Understanding disease outcome following acquisition of ...downloads.hindawi.com/journals/cjgh/1999/954361.pdf · Understanding disease outcome following acquisition of Helicobacter

Understanding diseaseoutcome following acquisitionof Helicobacter pylori infection

during childhoodAndrew S Day �� , Philip M Sherman ��

Helicobacter pylori infection generally is acquired duringearly childhood (1) when it induces a chronic active

type B gastritis. Risk factors for infection early in children in-clude residing in developing countries (2) or urban settings (3),and growing up under poor socioeconomic circumstances (4).The latter risk factor may reflect enhanced exposure to acommon, but as yet unidentified, environmental reservoir ofthe organism or heightened person to person transmissiondue to family crowding occurring as a result of financial dep-rivation (5). The increased prevalence of gastric infectionamong children cared for in institutional settings (6) sup-ports the contention that humans serve as a vehicle fortransmitting the organism.

Unless eradication therapy is introduced, colonization ofthe antrum of the stomach by H pylori and the accompanyingmucosal inflammation generally persist over the course of alifetime. Most infections remain asymptomatic, with only asmall subset of infected individuals developing complica-tions including peptic ulcer disease and gastric cancers.

Fennerty (7) estimated that the lifetime risk of developing agastric ulcer or duodenal ulcer as a complication of H pylori

infection is about 15%. The risk of developing a gastric ade-nocarinoma was estimated as 0.1% of all H pylori-infectedpersons. The estimated risk of H pylori causing a gastric lym-phoma was even lower – 0.001% (7).

There is an ongoing controversy regarding the merits ofinstituting eradication therapy in all individuals who are in-fected with H pylori (8). This question could be clarified if anaccurate method were available to predict which subjects areat greatest risk for the development of significant complica-tions of chronic gastric infection including peptic ulcera-tion, adenocarcinomas involving the antrum and body of thestomach, and gastric lymphomas. Such an approach wouldfocus attention and resources on the treatment of infectionin high risk individuals. Persons at low-risk of the complica-tions of H pylori infection would avoid the side effects oferadication therapy while minimizing financial costs to thehealth care system.

Can J Gastroenterol Vol 13 No 3 April 1999 229

Departments of Pediatrics and Laboratory Medicine & Pathobiology, University of Toronto, and Division of Gastroenterology and Nutrition,Research Institute, The Hospital for Sick Children, Toronto, Ontario

Correspondence: Dr PM Sherman, Division of Gastroenterology and Nutrition, Room 8409, The Hospital for Sick Children,555 University Avenue, Toronto, Ontario M5G 1X8. Telephone 416-813-6185, fax 416-813-6531, e-mail [email protected]

HELICOBACTER PYLORI CONSENSUS CONFERENCE

AS Day, PM Sherman. Understanding disease outcome follow-ing acquisition of Helicobacter pylori infection during child-hood. Can J Gastroenterol;13(3):229-234. Helicobacter pylori

causes chronic active (type B) gastritis in the overwhelming ma-jority of infected individuals. The relative contribution of viru-lence factors in the bacterium and host responses to the microbialinfection in determining which subjects will go on to developcomplications – such as peptic ulceration, gastric cancers and gas-tric lymphomas – is the subject of current investigative activities.

Key Words: Children, Cytotoxin, Gastric cancer, Helicobacter py-lori, Metaplasia, Ulcers

Comprendre le pronostic de la maladie aprèsune infection à Helicobacter pylori acquisependant l’enfance

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There is no accurate way to discriminate the person in-fected with H pylori who is at risk for developing peptic ulcerdisease from the large number of people infected with the or-ganism who will remain asymptomatic. An interesting re-port by Hansson et al (9) suggests that infected humans whodevelop duodenal ulcer disease are distinct from those whodevelop gastric cancers. The question is whether this evi-dence points towards the possibility of ulcerogenic and car-cinogenic strains of H pylori. Alternatively, all H pylori

strains may be equally virulent, but the disease manifesta-tions may reflect host responses to the chronic infection(10).

This critical review considers what is currently knownabout the bacterial and host factors that may play a role inthe development of peptic ulcer disease as a complication ofH pylori infection.

PREDICTING ULCER DISEASE AS ACOMPLICATION OF H PYLORI INFECTION

There is compelling evidence that H pylori infection causesboth gastric ulcers and duodenal ulcers. Eradication of infec-tion enhances ulcer healing (11) and resolution of clinicalsymptoms. The natural history of peptic ulcers to recur fol-lowing healing with acid suppression alone is dramaticallyaltered by eradication of H pylori colonization in the antrumof the stomach (12). Clinically, the reduction in ulcer recur-rence from 50% or more with acid suppression alone to lessthan 5% at one year of follow-up with eradication therapy isextremely relevant because the risk of recurrent bleeding –with its attendant morbidity and mortality – is also markedlyreduced (13).

