41. Hemorrhagic and Erosive Gastropathy - Endoscopy and Histology
On the left is the endoscopic picture from a 64 yr. old man with chronic obstructive pulmonary disease and a history of tobacco use who transferred to the intensive care unit with adult respiratory distress syndrome in shock. Three days later gastric aspirate contained “coffee ground” material. Endoscopy revealed extensive punctate and confluent mucosal hemorrhage (red areas) and evidence of slightly older recent bleeding (brown areas).
On the right is shown the histologic findings in the gastric biopsy. Spotty detachment of the superficial epithelium with erosions and fresh hemorrhage and edema in the lamina propria are evident. Note the absence of inflammatory infiltrate. These findings are consistent with the patient’s shock and with the descriptions and mechanisms given in slides 40, 44, and 45.

42. Rapid Reconstitution Of Ulcer Coverage By Proliferating Epithelium
The upper panel shows a gastric ulcer with loss of the mucosa and with inflammatory exudate at the ulcer base. The lower panel demonstrates the flat regenerating epithelium growing out over the base from the ulcer edge to rapidly seal-off the defect. The glandular components of the mucosa will eventually be completely reconstituted from this primitive-looking beginning. (See also slide 60.)

43. Aspirin Causes Loss Of Surface Mucous Cells In Human Stomach - Scanning Electron Micrographs
The slide demonstrates disruption of the gastric surface epithelial barrier occurring within a few minutes after gastric instillation of a standard dose of aspirin (two tablets) in healthy persons. Note that the individual epithelial cells, which are normally dome-shaped, developed a hollowed-out appearance. Light and transmission electron microscopy were confirmatory, showing focal cell disruption and loss of mucous granules. Tight junctions were seen to be intact. Damage was maximal midway between foveolae. Deeper structures (glands) were not affected. Parallel measurements of gastric potential difference showed a voltage drop (1).
These findings are in accordance with the principles of gastric mucosal protection and response to barrier compromise summarized in slides 44 and 45.
1) Baskin WN, Ivey KJ, Krause WJ, et al. Aspirin-induced ultrastructural changes in human gastric mucosa: correlation with potential difference. Ann Intern Med 1976;85:
2) Graham DY, Smith JL. Aspirin and the stomach. Ann Intern Med 1986;104:

44. The Gastric Mucosa Is Protected By A Multi-layered Defense
The gastric mucosa is protected from damage by acid-peptic gastric secretion and other endogenous and exogenous noxious materials by a multi-faceted barrier consisting of: 1) a mucus layer defense which is made up of the secreted surface mucus layer which, although permeable to H + , excludes large molecules such as pepsin from the epithelial surface. HCO3- is maintained at high concentration at the epithelial surface because its diffusion is limited by the mucus layer, 2) epithelial defense which has 3 components: first, a hydrophobic surface which limits access to the surface epithelium; second, epithelial cell-to-cell tight junctions which maintain a high transmucosal potential difference, and 3) rapid restitution of breaks in the epithelial layer. In that process epithelial cells adjacent to the interrupted area quickly flatten and spread to cover the defect. This is soon followed by increased cell division that restores normal surface epithelial cell density. Subepithelial defense is provided by the rich subepithelial blood supply which brings O2, nutrients, and HCO3- to the surface epithelium. For each H + ion secreted a HCO3- ion is provided by vessels delivering blood to the gastric surface epithelium.
Two factors have been identified which mediate these protective barrier functions: 1) increased prostaglandin (PG) release and 2) stimulation of a neural alarm system which is activated at the first indication that noxious substances, e.g. H + , bile salts, alcohol etc. have reached the gastric epithelium. These systems initiate a series of protective responses that increase epithelial resistance. It has been shown that prostaglandins sensitize the afferent nerves of the neural alarm system so that their response to a noxious stimulus is magnified thus increasing mucosal protection.
The nerves involved in this alarm system are spinal and vagal afferent (sensory) nerves. These nerves provide a dense plexus to the epithelium and vasculature. Calcitonin gene related peptide (CGRP), substance P (SP), and neurokinin A (NKA) are expressed by these nerves. Stimulation of these afferent nerve fibers leads to release of CGRP and NKA/SP. CGRP, acting through receptors on the arteriolar and venular walls lead to the biosynthesis of nitric oxide (NO) and consequent increased mucosal blood flow by arteriolar vasodilatation and prevention of venular constriction. However, not all protective effects of afferent nerve stimulation is by increased mucosal blood flow. Other effects not involving increased blood flow mechanisms, activated through the NK2 receptor, may also play an important role in protecting the integrity of the gastric mucosa. It is unclear whether all of the protection is through the release of CGRP, but redundancy is to be expected for such an important function as protection of the gastric mucosa.
1) Del Valle J, Cohen H, Lane L, Scheiman JM. Acid peptic disorders. In: Yamada T, ed. Textbook of Gastroenterology, Philadelphia; Lippincott Williams and Wilkins 1999:1370.
2) Holzer P, Livingston EH, Saria A, Guth PH. Sensory neurons mediate protective vasodilation in rat gastric mucosa. Am J Physiol 1991;260:G363.
3) Stroff T, Plate S, Ebrahim JS, Ehrlich KH, Respondek M, Peskar BM. Tachykinin-induced increase in gastric mucosal resistance: role of primary afferent neurons, CGRP and NO. Am J Physiol 1996;271:G1017.
4) Holzer P, Pabst MA. Visceral afferent neurons. Role in gastric mucosal protection. News Physiol Sci 1999;14:201.
5) Holzer P. Neural emergency system in the stomach. Gastroenterology 1998;114:823-9.
6) Tashima K, Korolkiewicz R, Kubomi M, Takeuchi K. Increased susceptibility of gastric mucosa to ulcerogenic stimulation in diabetic rats - role of capaicin-sensitive sensory neurons. Br J Pharmacol 1998;124:
7) Brzozowski T, Drozdowicz D, Szlachic A, Pytko-Polonczyk J, Majka J, Konturek SJ. Role of nitric oxide and prostaglandin in gastro protection-induced by capsaicin and papavesine. Digestion 1993;54:24-31.
8) Ferreira SH, Moncado S, Vane JR. Prostaglandin and mechanism of analgesia produced by aspirin-like drugs. Brit J Pharmacol 1973;99:86-97.
9) Boku K, Ohno T, Saeki T, et al. Adaptive cytoprotection mediated by prostaglandin I 2 is attributable to sensitization of CGRP-containing sensory nerves. Gastroenterology 2001;120:

