Helicobacter pyloriEradication DramaticallyImproves Inflammation in the Gastric CardiaPrateek Sharma, M.D., Margarita Topalovski, M.D., Matthew S. Mayo, Ph.D., Richard E. Sampliner, M.D.,and Allan P. Weston, M.D.Department of Medicine, Gastroenterology Section, University of Kansas and VA Medical Center, KansasCity; Department of Pathology, VA Medical Center, Kansas City; Department of Preventive Medicine,University of Kansas, Kansas City, Missouri; and Gastroenterology Section, University of Arizona and VAMedical Center, Tucson, Arizona

OBJECTIVES: Inflammation of the gastric cardia,i.e., “car-ditis,” has been associated withHelicobacter pylori (H.pylori) infection; however, some investigators believe car-ditis to be a histological marker for gastroesophageal refluxdisease. The aim of this study was to investigate the role ofH. pylori eradication on the grade of carditis scored accord-ing to the updated Sydney classification.

METHODS: Consecutive patients presenting for upper endos-copy underwent systematic gastric biopsies (eight antral, 12corpus, and four cardia). Patients withH. pylori infectionand carditis were identified and followed prospectively be-fore and afterH. pylori treatment. At pretreatment and, onaverage, 2 yr after eradication ofH. pylori, the degree ofinflammation in the gastric cardia andH. pylori status wereblindly assessed by a single pathologist.

RESULTS: A total of 31 patients withH. pylori infection andcarditis were identified. The mean age was 70 yr (range:37–81 yr); all were male. Four were African-American and27 were Caucasian. All patients were treated with standardanti-H. pylori therapy, including a proton pump inhibitor incombination with two antibiotics for 2 wk. Eradication ofH.pylori was successful in 23 patients (group I), whereas eightpatients had persistent infection (group II). Patients werefollowed after eradication therapy for a mean of 23.2months (range: 6–48 months). After eradication therapy,there was a significant decrease (p , 0.0001) in the carditisscores (activity and inflammation scores) in group I,whereas the scores remained unchanged in group II patients.In both groups, there were no significant changes in thedegree of intestinal metaplasia or atrophy. There were fourpatients with intestinal metaplasia, and one with atrophy.

CONCLUSIONS: There is a dramatic improvement in the de-gree of inflammation and activity scores in the gastric cardiaof patients with successfulH. pylori eradication comparedto those with persistent infection. By fulfilling one of

Koch’s postulates (i.e., improvement in the disease aftercure of the possible etiological organism), these data supportH. pylori as being the etiological agent for carditis in thisgroup of patients. (Am J Gastroenterol 2000;95:3107–3111.© 2000 by Am. Coll. of Gastroenterology)

INTRODUCTION

The presence of acute and chronic inflammatory cells lim-ited to the gastric cardia has been termed “gastric carditis”(1). It has been hypothesized that the gastric cardia, locatedat the gastroesophageal junction, is vulnerable to the inju-rious effects of exposure to gastric acid, and some studies (2,3) have demonstrated that carditis may be a histologicalmarker for gastroesophageal reflux disease (GERD). On theother hand, carditis has also been linked to gastric infectionwith Helicobacter pylori(H. pylori) (4, 5). Thus, there issignificant controversy in recent literature regarding theetiology of gastric carditisi.e., GERD versus H. pyloriinfection.

In gastric mucosa elsewhere in the stomach (i.e., theantrum, body, and fundus),H. pylori infection plays animportant role in the development of chronic gastritis, atro-phic gastritis, intestinal metaplasia, carcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma (6–8). Al-thoughH. pylori has been commonly known to colonize thegastric antrum and to cause antral gastritis, recent studieshave demonstrated that infection with this organism can alsobe documented within the cardia of.95% of H. pylori–infected patients (9, 10).

The hypothesis of the current study is that, if carditis isthe result of an infectious agent (i.e., H. pylori), eradicationof that agent should lead to an improvement in the degree ofinflammation within the gastric cardia. The aim of the cur-rent study was to identify a group of patients with carditisandH. pylori infection, to eradicate infection, and to followthese patients prospectively for any change in the degree ofcarditis as scored by the updated Sydney classification (11).

