Gastritis and Gastropathy

Epidemiology, Risk Factors, and Transmission

Hp infection is the most common chronic bacterial infection in humans. Estimates suggest that over 50% of the world’s population is infected with the bacterium, including 70% to 80% of populations in developing nations. Genetic sequence analysis suggests that humans have been infected for more than 60,000 years corresponding to the time when they first migrated from Africa.

A key risk factor for infection is socioeconomic status during childhood. Infection is commonly acquired at an early age, particularly in developing countries where the majority of children become infected before the age of 10. ^, During early childhood, spontaneous clearance of the bacteria is common, but often with subsequent reinfection. In older children and adults, infection usually persists, so that the prevalence of Hp infection can exceed 80% by ages 20 to 30 in the developing areas of the world. In developed countries, such as the USA, young children can also acquire Hp, but with spontaneous clearance there is a lower chance of reinfection, and consequently, persistent infection is less frequent. ^, In fact, serologic evidence of Hp infection is uncommon in children before age 10, but rises to 10% in adults between 18 and 30 years of age, and further increases to 50% in those age 60 or older. This increased prevalence of infection with age was initially thought to represent continuing acquisition throughout adult life. However, new adult infection and reinfection are quite uncommon, especially in developed countries, where reinfection is estimated to occur in less than 0.5% of cases per year. Epidemiologic evidence supports childhood-acquired infection even in developed nations, and thus the frequency of Hp infection for any age group in a locality reflects that particular birth cohort’s rate of bacterial acquisition early in life. In the USA, infection within any age group is less common in whites than in African Americans and Hispanics. Hispanic immigrants and their first-generation children are more likely to harbor Hp than their second-generation offspring. These differences probably relate to factors early in life that are linked to acquiring infection.

Housing density, crowded conditions in the home, number of siblings, sharing a bed, and lack of hot or running water have been linked to higher rates of infection. ^, In Japan, the declining prevalence of Hp infection appears to parallel the nation’s postwar economic progress with improvement in hygiene and sanitation. Among Japanese born before 1950, more than 70% are infected compared with 45% born between 1950 and 1960 and 25% born between 1960 and 1970. Currently, childhood infection in Japan is uncommon. A similar declining prevalence is being observed in the USA, suggesting that infection-related illnesses such as PUD will decrease as the current birth cohorts in developed countries reach older age.

Twin studies support a genetic susceptibility to Hp infection, because monozygotic twins who were raised in different households have a greater concordance of infection than dizygotic twins raised separately. However, twins growing up together have a higher concordance of Hp infection than twins growing up separately, suggesting environmental factors are also important for acquisition during childhood.

Humans appear to be the major reservoir of Hp. The precise mode of Hp transmission from person to person remains uncertain, and multiple mechanisms may be operative. Transmission of bacteria from gastro-oral, fecal-oral, or possibly oral-oral exposure seems the most probable explanation for person-to-person spread. ^, Within-family clustering of infection (often with genetically identical strains of Hp) also supports person-to-person transmission. Infected individuals are also more likely to have infected spouses or children than uninfected individuals. Support for sibling-to-sibling transmission comes from studies reporting that the likelihood of infection is correlated with the number of children in the household and that younger children were more apt to be infected if older siblings were also infected. In a study conducted in 6 countries in Latin America, household crowding and living with 4 or more children were risk factors for infection. Mother-to-child transmission is also quite likely. ^,

Gastro-oral and fecal-oral transmission of bacteria appear to be the dominant mechanisms by which Hp gain access to the human host. The bacterium can be cultured from vomitus, aerosolized vomitus, and diarrheal stools, suggesting the potential for transmission. Organism loads are 100-fold higher in vomitus when compared with stool and saliva; organisms are also present in aerosolized vomitus out to 1.2 m during the act of vomiting. Exposure to an infected family member during an acute GI illness, especially with vomiting, appears to be a risk factor for infection. Natural transmission could occur through contact with infected vomitus during an acute illness or with regurgitated material from an infected child. Such contact could explain the higher concordance of maternal/child Hp infection and the presumed child-to-child transmission that occurs in an infant daycare setting.

Especially in developing countries, Hp-contaminated water might serve as an environmental source of Hp, because the organism can remain viable in water for several days. Hp DNA can be found in samples of municipal water from endemic areas of infection, but whether the Hp detected by PCR are viable organisms remains to be proved. In countries where the prevalence of Hp infection is high, children who swim in rivers and streams, drink untreated stream water, or eat uncooked vegetables are more likely to harbor Hp, providing further indirect evidence of an environmental (water-borne) source of organisms.

How frequently bacteria are transmitted through oral-oral contact is not known. Although organisms can be identified in dental plaque, periodontal pockets, and saliva, the prevalence is low, as is the organism count ^, ; thus, it is questionable if the mouth can serve as a source or reservoir for Hp. Also, dentists and oral hygienists who have occupational exposure to dental plaque, periodontal pockets, and oral secretions do not have an increased prevalence of Hp infection. In developed countries, oral-oral transmission of infection to spouses also appears to be uncommon.

Infected gastric juice may serve as a source of bacterial transmission. Iatrogenic infection has also occurred during the use of a variety of inadequately disinfected gastric devices, endoscopes, and endoscopic accessories. Gastroenterologists and nurses appear to be at increased risk for acquiring Hp. Mandated universal precautions, hand washing, standardized equipment disinfection, and use of video-endoscopes that reposition the instrument channel away from the mouth may reduce such occupational and iatrogenic transmission.