Discriminating among strains of H pylori requires the de-velopment of methodologies to categorize the bacteriuminto subgroups. Typing systems are employed to identify bac-terial isolates that are identical. Such information can bevery helpful in identifying common outbreaks. A variety ofmethods have been employed with success in other Gram-negative pathogens. For example, serotyping systems havebeen developed to distinguish between commensal strainsand those causing clinical disease (14). Serotyping can bebased on antigenic variation in heat-labile antigens (such asflagella and outer membrane proteins) and heat stablelipopolysaccharide-derived antigens. An initial report sug-gested that monoclonal antibodies directed against the vari-ous Lewis antigens expressed by H pylori lipopolysaccharide(15) could be employed as a serotyping method to subcatego-rize clinical isolates. However, subsequent studies have

shown that the expression of the antigens detected by thesemonoclonal antibodies is subject to phase variation undergrowth conditions employed in the laboratory (16). There-fore, the lipopolysaccharide-based typing system has notbeen employed to discriminate successfully H pylori strainsisolated from patients with peptic ulcer disease from thosewith chronic active gastritis alone.

Susceptibility profiles to antibiotics have been used withsuccess to identify common sources of outbreaks of infectioncaused by other Gram-negative bacteria (17). However, therapid change in antibiotic susceptibility of H pylori in re-sponse to environmental exposure makes this an unsuitableapproach to discriminate bacterial strains likely to inducepeptic ulcer disease from those isolates that cause gastritisalone.

A genetic approach to the categorization of microbialpathogens has been employed successfully for a variety ofGram-negative bacteria infecting the intestinal tract. Themarked genetic heterogeneity of H pylori infecting the stom-ach has made this a less than successful approach to date.DNA fingerprinting of H pylori isolates reveals such a re-markable heterogeneity that every individual appears to beinfected with a different bacterial strain (18). Among strainscausing comparable disease outcomes, such heterogeneitycomplicates the development of an accurate typing systembased on genetic similarity. Plasmid profiles have not beenreported as a successful marker for use in the subtyping ofH pylori.

In summary, there is currently no suitable marker to dis-tinguish H pylori isolated from subjects with peptic ulcer dis-ease from those with gastritis alone by using phenotypic andgenotypic typing systems that are traditionally employed forGram-negative enteropathogens. This deficiency has led in-vestigators to consider whether virulence factors only pres-ent in bacteria isolated from patients with disease complica-tions might be employed in an effort to provide a method toidentify ulcerogenic H pylori isolates (Table 1).

VIRULENCE FACTORS OF H PYLORIVacuolating cytotoxin: Many H pylori isolates produce atoxin that causes cytopathic effects on a variety of cell linesgrown in tissue culture (19). The toxin exerts its effectsthrough the low molecular weight G protein Rab7 (20 ) bydisrupting trafficking in the late endosome compartment ofinfected eukaryotic cells (21). The role of the vacuolating cy-totoxin (VacA) in vivo is still uncertain because most inves-tigators do not describe vacuolization of gastric and duodenalepithelial cells as a histopathological feature of the infection.Nevertheless, some reports indicate the presence of vacuo-lated cells in vivo in subjects colonized with an H pylori strainthat produces VacA (22).

Regardless of its biological relevance, VacA may alsoserve as a marker of virulence. Indeed, some studies suggestthat VacA strains are isolated with a higher frequencyamong subjects with H pylori-associated peptic ulcer diseasethan in patients with H pylori-induced gastritis alone(23,24). Unfortunately, these initial reports have not been

230 Can J Gastroenterol Vol 13 No 3 April 1999

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TABLE 1Factors that may identify ulcerogenic Helicobacter pylori

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confirmed in subsequent studies by other investigators (25).The presence of the VacA phenotype in H pylori strains iso-lated from children and adolescents does not discriminatebetween those with duodenal ulceration or duodenitis andthose with gastritis alone (26,27).

Allelic variations in the gene encoding VacA have beenproposed as a more sensitive marker than the cytotoxic phe-notype for discriminating between ulcerogenic and non-ulcer-related H pylori isolates. Variations in the signal se-quence, ie, s1a variants in the vacA gene, are reported to bepresent more commonly in patients with duodenal ulcera-tion than in those with gastritis alone (28,29). These find-ings require confirmation in a variety of community settingsbecause not all investigators have been able to show that al-leles of vacA serve as useful predictors of disease outcome(30,31).Cytotoxin-associated outer membrane protein: A gene firstidentified in association with vacA, and, therefore, referredto as the cytotoxin-associated gene (cagA), may also serve asa marker of bacterial virulence. The gene codes for a 128 kDaouter membrane protein. Cover et al (32) reported the pres-ence of the gene in 82% of H pylori isolates obtained from pa-tients with duodenal ulcer disease versus only 59% of 39subjects with gastritis alone. Similarly, immune responses toCagA occur more frequently in H pylori-infected personswith duodenal ulceration than in those with gastritis alone(32,33). However, this discriminatory power is true only inNorth American and European studies. By contrast, infec-tion with CagA-producing H pylori is the norm in China, Ja-pan and other countries in the Far East, regardless of thepresence or absence of peptic ulcer disease as a complicationof infection (34,35).

