Clinical Features

Acute hemorrhagic gastritis is characterized by diffuse mucosal hyperemia associated with bleeding, erosions, and ulcers and precipitated by a sudden stress-induced imbalance between injurious and protective factors involved in the maintenance of mucosal integrity. This disorder has been a recognized nosologic entity for at least a century. Thomas Blizard Curling, a British surgeon, documented an association between severe burns and duodenal ulceration (i.e., Curling ulcer) in 1842. The prevalence and clinical importance of stress-induced gastric ulcers have been appreciated recently. Most patients in intensive care units have mucosal ulcers, approximately 20% develop overt bleeding, and as many as 5% succumb to life-threatening hemorrhage.

Ingestion of large doses of aspirin or other types of NSAIDs may cause acute mucosal injury, ranging from edema and hyperemia to erosion and ulceration. These lesions may occur suddenly, without prior pain or discomfort, in first-time and chronic NSAID users. Similar but usually less severe changes may be caused by ingestion of large quantities of alcohol. Because alcohol and aspirin act synergistically to alter mucosal defenses, many cases of hemorrhagic gastritis are caused by alcohol users who consume aspirin to prevent hangover sickness. The pathogenesis of stress-induced hemorrhagic gastritis is unknown, but luminal acid is essential. Acid exerts its noxious effect by inhibiting and causing loss of integrity of mucosal defense mechanisms (e.g., mucus-bicarbonate barrier). Vascular compromise associated with stasis, vasoconstriction, and increased vascular permeability also contributes to loss of mucosal integrity.

NSAIDs act by interfering with prostaglandin synthesis, whereas alcohol causes direct damage to the gastric mucosa. At a concentration of 12.5%, alcohol induces hyperemia and petechiae. At concentrations greater than 40%, alcohol causes necrosis of the surface epithelium and capillaries, and causes interstitial hemorrhage. Suppression of acid secretion with PPIs helps to reduce the severity of mucosal damage and facilitates mucosal healing.

Pathologic Features

Acute hemorrhagic gastritis is grossly characterized by hyperemic edematous mucosa, surface erosions, and active bleeding ( Fig. 15.25 ). The clinical history (e.g., shock, burns, ingestion of large doses of NSAIDs) rather than the pathologic features helps to determine the precise cause. In extreme cases, erosion of an underlying large blood vessel may cause catastrophic hemorrhage and death.

Two views showing the endoscopic appearance of acute hemorrhagic gastritis.

(Courtesy of David Y. Graham, MD, Houston, Tex.)

Microscopically, acute hemorrhagic gastritis, regardless of its cause, is characterized by dilation and congestion of mucosal capillaries, edema, and interstitial hemorrhage within the lamina propria. Surface erosions are usually small and appear ischemic. Aggregates of fibrin and neutrophils replace the eroded epithelium and often project above the mucosal surface to form small, elevated clumps of necrotic debris ( Fig. 15.26 ). The foveolar epithelium underneath and adjacent to erosions and ulcers show regenerative changes, such as elongation, increased tortuosity, mucin depletion, enlarged and hyperchromatic nuclei, and increased mitoses; the latter two features should not be misinterpreted as dysplasia. Recalling the location of the normal regenerative zones in the antrum (i.e., gland base) and corpus (i.e., mucous cell neck region) can help to mitigate an overdiagnosis of dysplasia. In the absence of concurrent H. pylori infection, unaffected areas of the stomach do not usually show increased chronic inflammation. In the setting of H. pylori infection, the pathologist may see chronic active inflammation in the mucosa, which may obscure or worsen the changes caused by NSAIDs or alcohol.

Superficial erosion in the corpus mucosa of a patient with acute hemorrhagic gastritis.

Clinical Features

Chronic H. pylori gastritis affects two thirds of the world’s population and is one of the most common chronic inflammatory disorders of humans. It is causally related to most non–NSAID-induced duodenal and gastric ulcers, and most gastric mucosa-associated lymphoid tissue (MALT) lymphomas. In certain regions of the world, atrophic gastritis develops in a considerable proportion of infected persons, and this condition is a precursor to gastric carcinoma. H. pylori gastritis is a strong risk factor for development of gastric cancer, particularly the intestinal type.

The early phase of H. pylori infection elicits an acute inflammatory response that is asymptomatic or has short-lived clinical manifestations, such as nausea and vomiting. Because most patients with early H. pylori gastritis do not undergo endoscopy, information regarding the clinical, endoscopic, and pathologic aspects of acute H. pylori infection is limited to a few well-documented case reports, human ingestion studies, and analyses of infections acquired from inadequately disinfected endoscopic instruments.