Presented at Digestive Diseases Week, May 17–19, 1999, Orlando, FL, as DDWPoster of Distinction.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 11, 2000© 2000 by Am. Coll. of Gastroenterology ISSN 0002-9270/00/$20.00Published by Elsevier Science Inc. PII S0002-9270(00)02050-5

MATERIALS AND METHODS

PatientsConsecutive patients withH. pylori infection who presentedto the GI endoscopy laboratory and who had a history ofpeptic ulcer disease or dyspepsia were invited to participatein the study and were followed prospectively. Patients witha history of previous treatment forH. pylori were excludedfrom the trial. Patients were also excluded if they had aknown allergy to penicillin or lansoprazole. The demo-graphics of the study group, their symptoms, and use of acidinhibition therapy during the study period were recorded.

The study was approved by the Human Subjects Com-mittee, and all patients gave written informed consent.

Endoscopy and Biopsy ProtocolAt study entry, all patients underwent an upper endoscopyusing a therapeutic (GIF1T100) video endoscope (Olympus,Lake Success, NY). Gastric biopsy specimens were ob-tained in the following fashion: eight from the antrum (foureach from the greater and lesser curve); 12 from the body(four from the distal body, four from the mid-body, and fourfrom the proximal body); and four from the gastric cardia(four quadrant biopsies directly below and within 1 cm ofthe gastroesophageal junction). Gastric cardia biopsy spec-imens were collected for histopathology using the turn andsection technique with the open span of a jumbo biopsyforceps (FK-13K-1, Olympus Lake Success, NY) abuttingthe gastric mucosa. The majority of the cardia biopsies(.90%) were obtained in the forward view position of theendoscope. Confirmation of the precise location of the car-dia biopsies was performed by direct endoscopic visualiza-tion of the four biopsy sites in relation to the anatomicgastroesophageal junction. The gastroesophageal junctionwas defined as the pinch at the end of the tubular esophaguscoinciding with the proximal margins of the gastric folds(12).

H. pylori Assessment and Grading of CarditisAll biopsy specimens were fixed in formalin, embeddedwith paraffin, and then stained with hematoxylin and eosin(hematoxylin and eosin) to grade carditis.H. pylori assess-ment was performed using a silver stain (Steiner). Infectionwith H. pylori was diagnosed by the presence of the organ-ism in any of the biopsy specimens obtained, whereas erad-ication was defined as absence of microorganisms by his-topathology on repeat endoscopy/biopsy—the total numberof specimens obtained per study protocol provided adequatetissue for this assessment.Histological sections of the gastric cardia were evaluatedand graded for the following parameters, according to theupdated Sydney classification (11): activity, chronic inflam-mation,H. pylori infection, intestinal metaplasia, and atro-phy on a scale of 0–3; 05 none, 15 mild, 2 5 moderate,and 35 severe. Inflammation was scored according to thepresence and the density of mononuclear cells and plasmacells in the lamina propria; activity by the presence and

density of neutrophils in the lamina propria and the epithe-lial layer; intestinal metaplasia by the presence of gobletcells; and atrophy by the loss of gastric glands. The cardiacmucosa was characterized by the presence of abundantmucus-secreting glands without the presence of parietalcells.

All sections (pre- and posttreatment biopsies) were eval-uated by a single experienced pathologist who was blindedto the data and had no knowledge of the clinical histories ofthe patients.

H. pylori Treatment and Follow-Up EndoscopyThe patients were treated with standardH. pylori eradicationtherapy. This included a proton pump inhibitor (lansopra-zole) in combination with two antibiotics (including amoxi-cillin, clarithromycin, metronidazole) for 2 wk. After aminimum of 6 months afterH. pylori eradication therapy, allpatients underwent repeat EGD, and gastric biopsy speci-mens in the format described above were collected forhistopathological examination. Subsequently, theH. pyloristatus and degree of carditis were reassessed.

Statistical AnalysisThe patients were classified into two groups. Group I con-sisted of those patients who had successfulH. pylori erad-ication (n 5 23), and group II consisted of those patientswho had failedH. pylori eradication (n5 8). The Wilcoxonrank sum test was used to compare pretreatment, posttreat-ment, and change in inflammation and activity scores be-tween the two groups. The Wilcoxon signed rank test wasused to compare the pairwise change in inflammation andactivity scores within each group separately. Because of thesmall sample size in each group, nonparametric procedureswere used for statistical inference, and the median and rangewere used to summarize quantitative variables.