Allelic variations in cagA may serve as a better marker ofdisease outcome, but further studies in both communities athigh risk and at low risk for the development of disease com-plications are required. For example, there is increasing in-terest in determining why the frequency of peptic ulcerationand bleeding complications is so low in persons living in Af-rica despite a very high prevalence of H pylori infection (36).Studies evaluating the cagA variants present in H pylori

strains isolated in Africa compared with those isolated inNorth America and Western Europe are awaited with inter-est.

PATHOGENICITY ISLANDUnlike vacA, cagA resides on a 38 kilobase segment of chro-mosomal DNA that comprises a guanine plus cytosine con-tent (35%) that is lower than that of the rest of the bacterialgenome (39%) (37). This suggests that cagA is part of apathogenicity island, which, in other bacterial pathogens,often encodes virulence properties (38).

The cag pathogenicity island contains a number of openreading frames that, as deduced by their similarity to relatedgenes in other Gram-negative bacteria, encode a type IV se-cretion pathway (39). Increasingly, it is recognized that pro-karyotes can use a variety of secretion pathways as a means ofdelivering bacterial products to infected eukaryotic cells

(40). It is possible, therefore, that protein products of the cag

pathogenicity island in H pylori are delivered into infectedepithelial cells and, thereby, influence disease outcome.

Current interest focuses on the role of cagE (also referredto as picB) because the presence of this gene correlates withH pylori isolates that induce a larger chemokine and resultingproinflammatory response in epithelial cells infected in vitro(41). Whether other gene products of the pathogenicity is-land correlate with the presence of peptic ulceration andother complications of H pylori infection is the subject ofcurrent investigation (42).

HOST RESPONSES TO H PYLORI INFECTIONAre all H pylori strains capable of causing peptic ulceration?Some studies suggest that this may be the case. For example,some reports indicate that there is a higher bacterial load inthe stomach of patients with documented duodenal ulcerthan in those without peptic ulceration (43,44). However,there frequently is considerable overlap in the number ofH pylori present in the antrum of subjects with and withoutduodenal ulcer disease.

Other studies have considered whether host responses toinfection may determine whether peptic ulceration will de-velop. As shown in Table 2, host responses to H pylori infec-tion that have been reported to increase the risk of pepticulceration include altered gastric acid and pepsin produc-tion, ectopic gastric mucosa developing in the first part ofthe duodenum, and inflammation of the duodenal mucosa inresponse to the production of chemokines by gastric epithe-lial cells and by immune cells in the inflamed lamina propriaof the antrum.Disruption of gastric acid homeostasis: Before the success-ful culture of H pylori and its identification as a gastric patho-gen in humans, peptic ulcer disease was assumed to have agenetic basis in children. Hyperpepsinogenemia appeared tobe transmitted in an autosomal dominant fashion in childrenwith recurrent peptic ulcer disease and a strong family historyof the same condition. Now, it is clear that the increased lev-els of serum pepsinogen simply reflect changes in the gastricmucosa occurring as a result of H pylori colonization (45,46).


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TABLE 2Host factors that may predispose H pylori-infectedindividuals to duodenal ulceration

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The observed familial nature is a marker of the familial clus-tering of infection.

In addition to changes in pepsinogen secretion, bacterialcolonization of the antral mucosa and the ensuing mucosalinflammation cause changes in the hormones controllingthe secretion of acid by parietal cells in the body of the stom-ach. Both transcription and protein translation of gastrin byG cells and somatostatin by D cells are altered in response toinfection and inflammation (47).

Both fasting and postprandial levels of gastrin are ele-vated in subjects with H pylori infection in comparison withage-matched uninfected controls (48). Elevated gastrin lev-els return towards normal following eradication of the infec-tion. In contrast, somatostatin levels are reduced in H py-