Endoscopically, manifestations of acute H. pylori gastritis are typically found in the antrum and characterized by hemorrhagic lesions and multiple erosions or ulcers. Virtually identical findings were previously reported in patients with epidemic gastritis and achlorhydria, a syndrome reported before the identification of H. pylori as the principal cause of most cases of chronic gastritis.

Although chronic H. pylori gastritis is asymptomatic in most infected individuals, its impact on human health is profound. H. pylori gastritis confers a 15% to 20% lifetime risk for peptic ulcer disease, and 70% of gastric cancers and most primary gastric MALT lymphomas are directly linked to chronic H. pylori infection. In one British community, H. pylori was estimated to be responsible for approximately 5% of all gastrointestinal (GI) ailments.

When H. pylori was initially identified, combination treatment with antibiotics and bismuth-containing compounds was recommended only for patients with gastric ulcers and known MALT lymphomas. In time, guidelines were developed to include treatment for patients with dyspepsia and, essentially, all patients in whom infection could be identified.

Although programs for global eradication of H. pylori have been advocated with the goal of preventing gastric carcinoma, insufficient supportive evidence has prevented widespread acceptance of the proposals. Critics of these programs cite the increasing resistance of H. pylori to the antibiotics used in current protocols. There is also much attention to the development of an effective vaccine to prevent H. pylori infection.

Epidemiology

The prevalence of H. pylori infection among adults approaches 90% in many developing countries, particularly those in the tropics. Cross-sectional studies have revealed a high prevalence of infection among children, indicating that exposure to the bacterium probably occurs relatively early in life. In industrialized parts of the world (e.g., Western Europe, United States, Canada, Australia), exposure tends to occur later in life, which results in a lower percentage of infected adults. An average of 20% to 30% of adults are infected by 50 years of age.

In eastern Asia (e.g., Japan, South Korea), where improved sanitation methods have been recently introduced, there is a clear trend toward a lower rate of H. pylori infection. The prevalence of H. pylori infection has been steadily declining in industrialized and emerging countries, which probably reflects the improved sanitary conditions and widespread use of antibiotics. Prevalence rates as low as 5% have been reported in Norwegian children between 1 month and 3 years of age, and even in China (Guangzhou province), the infection rate for children between 1 and 5 years was only 19% in 2003.

Despite declining rates of H. pylori infection overall, the prevalence of H. pylori among patients who undergo endoscopy remains significant. H. pylori should be considered in all gastric biopsy specimens examined, regardless of the patient’s age or history.

Pathologic Features

Grossly, there are no distinct endoscopic patterns of chronic H. pylori gastritis. Depending on the stage and type of gastritis, hyperemia, erosions, hypertrophy, and atrophy may coexist in various combinations. Unfortunately, none of these endoscopic features has proved useful for predicting the presence or absence of H. pylori gastritis. Endoscopists should not attempt to diagnose H. pylori gastritis based solely on the gross appearance of the gastric mucosa. The diagnosis of H. pylori gastritis rests on pathologic evaluation of gastric mucosal biopsies or detection of urease in mucosal specimens by the Campylobacter -like organism (CLO) test or the urea breath test. Polymerase chain reaction (PCR) testing is discussed later.

Microscopically, the gastric mucosa is covered by a thick layer of mucus that plays a protective role. This mucous layer, which is best visualized in Carnoy-fixed tissues, is the primary site of H. pylori colonization and often contains large numbers of organisms. When in contact with epithelium, H. pylori organisms characteristically attach to but do not penetrate the surface mucous cells. Intracellular invasion has been observed in surface mucous cells, chief cells, and parietal cells (rare), particularly in patients who have received PPIs ( Fig. 15.27 ). Although some authorities have suggested that penetration and intracellular invasion may be related to the organism’s ability to promote carcinogenesis, the significance remains unclear.

Helicobacter pylori organisms are identified in the deep portion of oxyntic glands and within canaliculi of oxyntic cells ( circles ). This feature is seen only in patients who use long-term proton pump inhibitors.

In severe acute infection, grossly visible pseudomembranes and pus adherent to inflamed mucosa have been described ( Fig. 15.28 ). In chronic H. pylori gastritis, epithelial degeneration is particularly prominent because of intimate contact of the H. pylori organisms with the surface cell membrane (see Fig. 15.6 ).

Acute severe Helicobacter pylori infection. Fibrinopurulent material is seen over a superficial erosion. The mucosa is extensively infiltrated by neutrophils.