Although humans are the main reservoir for Hp, domestic cats, captive primates, and sheep can also harbor these organisms. It is possible that these animals actually acquired their Hp from human sources. Isolation of viable bacteria from the saliva and gastric juice of cats suggests the possibility of transmission to humans. An Hp haplotype persists in the feline species in Africa, suggesting that infection may have transitioned to humans at some point in the distant past.

Pathogenesis

A unique aspect of Hp is that this pathogen confers disease despite residing in the stomach. Gastric Hp infection per se, however, is insufficient to fully explain the wide spectrum of associated gastroduodenal diseases. Pathogenicity and clinical outcome depend on both bacterial and host factors. Thus, virulence of Hp relates to both bacterial properties allowing colonization and adaptation to the gastric environment and to pathophysiologic alterations in the host. Studies describing the genome of distinct strains of Hp have advanced our understanding of the ecology of the organism and the potential bacterial gene expression patterns that can affect disease pathogenesis.

The pathogenesis of Hp gastritis is complex and not fully understood and a detailed description is beyond the scope of this chapter. Only key pathogenetic factors will be discussed, with the interested reader referred to other sources.

Hp contain 6 to 8 flagella at one end of their bodies and flagella-mediated motility is one of the few characteristics shown to be required for successful Hp colonization of the host. The organism’s flagella allow rapid migration of Hp to a more favorable gastric location below the gastric mucus layer.

Exposure of Hp to low gastric pH levels increases expression of bacterial genes encoding urease. Urease helps Hp adapt to the acidic gastric milieu, allowing a more neutral pH to occur near the bacteria as its urease splits urea into CO ₂ and ammonia (NH ₃ ), with the NH ₃ reacting with H ⁺ to produce ammonium ion (NH ₄ ⁺ ).

Hp show strict tropism for gastric-type mucosa, including in nongastric regions of the GI tract where there is gastric metaplasia. Conversely, Hp do not colonize epithelium in a stomach that has undergone intestinal metaplastic change (see later), possibly because antimicrobial factors produced by host metaplastic epithelium select against colonization. This possibility is supported by the finding that Hp rarely colonize the deeper portions of the gastric glandular mucosa, where antimicrobial O-glycans are found. Metaplasia may also be associated with hypochlorhydria/achlorhydria, encouraging overgrowth of the stomach with other (non-Hp) species of bacteria.

Toll-like receptors (TLRs) are a family of pattern recognition receptors with specificity for various bacterial molecules. ^, TLRs are components of the host’s innate immune system. Lipopolysaccharide PS from Hp stimulates gastric epithelial cell and monocyte responses via TLR4 and TLR2.2. ^,

A key interaction between Hp and gastric epithelium is mediated by a segment of bacterial DNA referred to as the cag pathogenicity island (cag PAI). Genes within the cag PAI encode for a type IV secretion apparatus, cagE, that allows other bacterial macromolecules, such as cagA, to be delivered directly into the host cell. ^, The cag PAI plays an important role in the pathogenesis of chronic Hp gastritis in humans. ^, Hp bearing the cag PAI are associated with increased interleukin (IL)-8 expression, mucosal inflammation, peptic ulceration, and apoptosis compared to cag PAI-negative strains. ^, Mongolian gerbils infected with mutated Hp strains lacking cagE exhibit less severe gastritis, fewer peptic ulcers, less intestinal metaplasia (IM), and less gastric cancer than gerbils infected with the wild-type strain. Different cagA proteins from distinct geographic Hp populations appear to be tyrosine phosphorylated by host cells in different manners, resulting in variable effects on intracellular signaling. Such heterogeneity in cagA may lead to different host responses that could account for some of the geographic differences seen in Hp-associated disease. Although tyrosine phosphorylation of the cagA protein may be important, it is not the only mechanism whereby this molecule regulates the host response. ^,

All strains of Hp possess the vacA gene, and more than half of strains produce a vacuolating cytotoxin (VacA). ^, VacA attaches to host epithelial cells via an interaction with cellular protein-tyrosine phosphatases. Thus, mice deficient in a protein-tyrosine phosphatase do not develop gastric ulceration when exposed to Hp that secrete VacA. Different vacA alleles have been detected in the 5′ signal region (s-region) and in the middle region (m-region) of Hp’s vacA gene. The s-region is present as allele s1 (which can be further distinguished as s1a, s1b, s1c) or as allele s2, whereas the m-region is present as allele m1 or m2. Production of VacA is designated by the allelic combinations (e.g., s1/m1, s1/m2, s2/m1, s2/m2). Specific vacA alleles (s1 and m1) are associated with peptic ulceration and the induction of host epithelial cell apoptosis.

Other bacterial virulence factors have also been associated with a putative increased risk of gastric adenocarcinoma. However, studies showing direct cancer causation for any of these bacterial factors in isolation have proved unfruitful. These findings support the notion that any bacterial or host factors that increase the host inflammatory response to infection may increase the risk of gastric cancer and that the degree of mucosal inflammation, cell injury, and gastric atrophy is the best determinant of cancer risk in an individual patient.