RESULTS

PatientsA total of 49 patients withH. pylori infection agreed toparticipate in the study and underwent EGD/biopsy per thestudy protocol. Of this study group, inflammation in thegastric cardia (carditis) was documented in only 31 patients.The mean age of this patient group was 70 yr (range: 37–81yr); all were male. There were 27 Caucasians and fourAfrican-Americans. None of the patients had erosive esoph-agitis or Barrett’s esophagus (i.e., the squamo-columnarjunction (SCJ) coincided with the gastroesophageal junc-tion). A similar number of patients in both groups were onproton pump inhibitor therapy for upper GI symptoms.

SuccessfulH. pylori eradication was achieved in 23 of 31patients (group I); whereas eight patients had persistentinfection (group II). The clinical characteristics and demo-graphics of the patients in both groups are given in Table 1.Patients were followed after eradication therapy for a meanof 23.2 months (range: 6–48 months). For the purposes of

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this study, only the cardia histological scores are reported, asthe effect ofH. pylori eradication therapy on antral andcorpus gastritis have been evaluated by previous studies (17,18).

Carditis ScoresAt pretreatment histological assessment, the grade of cardi-tis, along with the median values for activity and inflam-mation, were as shown in Table 2. There were no significantdifferences in the pretreatment carditis grades between thetwo groups. On long-term follow up, after successfulH.pylori eradication, the degree of activity and inflammationsignificantly improved (p , 0.0001 for each) in group Ipatients (Fig. 1A–C). There was a decrease in carditis scores(both activity and inflammation) in 21 of 23 patients afterH.pylori eradication; in two patients, the scores remainedunchanged. On the other hand, the final degree of carditisscores remained high (both inflammation and activityscores) in group II patients and did not differ from theirpretreatment values.

Four patients (two in each group) were detected withcardia intestinal metaplasia on their initial biopsy. The de-gree of intestinal metaplasia (moderate degree in all fourpatients) was similar in both groups at pretreatment assess-ment. After a mean of 2 yr of follow-up, the degree ofintestinal metaplasia remained unchanged compared to theirpretreatment values. Similarly, in the one patient with atro-phy in the gastric cardia (group II patient with severe degreeof atrophy), no significant change was detected on follow-up. Cardia dysplasia was not detected in any patient.

DISCUSSION

The gastric cardia has been a topic of great interest in recentyears, given the rapidly rising incidence of cancer in thislocation (13, 14). These cancers can arise from intestinalmetaplasia in the distal esophagus (i.e., Barrett’s esophagus)or from intestinal metaplasia within the gastric cardia (15,16). The detection of intestinal metaplasia in the cardia isusually associated with the presence of inflammation,i.e.,gastric carditis.

The exact roles ofH. pylori, GERD, and other factors inthe pathogenesis of gastric carditis and cardia intestinalmetaplasia are poorly understood. A strong association be-tween H. pylori and carditis has been defined in variousstudies; on the other hand, a relationship between GERDand carditis has also been documented. The results of arecent study by Oberget al. suggest a positive and strongassociation between the presence of carditis and cardiaintestinal metaplasia with GERD. as determined by symp-toms and 24-h pH results (2). These investigators conse-quently proposed carditis as an earlier and a more sensitivemarker for GERD than histological changes in the squa-mous epithelium. Chenet al. evaluated the presence ofH.pylori in cardia biopsy specimens (4). They concluded thatcarditis was significantly associated withH. pylori infectionand active corpus gastritis but not with symptoms or signs ofGERD. Similarly, Goldblumet al. studied patients withcarditis and documentedH. pylori infection in 97% of theirpatients with carditis (5).

Previous studies have examined the effect ofH. pylorieradication therapy on the severity of gastritis and atrophy inpatients with antral and body gastritis. Two studies havereported that eradication ofH. pylori led to improvement inthe acute and chronic inflammatory components of gastritis(17, 18).