The epithelial cells often become irregular and cuboidal, have a decreased apical mucin content, and occasionally drop out, leaving small gaps in the epithelium that contribute to a ragged, disorderly appearance. The characteristic alterations in H. pylori infection are caused by bacterial toxins such as VacA and CagA, urease, ammonia, acetaldehyde, and phospholipases, which have a direct effect on epithelial cells.

H. pylori causes mast cells to release platelet-activating factors, which leads to thrombosis. The disturbance of the local microcirculation results in ischemic loss of epithelial integrity and ultimately in surface erosions and ulcers.

Mucosal neutrophils are a distinctive histologic feature of H. pylori infection. Neutrophils are more abundant in the antrum and cardia than in the corpus, where they may be rare or completely absent despite the presence of organisms. Neutrophils may be seen in the lamina propria (where they are typically mixed with mononuclear cells and eosinophils) and within the surface and foveolar epithelium ( Fig. 15.29 ). Neutrophils may fill the lumen of the gastric pits, forming pit microabscesses and a surface exudate. In patients with atrophy, active neutrophilic inflammation only rarely occurs in areas of metaplasia. After successful eradication therapy, neutrophils disappear rapidly, and their continued presence is considered a valuable indicator of therapeutic failure.

A, In Helicobacter pylori infection, neutrophils typically infiltrate the lamina propria and the surface, foveolar, and glandular epithelium. B, In severe cases, pit abscesses may be found.

Gastric mucosa chronically infected by H. pylori typically shows a prominent mononuclear (lymphoplasmacytic) infiltrate. In the corpus, the mononuclear infiltrate is usually most intense in the superficial neck region of the lamina propria ( Fig. 15.30 ), which prompted the use of the term chronic superficial gastritis as a synonym for nonatrophic gastritis. In exceptional cases, the pathologist may also find a significant lymphocytic infiltrate within the glandular portion of the mucosa. In some cases, a diffuse intraepithelial infiltrate may be prominent, which can be mistaken for lymphocytic gastritis. In the setting of a focal and destructive lymphocytic infiltrate (i.e., lymphoepithelial lesion), additional evidence of extranodal marginal zone lymphoma should be sought. The intensity of the mononuclear cell infiltrate typically declines quite slowly after successful eradication of infection. As many as 30% of patients have chronic inactive gastritis that persists for several years after eradication of the organism.

Chronic superficial gastritis. Lymphocytes and plasma cells form a band that fills the lamina propria of the mucous cell neck region of the gastric body, a common feature in Helicobacter pylori gastritis. Although the term superficial gastritis accurately describes the distribution of inflammation, the Sydney System refers to it as mild chronic, active ( H. pylori ) , nonatrophic gastritis .

Lymphoid follicles with germinal centers are found in almost all H. pylori –infected patients, and their presence in the gastric mucosa is highly specific for H. pylori –associated gastritis (see Fig. 15.3 ). The density of lymphoid follicles is usually greatest in the region of the angulus and lowest in the proximal greater curve of the stomach. These anatomic sites correspond, respectively, to the most and least common sites of gastric MALT lymphoma. H. pylori infection is a major cause of acquired MALT in the stomach and is a critical factor in the development of primary gastric B-cell lymphoma (MALT lymphoma, which is now classified as extranodal marginal-zone B-cell lymphoma). Occasionally, lymphoid infiltrates may be large and irregular, with lymphoepithelial lesions at the periphery. In this circumstance, gastric lymphoma should be considered. Pathologic features that warrant further investigation with immunocytochemical and molecular techniques include: an expansile monotypic infiltrate, a monocytoid appearance of the lymphocytes, lymphoepithelial lesions associated with glandular destruction, and endoscopic evidence of a mass or nodularity. Immunohistochemical and molecular tests often yield equivocal results, and a diagnosis of atypical lymphoid infiltrate may be provided with elaboration of the inconclusive findings.

If H. pylori infection is detected by direct or indirect methods, including serology, eradication therapy with follow-up biopsies of the affected area is warranted. Lymphoid follicles normally decline in number and size, although very slowly, after successful treatment. In some patients, lymphoid follicles may persist indefinitely.

Subtypes of Helicobacter pylori Gastritis

H. pylori infection may show different patterns of gastritis and may ultimately be associated with the development of glandular atrophy. Different patterns of H. pylori gastritis are associated with various outcomes.