45. Pathogenesis Of Acute Hemorrhagic And Erosive Gastropathy
The gastric mucosal barrier may be compromised in three ways: 1) By direct injury (e.g., drugs, corrosives, irradiation, instrumentation, etc.), 2) inhibition of cyclooxygenase leading to decreased mucosal prostaglandins (PG). Inhibition of PG synthesis decreases mucus and HCO3- secretion, mucosal hydrophobicity, and epithelial restitution. In experimental animals 95% inhibition of gastric cyclooxygenase synthesis was not associated with erosions when NSAIDs were given parenterally but were associated with extreme erosions after intragastric administration. These experiments suggest that reduction of PG’s does not in itself produce gastric erosions but that reduced PG leads to increased mucosal sensitivity to damaging agents, and 3) decreased mucosal blood flow (e.g., as associated with hypovolemia, sepsis, shock, etc.) limits the supply of HCO3-, O2 and nutrients to the surface epithelium. As a consequence of one or a combination of multiple compromises to the gastric mucosa, the epithelial barrier is not maintained and hemorrhagic and erosive gastropathy may follow (1,2).
When the gastric epithelial barrier is compromised, H + , pepsin, and any refluxed duodenal peptidases, bile salts, etc. can enter the lamina propria, and cause both direct damage to deeper structures and also lead to release of a variety of biologically active agents such as histamine, bradykinin and cytokines which can also lead to damage to the mucosal vasculature. That damage is followed by edema and superficial hemorrhage and at times erosions which can eventually become ulcers with continued damage (3). The resulting pathological changes are commonly alluded to as gastritis. However, since there is typically minimal or no inflammation, we and others (4,5,6), prefer to designate the condition as a gastropathy .
1) Ligmumsky M, Golanska EM, Hansen DG, et al. Aspirin can inhibit gastric mucosal cyclooxygenase without lesions in the rat. Gastroenterology 1983;84:756.
2) Hawkey CJ. Review article: Aspirin and gastrointestinal bleeding. Aliment Pharmacol Ther 1994;8:141.
3) Lev R, Molot MD, McNamara J, Stremple JF. “Stress” ulcers following war wounds in Vietnam. Lab Invest 1971;25:
4) Yardley JH, Hendrix TR. Gastritis, duodenitis and associated ulcerative lesions. In Yamada T, ed Textbook of Gastroenterology. Philadelphia: J.B. Lippincott Co :1456.
5) Carpenter HA, Talley NJ. Gastroscopy is incomplete without biopsy: clinical relevance of distinguishing gastropathy from gastritis. Gastroenterology 1995;108:917.
6) Laine L, Weinstein WM. Histology of alcoholic hemorrhagic “gastritis”: a prospective evaluation. Gastroenterology 1988;94:1254.

46. Acute H pylori Gastritis (Primary Infection): Major Features
Acute infection with H pylori is recognized uncommonly, and those few cases that have been reported (1-3) are presumed to represent only a small fraction of the their actual prevalence. A possible explanation for the paucity of reports of acute H pylori gastritis is that the initial infection produces few or no symptoms in many if not most individuals. The most complete and accurate descriptions of acute upper GI symptoms have come from experimentally-induced H pylori infection (4,5).
1) Salmeron M, Desplaces N, Lavergne A, Hondast R. Campylobacter-like organisms and acute purulent gastritis. Lancet 1986;2:975.
2) Frommer DJ, Carrick J. Lee A, Hazell SL. Acute presentation of Campylobacter pylori gastritis. Am J Gastroenterol 1988;83:1168.
3) Rocha GA, Queiroz DMM, Mendes EN, Barbosa AJA, Lima GF, Jr, Oliveira CA. Helicobacter pylori acute gastritis: Histological, endoscopical, clinical and therapeutic features. Am J Gastroenterol 1991;86:1592.
4) Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ. Attempt to fulfil Koch’s postulate for campylobacter pylori . Med J Aust 1985;142:436.
5) Morris A, Nicholson G. Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol 1987;82:192.