Gastric epithelial cells play an integral part in the host response to Hp infection, in addition to being the target of infection. Epithelial cell responses to Hp include changes in their morphology, disruption of their tight junctional complexes, production of cytokines, increased proliferation, enhanced cell death via apoptosis, and induction of numerous host genes associated with the cellular stress that accompanies infection.

Expression of genes by epithelial cells infected with Hp is regulated by transcription factors, particularly nuclear factor-kappa B (NF-κB). As discussed in Chapter 2 , NF-κB regulates expression of a wide variety of proinflammatory cytokines and cellular adhesion molecules in response to infection or the local cytokine milieu. Enhanced gastric epithelial cell NF-κB activity correlates with the intensity of neutrophil infiltration and mucosal IL-8 levels.48 This pathway is of particular interest given that certain polymorphisms in the IL-8 gene are linked to increased mucosal IL-8 expression, inflammation, and other premalignant changes associated with gastric cancer. Hp infection appears to activate NF-κB in gastric epithelial cell lines through various signaling mechanisms, including mitogen-activated protein kinases. ^{, , ,} The mitogen-activated protein kinase cascades regulate a wide range of cell functions, including proliferation, inflammatory responses, and cell survival. ^,

Oxidative stress also regulates host gene expression during Hp infection. ^, Oxidation of host DNA by reactive oxygen species such as hydroxyl radicals (•OH) are thought to play a causal role in malignant transformation through the induction of DNA damage. For this reason, there is growing interest in the role of antioxidants in cancer prevention or treatment, because Hp infection is associated with decreased levels of ascorbic acid, a tissue antioxidant scavenger. Moreover, there is evidence that diets high in antioxidants or “nutraceuticals” of the isothiocyanate group, such as sulforaphane, may antagonize oxidative stress and protect the host from gastric cancer, perhaps by decreasing inflammation and attenuating bacterial load. In vitro and in vivo studies in Mongolian gerbils show that an N-acetylcysteine, a precursor to the antioxidant compound glutathione, reduces Hp gastritis if administered early after infection, but whether this compound would reduce carcinogenesis is uncertain.

Hp strains that express outer inflammatory protein A (OipA) are associated with increased bacterial density, higher mucosal IL-8 levels, and neutrophil infiltration, as well as more severe clinical consequences.

Peptidoglycan (murein) from Hp’s cell wall can translocate into gastric epithelial cells via the cagE encoded by the cag PAI. Once inside the host cell, nucleotide-binding oligomerization domain-1 recognizes this murein, providing a novel mechanism of bacterial sensing. Binding of murein to nucleotide-binding oligomerization domain-1 can lead to activation of NF-κB and the subsequent expression of various host genes encoding proinflammatory molecules, as discussed earlier.

Hp neutrophil-activating protein promotes neutrophil adhesion to endothelial cells and stimulates chemotaxis of neutrophils and monocytes, nicotinamide adenine dinucleotide phosphate hydrogen oxidase complex assembly at the plasma membrane, and the subsequent production of reactive oxygen intermediates. ^, Within the inflammatory environment present in Hp gastritis, the effects of Hp neutrophil-activating protein on neutrophils can be potentiated by TNF-α and interferon (IFN)-γ. After epithelial cells undergo apoptosis, phagocytes remove the dead cells. Engulfment of necrotic epithelial cells by phagocytes may be another important mechanism by which Hp can activate a host response. ^,

Recruitment and activation of neutrophils and macrophages cause the release of other inflammatory mediators. Increased expression of inducible nitric oxide synthase occurs in the gastric mucosa during Hp infection. The nitric oxide (NO) produced reacts with superoxide anion (O ₂ ⁻ ) produced by infiltrating neutrophils to form peroxynitrite (ONOO ⁻ ), a potent oxidizing and nitrating agent. NO and ONOO ⁻ have antimicrobial effects, but uncontrolled or inappropriate production could also play a role in the gastric mucosal cell damage observed during Hp infection. Furthermore, catabolism of urea by Hp urease produces NH ₃ and CO ₂ , the latter of which can rapidly neutralize the bactericidal activity of the peroxynitrite by reacting with it to form the intermediate ONOOCO ₂ ⁻ and then nitrate. Urease, thus, may favor Hp colonization by neutralizing some host cell responses, but this mechanism also enhances the nitration potential of ONOO ⁻ and may favor mutagenesis of host cell DNA.

Cytokines induced in macrophages by bacterial urease include TNF-α and IL-6,89, and IL-6 is also induced by heat shock protein 60.9 Cytokines secreted by epithelial cells complement those released by inflammatory cells in the lamina propria. Intact bacteria can induce the production of chemokines that recruit T cells, ^, as well as IL-12 ^{, , ,} and IL-18, ^, cytokines that favor the selection of Th1 cells, with their characteristic patterns of cytokine secretion. Th1 cells promote cell-mediated immune responses through the production of IFN-γ and TNF-α, whereas Th2 cells produce IL-4, IL-5, IL-10, and transforming growth factor-β (TGF-β). Th2 cells can promote mucosal IgA or IgE responses to helminths and other parasites, as well as diminish the inflammation caused by Th1 cytokines. Previous studies suggest that the Hp-infected gastric mucosa is preconditioned to favor Th1 development over Th2 cell development. ^,