However, the effect ofH. pylori eradication on the degreeof carditis has not been assessed. This is important becauseof the controversy surrounding the etiology of carditis. Inthis group of prospectively followed patients withH. pylori–associated carditis, significant improvement in the activityas well as inflammatory scores were observed 2 yr, onaverage, afterH. pylori eradication. Thus, by fulfilling oneof Koch’s postulates (i.e., improvement in the disease aftercure of the possible etiological organism), our study sup-ports the role ofH. pylori infection as an etiological agentfor inflammation in the gastric cardia. At retesting after amean of 24 months, those patients with continuingH. pyloriinfection (who were considered as having failed treatment)showed persistent activity and inflammation. These findingssuggest that in a subgroup of patients, H. pylori infectionindeed causes gastric carditis, and that eradication of theorganism leads to significant resolution in the grade ofcarditis.

Because this study did not evaluate for GERD symptomsor markers for gastroesophageal reflux (i.e., 24-h pH test-ing), the potential additive role of GERD in these patients

Table 1. Clinical Characteristics and Demographics of PatientsWith Successful and FailedP. pylori Eradication

Group I Group II

Successful eradication Yes NoNumber of patients 23 8Age, yr mean (range) 71.9 (55–81) 63.6 (37–80)Sex All male All maleEthnicity (Caucasian) 87% 87.5%PPI therapy 61% 62.5%

PPI 5 proton pump inhibitor.

Table 2. Effect of H. pylori Eradication on Carditis Scores

Group I Group II p Value

Patients 23 8Inflammation

Pre 2 (1–3) 2 (1–3) 0.8941Post 1 (0–1) 2 (1–3) ,0.0001Change 1 (0–2) 0 (22–1) ,0.0001

ActivityPre 1 (0–2) 1 (0–3) 0.7849Post 0 (0–0) 1 (0–2) ,0.0001Change 1 (0–2) 0 (21–2) 0.0067

Data are medians (range).p Values are calculated using the Wilcoxon rank-sum test.

3109AJG – November, 2000 H. pylori and Gastric Cardia Inflammation

with carditis remains to be evaluated. Similar prospectivestudies evaluating the role of acid suppressive therapy oncarditis need to be performed. The diagnosis ofH. pyloriinfection was made solely by histopathology. Obtainingmore biopsies from the stomach, urease testing, as well asserum antibody measurement may have increased the de-tection rate ofH. pylori infection. TheH. pylori eradicationrate in this study was 75%, which is less than generallyreported. Metronidazole was one of the antibiotics used inthe treatment regimen, and resistance to this antibiotic mayhave played a role. Also, patient compliance may have beenan issue, inasmuch as monitoring of adherence (e.g., pillcount) was not performed during the study period.

H. pylori infection as a major cause of chronic activegastritis in the body and the antrum of the stomach has beensubstantiated by a number of studies. The presence of neu-trophils (active infection) is a sensitive indicator for thepresence ofH. pylori infection. The presence ofH. pyloriand carditis supports the notion that inflammation in thegastric cardia represents the most proximal part ofH. pylori

infection, as this organism can be documented in the gastriccardia in.95% of the patients with documentedH. pyloriinfection. Thus, the findings of this study directly linkH.pylori infection and carditis but do not exclude the role ofother factors such as gastric acid in the etiology of carditis.

The etiology of carditis assumes importance (19, 20)given the rapidly rising incidence of cancer in the locationof the gastroesophageal junction. This is at a time when theprevalence ofH. pylori infection is actually on the decline(21). If carditis is in fact related toH. pylori infection, thencarditis and intestinal metaplasia in the gastric cardia maynot be playing a role in the rapidly rising incidence of cancerin this location.

In conclusion, infection withH. pylori is associated withactivity and inflammation of the gastric cardia in a subgroupof patients. After successful eradication therapy, the acuteand chronic inflammatory components of carditis are sig-nificantly improved. The effect ofH. pylori eradication onthe degree of intestinal metaplasia and atrophy could not beevaluated in this study, given the relatively small number of

Figure 1. (A) Biopsy obtained from the gastric cardia of a 74-yr-old white man withH. pylori infection, revealing acute and chronicinflammatory cells—gastric carditis. (B) Gastric cardia biopsy revealing the presence ofH. pylori organisms in the same patient. (C) Repeatbiopsy of the gastric cardia from the same patient 20 months afterH. pylori eradication, revealing significant improvement in the gradeof carditis

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patients with these lesions. These findings, however, suggestthat H. pylori is indeed an etiological agent for carditis.