47. Chronic H pylori Gastritis (Long-Term Infection): Major Features
If untreated the acute infection evolves into chronic H pylori gastritis. Epidemiological studies in the USA and elsewhere have established that chronic H pylori gastritis is widespread in developed countries and is especially common in developing countries (see slide 49). They have also confirmed its connections to peptic ulcer disease and gastric neoplasia (see slides 48 and others). There are no characteristic symptoms or endoscopic findings with the exception of an endoscopically seen antral nodularity (“plucked chicken-skin” appearance) in about 30% of H pylori infected patients (2,3). In addition there has been no convincing and broadly accepted evidence that H pylori infection can account for one of the commonest of all upper GI complaints — “nonulcer dyspepsia” (4).
The key pathologic feature in chronic H pylori gastritis is intense chronic inflammation, usually with associated active (acute) inflammation (see slide 53). The chronic inflammatory component is often referred to as Mucosa-Associated Lymphoid Tissue (MALT). MALT is typically accompanied by one or more lymphoid nodules with germinal centers (see slide 55).
1) Yardley JH, Hendrix TR. Gastritis, gastropathy, duodenitis and associated ulcerative lesions. In: Yamada T. Textbook of Gastroenterology, Chapter 66, Philadelphia, Lippincott, Williams and Wilkins, 1999:1464.
2) Laine L, Cohen H, Sloane R, Marin-Sorensen M, Weinstein WM. Interobserver agreement and predictive value of endoscopic findings for H pylori and gastritis in normal volunteers. Gastrointest Endosc.1995;42:420-3.
3) Cohen H, Laine L. Endoscopic methods for the diagnosis of Helicobacter pylori . Aliment Pharmacol Ther 1997;11(Suppl 1):3.
4) Van Zanten SJOV. The role of Helicobacter pylori in non-ulcer dyspepsia. Aliment Pharmacol Ther 1997;11(Suppl 1):63.

48. Clinical Outcomes And Sequelae Of Helicobacter pylori Infection
The strong evidence for association of H pylori infection with gastritis and peptic ulcer disease dates back to the initial published observations of Warren and Marshall regarding the organism in 1983 (1,2). Their seminal observations, which were initially received with great skepticism, have since been confirmed and expanded on by many investigators. Furthermore, important facts about the pathogenetic contributions of H pylori infection to peptic ulcer disease and gastric neoplasia are now understood, and continue to be expanded on (see slides 55,82-85,114,115,118 and 119).
Helicobacter pylori infects a large proportion of the world’s population. Prevalence has been estimated to be 30-50% in industrialized countries and as high as 90% in many developing countries. The arrival of H pylori in the stomach leads to an acute gastritis usually associated with temporary hypo- or achlorhydria. This acute gastritis produces little or no symptoms so acute H pylori infection is almost never diagnosed. All our information regarding this initial acute stage comes from experimentally-induced infections.
The acute phase subsides within a couple of weeks and gastric acid production returns and the gastritis evolves into chronic active gastritis which is a life long infection which is asymptomatic in the vast majority of those infected.
Peptic ulcers (DU and/or GU) develop in 10% of individuals with chronic active gastritis during their lifetime. In individuals with DU the chronic active gastritis is initially more severe in the antrum but with time it may spread into the corpus.
With long-standing H pylori infection so-called environmental metaplastic atrophic gastritis may develop. It is most frequently found in the transition zone in the region of the incisura (see slide 62). In the early stage it is spotty in distribution but may become confluent involving the entire antrum and much of the corpus. It is in the setting of this lesion that gastric ulcers and gastric cancers arise.
It was later suggested that H pylori infection can lead to autoimmune metaplastic atrophic gastritis (AMAG) or “autoimmune gastritis” (see slide 62). This possible association was overlooked initially because by the time the mucosa of the body has become atrophic, acid production has disappeared and H pylori cannot be detected in gastric biopsies because H pylori has lost is protected niche although serologic evidence of H pylori persists.
Damaged metaplastic mucosa is prone to progress to gastric cancer regardless of the source of the injury. It has been estimated that the lifetime risk of developing gastric cancer is 1% in H pylori infected individuals.
H pylori plays a direct role in the pathogenesis of MALT (mucosa associated lymphoid tissue) lymphomas (see slide 82). Indeed if H pylori is eradicated these lymphomas often regress or disappear.
1) Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983;1:1273.
2) Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:
3) Bodger K, Crabtree JE. Helicobacter pylori and gastric inflammation. Brit Med Bull 1998;54:
4) Calum J. Helicobacter pylori modulation of gastric acid. Yale J Biol Med 1999;72:
5) Farthing MJG. Helicobacter pylori infection: an overview. Brit Med Bull 1998;54:1-6.
6) Kuipers EJ. Review Article: exploring the link between Helicobacter pylori and gastric cancer. Aliment Pharmacol Ther 1999;13 (Suppl 1):3-11.
7) Kuipers EJ, Uyterlinde AM, Pena AS, Roosendaal R, Pals G, Nelis GF, Festen HPM, Meuwissen SGM. Long-term sequelae of Helicobacter pylori gastritis. Lancet 1995;345:
8) Correa P, Filipe MI, Torrado J. Gastritis and gastric neoplasia. In: Gastritis. Graham DY, Genta RM, Dixon MF. eds. Lippincott Williams & Wilkins, Philadelphia 1999.
9) Ernest P. Review Article: the role of inflammation in the pathogenesis of gastric cancer. Aliment Pharmacol Ther 1999;13 (Suppl 1):

