathology of alcoholic gastropathy. Hemorrhage is confined to the superficial portion of the mucosa, and there is a paucity of inflammatory cells.

The combined effects of alcohol and the NSAID ibuprofen were associated with more gastric mucosal damage by endoscopic assessment than with either agent alone. The combination of alcohol and aspirin also caused more damage in the stomach than either agent alone, though not to a significant degree.²⁰⁵ Alcohol appeared to be an acute triggering factor in 35% of patients admitted to an intensive care unit for massive upper gastrointestinal bleeding in Sweden.²⁰⁶ Chronic alcohol ingestion was related to an increased risk of chronic atrophic gastritis and hypochlorhydria in a study from Poland.²⁰⁷ Recent alcohol ingestion was also found to be a risk factor for gastric erosions and ulcers in cirrhotic patients referred for upper endoscopy.²⁰⁸

Other alcohols, besides ethanol, can injure the stomach. Even the topical application of isopropyl alcohol (rubbing alcohol) used to cool a child with fever has resulted in hemorrhagic gastropathy with hematemesis.²⁰⁹

PORTAL HYPERTENSIVE GASTROPATHY ²¹⁰^–²¹⁴

As discussed in more detail in Chapters 19 and 90, gastric mucosal lesions are common in portal hypertension, occurring in up to 65% of cirrhotic patients, and represent an important cause of gastrointestinal blood loss.²¹⁰ Portal hypertensive gastropathy was found in 33% of children after surgery for biliary atresia. Risk factors for portal hypertensive gastropathy were frequent endoscopic treatment of gastroesophageal varices, liver dysfunction, and hypersplenism.²¹³ Biopsies show vascular ectasia and congestion in the mucosal layer without a significant degree of inflammatory infiltrate. Portal hypertensive gastropathy (PHG) is a risk factor not only for upper gastrointestinal bleeding but also for gastroduodenal erosions and ulcers in cirrhotic patients.²⁰⁸ It has been suggested that perturbations in the tissue levels of TNF-α, prostaglandins, endothelin, and nitric oxide/peroxynitrite participate in the vascular congestion and mucosal damage characteristic of PHG.²¹¹ As discussed in Chapter 90, lowering portal pressure pharmacologically or by creation of a portosystemic shunt effectively treats PHG and reduces bleeding.

Some patients with cirrhosis and portal hypertension have gastric antral vascular ectasia (GAVE), which can bleed and is sometimes difficult to distinguish from PHG involving the gastric antrum.²¹² GAVE does not respond as readily as PHG to measures that reduce portal pressure.²¹²

COCAINE ²¹⁵^–²¹⁷

Gastrointestinal hemorrhage due to diffuse exudative erosion throughout the gastric fundus, body, antrum, and duodenal bulb has been reported with crack cocaine use. Gastrointestinal hemorrhage or pyloric perforation due to cocaine is well described.²¹⁵^–²¹⁷

STRESS ²¹⁸

Erosions of the gastric mucosa may occur rapidly after major physical or thermal trauma, shock, sepsis, or head injury. These are often referred to as stress ulcers and are discussed in Chapters 52 and 53.

RADIATION ²¹⁸^–²¹⁹ (see also Chapter 39)

Radiation effects on the stomach depend on the cell kinetics of the gastric mucosa, as well as the dose of the radiation. The gastric mucosal response to radiation is unique, however, in that the most radiosensitive epithelial cells are the differentiated cells (parietal and chief cells) rather than the germinative cells in the mucous neck region. Radiation injury to the stomach can be classified into acute (less than six months) and chronic (more than one year) phases. It is thought that the tolerance level for radiation-induced gastric ulceration is approximately 4500 cGy. After a gastric dose of 5500 cGy or more, 50% of patients will develop clinical evidence of gastric ulcer formation.²¹⁸ Radiation-induced gastric ulcers are usually solitary, from 0.5 to 2 cm in diameter, and located in the antrum. Massive hemorrhagic gastropathy requiring endoscopically administered therapy to control the bleeding has been reported.²¹⁹

BILE REFLUX ²²⁰^–²³¹

Bile reflux into the stomach is common after partial gastrectomy with anastomosis to the duodenum (Billroth I) or jejunum (Billroth II) and after truncal vagotomy and pyloroplasty for peptic ulcer (see Chapter 53). It has even been reported after parietal cell vagotomy.²²⁰ Bile reflux gastropathy also may occur after cholecystectomy or sphincteroplasty, which allows the continuous exposure of bile to the duodenum with the potential for duodenogastric reflux. Occasionally, bile reflux gastropathy is observed in adult or pediatric patients who have not had surgery.^221,²²³ Interleukins, particularly IL-8 and perhaps IL-6, may participate in the gastric damage.^224,²²⁵ Bile reflux contributes to muscosal lesions in the stomach and may facilitate H. pylori colonization in the corpus region.²²²

