Abstract
Objective
Gastric colonization with the Helicobacter pylori bacterium is a proposed protective factor against oesophageal adenocarcinoma, but its point of action is unknown. We evaluated its associations with Barrett’s oesophagus, a metaplastic change that is a probable early event in the carcinogenesis of oesophageal adenocarcinoma.
Design
A case-control study
Setting
The Kaiser Permanente Northern California population, a large health services delivery organization
Patients
Persons with a new Barrett’s oesophagus diagnosis (cases) were matched to subjects with gastrooesophageal reflux disease (GORD) without Barrett’s oesophagus and to population controls.
Main Measures
Subjects completed direct in-person interviews and antibody testing for Helicobacter pylori and its cagA protein.
Results
Serologic data were available on 318 Barrett’s oesophagus cases, 312 GORD patients, and 299 population controls. Patients with Barrett’s oesophagus were substantially less likely to have antibodies for Helicobacter pylori (odds ratio [OR] = 0.42, 95% confidence interval [CI] 0.26–0.70) than population controls; this inverse association was stronger among those with lower body mass indexes (BMI<25 OR=0.03, 95% CI 0.00 – 0.20) and those with cagA+ strains (OR=0.08, 95% CI 0.02–0.35). The associations were diminished after adjustment for GORD symptoms. The H. pylori status was not an independent risk factor for Barrett’s oesophagus compared to the GORD controls.
Conclusions
Helicobacter pylori infection and cagA+ status were inversely associated with a new diagnosis of Barrett’s oesophagus. The findings are consistent with the hypothesis that Helicobacter pylori colonization protects against Barrett’s oesophagus and that the association may be at least partially mediated through GORD.
Keywords: Barrett’s esophagus, Barrett’s oesophagus, helicobacter, GERD, GORD, esophageal adenocarcinoma, oesophageal adenocarcinoma
BACKGROUND
The incidence of oesophageal adenocarcinoma is rising more rapidly than that of any other malignancy in many countries, but relatively little is known about the carcinogenic sequence leading to cancer development.[1–4] Barrett’s oesophagus, a metaplastic change in the oesophageal lining that is associated with damage from gastrooesophageal reflux (GORD), may be a precursor to oesophageal adenocarcinoma.[5] Persons with Barrett’s oesophagus have a substantially increased risk of oesophageal adenocarcinoma; thus, the evaluation of risk factors for Barrett’s oesophagus may provide information on early events in the carcinogenic pathway for oesophageal adenocarcinoma.[5]
Helicobacter pylori (H. pylori) is a bacterium that frequently colonizes the gastric lining. H. pylori, especially the cagA+ strain, is an established risk factor for stomach cancer.[6] In contrast, H. pylori may be inversely associated with the risk of developing oesophageal adenocarcinoma, although few studies exist.[7–10] The hypothesized links between H. pylori, Barrett’s oesophagus, and oesophageal adenocarcinoma are intriguing for several reasons. The decreasing prevalence of H. pylori infection in many countries correlates with the recent marked increases in oesophageal adenocarcinoma incidence, and the prevalence of H. pylori infection is lower in demographic groups at higher risk of oesophageal adenocarcinoma, such as Caucasians.[11–14] If a potentially beneficial effect for H. pylori colonization were demonstrated, it would further inform the debate regarding the overall utility of routine H. pylori testing and eradication.[15]
Existing studies of the association between H. pylori and Barrett’s oesophagus have been conflicting, possibly from the lack of ideal comparison groups. Almost all existing studies consist of series of endoscopy patients and lack a true non-endoscopy control population.[16–24] Since patients undergo endoscopy for a variety of indications, subjects referred for endoscopy (but who lack Barrett’s oesophagus) may not represent the general population’s prevalence of H. pylori. Patients with nonulcer dyspepsia or peptic ulcer disease, for example, may be more likely to be colonized with H. pylori than the general population.[25–27] Comparisons of Barrett’s oesophagus vs. non-Barrett’s oesophagus patients in endoscopic series, therefore, may suggest that Barrett’s oesophagus patients have a lower prevalence of Helicobacter pylori when, in fact, it is the comparison group that has a higher than average prevalence. Case-control studies of the association between H. pylori and oesophageal adenocarcinoma may also be misleading: analyses using post-cancer diagnosis sera are potentially biased by the loss of antibody positivity over time or by treatment of H. pylori for gastrointestinal symptoms earlier in life;[28–30] these sera may thus not reflect the true infection status at the initiation of the carcinogenic pathway (such as when Barrett’s oesophagus may develop).[31] The evaluation of new diagnoses of Barrett’s oesophagus (at their first endoscopy that diagnosed Barrett’s oesophagus), the use of population controls, and the evaluation of treatment histories for H. pylori would provide insights less susceptible to such biases.