49. Prevalence Of Helicobacter pylori Infection In Developing Versus Developed Countries
The data shown here are the mean values for prevalence of H pylori with increasing age derived from the literature by Pounder and Ng (1). The developing countries included Algeria, Brazil, Chile, Ivory Coast, Nepal, Peru, Saudi Arabia, South Africa, Thailand, and Vietnam. Data on developed countries came from Belgium, Finland, France, Japan, United Kingdom (England & Wales), and United States (Whites). The results are mostly based on serological tests for anti- H pylori antibodies.
The data demonstrate two age-related patterns. The developing countries with a high prevalence of childhood H pylori infection stands in contrast to the low prevalence noted in industrialized, developed countries. The steady increase in prevalence with increasing age in countries in the second group (low childhood prevalence) had in the past been attributed to a steady rate of acquisition throughout life.
It has also been postulated that the greater prevalence of H pylori infection in the young in developing countries carries over to the present day adult population in those societies, i.e., there has been a “birth cohort” effect (3). If this hypothesis is correct, it also suggests that the current adult rates in developed societies may show decline in the future.
1) Pounder RE, Ng D. The prevalence of Helicobacter pylori infection in different countries. Aliment Pharmacol Ther 1995;9 (Suppl 2):33-39.
2) Graham DY, Malaty HM, Evans DG, Evans, Jr. DJ, Klein PD, Adams E. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Gastroenterology 100: ,1991.
3) Parsonnet J. The incidence of Helicobacter pylori infection. Aliment Pharmacol Ther 1995;9(Suppl 2):45-51.

50. Helicobacter pylori : Curved Organisms (HP) With Flagellae Over Gastric Epithelium
The typical gently curved shape of the H pylori bacilli (HP) and their characteristic localizing adherence to the surface and foveolar epithelium is seen in both the silver stained tissue for light microscopic (left) and electron microscopic (right) images. There is evidence for specific tropism of H pylori for gastric epithelium (1), a tropism that in all likelihood is mediated by specialized epithelial receptors and adhesion molecules at the H pylori surface (2,3) (see slide 55).
Also seen are the flagellae that give the organisms their motility. Their motile capability correlates well with the frequent presence of organisms, sometimes in large numbers, in the mucus layer over the gastric epithelium (see slide 52, right panel).
H pylori organisms are noted primarily in mucus and adjacent to mucous cells at the mucosal surface and in gastric foveolae. H pylori organisms generally do not involve gastric glands, although by electron microscopy it has been suggested that remnants of H pylori organisms can rarely be found in parietal cells (4). H pylori organisms are also not attracted to small intestinal epithelium in the duodenum, and they do not occur in the gastric lamina propria, except possibly in patients with acquired immunodeficiency syndrome (AIDS).
1) Morgan DR, Leunk RD. Pathogenesis of infection by C. pylori . In: Blaser MJ, Ed., Campylobacter pylori in gastritis and peptic ulcer disease. New York, Igaku-Shoin, 1989, pgs
2) Falk P, Roth KA, Boren T, Westblom TU, Gordon JI, Normark S. An in vitro adherence assay reveals that Helicobacter pylori exhibits cell lineage-specific tropism in the human gastric epithelium. Proc Natl Acad Sci USA 1993;90:
3) Evans DG, Karjalainen TK, Evans DJ Jr, Graham DY, Lee CH. Cloning, nucleotide sequence, and expression of a gene encoding an adhesion subunit protein of Helicobacter pylori . J Bacteriol 1993;175:
4) Chen XG, Correa P, Offerhaus J, et al. Ultrastructure of the gastric mucosa harboring Campylobacter -like organisms. Am J Clin Path 1986;86:575.