Differential Diagnosis

Methods of Detecting Helicobacter pylori

H. pylori normally infects antral and corpus mucosa, but in the cardia, organisms may be difficult to detect. H. pylori organisms rarely colonize intestinal epithelium, and in patients with extensive areas of metaplastic atrophy, organisms are usually confined to the nonmetaplastic, nonatrophic areas of mucosa. In patients who use PPIs, H. pylori organisms tend to be rare or absent in the antrum, and they may be difficult to detect in the corpus, even in the setting of chronic active inflammation. Similarly, patients treated with antibiotics before gastric biopsy may demonstrate a markedly reduced number of organisms and often have atypical (coccoid) forms ( Fig. 15.31 ).

Coccoid forms of Helicobacter pylori (which usually result from unsuccessful eradication therapy) are stained with the H. pylori blue stain ( A ) and with an anti– H. pylori immunohistochemical stain ( B ).

As many as 70% of gastric biopsy specimens from H. pylori –infected subjects reveal organisms by routine H&E staining. In the remaining 30% of cases, a more sensitive stain is usually needed. Many laboratories routinely stain all gastric biopsies, even those without significant inflammation, for H. pylori to ensure identification of organisms.

Commonly used and relatively inexpensive stains, such as Giemsa and Diff-Quik, are adequate for identification of most cases of H. pylori organisms. The Hp Blue/Hp Yellow stain (Anatech, Battle Creek, Mich.) is designed to make the organisms more discernable by staining the background mucin yellow. The yellow counterstain can be eliminated, which results in a cleaner background. The silver-based triple stain simultaneously allows visualization of H. pylori organisms while better featuring the histologic changes in the mucosa ( Fig. 15.32 ; see Figs. 15.6 and 15.11 ). Because this stain involves application of Alcian blue at pH 2.5, it also allows small, inconspicuous foci of intestinal metaplasia to be detected easily (see Fig. 15.11 ). Immunohistochemical stains for H. pylori increase sensitivity and are particularly useful for detecting coccoid forms of the organism, rare organisms located deep within the glands, and intracytoplasmic organisms. After H. pylori treatment, organisms may be best visualized with an immunohistochemical stain if chronic gastritis persists.

A, Innumerable Helicobacter pylori organisms (triple stain) are seen within the lumen of a pit and in the intercellular spaces of the foveolar cells. B, A gastric pit stained with an anti– H. pylori immunohistochemical stain.

Molecular techniques, specifically PCR, can be used to detect H. pylori organisms in tissue, and claims of higher sensitivity for histologic methods have been published. However, not all of these studies used immunohistochemistry for H. pylori detection as the reference group, and identification rates varied by technique (e.g., nested versus quantitative PCR). There is no gold standard to serve as the true infection rate to exclude false-positive PCR results, nor is there a clear understanding of the clinical relevance of finding trace bacterial DNA in gastric tissue. Gastroenterologists’ position papers have not specifically recommended use of PCR but do concede that it may be useful if the clinician is prepared to treat a patient with a positive result. It seems that the best application for those inclined to use this technique is for cases in which there is a histologic pattern of inflammation suggesting Helicobacter infection but no organisms detectable by immunohistochemistry.

PCR used on gastric tissue has been evaluated for possible identification of antibiotic sensitivity, which could be a valuable clinical application. Most patients are prescribed H. pylori treatment without antibiotic susceptibility testing, but first-line treatment regimens fail to eradicate the organism 20% of the time. The primary culprit appears to be resistance to clarithromycin, which can be significant (about 15% to 20%) in certain populations. Resistance has been related to point mutations in bacterial 23S rRNA, and genotypic (PCR) evaluation of resistance is more sensitive than phenotypic (culture) testing. However, PCR-based testing correlates less well than culture with treatment outcomes and therefore has a low predictive value.

Helicobacter heilmannii Infection

More than 50 species of Helicobacter have been described, but only a few cause gastritis in humans. They include Helicobacter felis , Helicobacter fennelliae, Helicobacter cinaedi, and Helicobacter heilmannii . Among these, H. heilmannii (formerly known as Gastrospirillum hominis ) is the most common, with an estimated prevalence of 1% of all human Helicobacter infections. In some rural areas in eastern Europe, infection with H. heilmannii is more common, supporting the hypothesis that it is acquired by zoonotic transmission. The organisms are 5 to 9 µm long (twice as long as H. pylori) and have five to seven spirals.

Although H. heilmannii organisms are easily visualized with any of the common histochemical H. pylori stains ( Fig. 15.33 ), their detection may be difficult because they tend to be less numerous and more focally distributed than H. pylori . Polyclonal immunohistochemical stains for H. pylori also react with H. heilmannii , as do some commercially available monoclonal stains. H. heilmannii can be missed by those who rely exclusively on these immunostains for their diagnosis.