We evaluated the associations between Helicobacter pylori antibody status and Barrett’s oesophagus using a case-control study of all persons with a new diagnosis of Barrett’s oesophagus in a non-referral, community-based population.
DESIGN AND METHODS
Study Population
We conducted a nested case-control study within the Kaiser Permanente, Northern California (KPNC) integrated health services delivery organization. Its membership contains approximately 3.3 million persons; the membership demographics closely approximate the underlying census population of Northern California.[32] Eligible subjects were all adult (ages 18–79 years) members who had at least 2 years of membership prior to their index date, met the case or control definitions outlined below, and understood spoken and written English. The population and GORD comparison groups were frequency matched to the Barrett’s oesophagus cases by gender, age at the index date, and geographic region (each subject’s home facility); controls were serially recruited coincident with case identification. The index date for cases was the date of Barrett’s oesophagus diagnosis and for controls was the midpoint of each 2–3 month selection interval for the cases.
Case Definition
Cases were eligible KPNC members with a new Barrett’s oesophagus diagnosis, using the International Classification of Disease, 9th revision (ICD-9) code 530.2 (which at KPNC is uniquely coded as “Barrett’s esophagitis”), or the College of American Pathologists code 73330 (“Barrett’s oesophagus”). A single board-certified gastroenterologist (DAC) then reviewed the endoscopy and pathology records of potentially eligible cases. Subjects were included if the endoscopist clearly described a visible length of columnar-type epithelium proximal to the gastrooesophageal junction/gastric folds, this area was biopsied, and the biopsies showed specialized intestinal epithelium.[5] Cases were serially enrolled (shortly after their diagnosis and record review) between October, 2002 and September, 2005. Pathology slides underwent a separate manual review by a gastrointestinal pathologist (GJR). The following patients were excluded: patients with only gastric-type metaplasia of the oesophagus on all pathologic evaluations; patients with columnar metaplasia without features of intestinal metaplasia on all pathology readings; patients without a biopsy of oesophageal origin; biopsies of only a mildly irregular squamocolumnar junction (i.e. an “irregular z-line”); and patients with a prior Barrett’s oesophagus diagnosis. The index date for cases was the date of Barrett’s oesophagus diagnosis.
Population Controls
Controls from the base population were randomly selected from the at-risk (no prior Barrett’s oesophagus) members of the entire Northern California Kaiser Permanente membership roster using risk set sampling.[33]
GORD Comparison Group
GORD comparison group members were randomly selected from among persons with the following characteristics prior to their index date: a GORD-related diagnosis code (ICD-9 codes 530.11 [reflux esophagitis] or 530.81 [gastrooesophageal reflux]); a prescription for at least 90 days supply of a histamine-2 receptor antagonist or a proton pump inhibitor (medications used for treating GORD symptoms) in the previous year (from electronic pharmacy records); no prior Barrett’s oesophagus; and an esophagogastroduodenoscopy close to the index date that did not demonstrate oesophageal columnar metaplasia of any type.
Exposure Measurements
All subjects completed: an in-person interview (most commonly at the subject’s home) of medication use, GORD symptoms and medical history; a food frequency questionnaire; phlebotomy; and anthropometric measurements. Participants reported exposures in the year prior to the index date.
The body mass index used the equation (BMI = weight (kilograms)/height(meters)2). GORD symptom frequency and severity were evaluated with a validated questionnaire.[34] GORD was defined as heartburn (a burning pain or discomfort behind the breastbone) or acid regurgitation (a bitter or sour-tasting fluid coming up into the throat or mouth). Severity was recorded as mild (could be ignored), moderate (could not be ignored, but didn’t affect lifestyle), severe (could not be ignored and did affect lifestyle), or very severe (markedly affected lifestyle). Frequency was defined as never, less than once a month, once a month, once a week, several times a week, or daily.