51. H pylori Organisms Have Specific Affinity For Gastric Mucous Cells But Not Intestinal Absorptive Cells
51. H pylori Organisms Have Specific Affinity For Gastric Mucous Cells But Not Intestinal Absorptive Cells.
The slide shows a gastric antral biopsy with focal intestinalization that was stained with modified Giemsa method to demonstrate H pylori organisms that have colonized in a thick sheet over gastric surface epithelium, reflecting a strong, specialized affinity by the organisms for gastric mucous cells (1,2). By contrast, as is well shown in the slide, the organisms are not attracted to adjacent metaplastic small intestinal-type absorptive cells. Blood group antigens are thought to play an important role in the specific adherence of H pylori to gastric mucous cell (1,3).
Comparable findings are noted when the duodenum is colonized by H pylori. In the duodenum, however, the organisms are restricted to metaplastic gastric mucous cells. These observations in the duodenum are critical to the pathogenesis of ACTIVE peptic duodenitis and duodenal ulcer disease (see slides 111, 112, 113, 114, 119).
1) Falk P, Roth KA, Boren T, et al. An in vitro adherence assay reveals that Helicobacter pylori exhibits cell lineage-specific tropism in the human gastric epithelium. Proc Natl Acad Sci USA 1993;90:2035.
2) Morgan DR, Leunk RD. Pathogenesis of infection by C. pylori . In: Blaser MJ, Ed., Campylobacter pylori in gastritis and peptic ulcer disease. New York, Igaku-Shoin, 1989, pgs
3) BorÇn T, Falk P, Roth KA, Gîran L, Normark S. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 262: ,1993.

52. Helicobacter pylori : Routine Stains For Detecting And Verifying Bacillary And Coccoid Forms
A definitive histopathologic diagnosis of H pylori (HP) infection depends on the unambiguous demonstration of the small curved rods seen here and in slide 50. While the organisms can often be identified in standard hematoxylin and eosin (H&E) stained tissue, in general that is an unreliable method that is inadequate as the regular and sole method for demonstrating HP (1). A variety of dependable special staining methods for HP are available. While silver staining gives high contrast, the techniques are lengthy and costly and results can be capricious. Overall, for routine use many pathologists prefer a rapid Giemsa method (e.g., using commercially available “Diff-Quik”) (left hand panel). The staining process is fast, easy to do, gives consistent results, and is relatively inexpensive.
A large number of immunostained HP organisms in luminal mucus are demonstrated (right panel). The immunostaining method is a standard “sandwich” technique that begins by exposing the tissue to anti-HP antibodies prepared in an animal. The organisms are then demonstrated by localizing the attached animal anti-HP antibodies with an appropriate anti-animal antibody. The latter is also bonded to a molecule that makes it visible in the microscope as a brown stain; the organisms are thereby “labeled” (right panel). The immunostaining method is very sensitive and highly specific (2). Detection of HP by immunostaining is especially useful when the organisms are sparse; it can also be helpful for definitive demonstration of HP when other bacterial species are also present.
In addition to the typical bacillary form of HP. a coccoid form can be seen occasionally in gastric biopsies (left panel, inset and right panel, arrows) (3). The coccoid forms can be identified as H pylori from their close association with conventional bacillary forms and by their uptake of the anti-HP immunostain (right panel, arrows). The coccoid forms occur in vitro under conditions of nutrient deprivation and antibiotic exposure and similar suboptimal conditions could also explain occurrence of in vivo coccoid HP, although the HP organisms are considered by some investigators to be a separate, non-degenerative form with distinctive antigenic makeup (4).
H pylori organisms can be detected in both antral and oxyntic mucosa in most patients, but either region can be the only site where they are found. Endoscopists are urged, therefore, not to obtain biopsy specimens for diagnosis of H pylori gastritis solely from the antrum or body.
Other laboratory methods for clinical demonstration of H pylori infection are listed and discussed in slide 107.
1) Molyneux AJ, Harris MD. Helicobacter pylori in gastric biopsies—should you trust the pathology report?. J R Coll Physicians Lond. 1993;27:119.
2) Ashton-Key M, Diss TC, Isaacson PG. Detection of Helicobacter pylori in gastric biopsy and resection specimens. J Clin Pathol ;49:107.
3) Moran AP. Coccoid forms of Helicobacter pylori . Helicobacter 1997;2:109.
4) Benaissa M, Babin P, Quellard N, Pezennec L, Cenatiempo Y, Fauchere JL. Changes in Helicobacter pylori ultrastructure and antigens during conversion from the bacillary to the coccoid form. Infect Immun 1996;64:2331.

53. Chronic Active H pylori Gastritis With Neutrophils (PMNs) In Gland
An antral biopsy shows the typical histopathology of H pylori infection presenting as “superficial gastritis”. At low magnification (left hand panel) a very hypercellular lamina propria due to marked increase in chronic inflammation (predominantly lymphocytes and plasma cells) is evident. The accompanying active (acute) inflammation is evident as polymorphonuclear neutrophil (PMN’s) infiltration of gland neck epithelium (right hand panel). A frequent feature of the chronic inflammation is presence of lymphoid follicles, (see slide 55).
While the antral mucosa most often shows readily demonstrable changes of H pylori gastritis, the oxyntic mucosa is usually also infected, and reveals similar inflammatory changes that are comparable to those in the antrum except that the inflammation in oxyntic mucosa in H pylori gastritis typically involves a much narrower band of subepithelial mucosa. Most importantly, some patients demonstrate only oxyntic mucosal involvement with detectable H pylori organisms. For this reason biopsy specimens should always be taken from both antrum and body in order to maximize chances of demonstrating an H pylori infection.
1) Karttunen T, Niemela S, Lehtola J, Heikkila J, Maentausta O, Rasanen O. Campylobacter-like organisms and gastritis: histopathology, bile reflux, and gastric fluid composition. Scand J Gastroenterol 1987;22:478.
2) Yardley JH , Hendrix TR. Gastritis, duodenitis, and associated ulcerative lesions. Chap 66 In: Yamada T, Alpers DH, Laine LA, Owyang C, Powell DW, eds. Textbook of gastroenterology Lippincott William & Wilkins, Philadelphia. 3rd Ed. Pgs