Helicobacter heilmannii organisms are at least twice as long and considerably thicker than Helicobacter pylori . Their characteristic tightly spiraled shape is clearly visible at high power with the triple stain ( A ), the H. pylori blue stain ( B ), and most polyclonal anti- Helicobacter immunohistochemical stains ( C ).

Gastritis caused by H. heilmannii differs from H. pylori gastritis. It is more common in children and usually milder and patchier, with fewer erosions and ulcers. The inflammation tends to be more circumscribed, mainly affecting the antrum, although cases of severe corpus active gastritis may be seen. The diagnosis rests on the morphologic recognition of the organisms, although differentiation of H. heilmannii from H. felis is not possible by light microscopy. These organisms have not been cultured successfully in vitro, and the specific antibiotic susceptibility of H. heilmannii has therefore not been well studied. Clinically, H. heilmannii patients are treated identically to those with H. pylori infection, and rates of successful outcomes are similar.

Similar to H. pylori , H. heilmannii infection has been linked to the development of gastric adenocarcinoma and MALT lymphoma. Regression of lymphoma after successful eradication therapy has been reported.

Natural History and Complications

H. pylori is a lifelong infection, and if left untreated, it may progress from nonatrophic to atrophic gastritis and, depending on its phenotype, may cause peptic ulcer disease, adenocarcinoma, and primary MALT lymphoma. The relative risk of each of these conditions varies greatly in different populations and is related to bacterial, environmental, and genetic factors. More than 90% of gastric MALT lymphomas are diagnosed in patients with chronic H. pylori infection, and more than 75% will regress for extended periods with successful eradication therapy for the infection. Gastric carcinoma and lymphoma are discussed in Chapters 25 and 31 , respectively.

Etiology

H. pylori infection is a major cause of peptic ulcers not associated with NSAIDs or the Zollinger-Ellison syndrome. H. pylori is detected in the stomach of almost all patients with duodenal peptic ulcer and in more than 90% of gastric ulcer patients who are not NSAID users. Eradication of H. pylori facilitates healing of peptic ulcers and essentially prevents their recurrence. In contrast, more than 80% of patients treated only with acid inhibitors experience recurrence within 1 year.

Benign and malignant tumors may cause gastric ulceration. Malignant ulcers occur most often with adenocarcinoma and stromal tumors and less commonly with lymphomas, metastases, and direct extension of an adjacent extragastric malignancy. In immunocompromised patients, cytomegalovirus and histoplasmosis (rare) may cause gastric ulceration.

Pathologic Features

Acute stress ulcers are usually multiple. They are more than 0.5 cm in diameter and form well-delineated craters of various depths. Fibrin mixed with an acute inflammatory exudate and necrotic debris is usually found within the ulcer bed. Because these ulcers often bleed, blood clots may fill the ulcer crater. The pathologist usually sees an abrupt transition between the necrotic edges of the ulcer and adjacent mucosa ( Fig. 15.34 ). The surrounding mucosa may be normal, or it may show features of the underlying chronic gastritis, depending on the cause of the ulcer.

Stress ulcer with clean borders in the antrum. Some ulcers have evidence of recent hemorrhage.

Most peptic ulcers occur on the lesser curvature of the stomach in the antrum close to the incisura angularis. Gastric ulcers that occur in the greater curvature and in other parts of the proximal stomach are more likely to be related to chronic NSAID use than H. pylori infection . Peptic ulcers are typically sharply demarcated lesions, which may appear erythematous, edematous, and only slightly elevated above the level of the surrounding mucosa ( Fig. 15.35 ). They are usually small (0.5 to 2.0 cm in diameter), but some can be more than 3.0 cm in diameter. Large (i.e., giant) ulcers may be misdiagnosed endoscopically as malignant.

Endoscopic view of an antral peptic ulcer. Notice the discrete border with adjacent flat, normal-appearing mucosa.

Perforating ulcers penetrate into adjacent structures, most commonly the pancreas. The mucosa surrounding ulcers may appear normal or show a radiating pattern to the rugal folds endoscopically, unless the ulcer is complicated by extensive fibrosis. This feature is useful in differentiating benign from malignant ulcers because malignancies usually show heaped-up mucosal borders and irregular rugal folds. However, ulcers associated with malignant lymphomas are often flat or only slightly elevated, frequently multiple, and may reach large sizes (10 to 12 cm in diameter).