T cell (e.g., Th1 cell) activation by Hp infection may contribute to more severe inflammation and gastroduodenal diseases. Increased levels of IL-17, a cytokine produced by activated CD4 ⁺ T lymphocytes, are found in the mucosa of Hp-infected patients. ^, IL-17, in turn, induces IL-8 expression by gastric epithelial cells, thereby enhancing neutrophil recruitment. Activation of transcription factors by IL-17 may also contribute to the increased levels of numerous other proinflammatory cytokines and enzymes observed during Hp infection, such as IL-1β, TNF-α, and COX-2. IFN-γ and TNF-α produced by Th1 cells can increase the expression of many genes in the epithelium, including IL-8. These cytokines also enhance bacterial binding and they may also increase bacterial load. In animal models, Th1 cells increase epithelial cell apoptosis as well as inflammation, glandular atrophy, and a tendency toward dysplasia. TNF-α, IFN-γ, and IL-1β also up-regulate gastric epithelial cell Fas antigen expression. Because Th1 cells express higher levels of Fas ligand (FasL) than Th2 cells, the relative increase in Th1 cells during Hp infection may induce epithelial cell death through Fas-Fas ligand (FasL) interactions. ^, This notion is substantiated by the observation that proton pump- (H ⁺ ,K ⁺ -ATPase-) specific Th1 cells in the gastric mucosa kill target epithelial cells via Fas-FasL interactions and may act as effector cells in autoimmune gastritis (discussed later).

IgA antibodies, normally produced in the GI tract (see Chapter 2 ), are highly adapted for mucosal protection, conferring protective immunity without activating the complement cascade and causing deleterious amounts of cell damage and inflammation. The number of IgA-producing plasma cells increases in Hp infection. However, increased numbers of IgG- and IgM-producing plasma cells are also detected, along with activated complement. Monoclonal antibodies that recognize Hp can cross-react with human and murine gastric epithelial cells. ^, Transfer of these antibodies to recipient mice induces gastritis, as does the transfer of B cells that recognize heat shock proteins from individuals with MALToma.

With few exceptions, infection with Hp persists for the life of the host unless there is some intervention with antibiotics. This observation has led to investigations as to whether immunologic tolerance impairs immunity. Several bacterial factors, including urease and catalase, thwart innate host responses to infection. Furthermore, production of arginase by Hp inhibits NO production and may favor bacterial survival, whereas virulent strains of Hp impair phagocytosis and mucus production. The VacA toxin can impair bacterial antigen presentation by macrophages by inhibiting the antigen presentation pathway. Moreover, Hp produce molecules that mimic host molecules, such as Lewis antigens, that theoretically could stimulate T cells to release cytokines that help avoid autoimmune reactions. However, as already discussed, the cytokine profile associated with Hp infection is not one that would be expected to occur in a tolerant environment. For example, IL-4, IL-10, and TGF-β (which could mediate an anti-inflammatory effect) are not expressed to the same levels as proinflammatory Th1 cytokines such as IFN-γ and TNF-α. Because the infected gastric mucosa is characterized by chronic active inflammation, tolerance, if it has occurred, may favor persistent infection even though it cannot prevent the chronic inflammatory response.

Genetic heterogeneity in the regions of the host genome that controls the magnitude of inflammation is associated with gastric cancer development ( Chapter 54 ). Polymorphisms in the regions controlling IL-1 are associated with an increased incidence of hypochlorhydria and gastric cancer in Hp-infected individuals and decreases the incidence of DU recurrence. Increased IL-1 expression may not only drive inflammation but also lead to a physiologic change known to precede gastric cancer development, because IL-1 potently inhibits gastric acid secretion (see Chapter 51 ). Other genes that regulate the magnitude of the inflammatory response to Hp, including IL-10, TNF-α, and IL-8, have also been associated with the sequence of events leading to cancer. ^,

Elevated fasting and meal-stimulated serum gastrin levels are well documented in individuals with Hp infection. The net effect of Hp infection on gastric acid secretion in an infected individual is variable, however, depending on the duration and distribution of Hp infection and presence or absence of atrophy of the oxyntic glandular mucosa (see Chapters 51 and 53 ). Hp infection also reduces gastric mucin secretion and mucosal hydrophobicity, abnormalities that can be reversed after eradication of infection. Epithelial barrier function is altered during Hp infection as a consequence of both direct effects of Hp infection and the accompanying inflammatory responses that collectively increase epithelial cell proliferation and programmed cell death.

Bacterial (Hp)-related factors involved in the pathogenesis of Hp gastritis in the host discussed earlier are summarized in Box 52.1 . Environmental factors can have a moderating role in the Hp-host interactions. Such factors as smoking, a high-salt diet, and various environmental mutagens can heavily influence both the degree and rate of progression of mucosal injury. In Japan, for example, the incidence of gastric cancer fell by 60% between 1965 and 1995 despite no change in the virulence of the most common strain of Hp. This dramatic drop has been attributed to societal changes such as refrigeration (vs. salt preservation), westernization of the diet, and smoking reduction.

Diagnosis

There are endoscopic and nonendoscopic tests available to diagnose Hp infection. Such techniques may detect Hp directly (gastric histology, stool bacterial antigen, culture) or indirectly (urease detection or antibody response). ^, The appropriate method to choose depends on the clinical situation, prevalence of infection in the population, pretest probability of infection, test availability, and cost. Recent use of antibiotics or PPIs can influence the results of certain tests. The commonly used diagnostic tests and their advantages and disadvantages are summarized in Table 52.1 .