54. Pathogenesis Of H pylori Gastritis
Gastritis is an invariable finding in patients infected with H pylori. The organism does not invade the gastric mucosa but rather resides in the mucus layer and attaches to gastric mucus surface cells. H pylori is protected from the hostile environment of the stomach by creating a favorable microenvironment through the action of its abundant urease which hydrolyses urea to ammonia thus providing the organism with a surrounding region of high pH. The host responds to products released by the organism which gain access to the mucosa and set in motion a complex immune response. The resulting gastritis may be considered as a culmination of 3 stages: 1) recruitment of inflammatory cells, 2) activation of inflammatory cells, and 3) epithelial damage by inflammatory cell activity. Recruitment. H pylori may alter the surface epithelium by a variety of mechanisms which increases epithelial permeability resulting in enhanced antigen exposure. The cytokines released as a consequence are involved in the recruitment and activation of immune cells. IL-8 has specific chemotactic activity for neutrophils and RANTES has activity for monocytes and lymphocytes. These chemotactic signals from H pylori-stimulated surface epithelial cells cause the inflammatory cells to leave the capillaries and enter the lamina propria. Activation. Neutrophils are activated by cytokines from the epithelium as well as by a variety of bacterial products including lipopolysaccharide (LPS). Macrophages (mononuclear phagocytes) are an important source of pro-inflammatory cytokines as well as serving as antigen presenting cells in the specific immune response to H pylori antigens. Epithelial Damage. Damage to the epithelium has a dual origin. First direct damage by H pylori. H pylori adherence to gastric epithelium produces loss of microvilli and intracellular changes. Approximately 50% of H pylori strains produce Vac A toxin which produces injury associated with vacuole formation in cultured cells. Urease, phospholipases and other bacterial enzymes damage the gastric epithelium. Many of these damaging activities have been demonstrated in in vitro systems leaving unanswered which occur in vivo.
Cytotoxin associated gene A (CagA) is part of a “pathogenicity island” in the organism that contains over 30 genes. Gene products produced by this pathogenicity island stimulate epithelial cytokine responses. CagA appears to be a phenotypical marker for strains that stimulate epithelial cytokine response (IL-8) although it has no direct damaging activity itself.
Much of the damage to the gastric mucosa is the consequence of activation of the recruited inflammatory cells. Activated macrophages secrete a series of pro-inflammatory cytokines, TNF-, IL-1, IL-6, and IFN-. Activated inflammatory cells, PMN as well as macrophages, release oxygen radicals which damage the epithelium and increase the rate of apoptosis. The importance of the host’s inflammatory response to H pylori in the production of gastritis is emphasized by studies on mutant mice. Mutants deficient in mature B cells had the same gastric inflammatory response to H. felis as did normal mice. On the other hand, mice with no mature T cells did not develop gastritis after colonization of their stomachs with H. felis.
Although H pylori gastritis has an acute phase, which is rarely identified clinically, it passes into an active chronic phase which usually lasts a lifetime without any clinical symptoms. This chronic asymptomatic stage is believed to be the consequence of down-regulating the inflammatory process. Macrophages present processed antigens to T cells which in turn activate B helper cells to stimulate production of specific antibodies as well as stimulating T helper cells. As the process becomes chronic Th1 cells predominate.
1) Roth KA, Kapadia SB, Martin SM, et al. Cellular immune responses are essential for development of Helicobacter felis-associated gastric pathology. J Immunol 1999;163:1490.
2) Bodger K, Crabtree JE. Helicobacter pylori and gastric inflammation. Brit Med Bull 1998;54:139.
3) Bamford KB, Fan X, Crowe SE, et al. Lymphocytes in human gastric mucosa during Helicobacter pylori infection have a T helper phenotype. Gastroenterology 1998;114:482.
4) Genta RM. Helicobacter pylori , inflammation, mucosal damage and apoptosis: Pathogenesis and definition of gastric atrophy. Gastroenterology 1997;113:351.
5) Moss SF, Calam J, Agarwal B, et al. Induction of gastric epithelial apoptosis by Helicobacter pylori . Gut 1996;38:498.
6) Gotz JM, Van Kan CI, Verspaget HW, et al. Gastric mucosal superoxide dismutase in Helicobacter infection. Gut 1996;502.