Microscopically, the mucosa surrounding peptic ulcers typically shows chronic active inflammation and marked regenerative changes, increased mitoses, mucin depletion, and foveolar hyperplasia—features that can mimic dysplasia ( Fig. 15.36 ). Features that support regeneration include evidence of surface maturation, mitotic activity confined to the deeper foveolar regions, and nuclei without loss of polarity that have even chromatin, thin nuclear membranes, and uniform, central punctate nucleoli. A gradual transition from atypical to normal epithelium favors regeneration.

Low magnification of a gastric peptic ulcer. The ulcer crater contains a small amount of fibrin and necrotic debris with underlying granulation tissue. The mucosa immediately adjacent to the ulcer shows regeneration.

The base or crater of peptic ulcers consists of necroinflammatory debris, granulation tissue, and fibrosis with chronic inflammation from the luminal surface to the deep portions of the gastric wall. Adjacent to ulcers may be found a substantial lymphoid infiltrate arranged in follicles, in some cases mimicking malignant lymphoma. At the ulcer’s base, blood vessels proliferate, often showing prominent inflammation and arteritis obliterans. When disrupted, these arteries may bleed profusely.

Complications

The most common complications of peptic ulcer disease, in order of frequency, are hemorrhage, perforation, and obstruction. Approximately one third of patients experience at least one of these complications during the course of disease. Pyloric channel ulcers are most commonly associated with complications, particularly obstruction. Bleeding occurs when ulcers erode underlying blood vessels.

Proton Pump Inhibitor Use

PPIs, some of the most commonly prescribed GI medications worldwide, have become available over the counter in the United States and in many other countries. PPIs are highly effective for chronic gastroesophageal reflux disease, for prevention of gastric damage associated with NSAIDs, and for dyspepsia. After they are recommended, most people continue taking them indefinitely.

Most patients who undergo endoscopy are taking PPIs, and gastroenterologists consider any attempt to discontinue the medication for 2 weeks before the procedure futile. As a consequence, most gastric biopsies show a presumed PPI effect: focally dilated oxyntic glands with flattened or hypertrophic parietal cells protruding into the lumen. Patients with H. pylori gastritis may have additional PPI-related changes, especially a milder intensity of antral inflammation accompanied by a greater intensity in the corpus, few or no detectable organisms in the antrum, and a peculiar redistribution of H. pylori organisms in the deeper portions of the oxyntic glands, even reaching the intracellular canaliculi of the parietal cells ( Fig. 15.38 ). PPI use can cause false-negative results for urea breath tests.

Patients with Helicobacter pylori gastritis may have additional proton pump inhibitor–related changes. These changes include a milder intensity of antral inflammation accompanied by a greater intensity in the corpus, few or no detectable organisms in the antrum, and a peculiar redistribution of H. pylori in the deeper portions of the oxyntic glands, even reaching the intracellular canaliculi of the parietal cells, as demonstrated by this section from the corpus stained with an anti- Helicobacter immunohistochemical stain.

Recent Antibiotic Treatment

Innumerable persons receive antibiotic treatments for a variety of verified or suspected infections; among the most common are dental procedures and ear, throat, and urinary tract infections. Because these treatments are usually not coordinated with gastroenterologists, procedures may be done on patients who recently received or are still on antibiotics. Some of these antibiotics affect H. pylori , but when used outside of a coordinated triple or quadruple therapy, they rarely cure the infection. They may, however, temporarily decrease the bacterial load and make the infection, which is still active and capable of inducing inflammation, visually undetectable. We suspect that these incidental antibiotic treatments are one of the most common causes of H. pylori –negative gastritis.

Antibiotics may also be prescribed by the gastroenterologist. Because almost no gastroenterologist performs endoscopy in a patient treated for H. pylori infection earlier than 3 to 6 months after completion of therapy, biopsies from these patients are likely to reveal one of two findings. If the therapy was successful (i.e., H. pylori infection was eradicated), the gastric mucosa shows various degrees of chronic gastritis, possibly some lymphoid follicles, and no active inflammation. If the therapy failed, a recrudescence occurs, and the chronic active gastritis is often more severe than before the unsuccessful therapeutic trial. Biopsies after eradication treatment are an exceedingly uncommon source of H. pylori –negative active gastritis.

Causes of Chronic Active Gastritis Unrelated to Helicobacter Infection

In some biopsy specimens, the features of reactive gastropathy are accompanied by those of chronic gastritis with or without foci of active inflammation. Because the features of H. pylori gastritis may overlap with those of reactive gastropathy (and the two types may coexist), a careful search for H. pylori organisms is imperative.