Endoscopic tests. Performing EGD solely to obtain gastric biopsies for the diagnosis of Hp infection is not appropriate. When EGD is clinically indicated, there are 3 methods to identify Hp in a gastric biopsy specimen: biopsy urease testing, histology, and culture. The choice of method depends on the clinical situation, cost, availability, and test accuracy. For each method, either 1 or 2 biopsies are obtained from both the antrum and corpus.

Biopsy urease testing is recommended initially because the method is efficient, relatively inexpensive, and generally accurate. ^, Gastric biopsy material is tested for urease activity by placing tissue in a medium containing urea and a pH reagent such as phenolphthalein. Hp urease hydrolyzes urea, liberating ammonia, which produces an alkaline pH and a resultant color change of the phenolphthalein test medium. Test results can be positive within minutes to hours. Several urease test kits are commercially available, differing only regarding medium (agar gel or membrane pad) and testing reagents. These kits are generally inexpensive, but in western centers there may be added costs associated with obtaining gastric tissue samples (e.g., up-coding a diagnostic endoscopy). Nevertheless, biopsy urease testing is less expensive than histology. Sensitivity and specificity of biopsy urease tests are 90% to 95% and 95% to 100%, respectively. ^, Accuracy can be negatively affected by blood in the stomach or by use of antibiotics, bismuth-containing compounds, or acid antisecretory drugs, especially PPIs. Therefore, a negative urease test does not exclude Hp infection in an individual taking antisecretory medication, a common scenario in patients referred for EGD. To improve sensitivity in such patients, stopping the potentially problematic medication and delaying EGD for 2 weeks (if possible) can be considered, and testing multiple (>2) biopsy samples from the antrum and corpus may be attempted.

Gastric mucosal histology assessment is generally not necessary to diagnose Hp, but it can provide information regarding the severity of mucosal inflammation (see Fig. 52.3 A ) and for the detection of Hp-associated precancerous lesions such as metaplastic (chronic) atrophic gastritis (discussed later) and dysplasia. Histologic examination had been considered the gold standard for identifying infection, with reported sensitivity and specificity as high as 95% and 98%, respectively. However, the distribution and density of organisms can vary within the stomach, with the potential for sampling error, particularly in patients taking antisecretory medications. Detection of organisms is common with standard H&E staining, but is improved with special stains such as Giemsa, silver, Genta, or specific immunohistochemical stains ( Fig. 52.4 ). ^{, ,}

Culture of mucosal biopsies is difficult because Hp is fastidious and slow growing, requiring specialized media and growth environment. ^, Culturing Hp is not routinely available in contemporary US practice. When culturing gastric mucosal biopsies for Hp, tissue should be obtained before biopsy forceps are exposed to formalin. Tissue is then placed in a container with only a few drops of saline or appropriate media to preserve the specimen during transport to a local or offsite microbiology facility. Although mucosal culture is not generally recommended, culture with antibiotic sensitivity testing can guide subsequent treatment in patients with refractory infection, with the understanding that in vitro sensitivity testing does not always predict clinical treatment outcome. ^,

Nonendoscopic tests . Serology is the most popular noninvasive test in clinical practice and is used for its convenience and relatively low cost. As described earlier, infection incites a systemic immune response, and enzyme-linked immunosorbent assay technology can detect IgG serum antibodies to a variety of bacterial antigens. ^, Tests for IgA and IgM antibodies are less reliable, and their use is discouraged. Office-based kits that test whole blood can provide results within 30 minutes and permit “point of service” testing. Although serology is relatively inexpensive, noninvasive, and ideally suited to a primary care setting, the prevalence of Hp in the population being tested influences its accuracy. The sensitivity of serology is generally quite high (90% to 100%), but its specificity is variable (76% to 96%). Therefore, in populations where infection is less common (including the USA), the negative predictive value of serology is high, but the positive predictive value is not, with many false positive results. Use of another test, such as a urea breath test or stool antigen (discussed later), is recommended in low-prevalence populations before embarking on therapy for Hp. Serology can remain positive for months or longer even after successful treatment of infection; thus, seroconversion (i.e., from a positive to negative result), though specific for treatment success, is not a practical way of testing for eradication.

Urea breath testing (UBT) detects active Hp infection and is useful for making the diagnosis and for documenting successful treatment. UBT relies on bacterial hydrolysis of orally administered urea tagged with a carbon isotope, either nonradioactive ¹³ C or radioactive ¹⁴ C ( Fig. 52.5 ). Hydrolysis of urea generates ammonia and tagged CO ₂ ( ¹³ CO ₂ or ¹⁴ CO ₂ ), which can be detected in breath samples. The nonradioactive ¹³ C test is preferred for children and the rare cases in which pregnant women need testing, as opposed to delaying testing until after pregnancy, as treatment of Hp in pregnancy is rarely indicated. The radiation dose with the ¹⁴ C test is low (1 μC), equivalent to 1 day of background radiation exposure. The specificity of the UBT exceeds 95%, making false-positive results uncommon. The sensitivity of the test is 88% to 95%, with false-negative results reported in patients taking antisecretory therapy such as PPIs, bismuth compounds, or antibiotics. To improve diagnostic accuracy, PPIs, bismuth salts, and antibiotics should ideally be stopped 1 to 2 weeks before UBT. UBT is not accurate in patients who have had a gastric resection.