H. pylori assays were blinded to the case status and run in mixed batches of cases and controls. These in-house ELISA assays have been used extensively in the Kaiser Permanente population and validated in different ethnic groups.[35–37] The assay sensitivity and specificity for a current, active infection (compared to histopathologic diagnosis) have been 94% and 91%, respectively. All subjects were also tested for antibodies to the H. pylori CagA protein (OraVax, Inc, Cambridge, MA).[38]
Confounding and Effect Modification
We evaluated the following as potential confounders: BMI, ethnicity (Caucasian vs. non-Caucasian), smoking, recent alcohol use, aspirin or nonsteroidal anti-inflammatory drug (NSAID) use (including over-the-counter use from the interview), a comorbidity index (the DxCg score, which creates a predictive comorbidity score based on demographic data, medical coding, and pharmacy utilization),[39, 40] calorie intake, waist circumference, socioeconomic data (grade level and household income), and multivitamin use. We evaluated for non-response bias (differences between participants vs. eligible non-participants) using available information from electronic databases (BMI, smoking status, ethnicity, age, gender, DxCg score, GORD diagnosis) on eligible subjects. In addition, contacted subjects who declined an in-person interview were asked to complete a brief telephone interview for several risk factors.
Statistical Analysis
We utilized standard analytic techniques for case-control studies including unconditional logistic regression and the binomial distribution.[33, 41–43] Confounders were incorporated if their inclusion altered the odds ratio for the main effects by >10% (education level or multivitamin use), they were a frequency matched variable (gender, age, and medical facility) or if published data suggested potential associations (ethnicity, BMI and smoking status). We evaluated for effect modification (e.g. differences in the associations by gender or BMI) by evaluating cross product terms in the logistic regression model and contrasting stratum specific odds ratios.[43] The attributable fraction calculations utilized maximum likelihood estimates from the logistic regression models.[44]
The study and analyses were approved by the institutional review board and all subjects provided written informed consent. Analyses used the STATA statistical package (version 8, STATA Corporation, College Station, TX).
RESULTS
Study Population
We interviewed 953 subjects; serologic data were available for 929 subjects (97% of interviewed subjects): 318 Barrett’s oesophagus cases, 312 GORD patients, and 299 controls. The interviewed subjects represented 57% of all living, eligible subjects able to be contacted by phone and 43% of all potentially eligible subjects. Reasons for non-participation included: declined to participate (33%), unable to contact (18%), severe physical or mental disorders (5%) (primarily excluded by their physician prior to contact), or deceased (1%). The general subject characteristics are provided in Table 1. Equivocal H. pylori assays were found in 24 subjects; after their exclusion, there were 309 Barrett’s oesophagus cases, 301 GORD patients, and 295 controls for the main analyses. Among the cases, the length of the Barrett’s segment was <3 centimeters in 117 subjects (37%), ≥3 centimeters in 150 subjects (47%), and the length was not reported in 51 subjects (16%).
Table 1.
Characteristics of study groups
Barrett’s Oesophagus Cases | GORD controls | Population controls | |
---|---|---|---|
Number or Mean (% or standard deviation) | Number or Mean (% or standard deviation) | Number or Mean (% or standard deviation) | |
Number of subjects | 318 | 312 | 299 |
Age (years) | |||
20–39 | 9 (3) | 12 (4) | 9 (3) |
40–59 | 120 (38) | 113 (36) | 101 (34) |
60–79 | 189 (59) | 187 (60) | 189 (63) |
Race | |||
White | 276 (87) | 250 (80) | 254 (85) |
Black | 4 (1) | 20 (6) | 16 (5) |
Hispanic | 25 (8) | 20 (6) | 11 (4) |
Asian | 3 (1) | 7 (2) | 8 (3) |
Others | 8 (3) | 13 (4) | 9 (3) |
Unknown | 2 (1) | 2 (1) | 1 (0) |
Gender | |||
Male | 232 (73) | 215 (69) | 206 (69) |
Smoking status (Ever smoked) | 210 (66) | 184 (59) | 164 (55) |
GORD | |||
Any GORD | 297 (93) | 293 (94) | 180 (60) |
At least weekly | 256 (81) | 230 (74) | 84 (28) |
Mean body mass index (kg/m2) | 29.5 (±6.1) | 28.8 (±5.3) | 29.5 (5.8) |
Eligible Barrett’s oesophagus cases were frequency matched to control groups by gender, age (by 5 year age groups) and center of diagnosis.
Helicobacter pylori antibody status
The prevalences of H. pylori infection were 11.7%, 9.6%, and 22.7% in the Barrett’s oesophagus cases, GORD patients, and controls, respectively. There was an inverse association between a positive H. pylori antibody status and the risk of Barrett’s oesophagus (Table 2) (OR 0.42, 95% CI 0.26–0.70) compared with the population controls. There were no differences between subjects with a long segment of Barrett’s oesophagus (≥3 centimeters) (OR=0.37, 95% CI 0.19–0.70) vs. subjects with shorter segments (OR=0.45, 95% CI 0.22–0.91). The H. pylori status was not an independent risk factor for Barrett’s oesophagus compared to the GORD controls (Table 2).