55. H pylori Gastritis: Mucosa-Associated Lymphoid Tissue (MALT) With Lymphoid Follicle (Arrows)
Lymphoid follicles are a major and defining feature of the mucosa-associated lymphoid tissue (MALT) that develops in the stomach as a result of chronic Helicobacter pylori gastritis. Similar changes can also be found with the other form of Helicobacter infection in humans, that caused by Helicobacter heilmannii (see slide 89).
There is strong reason for presuming either current or past infection with H pylori in any patient who shows one or more intramucosal lymphoid follicles in a gastric biopsy. This slide depicts such a lymphoid follicle (arrows). It consists of a discrete collection of lymphocytes with a centrally placed germinal center made up of larger, paler mononuclear cells. (The germinal center will only be seen in histologic sections that intercept it.) Lymphoid follicles in H pylori gastritis are thought to play an essential initiating role in genesis of gastric MALT lymphoma (see slide 82).
Lymphoid follicles can appear in the gastric mucosa within one week after onset of acute H pylori infection (1), and are only rarely encountered in biopsy specimens from persons who give no evidence of ever being infected with H pylori (2). Genta and colleagues, who used jumbo forceps and obtained numerous biopsy specimens, demonstrated follicles in all H pylori-positive patients, whereas no follicles were seen in H pylori-negative control patients (3).
1) Graham DY, Alpert LC, Smith JL, Yoshimura HH. Iatrogenic Campylobacter pylori infection is a cause of epidemic achlorhydria. Am J Gastroenterol 1988;83:974.
2) Wyatt JI, Rathbone BJ: Immune response of the gastric mucosa to Campylobacter pylori. Scand J Gastroenterol 1988;23(Supplˇ2012):44.
3) Genta RM. Gastric lymphoid follicles in Helicobacter pylori infection: Frequency, distribution, response to triple therapy. Hum Pathol 1993;24:577.

56. Chronic Chemical Gastropathy: Principal Features
This chronic condition, with its defining pathologic characteristics of paucity of inflammation, foveolar hyperplasia, increased smooth muscle cells in the lamina propria, and vascular ectasia, has been given a variety of names, each emphasizing a different aspect of or perception about its pathogenesis or pathology (see SYNONYMS in this slide, and slide 38)(1). The designation “chemical”, first proposed in ref. 2, provides an appropriate umbrella term that covers the whole range of irritants (e.g., bile acid, NSAIDs) that can account for chemical injury and thus chemical gastropathy (see slides 57 and 58). The histologic changes, which are seen chiefly in the antral mucosa, supply the only unequivocal means for recognizing chemical gastropathy (3); it cannot be recognized endoscopically. See slides 59 and 60 for additional pathological details.
Chronic chemical gastropathy is frequently associated with no symptoms or it is found in biopsies taken from patients being evaluated for non-specific upper GI symptoms. Patients found to have chemical gastropathy commonly give a history of chronic NSAIDs use (see slide 58), and it is frequently seen in patients who have had a gastroenterostomy, since this facilitates bile reflux (see slide 57).
The changes seen in the mucosa are histopathologically nonspecific in nature, and similar findings are noted in other reactive and reparative responses to injury, e.g., following eradication of the infection in H pylori gastritis. Thus it is likely that other irritants will eventually be shown to produce the histologic picture of chemical gastropathy.
1) Yardley JH , Hendrix TR. Gastritis, duodenitis, and associated ulcerative lesions. Chap 66 In: Yamada T, Alpers DH, Laine LA, Owyang C, Powell DW, eds. Textbook of gastroenterology Lippincott. Philadelphia. 3rd Edition. Pgs
2) Sobala GM, King RFG, Axon ATR, Dixon MF. Reflux gastritis in the intact stomach. J Clin Pathol 1990;43:
3) Haber MM, Lopez I. Gastric histologic findings in patients with nonsteroidal anti-inflammatory drug-associated gastric ulcer. Mod Pathol 1999;12:

57. Chemical Gastropathy vs Gastric Bile Reflux After Gastroenterostomy
The evidence that bile reflux in patients with surgically modified stomachs causes chemical gastropathy is as follows:
• Close associations are noted among foveolar hyperplasia, bile salt concentration, and proximity to the stoma. The correlations are most striking after a Billroth 2 subtotal gastrectomy with gastrojejunostomy, assuming there is no other likely cause, e.g., regular use of NSAIDs (see slide 58); that type of gastric surgery is also most strongly associated with reflux of intestinal contents into the stomach (1-3)
• Foveolar hyperplasia regresses after bile is diverted from the gastroenterostomy site.(4)
The graphed data presented here, which are based on the seminal studies by Bechi, et al (2), demonstrate a strong correlation between presence of chemical gastropathy and elevated gastric luminal concentrations of bile acid in patients who had undergone either a Billroth 1 (n=17) or Billroth 2 (n=27) type gastroenterostomy. (The original data were compared to presence of foveolar hyperplasia, but its equivalence to chemical gastropathy can be inferred from descriptions of the hyperplasia and associated mucosal changes.)
A precautionary note: Chemical gastropathy should not be attributed to exposure to bile in patients with nonoperated stomachs except when there is reliable evidence of duo-denogastric bile reflux (e.g., visualization through the endoscope, bile salt analysis in gastric juice, or external detection using a radioactive hepatobiliary tracer).(5-7)
1) Dixon MF, O’Connor HJ, Axon ATR, King RFGJ, Johnston D. Reflux gastritis-distinct histological entity? J Clin Pathol 1986;39:524.
2) Bechi P, Amorosi A, Mazzanti R, Romagnoli P, Tonelli L. Gastric histology and fasting bile reflux after partial gastrectomy. Gastroenterology 1987;93:
3) Weinstein FM, Buch KL, Elashoff J, et al. The histology of the stomach in symptomatic patients after gastric surgery: a model to assess selective patterns of gastric mucosal injury. Scand J Gastroenterol 1985;20 (Suppl 109):77.
4) Bechi P, Amorosi A, Mazzanti R, Buccarelli A, Pantalone D, Cortesini C. Short-term effects of bile diversion on postgastrectomy gastric histology. Dig Dis Sci 1988;33:1288.
5) Niemela S. Duodenogastric reflux in patients with upper abdominal complaints or gastric ulcer with particular reference to reflux-associated gastritis. Scand J Gastroenterol 1985;115:1.
6) Stein HJ, Smyrk TC, DeMeester TR, Rouse J, Hinder RA. Clinical value of endoscopy and histology in the diagnosis of duodenogastric reflux disease. Surgery 1992;112:796.
7) Niemela S, Karttunen T, Heikkila J, Lehtola J. Characteristics of reflux gastritis. Scand J Gastroenterology 1987;22:349.