Stool antigen testing is an immunoassay that detects Hp antigens and is the other principal noninvasive modality to diagnose active Hp infection and confirm eradication following treatment. Overall sensitivity and specificity of the stool antigen test are comparable to the UBT (94% and 97%, respectively). A rapid Hp stool antigen test is available that permits testing during a clinic visit, but it is slightly less accurate than a traditional laboratory-based stool test. The sensitivity of stool testing is also reduced by PPIs, bismuth salts, and antibiotics, which can decrease bacterial load; thus, similar precautions as described earlier for UBT are recommended when using stool antigen tests.

PCR is a sensitive method to detect Hp and to detect antibiotic resistance genes, but it is not yet practical for routine clinical diagnosis. It is useful for research purposes to identify bacteria in gastric biopsies, stool, or drinking water in a community setting, to type organisms in epidemiologic or transmission studies, and for testing for antibiotic resistance genes.

When clinically indicated, it is appropriate to confirm successful eradication of infection with either a UBT or stool antigen test. Current USA treatment guidelines (discussed later) suggest that all infected individuals should undergo testing to confirm successful eradication of infection. ^, The European guidelines favor offering noninvasive tests to all individuals treated for Hp to confirm eradication. Post-treatment endoscopy with biopsy is only necessary if a repeat procedure is clinically indicated. In such patients, sampling multiple areas of the stomach is important to avoid missing persistent infection due to alteration of the bacterial density and distribution by prior antibiotics and antisecretory medications. These tests should not be performed sooner than 6 to 8 weeks after completion of treatment, because earlier testing might yield false-negative results. Also, medications that could affect test results, such as PPIs, should be discontinued for at least 1 to 2 weeks before testing to improve accuracy. The chronic inflammation associated with Hp infection may take months and sometimes over a year to subside following eradication of the organism, so its presence in biopsy material should not be interpreted as persistent infection.

EMAG

EMAG is characterized by involvement of both the gastric antrum and corpus with glandular atrophy and IM ( Fig. 52.3 B ). It is important for endoscopists to obtain at least 2 biopsies from the antrum, 1 from the incisura angularis, and 2 from the gastric body in order for the pathologist to be able to render a diagnosis of EMAG. Atrophic gastritis involving the corpus may be associated with pseudopyloric metaplasia, in which the mucosa resembles antral mucosa but stains for pepsinogen I (PGI), a proenzyme normally expressed in corpus mucosa. Other types of metaplasia (pancreatic, squamous, and ciliated) may also occur.

Gastroscopy may show a pale mucosa, shiny surface, and prominent submucosal vessels due to mucosal thinning (see Fig. 52.6 ). However, endoscopy is neither sensitive nor specific in diagnosing chronic atrophic gastritis, especially in patients younger than age 50. Magnifying endoscopy and autofluorescence imaging video endoscopy may be more sensitive in detecting atrophy. ^,

The pathogenesis of EMAG is multifactorial, but Hp infection plays the most important role and has been incriminated in about 85% of patients. EMAG can occur early in life in Hp-infected individuals. 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 China, a model has been developed based on gender, general health, family history of cancer, and diet/alcohol use to stratify the risk of gastric cancer in patients with EMAG and to determine the need for screening gastroscopy. IM is a risk factor for dysplasia and gastric cancer, usually the intestinal type (see Chapter 54 ). The incidence of gastric neoplasia (dysplasia, cancer) in intestinal metaplastic lesions of the stomach has been estimated to be 1% per year, although most of these incident neoplastic lesions were dysplastic lesions and not invasive cancers. IM of the gastric mucosa can be classified into 3 subtypes depending on the morphology of the epithelium and the types of mucins produced.

AMAG

AMAG, also called diffuse corporal atrophic gastritis, is an autoimmune destruction of glands in the corpus of the stomach. AMAG is the pathologic process underlying pernicious anemia, an autoimmune disorder typically occurring in patients of northern European or Scandinavian background and in African Americans. It may be associated with other autoimmune disorders, especially autoimmune thyroiditis. Although some patients with AMAG are asymptomatic, many complain of dyspepsia with postprandial distress.

Patients with AMAG exhibit achlorhydria or hypochlorhydria, hypergastrinemia with antral G-cell hyperplasia secondary to low or absent gastric acid, and low serum PGI concentrations with low ratios of serum PGI/PGII. ^, Affected patients often have circulating antibodies to parietal cell antigens and to IF; the antibodies to IF are less sensitive for AMAG but more specific, whereas antibodies to parietal cell antigens are more sensitive but less specific. Autoreactive T cells and subsequent production of autoantibodies against the α and/or β chains of the H ⁺ , K ⁺ -ATPase (ATP4A and ATP4B) by B/plasma cells are thought to play a role in the pathogenesis of AMAG. Pseudopyloric metaplastic (sometimes called spasmolytic polypeptide-expressing metaplasia) and metaplastic pancreatic acinar cells are also a feature of AMAG.

Histologically, atrophic glands with extensive IM are confined to the corpus mucosa ( Fig. 52.3 C ). Atrophy is usually focal and the preserved islands of relatively normal oxyntic mucosa may appear polypoid endoscopically or radiologically (pseudopolyps). Rarely, AMAG progresses to diffuse (complete) gastric atrophy. Hypergastrinemia, a consequence of achlorhydria, is associated with enterochromaffin-like cell hyperplasia and gastric carcinoid tumors, discussed in more detail in Chapter 34 .