Table 2.
Antibody status for Helicobacter pylori infection, cagA antibody status, and the risk of Barrett’s oesophagus.
Number of Subjects | Odds Ratio1 (95% Confidence Interval) | Odds Ratio1 (95% Confidence Interval) | ||
---|---|---|---|---|
Helicobacter pylori Antibody Status | CagA+ Antibody Status | Barrett’s Oesophagus/GORD/Controls | Barrett’s Oesophagus vs. Controls | Barrett’s Oesophagus vs. GORD patients |
Negative | Negative | 263/259/225 | 1.00 | 1.00 |
Positive | 10/13/3 | 1.95 (0.48–7.83) | 0.78 (0.30–2.00) | |
Positive | Negative | 31/19/44 | 0.61 (0.35–1.04) | 1.66 (0.89–3.13) |
Positive | 5/10/23 | 0.08 (0.02–0.35) | 0.30 (0.06–1.45) | |
All H. Pylori Positive subjects2 | 36/29/67 | 0.42 (0.26–0.70) | 1.24 (0.71–2.18) |
Adjusted for gender, age, home facility location, body mass index, ethnicity, smoking status, educational status and multivitamin use
These include both cagA positive and cagA negative subjects.
CagA+ status
The risk of Barrett’s oesophagus was substantially lower among subjects with a cagA+ H. pylori antibody status (OR=0.08, 95% CI 0.02–0.35) (compared to the population controls) (Table 2). There was a weaker inverse association among subjects who were H. pylori antibody positive but cagA antibody negative (OR=0.61, 95% CI 0.35–1.04).
Mediation by GORD Symptoms
The absence of H. pylori has been hypothesized to increase the risk of GORD, which may, in turn, directly increase the risk of Barrett’s oesophagus. We evaluated whether the association between H. pylori antibody status and Barrett’s oesophagus was potentially mediated through GORD symptoms by contrasting logistic models with and without the inclusion of GORD symptoms. If GORD is in the causal pathway between H. pylori and Barrett’s oesophagus, then “adjusting” for GORD symptoms in the logistic model should diminish or eliminate any association between H. pylori and Barrett’s oesophagus. Adjustment for GORD symptom severity (among persons with at least weekly GORD symptoms) decreased the association between a positive H. pylori antibody and Barrett’s oesophagus from OR=0.42 (95% CI 0.26–0.70) to OR=0.71 (95% CI 0.36–1.38); adjustment for GORD symptom frequency alone decreased the association to OR=0.54 (95% CI 0.30–0.98) (Table 3).
Table 3.
Association between Helicobacter pylori infection and Barrett’s Oesophagus: evaluation of mediation by GORD symptoms. This analysis evaluates whether the association between Helicobacter pylori and Barrett’s oesophagus (for Barrett’s oesophagus cases vs. population controls) is potentially mediated by the frequency or severity of GORD symptoms.
Number of Subjects | Odds Ratio1 (95% Confidence Interval) | Odds Ratio1 (95% Confidence Interval) | Odds Ratio1 (95% Confidence Interval) | ||
---|---|---|---|---|---|
Helicobacter pylori Antibody Status | CagA+ Antibody Status | Barrett’s Oesophagus/GORD/Controls | Barrett’s Oesophagus vs. Controls (Without GORD in model) | Barrett’s Oesophagus vs. Controls (With GORD frequency in model)2 | Barrett’s Oesophagus vs. Controls (With GORD severity in model)2 |
Negative | Negative | 263/225 | 1.00 | 1.00 | 1.00 |
Positive | Negative | 31/44 | 0.61 (0.35–1.04) | 0.80 (0.42–1.51) | 1.29 (0.60–2.80) |
Positive | 5/23 | 0.08 (0.02–0.35) | 0.08 (0. 15–0.45) | 0.08 (0.12–.49) | |
All H. Pylori Positive subjects3 | 36/67 | 0.42 (0.26–0.70) | 0.54 (0.30–0.98) | 0.71 (0.36–1.38) |
Adjusted for gender, age, home facility location, body mass index, ethnicity, smoking status, educational status and multivitamin use
The GORD severity analysis compared severity among persons with at least weekly GORD to persons with no GORD symptoms. Severity was recorded as mild (could be ignored), moderate (could not be ignored, but didn’t affect lifestyle), severe (could not be ignored and did affect lifestyle), or very severe (markedly affected lifestyle). Frequency was defined as never, less than once a month, once a month, once a week, several times a week, or daily.