Reprint requests and correspondence:Prateek Sharma, M.D.,Assistant Professor of Medicine, University of Kansas, Gastroen-terology Section –111, VA Medical Center, 4801 East LinwoodBoulevard, Kansas City, MO 64128.

Received Apr. 7, 2000; accepted Aug. 2, 2000.

REFERENCES

1. Riddell, RH. The biopsy diagnosis of gastroesophageal refluxdisease, “carditis,” and Barrett’s esophagus, and sequelae oftherapy. Am J Surg Pathol 1996;20(suppl 1):S31–50.

2. Oberg S, Peters JH, DeMeester TR, et al. Inflammation andspecialized intestinal metaplasia of cardiac mucosa is a man-ifestation of gastroesophageal reflux disease. Ann Surg 1997226:522–32.

3. Csendes A, Smok G, Burdiles P, et al. ‘Carditis’: An objectivehistological marker for pathologic gastroesophageal reflux dis-ease. Dis Esophagus 1998;11:101–5.

4. Chen Y, Antonioli DA, Spechler SJ, et al. Gastroesophagealreflux diseaseversus Helicobacter pyloriinfection as the causeof gastric carditis. Modern Pathol 1998;11:950–6.

5. Goldblum JR, Vicari JJ, Falk GW, et al. Inflammation, andintestinal metaplasia of the gastric cardia: The role of gastro-esophageal reflux andH. pylori infection. Gastroenterology1998;114:633–9.

6. NIH Consensus Conference. Helicobacter pylori in pepticulcer disease. JAMA 1994;272:65–9.

7. Parsonnet J, Friedman, GD, Vandersteen DP, et al.Helico-bacter pylori infection, and the risk of gastric carcinoma.N Engl J Med 1991 325:1127–31.

8. Graham DY.Helicobacter pyloriinfection in the pathogenesisof duodenal ulcer and gastric cancer: A model. Gastroenter-ology 1997;113:1983–91.

9. Genta RM, Huberman RM, Graham DY. The gastric cardia inHelicobacter pyloriinfection. Hum Pathol 1994;25:915–9.

10. Hackelsberger A, Gunther T, Schultze V, et al. Prevalence andpattern ofHelicobacter pylorigastritis in the gastric cardia.Am J Gastroenterol 1997;92:2220–4.

11. Dixon MF, Genta RM, Yardley JH, et al. Classification andgrading of gastritis. Am J Surg Pathol 1996;20:1161–81.

12. McClave SA, Boyce HW, Gottfried MR. Early diagnosis ofcolumnar-lined esophagus: A new endoscopic criterion. Gas-trointest Endosc 1987;33:413–6.

13. Blott WJ, Devesa SS, Kneller RW, et al. Rising incidence ofadenocarcinoma of the esophagus and gastric cardia. JAMA1991;265:1287–9.

14. Pera M, Cameron AJ, Trastek VF, et al. Increasing incidenceof adenocarcinoma of the esophagus and esophagogastricjunction. Gastroenterology 1993;104:510–3.

15. Clark GWB, Smyrk TC, Burdiles P, et al. Is Barrett’s meta-plasia the source of adenocarcinomas of the cardia? Arch Surg1994;129:609–14.

16. Cameron AJ, Lomboy CT, Pera M, et al. Adenocarcinoma ofthe esophagogastric junction and Barrett’s esophagus. Gastro-enterology 1995;109:1541–6.

17. Van Der Hulst RWM, Van Der Ende A, Dekker FW, et al.Effect of Helicobacter pylorieradication on gastritis in rela-tion to cagA. A prospective 1-year follow-up study. Gastro-enterology 1997;113:25–30.

18. Witteman EM, Mravunac M, Becx MJCM, et al. Improvementof gastric inflammation and resolution of epithelial damageone year after eradication ofHelicobacter pylori. J Clin Pathol1995;48:250–6.

19. Tygat GNJ. The gastric cardia: The current battlefield. Gas-troenterology 1998;115:257.

20. Spechler SJ. The role of gastric carditis in metaplasia andneoplasia at the gastroesophageal junction. Gastroenterology1999;117:218–28.

21. el-Serag HB, Sonnenberg A. Opposing time trends of pepticulcer and reflux disease. Gut 1998;43:327–33.

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