Helicobacter pylori infection pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yamuna Kondapally, M.B.B.S[2]

Overview

Helicobacter pylori (H. pylori) is a bacterium that lives on the lining of the stomach. Although we used to think that spicy food, acid, and stress were the major causes of ulcers, we now know that nine out of ten ulcers are caused by H. pylori. Medicines that reduce stomach acid may make you feel better, but your ulcer may come back. Here's the good news: Since most ulcers are caused by this bacterial infection, they can be cured with the right antibiotics.

Pathophysiology

  • The mode of transmission of H.pylori is poorly understood.[1][2][3]
  • Person to person transmission is considered to be the most likely route.
  • It is almost always acquired during childhood and infection is lifelong if left untreated.[4]
  • Helicobacter pylori is usually transmitted via the following routes:
  • Iatrogenic
  • Via tubes and endoscopes that have been in contact with the gastric mucosa of one individual are used for another patient
  • Between patient and staff especially among endoscopists and gastroenterologists
  • Fecal-oral route
  • Fecal contamination of water and food may be the source of infection especially in developing countries[4]
  • Oral-oral route
  • Via saliva especially in developed countries[4]
  • Distal adenocarcinoma is the most common gastric adenocarcinoma which is caused by H.pylori.
  • The colonisation of H.pylori in gastric mucosa depends on the following factors:
  • Motility of H.pylori (The corkscrew motility is due to its multiple flagella and spiral shape)
  • Chemotaxis
  • Environmental sensing
  • Acid resistance
  • Iron acquisition
  • H.pylori primarily colonizes in gastric mucosa but occasionally found at other sites also. The few of the sites include eyes, nasal cavity, gallbladder, peritoneum, oral cavity.

Pathogenesis

  • H.pylori is a non invasive organism. It is found over mucus secreting cells but not in deeper gastric glands. Hence it can only inhabit gastric-type mucus but cannot colonize the esophagus or duodenum. [5]. The pathogenesis of H.pylori depends up on the following:[6]

Bacterial factors

  • Bacterial enzymes[7]
  • Lipase and protease
  • Lipase and protease leads to degradation of protective mucous layer of the stomach
  • Protease leads to disintegration of the polymeric structure of mucin
  • Phospholipase A2 and lipase leads to loss of mucosal surface hydrophobicity, mucus lipid degradation and lysoophospholipid generation[8][9]
  • Lysophospholipids disrupts the phospholipid rich layer at the apical surface of mucous cells
  • Urease
  • Acid resistence plays a crucial role in pathogenesis of H.pylori infection.[10][11]
  • Urease is one of the most abundant protein produced by H.pyloi, whose production is regulated by one of the genes associated with acid resistance.
  • The urease of H.pylori has two subunits, UreA and UreB[12][13]
  • This enzyme hydrolyzes urea to ammonia and carbondioxide, which increases the cytoplasmic pH in the microenvironment around the organism, hence protects the bacteria from acid.
  • The H+-gated urea channel(Urel) regulates the urea entry into cytoplasm of h.pylori cell which helps in quick adaptation of organism to acidic environment.[14]
  • Ammonia and ammonium chloride inhibit the growth of gastric cells in S phase, leading to gastric mucosal atrophy[15]
  • Bacterial Virulence factors
  • The cytotoxin-associated gene (Cag) pathogenecity island (PAI) and cytotoxin-associated gene A (cagA)
  • Large amounts of the pro-inflammatory cytokine interleukin-8 are expressed in H.pylori strains with CagPal.
  • The protein CagA is encoded by CagA gene and type IV bacterial secretion system (T4SS) is encoded by CagPAI.
  • Type IV bacterial secretion apparatus helps in translocation of CagA into host target cells and stimulates epithelial cell pro-inflammatory cytokine expression and gastric inflammation
  • CagA undergoes phosphorylation in host target cells
1: CagA
  • The CagA protein is encoded by CagA gene and is translocated to epithelial cell cytosol through type IV bacterial secretion apparatus.
  • It is activated by phosphorylation on tyrosine residues by host scr kinases.[16][17]
  • After phosphorylation, it interacts with SHP-2 and activates MAP kinase signalling leading to abnormal proliferation of gastric epithelial cells.
  • It also binds to Crk proteins leading to disruption of epithelial cell tight junctions and tissue damage.
  • The type and number of CagA tyrosine phosphorylation motifs differ in the individual strains.
  • Strains having CagA with more phosphorylation motifs cause atrophy and gastric carcinoma than strains with fewer motifs.
  • [18][19][20]
  • The IL-8 secretion is independent of tyrosine phosphorylation of CagA but dependent on the region having phosphorylation motifs.
2: Outer inflammatory protein A (OipA)
  • OipA strain is associated with duodenal ulceration and gastric cancer[21][22]
  • This protein is regulated by slipped strand mispairing[23]
3: Duodenal ulcer promoting gene A (dupA)
  • This gene is associated with duodenal ulceration but appeared to protect from gastric cancer in patients from columbia, Japan and South Korea.[24]
4: Blood group antigen binding adhesion A (BabA)
  • BabA2 gene encodes the active form of BabA which binds to fucosylated Le antigens which are expressed on gastric epithelial cells.[25]
  • BabA increases the adhesion of H.pylori to epithelial cells which leading to increased delivery of factors associated with inflammation.
  • Active form of BabA is associated with increased association of cag+ strains with gastric cancer and duodenal ulceration.[26]
5: The RNA polymerase β-subunit (RpoB)
  • The RpoBThr is associated with increased secretion of IL-8 from MKN45 cells compared to RpoBAla.
  • H.pylori strains possessing RpoBThr is seen in 67.6% of East Asians and hence associated with increased risk of development of more severe gastroduodenal diseases.[27]
6: The vacuolating cytotoxin (VacA)
  • VacA is associated with cellular damage rather than pro-inflammatory cytokine release.
  • The active forms of VacA are associated with increased risk of gastric carcinoma

Host genetic susceptibility

The risk of gastric carcinoma increases due to :[28][29]

  • The stable polymorphisms of several cytokine gens
  • Increased expression of IL-1β or tumor necrosis factor (TNF)α
  • The reduced expression of the anti-inflammatory cytokine IL-10 due to single necleotide polymorphism

The immune response to H.Pylori

The innate immune response
  • H.pylori colonization of the gastric mucosa is associated with innate host defense mechanisms leading to the expression of pro-inflammatory and anti-bacterial factors.[30][31]The expression of these factors results in gastritis.
  • The severity of the H.pylori disease and gastric carcinogenesis is associated with the innate immune response.
  • The innate immune mechanisms are dependent on the Nod1, which is a pattern recognition receptors (PRR) stimulated by cag+ strains.[32]
  • Defensins are the antimicrobial peptides which are secreted as a response to H.pylori infection.Elevated levels of human β defensin 2 (hBD2) and the neutrophil-derived alpha defensins are detected in gastric juice of infected patients.[33]
  • The infected gastric epithelial cells have increased expression of hBD2, hBD3, angiogenin adrenomedulin, and the human cationic antimicrobial peptide 18 (LL-37).[30]
  • Due to high secretion of cytokines and chemokines by the gastric epithelial cells, there is increased migration of granulocytes, lymphocytes and monocytes leading to severe inflammatory pathology.[34]
  • The H.pylory after phagocytosis survive inside the phagosome and all phagosomes fuse to become megasomes. This provides a protected intracellular cavity in the macrophage, contributing to the perisitence of infection.[35][36]
The acquired immune response
  • H.pylori stimulates the production of mucosal and systemic IgA and IgG antibodies which induces local inflammation and damage by cross reacting with the parietal cell H+,K+-ATPase and antigens on gastric epithelial cells.[37][38]
  • The T-helper 1 (Th1) response in the gastric mucosa dominates the T-cell response to H.pylori. The Th1 cells release type 1 cytokines (IFNγ) which activate macrophages resulting in secretion of pro-inflammatory factors (TNFα, IL-12 and IL-18) and increase bactericidal activity compared to those activated by Th2 cytokines. The severity of gastritis depends on the number of IFNγ-secreting cells in the infected gastric mucosa.[39][40][41][42]
  • H.pylori suppress immune and inflammatory responses by eliciting Treg (T-cell regulatory) responses and thus maintain chronic colonization. They also supress human memory T-cells in response to H.pylori antigens.[43]

Hormonal changes and acid homeostasis changes

Somatostatin and gastrin changes

  • The inflammatory mediators produced due to H.pylori infection, including nitric oxide suppress somatostatin release. The infection is also associated with reduced numbers of somatostatin-producing D cells in the stomach.[44][45][46]
  • The gastrin production from G cells is increased due to direct stimulatory action of cytokines and supression of somatostatin.
  • Hypergastrinemia stimulates MAP kinase which results in upregulation of the cox-2 gene which is potentially has potentially prooncogenic effect. It may also leads to gastric atrophy by upregulation of the Reg protein.[47][47]
  • Hypergastrinemia leads to excess acid production leading to dyspepsia.

Environmental cofactors

The environmental cofactors associated with H.pylori are:

  • Age at infection
  • Degree of crowding
  • Smoking
  • Malnutrition
  • High salt intake
  • Vitamin deficiency

Based on location

Based on the location of inflammation, the pathogenesis depends on:[6]

1: Antral-predominant inflammation: The uninflamed corpus produces large amount of acid predisposing to duodenal ulceration

2: Corpus-predominant inflammation: This leads to gastric ulceration and adenocarcinoma due to hypochlorhydria

Gross pathology

On gross pathology, H.pylori infection is associated with thickened gastric folds and erythema.[48]

Microscopic Histopathological analysis

The microscopic histopathological analysis depends on the the following stages:[49]

Acute H.pylori infection

  • Most of the initial H.pylori colonization occur during childhood but new infections may occur in adults occasionally.[50][51]
  • Associated with transient profound gastric hypochlorhydria

Histopathogenesis

  • Surface epithelial degeneration
  • Heavy neutrophilic infiltration in lamina propria of antrum and corpus and infiltrating the foveolar and surface epithelium
  • Gradual infiltration of other inflammatory cells, especially lymphocytes

Chronic H.pylori infection

  • Chronic antral predominant inflammation:
  • Associated with increased stimulated acid production leading to duodenal ulceration
  • Chronic corpus-predominant or pangastritis
  • Associated with reduced acid production
  • Predisposes to gastric ulceration and gastric adenocarcinoma
  • Histopathogenesis
  • Epithelial degeneration
  • Neutrophil infiltration
  • predominantly lymphocyte, monocyte and/ or plasma cell infiltration in the superficial lamina propria
  • Glandular atrophy
  • Intestinal metaplasia
  • Lymphoid tissue aggregates

References

  1. ↑ Brown LM (2000). "Helicobacter pylori: epidemiology and routes of transmission". Epidemiol Rev. 22 (2): 283–97. PMID 11218379.
  2. ↑ Cave DR (1997). "How is Helicobacter pylori transmitted?". Gastroenterology. 113 (6 Suppl): S9–14. PMID 9394753.
  3. ↑ Transmission http://www.who.int/bulletin/archives/79(5)455.pdf (2001) Accessed on December 27, 2016
  4. ↑ 4.0 4.1 4.2 Das JC, Paul N (2007). "Epidemiology and pathophysiology of Helicobacter pylori infection in children". Indian J Pediatr. 74 (3): 287–90. PMID 17401270.
  5. ↑ Jhala NC, Siegal GP, Klemm K, Atkinson BF, Jhala DN (2003). "Infiltration of Helicobacter pylori in the gastric mucosa". Am J Clin Pathol. 119 (1): 101–7. doi:10.1309/YDTX-KE06-XHTH-FNP2. PMID 12520704.
  6. ↑ 6.0 6.1 Atherton JC (2006). "The pathogenesis of Helicobacter pylori-induced gastro-duodenal diseases". Annu Rev Pathol. 1: 63–96. doi:10.1146/annurev.pathol.1.110304.100125. PMID 18039108.
  7. ↑ Smoot DT (1997). "How does Helicobacter pylori cause mucosal damage? Direct mechanisms". Gastroenterology. 113 (6 Suppl): S31–4, discussion S50. PMID 9394757.
  8. ↑ Berstad K, Sjödahl R, Berstad A (1994). "Phospholipase A2 activity in gastric juice from patients with active and H. pylori-eradicated healed duodenal ulcer". Aliment Pharmacol Ther. 8 (2): 175–80. PMID 8038348.
  9. ↑ Mauch F, Bode G, Ditschuneit H, Malfertheiner P (1993). "Demonstration of a phospholipid-rich zone in the human gastric epithelium damaged by Helicobacter pylori". Gastroenterology. 105 (6): 1698–704. PMID 8253346.
  10. ↑ Wen Y, Marcus EA, Matrubutham U, Gleeson MA, Scott DR, Sachs G (2003). "Acid-adaptive genes of Helicobacter pylori". Infect Immun. 71 (10): 5921–39. PMC 201084. PMID 14500513.
  11. ↑ McGowan CC, Necheva AS, Forsyth MH, Cover TL, Blaser MJ (2003). "Promoter analysis of Helicobacter pylori genes with enhanced expression at low pH". Mol Microbiol. 48 (5): 1225–39. PMID 12787351.
  12. ↑ Smoot DT, Mobley HL, Chippendale GR, Lewison JF, Resau JH (1990). "Helicobacter pylori urease activity is toxic to human gastric epithelial cells". Infect Immun. 58 (6): 1992–4. PMC 258755. PMID 2341188.
  13. ↑ Micots I, Augeron C, Laboisse CL, Muzeau F, Mégraud F (1993). "Mucin exocytosis: a major target for Helicobacter pylori". J Clin Pathol. 46 (3): 241–5. PMC 501178. PMID 8463418.
  14. ↑ Weeks DL, Eskandari S, Scott DR, Sachs G (2000). "A H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization". Science. 287 (5452): 482–5. PMID 10642549.
  15. ↑ Matsui T, Matsukawa Y, Sakai T, Nakamura K, Aoike A, Kawai K (1995). "Effect of ammonia on cell-cycle progression of human gastric cancer cells". Eur J Gastroenterol Hepatol. 7 Suppl 1: S79–81. PMID 8574744.
  16. ↑ Selbach M, Moese S, Hauck CR, Meyer TF, Backert S (2002). "Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo". J Biol Chem. 277 (9): 6775–8. doi:10.1074/jbc.C100754200. PMID 11788577.
  17. ↑ Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A (2002). "c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs". Mol Microbiol. 43 (4): 971–80. PMID 11929545.
  18. ↑ Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC (2004). "Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori". Gastroenterology. 127 (2): 514–23. PMID 15300584.
  19. ↑ Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y; et al. (2002). "Correlation between variation of the 3' region of the cagA gene in Helicobacter pylori and disease outcome in Japan". J Infect Dis. 186 (11): 1621–30. doi:10.1086/345374. PMID 12447739.
  20. ↑ Yamaoka Y, Kodama T, Kashima K, Graham DY, Sepulveda AR (1998). "Variants of the 3' region of the cagA gene in Helicobacter pylori isolates from patients with different H. pylori-associated diseases". J Clin Microbiol. 36 (8): 2258–63. PMC 105028. PMID 9666002.
  21. ↑ Yamaoka Y, Kikuchi S, el-Zimaity HM, Gutierrez O, Osato MS, Graham DY (2002). "Importance of Helicobacter pylori oipA in clinical presentation, gastric inflammation, and mucosal interleukin 8 production". Gastroenterology. 123 (2): 414–24. PMID 12145793.
  22. ↑ Yamaoka Y, Ojo O, Fujimoto S, Odenbreit S, Haas R, Gutierrez O; et al. (2006). "Helicobacter pylori outer membrane proteins and gastroduodenal disease". Gut. 55 (6): 775–81. doi:10.1136/gut.2005.083014. PMC 1856239. PMID 16322107.
  23. ↑ Yamaoka Y, Kwon DH, Graham DY (2000). "A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori". Proc Natl Acad Sci U S A. 97 (13): 7533–8. doi:10.1073/pnas.130079797. PMC 16580. PMID 10852959.
  24. ↑ Zhang Z, Zheng Q, Chen X, Xiao S, Liu W, Lu H (2008). "The Helicobacter pylori duodenal ulcer promoting gene, dupA in China". BMC Gastroenterol. 8: 49. doi:10.1186/1471-230X-8-49. PMC 2584642. PMID 18950522.
  25. ↑ Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET; et al. (1998). "Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging". Science. 279 (5349): 373–7. PMID 9430586.
  26. ↑ Gerhard M, Lehn N, Neumayer N, Borén T, Rad R, Schepp W; et al. (1999). "Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin". Proc Natl Acad Sci U S A. 96 (22): 12778–83. PMC 23096. PMID 10535999.
  27. ↑ Lee KH, Cho MJ, Yamaoka Y, Graham DY, Yun YJ, Woo SY; et al. (2004). "Alanine-threonine polymorphism of Helicobacter pylori RpoB is correlated with differential induction of interleukin-8 in MKN45 cells". J Clin Microbiol. 42 (8): 3518–24. doi:10.1128/JCM.42.8.3518-3524.2004. PMC 497570. PMID 15297492.
  28. ↑ El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA; et al. (2000). "Interleukin-1 polymorphisms associated with increased risk of gastric cancer". Nature. 404 (6776): 398–402. doi:10.1038/35006081. PMID 10746728.
  29. ↑ Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S; et al. (2003). "A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma". Gastroenterology. 125 (2): 364–71. PMID 12891537.
  30. ↑ 30.0 30.1 George JT, Boughan PK, Karageorgiou H, Bajaj-Elliott M (2003). "Host anti-microbial response to Helicobacter pylori infection". Mol Immunol. 40 (7): 451–6. PMID 14568391.
  31. ↑ Jung HC, Kim JM, Song IS, Kim CY (1997). "Helicobacter pylori induces an array of pro-inflammatory cytokines in human gastric epithelial cells: quantification of mRNA for interleukin-8, -1 alpha/beta, granulocyte-macrophage colony-stimulating factor, monocyte chemoattractant protein-1 and tumour necrosis factor-alpha". J Gastroenterol Hepatol. 12 (7): 473–80. PMID 9257236.
  32. ↑ Netea MG, van der Graaf C, Van der Meer JW, Kullberg BJ (2004). "Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system". J Leukoc Biol. 75 (5): 749–55. doi:10.1189/jlb.1103543. PMID 15075354.
  33. ↑ Isomoto H, Mukae H, Ishimoto H, Date Y, Nishi Y, Inoue K; et al. (2004). "Elevated concentrations of alpha-defensins in gastric juice of patients with Helicobacter pylori infection". Am J Gastroenterol. 99 (10): 1916–23. doi:10.1111/j.1572-0241.2004.40334.x. PMID 15447750.
  34. ↑ Ernst PB, Gold BD (2000). "The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer". Annu Rev Microbiol. 54: 615–40. doi:10.1146/annurev.micro.54.1.615. PMID 11018139.
  35. ↑ Allen LA, Schlesinger LS, Kang B (2000). "Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages". J Exp Med. 191 (1): 115–28. PMC 2195807. PMID 10620610.
  36. ↑ Schwartz JT, Allen LA (2006). "Role of urease in megasome formation and Helicobacter pylori survival in macrophages". J Leukoc Biol. 79 (6): 1214–25. doi:10.1189/jlb.0106030. PMC 1868427. PMID 16543403.
  37. ↑ Appelmelk BJ, Simoons-Smit I, Negrini R, Moran AP, Aspinall GO, Forte JG; et al. (1996). "Potential role of molecular mimicry between Helicobacter pylori lipopolysaccharide and host Lewis blood group antigens in autoimmunity". Infect Immun. 64 (6): 2031–40. PMC 174033. PMID 8675304.
  38. ↑ Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C; et al. (2003). "Molecular mimicry between Helicobacter pylori antigens and H+, K+ --adenosine triphosphatase in human gastric autoimmunity". J Exp Med. 198 (8): 1147–56. doi:10.1084/jem.20030530. PMC 2194239. PMID 14568977.
  39. ↑ Bamford KB, Fan X, Crowe SE, Leary JF, Gourley WK, Luthra GK; et al. (1998). "Lymphocytes in the human gastric mucosa during Helicobacter pylori have a T helper cell 1 phenotype". Gastroenterology. 114 (3): 482–92. PMID 9496938.
  40. ↑ D'Elios MM, Manghetti M, De Carli M, Costa F, Baldari CT, Burroni D; et al. (1997). "T helper 1 effector cells specific for Helicobacter pylori in the gastric antrum of patients with peptic ulcer disease". J Immunol. 158 (2): 962–7. PMID 8993017.
  41. ↑ Fan XJ, Chua A, Shahi CN, McDevitt J, Keeling PW, Kelleher D (1994). "Gastric T lymphocyte responses to Helicobacter pylori in patients with H pylori colonisation". Gut. 35 (10): 1379–84. PMC 1375009. PMID 7959191.
  42. ↑ Lehmann FS, Terracciano L, Carena I, Baeriswyl C, Drewe J, Tornillo L; et al. (2002). "In situ correlation of cytokine secretion and apoptosis in Helicobacter pylori-associated gastritis". Am J Physiol Gastrointest Liver Physiol. 283 (2): G481–8. doi:10.1152/ajpgi.00422.2001. PMID 12121897.
  43. ↑ Lundgren A, Suri-Payer E, Enarsson K, Svennerholm AM, Lundin BS (2003). "Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals". Infect Immun. 71 (4): 1755–62. PMC 152046. PMID 12654789.
  44. ↑ Moss SF, Legon S, Bishop AE, Polak JM, Calam J (1992). "Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease". Lancet. 340 (8825): 930–2. PMID 1357347.
  45. ↑ Odum L, Petersen HD, Andersen IB, Hansen BF, Rehfeld JF (1994). "Gastrin and somatostatin in Helicobacter pylori infected antral mucosa". Gut. 35 (5): 615–8. PMC 1374743. PMID 7911115.
  46. ↑ Arebi N, Healey ZV, Bliss PW, Ghatei M, Van Noorden S, Playford RJ; et al. (2002). "Nitric oxide regulates the release of somatostatin from cultured gastric rabbit primary D-cells". Gastroenterology. 123 (2): 566–76. PMID 12145809.
  47. ↑ 47.0 47.1 Guo YS, Cheng JZ, Jin GF, Gutkind JS, Hellmich MR, Townsend CM (2002). "Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor". J Biol Chem. 277 (50): 48755–63. doi:10.1074/jbc.M209016200. PMID 12239223.
  48. ↑ H.pylori infection https://librepathology.org/wiki/Helicobacter_gastritis (May,2016) Accessed on January 4, 2017
  49. ↑ Faigel DO, Furth EE, Childs M, Goin J, Metz DC (1996). "Histological predictors of active Helicobacter pylori infection". Dig Dis Sci. 41 (5): 937–43. PMID 8625766.
  50. ↑ Sobala GM, Crabtree JE, Dixon MF, Schorah CJ, Taylor JD, Rathbone BJ; et al. (1991). "Acute Helicobacter pylori infection: clinical features, local and systemic immune response, gastric mucosal histology, and gastric juice ascorbic acid concentrations". Gut. 32 (11): 1415–8. PMC 1379180. PMID 1752479.
  51. ↑ Dixon MF (1995). "Histological responses to Helicobacter pylori infection: gastritis, atrophy and preneoplasia". Baillieres Clin Gastroenterol. 9 (3): 467–86. PMID 8563048.

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