These include both cagA positive and cagA negative subjects.
Attributable Fraction
The attributable fraction for any H. pylori infection (i.e. the proportion of Barrett’s oesophagus in the population theoretically independently attributable to the absence of any H. pylori infection, if we assume the associations are causal) was 32.9% (95% CI 12.5%, 48.6%). The attributable fraction for a cagA+ H. pylori infection was 82.0% (95% CI 33.0%, 95.0%). These estimates are adjusted for the listed potential confounders.
Supplemental Analyses
The inverse association for a positive H. pylori antibody was stronger among subjects with lower BMIs (BMI<25 OR=0.03, 95% CI 0.00 – 0.20) than among those with higher BMIs (BMI≥30 OR=0.43, 95% CI 0.20–0.91), p-value on interaction term p=0.16 (comparisons used population controls).
There was no evidence of confounding by caloric intake, smoking status, alcohol use, aspirin use, nonsteroidal anti-inflammatory agents, household income, or comorbidity status (DxCg score). The exclusion of educational status or multivitamin use had a small influence, thus these were included in the main models. A fully adjusted model for H. pylori antibody status (containing all the listed factors plus age, gender, facility, and ethnicity) (OR=0.42, 95% CI 0.25, 0.69) was very similar to a model that contained only the bivariate association between case status and H. pylori antibody status (OR=0.46, 95% CI 0.30, 0.72).
Although Barrett’s oesophagus itself is asymptomatic, and GORD symptoms are not typically treated with effective H. pylori eradication regimens, we evaluated for the possibility of reverse causation whereby gastrointestinal symptoms (prior to the Barrett’s oesophagus diagnosis) resulted in taking medications that decreased H. pylori prevalence at the time of the Barrett’s oesophagus diagnosis. The pharmacy database included a total of 57 subjects (a combination of cases and controls) who had received effective two or three drug anti- H. pylori antibiotic regimens prior to their index dates. Barrett’s oesophagus cases were not significantly more likely to have received treatment (p=0.16) and an analysis that adjusted for prior treatment status also did not alter the main association between H. pylori and Barrett’s oesophagus (OR=0.42, 95% CI 0.26–0.69).
The evaluation for non-response bias utilized available electronic medical data on all subjects (see methods). Participants did not differ significantly from non-participants by gender, smoking status, or BMI (using electronic data). Participants were somewhat less likely to be Asian or Hispanic, more likely to have an electronic GORD diagnosis (63% vs. 52%), slightly older (62 years vs. 59 years), and had a slightly higher comorbidity score (3.1 vs. 2.7, p<0.01). Similar relationships were seen in analyses confined to the population controls and for aspirin/NSAID use (among population controls who participated in a brief telephone interview).
DISCUSSION
To our knowledge, this is the first study of the association between Helicobacter pylori antibody status and Barrett’s oesophagus in a large community-based population; there were several findings. First, there was a strong inverse association between the presence of antibodies against H. pylori and Barrett’s oesophagus, for comparisons with the population controls. Second, H. pylori infection did not have an inverse association for Barrett’s oesophagus compared with GORD patients; this suggests that, among patients who have GORD, H. pylori is not an additional risk factor for Barrett’s oesophagus. Third, the association between H. pylori and Barrett’s oesophagus among the population controls was diminished after adjustment for GORD symptom severity. These analyses suggest that, if the associations are causal, a portion of the risk for Barrett’s oesophagus may be associated with the absence of Helicobacter pylori and this association may be at least partly mediated through H. pylori’s associations with GORD.
This study extends the findings of previous analyses, which found that persons without Helicobacter pylori colonization were more likely to develop oesophageal adenocarcinoma.[7–10] Some prior studies also suggested an increased risk of Barrett’s oesophagus in patients without Helicobacter pylori, but these almost exclusively consisted of endoscopy studies that contrasted patients with Barrett’s oesophagus with patients referred for other gastrointestinal problems, possibly contributing to the conflicting results.[16, 23, 45–47] In addition, no prior study to our knowledge evaluated for prior treatment of H. Pylori.