Antibodies to parietal cell antigens, most notably the H ⁺ , K ⁺ -ATPase, are frequently present in patients with AMAG. These antibodies can also be detected in patients with various other autoimmune diseases, including type 1 diabetes mellitus and autoimmune thyroid diseases (Graves disease and Hashimoto thyroiditis), ^, explaining the association of these conditions with pernicious anemia. The risk of AMAG is increased 3- to 5-fold in type 1 diabetic individuals, and some authors have suggested screening type 1 diabetics with gastroscopy and mucosal biopsy. AMAG has also been associated with autoimmune pancreatitis, as well as celiac disease/dermatitis herpetiformis. ^,

In patients with AMAG, a proportion of the CD4 ⁺ lymphocytes present in the chronic inflammatory infiltrate within the gastric mucosa proliferate in response to H ⁺ , K ⁺ -ATPase. Most CD4 ⁺ cells secrete Th1 cytokines such as IFN-γ and TNF-α, provide help for B cell immunoglobulin production, and enhance perforin-mediated cytotoxicity, as well as Fas-Fas ligand-mediated apoptosis. These factors in combination may contribute to gland destruction in AMAG.

Many patients with AMAG have circulating antibodies to Hp and/or have Hp detectable in their gastric-oxyntic mucosa. Thus, Hp may play a role in the pathogenesis of AMAG. It appears Hp strains producing cagA and VacA are most likely to cause AMAG. These particular Hp are often the s1m1 VacA subtype that also express Lewis blood group antigens X and Y. Lewis antigens on the Hp may help camouflage the organism because these antigens are also present on human gastric epithelial cells. It has been suggested that when antibodies to Lewis antigens X and Y from Hp develop, they cross-react with similar antigens on epithelial cells resulting in AMAG (molecular mimicry). If chronic atrophic gastritis with IM develops in such patients over time, the prevalence of active Hp infection will then decrease.

Immune checkpoint inhibitors that block programmed death receptors (e.g., PD-1) are being used more often in cancer patients, and one such agent, nivolumab, has been reported to cause an autoimmune hemorrhagic gastritis.

CMV

CMV is a human herpesvirus (HHV5) that may infect the stomach. Although gastric CMV infection may occur in an immunocompetent host, infection usually occurs in the immunocompromised. Patients with solid organ or hematopoietic cell transplants (see Chapter 36 ), AIDS (see Chapter 35 ), cancer, or who are taking immunosuppressive drugs (especially glucocorticoids) are at increased risk.

Patients with CMV infection of the stomach can experience epigastric pain with fever and atypical lymphocytosis. Gastric imaging may reveal marked thickening of gastric folds and a rigid and narrowed gastric antrum suggestive of an infiltrating antral neoplasm. Gastroscopy may reveal thickened hemorrhagic folds with a congested and edematous antral mucosa, covered with multiple ulcerations, suggestive of gastric malignancy, submucosal antral mass, or PUD. A hypertrophic and/or polypoid type of gastritis resembling Ménétrier’s disease (discussed later) with protein-losing gastropathy may occur, especially in children, including one case with CMV/Hp coinfection.

Examination of mucosal biopsy specimens shows inflammatory debris, chronic active gastritis, and enlarged cells with CMV inclusion bodies indicative of an active infection ( Fig. 52.7 A ). “Owl-eye” intranuclear inclusions are the hallmark of CMV infection in routine H&E 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 (see Fig. 52.7 B ). When typical inclusions are hard to find in H&E-stained sections, immunohistochemical stain for CMV may be helpful. Usual treatment is with IV ganciclovir or foscarnet, along with reducing immunosuppression, if feasible. In patients with AIDS, antiretroviral therapy is required to prevent relapse of CMV infection.

Other Herpesviruses

Gastritis from HSV-1 (HHV1) or varicella-zoster virus (HHV3) is rare. ^, Infected individuals typically experience the initial infection at an early age, and the virus then remains dormant until reactivation. Reactivation has been related to cancers (including lymphoma) and to radiation therapy and/or cancer chemotherapy agents. The typical immunocompromised patient with these herpesvirus gastritides may experience nausea, vomiting, abdominal pain, fever, chills, fatigue, and weight loss. 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. Gastroscopy reveals multiple, small, raised, ulcerated plaques or linear, superficial ulcers in a crisscrossing pattern, giving the stomach a cobblestone appearance. Brush cytology and biopsies should be performed at the time of endoscopy. Brush cytology has the advantage of sampling a wider area of mucosa. Grossly, the ulcers are multiple, small, and of uniform size. Microscopically, cytological smears and biopsy specimens show nonspecific active inflammation, containing scattered multinucleated cells with smudged (ground glass) intranuclear inclusions. HHV1 and HHV3 show identical histology in tissue. Immunohistochemistry, viral culture, or PCR of an appropriate swab or tissue specimen is required to differentiate these 2 infections. Treatment with acyclovir is reasonable but of unproved value.

EBV (HHV4) is not present in normal gastric mucosa, but can be present in the stomach in almost half of the patients with gastritis. Whether EBV is a cause of the gastritis in these cases is uncertain. EBV infection has been linked to gastritis cystica profunda (GCP; discussed later) and with gastric cancer. Infectious mononucleosis due to acute EBV infection may lead to gastric lymphoid hyperplasia with atypical lymphocytes.