Endoscopy shows swelling, redness, erosions, and bile staining of the gastric mucosa. Biopsy specimens show foveolar hyperplasia, dilated cystic glands, atypical glands that may be misdiagnosed as dysplasia or carcinoma, and a paucity of acute and chronic inflammatory cells. Gastric atrophy may result and increase the risk of carcinoma in the gastric stump (see Chapter 54). In fact, bile reflux into the unoperated stomach has been proposed to be a risk factor for intestinal metaplasia in the distal stomach, at the gastroesophageal junction (cardia), and in the distal esophagus (Barrett’s esophagus).²²⁶^–²²⁸ Unfortunately, bile-diverting procedures performed because of severe bile gastropathy do not reverse gastric atrophy or intestinal metaplasia.²²⁹ It may be worthwhile, at the time of the original gastric surgery for gastric cancer or peptic ulcer, to construct a 30-cm Roux-en-Y limb¹⁷⁶ or perform a 10- to 12-cm isoperistaltic jejunal interposition²³⁰ to prevent bile gastropathy and subsequent metaplastic changes.

In selected, previously unoperated patients with primary bile gastropathy, surgery using a Roux-en-Y choledochojejunostomy without gastric resection has been successful.²²¹ In unoperated patients with bile gastropathy following cholecystectomy, the proton pump inhibitor rabeprazole and sucralfate were equally effective in relieving symptoms and improving gastroscopic evidence of mucosal damage as compared with observation alone (no placebo was given).²³¹ At present, lacking definitive studies, medical therapy should precede surgical therapy for bile gastropathy occurring in the unoperated stomach such as it does spontaneously or after cholecystectomy or biliary sphincterotomy.

ISCHEMIA ²³²^–²³⁷

Chronic ischemic gastropathy may occur secondary to chronic mesenteric insufficiency and can be reversed after a revascularization operation.^191,¹⁹² Chronic ischemic gastropathy, as well as chronic ischemic gastric ulcers, may also occur in association with atheromatous embolization.^193,¹⁹⁴ Athletes involved in intense physical activity, especially long-distance running, may experience recurrent ischemic gastropathy and chronic gastrointestinal bleeding with anemia.^195,¹⁹⁶

PROLAPSE ²³⁸^–²³⁹

The mucosa of the gastric cardia may prolapse into the esophageal lumen during retching and vomiting.²³⁸ The resulting mechanical injury to the cardia has been proposed to be a cause of upper gastrointestinal hemorrhage, but this association has been questioned.²³⁹ Esophagoscopy may demonstrate the prolapsed gastric mucosa. The congested mucosa may show erosions and superficial ulcerations.

LINEAR EROSIONS IN A HIATAL HERNIA (CAMERON LESIONS)²⁴⁰^–²⁴¹

Linear gastric erosions in a hiatal hernia are discussed in Chapters 19, 24, and 52.

AGING GASTROPATHY ^242,²⁴³

Normal aging is associated with impaired gastric mucosal defense against injury in animals and humans.²⁴² Two proteins have been implicated in aging gastropathy: PTEN (phosphatase and tensin homolog deleted on chromosome 10), which is overexpressed with aging, and survivin, which is underexpressed.²⁴³

HYPERPLASTIC GASTROPATHIES ²⁴⁴^–²⁵¹

MÉNÉTRIER’S DISEASE AND HYPERPLASTIC, HYPERSECRETORY GASTROPATHY

Hyperplastic gastropathy is a rare condition characterized by giant gastric folds associated with epithelial hyperplasia. Two clinical syndromes have been identified: Ménétrier’s disease and a variant of it referred to as hyperplastic, hypersecretory gastropathy, and Zollinger-Ellison syndrome, which is discussed in Chapter 32. Figure 51-12A and B demonstrates enlarged gastric folds in these conditions.

Figure 51-12. Radiologic and histopathologic examples of hyperplastic gastropathy with giant gastric folds. A, Zollinger-Ellison syndrome (barium radiograph). B, Ménétrier’s disease (barium radiograph). C, Total gastrectomy specimen in a patient with Ménétrier’s disease (right: body, revealing hyperplastic mucosa and cerebriform rugal folds; left: antrum, with relative sparing). D, Histopathology of Ménétrier’s disease showing enlarged folds with foveolar hyperplasia, cystically dilated glands, and minimal gastritis.

Ménétrier’s disease is typically associated with protein-losing gastropathy (see Chapter 28) and with hypochlorhydria, whereas the hyperplastic, hypersecretory variant is associated with increased or normal acid secretion and parietal and chief cell hyperplasia, with or without excessive gastric protein loss.