lori-infected individuals. Somatostatin increases to valuesobserved in uninfected persons following anti-helicobactertherapy. The net result of increased gastrin and reduced so-matostatin in patients infected with the gastric pathogen isan imbalance in the control of acid secretion that should re-sult in higher levels of acid output from parietal cells. Initialresults suggest that this is the case because acid output ishigher in patients with H pylori infection than in uninfectedage-matched and sex-matched controls (49). More impor-tantly, acid output in response to both gastrin-releasing pep-tide (50) and gastrin (51) is enhanced to a greater extent insubjects with documented duodenal ulcer disease than inH pylori-infected patients who have not suffered from pepticulceration. Other investigators suggest that acid output maybe higher in H pylori-infected individuals due to a loss of thenormal inhibitory effects of antral distension on parietal cellproton output (52).Gastric metaplasia: H pylori colonizes sites outside of thestomach only if there is ectopic gastric mucosa such as in aMeckel’s diverticulum in the small bowel (53), Barrett’s epi-thelium in the lower esophagus (54) or gastric rest along thelength of the intestinal tract (55). Similarly, H pylori is notpresent in the proximal duodenum in patients with mucosalulceration unless there are sites of gastric metaplasia.

Initial reports considered the possibility that gastric meta-plasia in the first and second parts of the duodenum is an in-herited condition predisposing an individual to peptic ulcerdisease following infection with H pylori during childhood(56). Subsequent studies have shown that this is not thecase. Rather, gastric metaplasia occurs in the duodenum inresponse to H pylori infection (57) and regresses followingeradication of the bacterial infection from the stomach (58).

Studies in children and adolescents document ectopicgastric mucosa in the duodenum only in children with bacte-rial colonization of the antrum and not in age-matched con-trols without infection (59). A prospective study in Irishchildren showed the presence of gastric mucosa in the proxi-mal duodenum in 86% of those with documented pepticulcer disease compared with only 20% of 141 children andadolescents with H pylori-induced gastritis alone (60). Colo-nization of the extragastric site may perturb local hostdefences to an extent sufficient to result in mucosal ulcera-tion. Persisting gastric metaplasia following failure of anti-

helicobacter therapy may serve as a marker to identify sub-jects at increased risk of recurrent peptic ulceration.Duodenitis: Even more common than ectopic gastric mu-cosa in the duodenum of subjects with duodenal ulcer diseaseis the presence of mucosal inflammation (61). Duodenitis is anearly universal finding in patients with H pylori infectionand duodenal ulcer disease. It is much less common in sub-jects with H pylori gastritis alone. This difference suggeststhat the mucosal inflammation may serve as a marker forthose at risk of peptic ulceration. It also indicates that inflam-mation in the duodenum occurring in response to H pylori in-fection in the antrum may be involved in the pathophysiol-ogy of disease (62).

It is clear that H pylori induces both epithelial cell and im-mune cell activation of nuclear factor kappa B (63), which,in turn, activates transcription of chemokines includinginterleukin-8, macrophage inflammatory protein-1alpha,and RANTES (64,65). The chemokines serve as potent che-moattractants that draw polymorphonuclear leukocytes intothe gastroduodenal mucosa. A number of other host cyto-kine responses, including production of interleukin-1,interleukin-6 and tumour necrosis factor-alpha, are also ini-tiated in the H pylori-infected gastric epithelium (66,67).Initial studies report that the chemokine and resulting in-flammatory responses are more vigorous in infected subjectswith duodenal ulcer disease than in those with gastritisalone.

The brisk inflammatory response to H pylori colonizationof the gastric mucosa also results in the recruitment of T cells(68), plasma cells, mast cells (69), eosinophils (70) and baso-phils (71) to sites of inflammation. Future studies should de-termine whether these host inflammatory responses differbetween those who have infection complicated by peptic ul-ceration and those with gastritis alone.

CONCLUSIONSThe final verdict on whether the microbe or the host ulti-mately determines the outcome of chronic infection remainsto be determined. As with many other infections (72,73), alikely possibility is that both the virulence of the infectingorganism and the host response to infection work in concertto determine which individuals will remain asymptomaticthroughout their lifetime and which will develop complica-tions of infection, including peptic ulceration and malignan-cies involving either epithelial cells or immune cells in thestomach.

A reproducible model of peptic ulcer disease in an animalmodel of H pylori infection is required to determine the rela-tive contributions of the microbe and the host. Reports ofgastric ulcer in the gnotobiotic piglet following challengewith H pylori (74) and in the ferret infected with the relatedgastric pathogen Helicobacter mustelae (75) indicate thatthese are the models that should be employed in future re-search endeavours. Currently, a model of duodenal ulcer dis-ease complicating Helicobacter species infection is lacking.The development of such an animal model should be an ur-gent and immediate research priority because it ultimately


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will provide answers to the questions arising from the issuesconsidered in this review of the virulence properties of H py-

lori and host responses to the gastric infection.

ACKNOWLEDGEMENTS: Andrew S Day is the recipient of aCanadian Association of Gastroenterology/Solvay Pharma/Medical Research Council of Canada Research Fellowship Award.Philip M Sherman is the recipient of the AC Finkelstein Awardfrom the Medical Research Council of Canada.

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