The two causes can usually be discerned. In contrast to H. pylori gastritis, the chronic infiltrate of reactive gastropathy is loose, does not form a subepithelial band (formerly designated superficial gastriti s), and rarely has significant numbers of plasma cells. Any polymorphonuclear neutrophils tend to be confined to the lamina propria, sparing the glandular epithelium, where they are often associated with eosinophils. Intraepithelial neutrophils, aggregates of neutrophils, and regenerative epithelium are usually found only in the vicinity of erosions, which are often revealed by additional sections into the block.

Focally Active Gastritis

The finding of individual or few gastric foveolae or glands discretely surrounded and infiltrated by lymphocytes, macrophages, plasma cells, and occasional neutrophils in a background of normal gastric mucosa has been referred to as focally enhanced gastritis ( Fig. 15.39 ). Although the meaning of the word enhanced in this context remains puzzling to many pathologists, the term has become tacitly accepted.

Two examples of focally enhanced ( Helicobacter pylori –negative), chronic active gastritis. It is characterized by patchy lymphoplasmacytic and neutrophilic infiltrates, sometimes limited to only one or a few glands. The intervening mucosa is completely normal ( top , triple stain; bottom , hematoxylin and eosin [H&E] stain).

Focal and often intense gastritis has been described in a high percentage of patients with inflammatory bowel disease, most notably children with Crohn’s disease, but it can be seen in many patients with no inflammatory bowel disease. H. pylori infection can also be patchy, although typically with a less striking contrast between inflamed and adjacent, normal-appearing mucosa than seen with inflammatory bowel disease. Nevertheless, when focal gastritis is seen, an effort should be made to detect organisms. If none is found, a measured comment can be made indicating that one of the possible causes is inflammatory bowel disease elsewhere in the GI tract.

Other Infections

Other bacteria, fungi, and viruses may infect the gastric mucosa, but only rarely do they produce the histopathologic appearance of chronic active gastritis. Rather, they typically elicit a more mixed inflammatory infiltrate that is less superficial, as in the case of cytomegalovirus gastritis ( Fig. 15.40 ). Unless specific clinical information is available (e.g., an immunosuppressed patient, a case of disseminated aspergillosis), a search for infectious agents other than Helicobacter species in the gastric mucosa is likely to be laborious and, ultimately, unrewarding.

Chronic active gastritis with no detectable Helicobacter pylori organisms. A, The chronic inflammation is located in the lower half of the antral mucosa, and the density of plasma cells is relatively low. B, A single cytomegalovirus inclusion (arrow) is magnified.

Reported Conclusions

After the pathologist has reviewed the slides, restained, and used alternate techniques, a well-worded report should state that no H. pylori organisms were found after a meticulous search, despite the characteristic histologic appearance. These reports, however, are unlikely to gratify an inquisitive clinician, who will be left wondering what should be done.

Calling the clinician and explaining the circumstances that led to an equivocal diagnosis is probably the best way to avoid being perceived as a timid pathologist. Before discussing a case, however, it is necessary to be fully informed. If the pathologist can elicit a history of recent incidental antibiotic treatment, he or she can suggest a plausible explanation for H. pylori –negative chronic active gastritis. The pathologist can indicate that the inadequately treated infection may reemerge and that a new set of biopsies after a few weeks may show organisms. A tactfully delivered reminder on the effects of PPIs may also help to persuade clinicians to start regularly sampling the antrum and the corpus. It is important not to leave the impression that H. pylori –negative chronic active gastritis is a final diagnosis without need for further workup.

Clinical Features

Autoimmune gastritis is a type of corpus-restricted, chronic atrophic gastritis associated with serum anti–parietal cell and anti–intrinsic factor antibodies with resultant intrinsic factor deficiency with or without anemia. Autoimmune gastritis does not cause specific clinical manifestations until a critical decrease has occurred in the parietal cell mass, beyond which anemia develops. Years before the onset of anemia, patients may show various degrees of hypochlorhydria, hypergastrinemia, and loss of pepsin and pepsinogen secretion.

Achlorhydria, which is a direct result of destruction of acid-producing parietal cells, typically occurs in the most advanced stage of disease. However, hypochlorhydria may occur in patients with a large number of preserved parietal cells, which suggests that there may be a possible role for anti–proton pump antibodies or inhibitory lymphokines released by inflammatory cells in the pathogenesis of this disease. Patients with atrophy of the corpus and achlorhydria have a high level of hypergastrinemia that tends to correlate with disease severity. Damage to chief cells leads to a reduction in pepsin activity in gastric juice and in the level of pepsinogen in serum. The finding of a low pepsinogen I level (<20 ng/mL) is a sensitive and specific indicator for corpus atrophy.