Measles

Measles, caused by rubeola virus, has many GI manifestation, including, rarely, gastritis. The characteristic histologic pattern is of numerous multinucleated giant cells (Warthin-Finkeldey cells) within gastric epithelial and stromal cells, with background mild chronic inflammation.

Mycobacteria

Gastric infection with Mycobacterium tuberculosis is rare. Patients typically present with abdominal pain, nausea and vomiting, GI bleeding from a tuberculous gastric ulcer, anemia, fever, and weight loss. Gastric TB may be associated with gastric outlet obstruction. Imaging studies reveal an enlarged stomach with a narrowed, deformed antrum and pre-pyloric ulcerations. Upper endoscopy demonstrates ulcers, masses, or gastric outlet obstruction. Duodenal TB can also cause gastric outlet obstruction. Grossly, the stomach may demonstrate multiple small mucosal erosions, ulcers, an infiltrating mass (hypertrophic form), sclerosing inflammatory disease, or pyloric obstruction either by extension from peripyloric nodes or by invasion from other neighboring organs. Biopsies show caseating granulomas containing Langhan’s giant cells and rare tiny bacilli, visualized only with an acid-fast stain. Treatment is discussed in Chapter 84 .

Although infection with the Mycobacterium avium complex ( M. avium, M. intracellulare, M. chimaera ) is a common opportunistic infection among patients with AIDS (see Chapter 35 ), the stomach is rarely involved. Microscopically, the gastric mucosa demonstrates numerous foamy histiocytes containing many acid-fast bacilli. Treatment is with a macrolide (clarithromycin or azithromycin) plus rifampicin and ethambutol.

Actinomycosis

Primary gastric actinomycosis is a rare, chronic, progressive, suppurative disease characterized by formation of multiple abscesses, draining sinuses, and abundant granulation and dense fibrous tissue. The presenting symptoms of gastric actinomycosis include fever, epigastric pain, epigastric swelling, abdominal wall abscess with fistula, and UGI bleeding. Radiographic studies frequently suggest a malignant tumor or a peptic (gastric) ulcer. Endoscopy is suggestive of a circumscribed and ulcerated gastric carcinoma, and the diagnosis can be made with endoscopic biopsy.

Grossly, the resected stomach demonstrates a large, ill-defined, ulcerated mass in the wall of the stomach. Microscopically, multiple abscesses show the infective agent, Actinomyces israelii , a gram-positive filamentous anaerobic bacterium that normally resides in the mouth. A biopsy of a mass containing pus, or a biopsy of a draining sinus, may reveal actinomycosis. If the disease is recognized only by histologic examination, the prognosis is good. Prolonged (6- to 12-month) high-dose antibiotic treatment with penicillin or amoxicillin/clavulanic acid is recommended.

Syphilis

The incidence of primary and secondary syphilis is increasing in the USA, with over 27,000 cases reported in 2016, a 17.6% increase compared with 2015. Case reports and small case series emphasize the importance of the gastroenterologist and pathologist remaining alert to the protean manifestations of syphilis and being familiar with the histopathologic pattern of the disease. ^, Gastric involvement in secondary or tertiary syphilis is rarely recognized clinically, and its diagnosis by examination of endoscopic biopsy specimens has been reported infrequently. The features of syphilis in the stomach should be recognized because they can provide a window of opportunity for effective antibiotic therapy before the disease progresses and causes permanent disability. Syphilitic gastritis can occur in conjunction with hepatitis and proctitis. Gastric syphilis can occur in the setting of HIV infection.

Patients typically present with symptoms of PUD, often with UGI bleeding. Diseases that may mimic gastric syphilis include PUD and gastric adenocarcinoma, lymphoma, TB, and Crohn disease. The acute gastritis of early secondary syphilis produces the earliest radiologically detectable signs of the disease, with diffusely thickened folds that may become nodular, with or without ulcers. Strictures in the mid-stomach (“hourglass” stomach) may be present ( Fig. 52.8 A ). Endoscopy shows numerous shallow, irregular ulcers with overlying white exudate and surrounding erythema (see Fig. 52.8 B ). The surrounding mucosa may also demonstrate a nodular appearance. Gastroscopy may also demonstrate prominent, edematous gastric folds.

Grossly, the stomach may be thickened and contracted and may show multiple serpiginous ulcers. Partial gastrectomy specimens may show compact, thick, mucosal folds and numerous small mucosal ulcers. Microscopically, biopsies show severe gastritis with dense plasma cell infiltrate in the lamina propria, varying numbers of neutrophils and lymphocytes, gland destruction, vasculitis, and granulomas. Warthin-Starry silver stain or modified Steiner silver impregnation stain reveals numerous spirochetes. Serum Venereal Disease Research Laboratory and Treponema immunofluorescence studies may be positive, and PCR may detect the Treponema pallidum gene. Treatment with penicillin is highly effective (see Fig. 52.8 C ).

Other Bacteria

Helicobacter heilmannii are spiral bacteria and an infrequent cause of chronic active gastritis; this infection may be a risk factor for gastric MALToma. These organisms, originally known as Gastrospirillum hominis , are longer than Hp and have multiple spirals. One of these H. heilmannii species, Helicobacter bizzozeronii , has been isolated from human gastric mucosa. Another organism that, like Hp, can stain with the Giemsa reagent is Campylobacter hyointestinalis . The clinical significance of these non-Hp curved bacilli remains to be established.