Other more common conditions can also cause enlarged gastric folds or protein-losing gastropathy including gastric neoplasm (lymphoma, carcinoma), granulomatous gastritides, gastric varices, infectious gastritis (particularly H. pylori and CMV ⁵⁸), eosinophilic gastritis, and Zollinger-Ellison syndrome. The enlarged gastric folds in Ménétrier’s disease are due to foveolar cell hyperplasia, edema, and variable degrees of inflammation. Patients may present with weight loss, epigastric pain, vomiting, anorexia, dyspepsia, hematemesis, and positive fecal occult blood tests. Most patients with a clinical syndrome associated with hyperplastic gastritis showed histology typical for the syndrome; however, clinical-histologic concordance was not absolute.²⁴⁷ The mechanism responsible for the low gastric acid secretion is unclear, but it could be related to overexpression of transforming growth factor-α (TGF-α), a ligand for epidermal growth factor receptor (EGFR), a receptor tyrosine kinase.²⁴⁴ Although mucus hypersecretion is often seen in Ménétrier’s disease, abnormalities in mucins have not been consistent in a few cases that have been examined.^245,²⁴⁶

Ménétrier’s disease may be associated with hypertrophic lymphocytic gastritis and a carcinoid-like syndrome due to increased gastric mucosal production of prostaglandin E₂ concentrations. Ménétrier’s disease may be self-limited and may completely resolve in patients younger than 10 years of age and when it occurs in the postpartum period. The cause of Ménétrier’s disease of childhood may be infection with CMV and activation of TGF-α. The risk of developing carcinoma in association with Ménétrier’s disease is an open question, and some authors question whether there is a significant risk. Of the 200 cases of Ménétrier’s disease reported in the literature, 30 (15%) have been associated with carcinoma.

The mucosa of patients with Ménétrier’s disease demonstrates irregular hypertrophic folds that involve the entire gastric body. The mucosa also demonstrates a swollen, spongy appearance subdivided by creases, creating a picture similar to cerebral convolutions. A polypoid variant of Ménétrier’s disease that resembles multiple hyperplastic gastric polyps has been described (see Chapter 54).

Gastric resections from patients with Ménétrier’s disease typically show large polypoid gastric folds or large cerebriform gastric folds with antral sparing (see Fig. 51-12C). In the absence of a gastrectomy, a full-thickness gastric mucosal biopsy is required to adequately assess the gastric histology in patients with hyperplastic gastropathy. The predominant microscopic feature of Ménétrier’s disease and hyperplastic, hypersecretory gastropathy is foveolar hyperplasia with cystic dilation (see Fig. 51-12D). The parietal and chief cells may be decreased and replaced by mucous glands. Inflammation in hyperplastic gastropathies is variable and may be absent.

The etiology of Ménétrier’s disease is unknown, although some cases have undoubtedly been infections with CMV or H. pylori. Genetic factors have recently been emphasized after the report of the disorder in identical twin men who presented at ages 29 and 35, respectively.²⁴⁷ Hyperplasia of surface mucous cells may be due to enhanced EGFR signaling in the gastric mucosa due to local overproduction of TGF-α.²⁴⁴

Ideal treatment of hyperplastic gastropathy is unclear because the condition is rare and controlled trials are lacking. Spontaneous resolution may occur, especially in children. It is likely that some cases, particularly in children, were actually cases of CMV gastritis (see earlier discussion). Ganciclovir has been used successfully in children with Ménétrier’s disease associated with CMV gastritis.²⁴⁹ H. pylori infection should be treated, if present, and the entire syndrome may resolve.²⁵⁰ Symptoms may improve with antisecretory agents (histamine-2 [H₂] receptor antagonists, anticholinergic agents, proton pump inhibitors), especially if the patient has Zollinger-Ellison syndrome or normogastrinemic hyperplastic, hypersecretory gastropathy. It has been suggested that H₂ blockers and anticholinergics reduce gastric protein loss by strengthening intercellular tight junctions. Some patients with Ménétrier’s disease have responded to glucocorticoids, octreotide, antifibrinolytic agents, or monoclonal antibody against the EGFR.²⁵¹ Partial or total gastric resection is reserved for severe complications such as refractory or recurrent bleeding, obstruction, severe hypoproteinemia, or cancer development.

ZOLLINGER-ELLISON SYNDROME

(see Chapter 32)

DIFFERENTIAL DIAGNOSIS OF GASTRITIS AND GASTROPATHY

The most important disorders that can simulate gastritis and gastropathy are gastric polyps (non-neoplastic and neoplastic) and gastric neoplasms such as adenocarcinoma and lymphoma (see Chapter 54).^252,²⁵³ Although CT criteria have been useful in distinguishing benign gastritis or gastropathy from gastric malignancy,²⁵⁴ endoscopy and gastric biopsy with review by an expert pathologist are the most useful diagnostic procedures. B cell clonality using advanced PCR technology can also help distinguish gastric marginal zone lymphomas from chronic gastritis.²⁵⁵ At the other end of the spectrum, many patients with gastritis have a normal endoscopic appearance,²⁵⁶ so the differential diagnosis of gastritis also includes functional dyspepsia (see Chapter 13), in which case the gastric biopsy is usually normal.