Iron deficiency anemia or pernicious anemia develops in many patients with autoimmune gastritis, and achlorhydria is a major contributor to the pathogenesis of anemia. Gastric acid is important for absorption of nonheme iron, which supplies at least two thirds of the nutritional iron supply in most Western diets. Pernicious anemia, which results from loss of intrinsic factor production by parietal cells, is usually preceded by corpus-restricted chronic atrophic gastritis (usually end stage) and reduced or absent acid secretion of at least 10 years’ duration. Autoimmune gastritis is a risk factor for hyperplastic and dysplastic polyps, carcinoma, and endocrine tumors. Polyps are detected in 20% to 40% of patients with pernicious anemia; they are mostly sessile, less than 2 cm in diameter, and often multiple. Most are hyperplastic, but as many as 10% contain foci of dysplasia. Gastric cancers associated with pernicious anemia are mostly intestinal type and arise from intestinal metaplasia, suggesting that carcinoma in autoimmune gastritis likely develops through a metaplasia–dysplasia–carcinoma pathway.

Epidemiology

Pernicious anemia is an uncommon disease with a reported prevalence rate of approximately 1%, even among older people and in high-incidence regions of the world. However, autoimmune gastritis may be underdiagnosed because most patients have microcytic or macrocytic anemia and are treated with iron, folate, and cobalamin without undergoing a thorough investigation of the underlying cause. However, targeted studies suggest an overall prevalence of 2%, with a peak of 4% to 5% among elderly women.

Pathogenesis

The cause of autoimmune gastritis is unknown. One theory suggests the disease may be initiated by H. pylori infection. A high prevalence of antibodies with specificity for gastric mucosal antigens has been reported for patients with H. pylori –associated gastritis. Twenty percent of H. pylori –positive individuals have autoantibodies that react with the canaliculi of parietal cells, which are a primary antibody target in autoimmune gastritis. Studies with cloned T cells from H. pylori –infected patients and patients with autoimmune atrophic gastritis have identified molecular mimicry between H. pylori and hydrogen and potassium receptors and ATPase, suggesting that infection may stimulate T cells that target parietal cells. These studies provide support for the concept of a cross-reactive mechanism between H. pylori organisms and gastric epithelial antigens that may be responsible for or at least participate in the pathogenesis of autoimmune gastritis. The role of immunoglobulin G4 (IgG4) in autoimmune gastritis may be similar to that in autoimmune pancreatitis, and a study found IgG4-immunoreactive plasma cells in gastric biopsies to be 100% specific (albeit not highly sensitive) for autoimmune atrophic gastritis and pernicious anemia.

Pathologic Features

Grossly, the mucosa of the corpus in patients with autoimmune gastritis is usually thinner than normal and shows a reduction or complete absence of rugal folds. Fine submucosal vessels are usually easily recognizable on endoscopic examination in advanced cases. Hyperplastic polyps are also common in advanced-stage disease.

Microscopically, the main pathologic features of uncomplicated autoimmune gastritis are diffuse corpus-restricted chronic atrophic gastritis with some degree of intestinal metaplasia. In the absence of comorbidities, such as concurrent H. pylori infection or bile reflux, the antrum is typically normal. This pattern of involvement is characteristic of patients with advanced disease and is found in patients with pernicious anemia. Patients without pernicious anemia but with anti–parietal cell antibodies have a spectrum of atrophic changes that range from minimal to severe and diffuse atrophy of the oxyntic mucosa, and they have some degree of ECL cell proliferation (see Table 15.3 ).

Three pathologic phases can be identified during the course of autoimmune gastritis in corpus mucosa: early, florid, and end stage. The early phase is characterized by diffuse or multifocal, dense lymphocytic and plasma cell infiltration involving the entire thickness of the lamina propria and often mixed with eosinophils and mast cells. Patchy destruction of individual oxyntic glands by lymphocytes may be seen at this stage ( Fig. 15.41 ). The pathologist may see patchy pseudopyloric metaplasia and hypertrophic changes of the remaining parietal cells. Hypertrophic changes indicate a high level of functional stimulation, which may be related to hypergastrinemia and can be found in the parietal cells of patients with autoimmune atrophic gastritis, those who have received PPI therapy, and a subset of patients with peptic ulcer disease.

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