58. Prevalence Of Exposure To Gastric Irritants In Patients With Non-Ulcer Dyspepsia Found To Have Chemical Gastropathy Or Normal Histology
58. Prevalence Of Exposure To Gastric Irritants In Patients With Non-Ulcer Dyspepsia Found To Have Chemical Gastropathy Or Normal Histology.
Chemical gastropathy is recognized by its distinctive histologic picture with foveolar elongation and tortuosity and a paucity of inflammatory cells in the lamina propria being prominent features (hence gastropathy rather than gastritis) (see slides 56, 57, 59, and 60)(1,2).
Slide 58 shows the findings in 35 patients with chemical gastropathy compared with 76 with normal histology identified in 205 non-surgical patients participating in a study of non-ulcer dyspepsia (3). Bile acid concentration greater than 1 mmol/l in gastric juice was found in only one patient with chemical gastropathy. Of the gastric irritants considered, bile acids, NSAIDs, alcohol, and smoking, only NSAIDs use was significantly greater in patients with chemical gastropathy than in patients with normal histology (3).
1) Dixon MF, O’Connor HJ, Axon ATR, King RFJG, Johnston D. Reflux gastritis: distinct pathological entity? J Clin Pathol 1986;39:
2) Bechi P, Amorosi A, Mazzanti R, Romagnoli P, Tonelli L. Gastric histology and fasting bile reflux after partial gastrectomy. Gastroenterology 1987;93:
3) Sobala GM, King RFG, Axon ATR, Dixon MF. Reflux gastritis in the intact stomach. J Clin Pathol 1990;43:

59. Chronic Chemical Gastropathy (NSAID) With Vascular Ectasia (Arrows) And Smooth Muscle Hyperplasia
Histologic changes of chronic chemical gastropathy (1,2) in an antral biopsy from a patient who was chronically exposed to nonsteroidal antiinflammatory drugs (NSAIDs). Left hand panel: There is a paucity of inflammation in comparison with patients showing “gastritis”, e.g., in chronic H pylori gastritis (see slide 53). Note also the foveolar hyperplasia with villiform architecture due to foveolar lengthening and the associated tall, ruffled epithelial outline. Right hand panel: Details of indicated area on left. Only scattered mononuclear inflammatory cells are seen in the lamina propria and there is vascular ectasia (arrows) and prominent smooth muscle proliferation.
1) Sobala GM, King RFG, Axon ATR, Dixon MF. Reflux gastritis in the intact stomach. J Clin Pathol 1990;43:
2) Haber MM, Lopez I. Gastric histologic findings in patients with nonsteroidal anti-inflammatory drug-associated gastric ulcer. Mod Pathol 1999;12:

60. Severe Chemical Gastropathy In Long-term NSAIDs Use With Ulcers, Regenerating Epithelium, And Neutrophilic Exudate (PMNs)
60. Severe Chemical Gastropathy In Long-term NSAIDs Use With Ulcers, Regenerating Epithelium, And Neutrophilic Exudate (PMNs).
Demonstration of the distal (antral) resection specimen from a patient with rheumatoid arthritis taking daily NSAIDs who developed upper gastrointestinal bleeding. In the right panel a shallow ulcer shows the advancing edge of overlying thinned regenerative epithelium and neutrophilic exudate (PMNs). Intact mucosa from elsewhere in the specimen (left panel) reveals marked hyperplasia and distortion. Note that the underlying muscularis mucosae in both locations shows fraying and fibrosis consistent with earlier deeper injury from ulceration.
Ulcers accompanied by upper gastrointestinal bleeding of the type noted in this patient is a serious and frequent complication of NSAIDs treatment, especially among older individuals (1,2).
1) Yardley JH, Hendrix TR. Gastritis, gastropathy, duodenitis and associated ulcerative lesions. In: Yamada T. Textbook of Gastroenterology, Chapter 66, Philadelphia, Lippincott, Williams and Wilkins, 1999:1464.
2) Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340: