Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 Barrett's
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OESO©2015
 
Volume: The Esophageal Mucosa
Chapter: Mucosa and histology
 

Does Helicobacter pylori colonize the gastric metaplasia of CLE and induce additional disease in that site?

P. Vincent (Lille)

It is now accepted that Helicobacter pylori is the causal agent of type B gastritis and an etiological agent in the pathogenesis of most peptic ulcers. An association between H. pylori infection and gastric precancerous lesions has also been established and H. pylori infection might occupy a key position in the sequence of events leading to gastric cancer.

Little is known about the potential pathogenesis of H. pylori in the esophagus where the bacteria is not usually found. However, since H. pylori can only colonize the gastric mucosa specifically, one can wonder whether it can colonize the gastric metaplastic area of Barrett's esophagus and promote additional pathology. A review shows that the relationship between H. pylori and esophageal pathology is inconstant and suggests that the bacteria might be only a contaminant. Clinical relevance of H. pylori in the esophagus remains to be demonstrated.

Helicobacter pylori and pathogenicity

Microbiology

Since H. pylori (originally called Campylobacter pyloridis and then changed to Campylobacter pylori) was first isolated in 1983 [1], efforts have been focused on isolating gastric bacteria and studying their potential pathogenesis. Several species of mucus-associated bacteria have been discovered. They are curved, spiral, microaero-philic, asacharolytic and non-spore-forming Gram-negative rods. Although they look like campylobacteria, significant morphologic, structural, biochemical and genomic features indicated that they should be placed in a new genus now named Helicobacter [2]. In humans, H. pylori is found commonly in gastric biopsies from symptomatic patients undergoing upper gastrointestinal endoscopy. Many studies have demonstrated that H. pylori can also frequently be found in asymptomatic, otherwise healthy, persons. All such infected persons have histologic gastritis. H. pylori is arguably the commonest chronic bacterial infection in man. In industrialized countries, prevalence of infection rises with age and in low social classes. Approximately 50% of adults are colonized by the age of 60. In developing countries, 80-90% rates are commonly found, even in children [3]. The lack of a plausible environmental reservoir, the extensive prevalence of infection in humans and the clustering of cases in families and cohabiting persons suggest that humans might be the unique reservoir of H. pylori and that person-to-person contacts might be the

major way of spread. However, whether the origin of contamination is fecal or oral is still questioned [4],

Colonization of mucosa

All evidence to date is consistent with the hypothesis that H. pylori is the human associated Helicobacter species [5]. It has evolved with its human host and has acquired properties to withstand the hostile gastric environment. So it is well suited for survival in its ecological niche of antral mucus [6]. Urease production is the major factor of adaptation. This enzyme is essential for initial colonization. Unlike other urease enzymes, the gastric H. pylori urease retains significant activity at low pH. Neutralization of local gastric acidity by ammonia (which is the end product of the breakdown of mucosal urea) protects the bacteria against prolonged acidity. Thus, as the organism enters the stomach it is protected long enough to allow penetration of mucus. Motility, due to the flagellae and the spiral shape of the bacteria, is another adaptation factor. It allows the organism to move quickly from the gastric lumen into the viscous environment of gastric mucus [7]. It has been shown that nonmotile variants of H. pylori cannot colonize gnotobiotic piglets [8]. Microaerophily is another factor of adaptation, since the atmosphere in the mucus overlaying the gastric cells is microaerobic. Growth of H. pylori is possible down to 5% oxygen concentration. Once H. pylori has penetrated the mucus layer, adhesion allows the bacterium to settle in intercellular spaces. H. pylori has some lectin-like proteins, and gastric type epithelial cells owns a glycerolipid which is a specific receptor for H. pylori adhesins [9]. Consequently, natural barriers to microbial colonization of the stomach are inefficient against H. pylori. It can colonize all sites where mucus and gastric-type epithelial cells are present, whether normally present in the stomach or metaplastic. This specificity is high and H. pylori cannot colonize squamous epithelial cells of the esophagus or absorptive-type duodenal epithelial cells, even when these are metaplastic in the stomach [10].

Induced lesions

H. pylori infection is specifically associated with the presence of type B gastritis but not with type A gastritis (autoimmune gastritis), bile reflux or secondary gastritis. Thus when H. pylori is present, gastric inflammation is not the cause of bacterial colonization but its consequence. Several bacterial factors are implied in H. pylori induced lesions. Ammonia, produced close to the cell surface by urease activity, has a cytotoxic action on epithelial cells [11]. H. pylori produces a phospholipase C [12], which is basically a hemolytic enzyme. Cell alterations can occur equally due to a cytotoxin which is found for many strains, especially in patients with peptic ulcer [13]. Other effects found in H. pylori epithelium colonization are modifications in the mucus environment. The presence of the organism decreases the mucus hydrophobic-ity and reduces the mucus gel thickness. Although the mucus synthesis is not modified, H. pylori adherence pedestals obstruct mucin exoxytosis. H. pylori secretes a chemotactic factor for neutrophils and monocytes. There is then a lymphocyte

activation and a cytokine release. A local secretory immunoglobulin-A response occurs. IgA can overlay bacterial cells [14], but is inefficient to fetter the bacterium and any bacterial toxin. The presence of endotoxins and other bacterial products in the gastric tissue promotes complement activation resulting in a vigorous local and systemic immune response. However, phagocytosis of H. pylori by polymorpho-nuclear cells is unusual due to an environment hostile to phagocytic cells. The host's response to infection fails to eradicate bacteria and a chronic infiltration of inflammatory cells occurs, with a persistent systemic humoral immune response to the organism.

Pathology

The role of H. pylori in nonulcer dyspepsia is still questioned. However, it is now evident that the type B form of atrophic gastritis (symptomatic or not) is a sequel to long-standing chronic H. pylori infection in the mucosa. An increasing prevalence of glandular atrophy with age has been shown, implying a transition from nonatrophic to atrophic gastritis, according to the duration of inflammation [15].

Into the duodenum, where gastric metaplasia occurs in case of increased acid production, H. pylori colonizes metaplastic mucus-secreting mucosa. This duodenal colonization leads to active duodenitis (which, strictly from an histological point of view, is "gastritis" in the duodenum), glandular atrophy and ultimately ulceration of metaplasia. It has been widely shown that eradication of H. pylori was necessary to allow duodenal ulcers to heal with lower relapse rates.

The key position of H. pylori infection in the sequence of events leading to gastric cancer is now in question [16], since cohort follow-up studies support a dynamic progression through chronic atrophic gastritis, intestinal metaplasia to dysplasia and gastric cancer [17]. H. pylori infection seems to be associated to a decrease of gastric ascorbic acid [18] whose protective role is known (by preventing the formation of carcinogenetic nitrosamines) [19].

//. pylori and esophagus

Role in gastroesophageal reflux

The relationship between gastric H. pylori infection and gastroesophageal reflux (GER) has been studied. In children, the bacteria was found in a minority with reflux (3/80) without relation to macroscopic esophagitis (1/26). Authors concluded that H. pylori is unlikely to have an etiologic role in reflux esophagitis [20]. In adults, a paper reported seven cases of gastric infection among 21 patients with reflux [21], which is not a higher prevalence rate than expected in general population of the same range of age in industrialized countries. In this study, the presence of infection seemed to correlate with the grade of esophagitis (according to Savary and Miller's classification). However, the authors discussed neither the small size of their sample nor the possible confounding role of age.

In Barrett's esophagus, the role of H. pylori gastric infection has not yet been demonstrated. In the same paper, infection rate was about the same in Barrett's esophagus and esophagitis alone (4/11 vs. 2/6). Another study reported similar frequency of gastric infection in patients with Barrett's esophagus and in age- and sex-matched controls: 10/26 vs. 11/26 [22].

Colonization of esophageal mucosa

The colonization of normal esophagus by H. pylori from the gastric area of infection has never been reported. Animal experimentation found no case of implantation of the bacteria in esophagus of gnotobiotic piglets [23]. Among seven gastric infected patients [21] and 25 [22], H. pylori was never found in esophageal biopsy specimens. In dyspeptic patients undergoing esogastroduodenoscopy with endoscopic abnormality or histological inflammation of upper gastrointestinal tract, H. pylori was cultured in 8/30 cases from the esophagus [24]. However, the bacteria could not be seen in the mucosa at this site by light microscopy or electron microscopy. Authors concluded that isolated H. pylori was either a commensal or a contaminant probably originating from the stomach.

H. pylori which specifically colonizes acid secreting gastric epithelium can only settle into Barrett's esophagus where columnar epithelium lines the esophagus, instead of the usual stratified squamous epithelium. Although no H. pylori was found by Giemsa staining in esophageal biopsies from 34 patients in the Barrett's esophagus [25] and was not cultured from the esophagus of 11 patients [21], colonization of acid secreting gastric epithelium in the esophageal tissue has been reported a great number of times [22,24,26-33]. In all cases, H. pylori was found to be colonizing only the gastric-type tissue in the esophagus. The prevalence of colonized Barrett's esophagus was variable: with the exception of 12 Yemeni patients with Barrett's esophagus, all (100%) colonized [33], the prevalence rate in western countries ranged from 15 to 52% in five series of seven to 100 patients with Barrett's esophagus [22,24,28,29,32]. The absence of Barrett's esophagus colonization without gastric infection demonstrates that esophageal H. pylori comes from the stomach. However, as shown in several series, less than half of antral H. pylori infection extends to the columnar epithelium of Barrett's esophagus. These findings suggest a difference in mucosal reactivity of columnar epithelium between esophagus and stomach towards H. pylori invasion. This might be due to a distinct immunologic reactivity or to a protection by a relatively high acid output, as seen in the gastric corpus. Furthermore, junctional-type epithelium (the type most closely resembling antral mucosa) is found in only about 25% of Barrett's esophagus [25,34]. Thus, it is possible that the metaplastic epithelium of Barrett's esophagus lacks in some cases the prerequisite receptor for attachment of the bacteria.

Esophagitis

Since it can cause inflammation of gastric tissue in the stomach, H. pylori has been assumed to have the same effect on gastric tissue in esophagus and thus to contribute

to the overrated risk of ulceration and adenocarcinoma in Barrett's esophagus [35-37]. It has been reported a coincidence between the presence of H. pylori with areas of esophagitis in a 14-year-old child [27] and an association with acute inflammation of the esophageal columnar mucosa, as compared with Barrett's mucosa from patients with gastric but not esophageal colonization: 4/4 vs. 1/6 [22]. However, further studies show that the relationship is inconstant. Acute esophageal inflammation (polymorphonuclear leukocytes infiltration) was found in only one case among 23 patients with H. pylori infection in Barrett's epithelium [29] and in eight cases among 19 [32]. On the other hand, polymorphonuclear cells have been found even when H. pylori infection of esophageal columnar epithelium was absent: among 20 patients with endoscopic and histological Barrett's inflammation, 15 had no H. pylori infection [24]. Among 81 Barrett's esophagus without H. pylori infection, 27 had an active inflammation [32],

Other infections of esophageal columnar epithelium have been described. Candida and moniliasis for instance, were found in association with 6/25 (24%) of cases of Barrett's esophagus (vs. 19% of H. pylori infection) [28]. Candidiasis is generally regarded as an opportunistic infection in peptic ulcer and it is possible that the presence of esophagitis lesions promotes colonization by H. pylori as well as Candida. Such contaminant organisms might have no etiologic role in esophageal inflammation.

Ulcer and adenocarcinoma

Ulceration and adenocarcinoma are well known complications associated with Barrett's esophagitis [38] and the possible role of H. pylori has been studied. Barrett's esophagus ulceration has been found no more frequently in H. pylori infected patients than in noninfected patients: 4/10 vs. 5/16 [22]. In another study, among 25 Barrett's esophagus ulceration, only six patients (24%) were H. pylori infected (vs. 17% in nonulcerated cases, the difference was not significant) [28]. These two studies reported that about half H, pylori infected patients had no ulceration of their Barrett's mucosa (6/10 and 6/12, respectively).

Association of H. pylori with carcinoma of Barrett's esophagus has been rarely documented. Among 30 patients with esophageal columnar epithelium, from which 27% were H. pylori infected, one patient had a carcinoma but was not H. pylori infected [24]. In 12 cases of H. pylori infected Barrett's esophagus, the gastric-type mucosa showed no evidence of dysplasia in any cases but intestinal metaplasia was present in three patients [33]. Among 64 cases of Barrett's esophagus, from which 19% were H. pylori infected, one patient had a dysplasia but was not infected.

Conclusion

H. pylori, which may be isolated from gastric juice in infected subjects, can be transmitted by means of GER of contaminated gastric juice to acid secreting gastric-type epithelium of esophagus. The potential analogy to duodenal ulcer of patients

with H. pylori infected Barrett's esophagus remains evocative. However, the relationship between colonization and esophagitis, ulceration or adenocarcinoma of Barrett's esophagus is inconstant. H. pylori, which is not of relevance in GER and not an acquisition of Barrett's esophagus, does not seem to contribute to the natural history of this affection. It is possible that, through migrating from the stomach to the lower third of the esophagus, H. pylori undergoes environmental alteration. Observations do not support the hypothesis that H. pylori causes inflammatory, ulcerative or precancerous lesions of Barrett's esophagus. Whether or not colonization of esophageal gastric-type epithelium is more than an overinfection of pre-existent lesions by a transient contaminant, remains to be proved.

References

1. Warren JR, Marshall BJ. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet 1983;2: 1273-1275.

2. Goodwin CS, Armstrong JA, Chilvers T, Peters M, Collins M, Sly L, McConnell W, Harper WES. Transfer of Campylobacter pylori and Campylobacter mustelae to Helicohacter gen. nov. as Helicobacter pylori comb. nov. and Helicohacter mustelae comb, nov., respectively. Int J Syst Bacteriol 1989:39:397-405

3. Taylor DN, Blaser MJ. The epidemiology of Helicobacter pylori infection. Epidemiol Rev 1991;13:42-59.

4. Vincent P. Epidémiologie de l'infection a Helicohacter pylori: quand et comment risque-t-on de s'infecter? La lettre de I'infectiologue 1993:8:184-189.

5. Lee A, Hazell SL. Campylobacter pylori in health and disease: an ecological perspective Microbial Ecol Health Dis 1988;1:1-16.

6. Lee A. Infection causes of gastroduodenal inflammation in humans Eur J Gastroenterol Hepatol 1992,4:51-57.

7. Hazell SL, Lee A, Brady L, Hennessy W. Campylobacter pyloridis and gastritis: association with intercellular spaces and adaptation to an environment of mucus as important factors in colonization of the gastric epithelium. J Infect Dis 1986; 153: 658-663.

8. Eaton KA, Morgan DR, Krakowka S. Campylobacter pylori virulence factors in gnotobiotic piglets. Infect Immun 1989;57: 1119-1125.

9. Lingwood CA, Pellizani A, Law H, Sherman P, Drumm B. Gastric glycerolipid as a receptor for Campylobacter pylori. Lancet I989;2:238-241.

10. Buck GE, Gourley WK, Lee WK, Subramanyam K, Latimer JM, Di Nuzzo AR Relation of Campylobacter pyloridis to gastritis and peptic ulcer. J Infect Dis 1986:153:664-669.

11. Megraud F, Neman-Simha, Brugmann D. Further evidence of the toxic effect of ammoniac produced by Helicobacter pylori urease on human epithelial cells. Infect Immun 1992,60:1858.

12. Daw MA, Keane CT, O'Moore R, O'Morain C. Phospholipase C activity: new pathogenicity marker for Helicobacter pylori. Ital J Gastroenterol 1991;23(S2):37-38.

13. Figura N, Guglielmetti P, Rossolini A. Cytotoxin production by Campylobacter pylori strains isolated from patients with peptic ulcers and from patients with chronic gastritis only. J Clin Microbiol 1989:27:225-226.

14. Wyatt JI, Rathbone BJ, Heatley RV. Local immune response to gastric Campylobacter in nonulcer dyspepsia. J Clin Pathol 1986:39:863-870.

15. Correa P. Precursors of gastric and esophageal cancer. Cancer 1982:50:2554-2565.

16. Forman D. Helicobacter pylori infection and gastric carcinogenesis. Eur J Gastroenterol Hepatol 1992:4:531-535.

17. Correa P, Haenzel W, Cuello C, Zavala D, Fontham E, Zarama G. Gastric precancerous process in a high risk population: cohort follow-up study. Cancer Res 1990:50:4737-4740

18. Sobala GM, Schorah CJ, Shires S, Axon ATR. Impairment of gastric ascorbic acid concentration by acute Helicobacter pylori infection. Gut 1990;31:A1180.

19. Mirvish SS. The etiology of gastric cancer intragastric nitrosamide formation other theories. J Natl Cancer Inst 1983:71:631-647.

20. Stewart RJ, Boston VE, Dodge JA, Emmerson AM. Campylobacter pylori and reflux oesophagitis. Acta Paediatr Scand 1990:79:107.

21. Francoual S, Lamy Ph, Le Quintrec Y, Luboinski J, Petit JC, Helicohacter pylori: has it a part in the lesion of the gastroesophageal reflux? J Infect Dis 1990:161:626-633.

22. Paull G, Yardley JH. Gastric and esophageal Campylobacter pylori in patients with Barrett's esophagus. Gastroenterology 1988:95:216-218.

23. Lambert J, Borromeo M, Pinkard K, Turner H, Chapman C, Smith M. Colonization of gnotobiotic piglets with Campylo-

barter pyloridis - an animal model? J Infect Dis 1987;155:1344.

24. Walker SJ, Birch PJ, Stewart M, Stoddard CJ, Hart CA, Day DW. Patterns of colonisation of Campylobacter pylori in the oesophagus, stomach and duodenum. Gut 1989;30:1334-338.

25. Houck JA, Lucas JG. Absence of Campylobacter-like organisms in Barrett's esophagus. Arch Pathol Lab Med 1989;! 13: 470-472.

26. Goodwin CS, Blincow ED, Warren JR. Evaluation of cultural techniques for isolating Campylobacter pyloridis from endoscopic biopsies of gastric mucosa. J Clin Pathol 1985;38:1127-1131.

27. Mitchell HM, Bohane TD, Berkowicz J, Hazell SL, Lee A. Antibody to Campylobacter pylori in families of index children with gastrointestinal illness due to C. pylori. Lancet 1987:2:681-682.

28. Kalogeropoulos NK, Whitehead R. Campylobacter-tike organisms and Candida in peptic ulcers and similar lesions of the upper gastrointestinal tract: a study of 247 cases. J Clin Pathol 1988:41:1093- 1098.

29. Talley NJ, Cameron AJ, Shorter RG, Zinsmeister AR, Phillips SF. Campylobacter pylori and Barrett's esophagus Mayo Clin Proc 1988;63:1176-1180.

30. Flejou JF, Potet F, Molas G et al. Campylobacter-like organisms in heterotopic gastric mucosa of the upper oesophagus. J Clin Pathol 1990;43:961-968.

31. Lapertosa G. Helicobacter pylori in Barrett's oesophagus Histopathology 1991:18:568-570.

32. Gospe (Precancerous lesions of the esophagus task force). Analysis of the clinical and biological features of the Barrett's esophagus and risk for developing an esophageal adenocarcinoma in patients with this metaplastic condition: a multicentric study. Acta Endoscopica 1987;17:189-194.

33. Guneid AEL, Sherif AMEL, Murray-Lyon IM, Zureikat N, Shousha S. Effect of chewing Qat on mucosal histology and prevalence of Helicobacter pylori in the oesophagus, stomach and duodenum of Yemeni patients. Histopathology 1991; 19: 437-443.

34. Paull A, Trier JS, Dalton MD, Camp RC, Loeb P, Goyal RK. The histologic spectrum of Barett's oesophagus. N Engl J Med 1976:295:476-480.

35. Van der Veen AH, Dees J, Blankenstein M. Adenocarcinoma in Barrett's esophagus in patients: an overrated risk. Gut 1989:30:14-18.

36. Munoz N, Crespi M, Grassi A, Qing WC, Qiong S, Cai LZ. Precursor lesions of oesophageal cancer in high-risk populations in Iran and China. Lancet 1982:1:876-879.

37. Hameeteman W, Tytgat GNJ, Houthoff HJ, Van den Tweel JC. Barrett's esophagus: development of dysplasia and adenocarcinoma. Gastroenterology 1989:96:1249-1256.

38. Sjogren RW, Johnson L. Barrett's esophagus: a review. Am J Med 1983:74:313-321.


Publication date: May 1994 OESO©2015