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.

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.