The mechanism through which the absence of Helicobacter pylori colonization is associated with Barrett’s oesophagus is unknown, but there are several potential possibilities. First, Helicobacter pylori infection, in particular the more virulent cagA+ strain, may suppress acid production and lead to gastric atrophy; this may lower the risk of Barrett’s oesophagus and oesophageal adenocarcinoma (both or which are directly associated with GORD).[7, 38, 48–50] Epidemiologic data linking an absence of H. pylori and GORD, however, are somewhat conflicting, likely due to patient selection, the use of different comparison groups, and the lack of population-based studies.[24, 51, 52] A recent large (604 patients) cross-sectional study of endoscopy patients actually suggested an increased risk of Barrett’s oesophagus and GORD among patients with H. pylori.[16] Randomized trials of H. pylori treatment have not demonstrated increased GORD symptoms after eradication, though eradication in adulthood may not have a similar effect on gastric acid production as the life-long absence of H. pylori, since most H. pylori infections start in childhood.[53–55] Our results suggest some of the association between H. pylori and Barrett’s oesophagus is mediated through GORD symptoms; if it was entirely mediated through GORD symptoms we might expect the association to be abolished rather than only diminished. However, this is also consistent with the imperfect correlation between GORD symptoms and GORD-induced reflux damage, and the lack of reflux symptoms among a portion of persons with documented Barrett’s oesophagus or oesophageal adenocarcinoma.[56–60] Second, the presence of H. pylori may enhance gastric emptying (thereby decreasing acid reflux) in younger persons.[61, 62] Third, the absence of H. pylori may increase ghrelin levels,[63–65] a peptide that increases appetite and facilitates fat storage, and lead to weight gain,[66] a risk factor for both GORD and for oesophageal adenocarcinoma.[67, 68] Although our finding that the absence of H. pylori was more strongly associated with Barrett’s oesophagus at lower BMI’s does not provide general support for this hypothesis, it is possible that an increased risk of GORD at higher BMI’s unrelated to H. pylori infection may dilute the association between H. pylori and Barrett’s oesophagus among obese patients. The biologic role of H. pylori is complex, given the positive associations between H. pylori infection and the risks of gastric cancer and peptic ulcer disease.[6, 69]
There are several strengths of this analysis. First, the subjects came from a diverse population base that closely approximates the region’s census demographics; thus, the results can likely be generalized to similar large populations.[32] Second, this is the first study to use only patients with serially identified new diagnoses of Barrett’s oesophagus and the study identified essentially all patients with a new diagnosis within the population. Prevalent or referral cases may represent patients with a different clinical course, patients compliant with follow-up, or persons who initiated medical or behavioral changes after their diagnosis. [70] In particular, patients may have H. pylori identified and treated at the time of endoscopy. Given H. pylori antibody titers can fall after treatment, the use of only new diagnoses decreases the potential for bias.[28, 29] Third, the GORD comparison group provided information on the risk of Barrett’s oesophagus among patients with GORD. Fourth, we were able to stratify by length of Barrett’s oesophagus; the analyses confined to long segments of Barrett’s oesophagus minimize the chance of misclassifying persons with hiatal hernias or irregular gastrooesophageal junction boundaries as having Barrett’s oesophagus. Finally, the data was of high quality and contained information for multiple potential confounders including socioeconomic status and treatment in recent years for H. Pylori. Measurements used trained personnel, a systematic protocol, an established laboratory, validated questionnaires, direct review of pathology and endoscopic examinations, and comprehensive pharmacology databases.
There are several potential limitations of this analysis. First, case-control studies cannot definitively establish cause and effect.[33] Second, observational studies are subject to bias. Although analyses of multiple variables provided little evidence of confounding, we cannot exclude incomplete control of confounding and we cannot exclude a component of reverse causation whereby patients with Barrett’s oesophagus had been previously treated for H. pylori in the more distant past, thereby decreasing their antibody titers and the study’s use of new diagnoses of Barrett’s oesophagus should decrease the effect of interventions associated with the endoscopy itself. Similarly, although cases should be representative of new diagnoses of Barrett’s oesophagus, as with most chronic diseases, the date the Barrett’s oesophagus first developed is unknown. Patients diagnosed with Barrett’s oesophagus may differ from subjects with undiagnosed Barrett’s oesophagus. However, since H. pylori colonization most commonly begins in childhood, it is unlikely that the Barrett’s oesophagus preceded the exposure. Third, the presence of nonresponders may lead to bias; however, the electronic data suggested that nonresponders were, on average, somewhat healthier than the responders, with slightly lower comorbidity scores. This finding, combined with the lack of major confounding factors in the primary analyses, would suggest the effect of nonresponse, if any, may be to bias the results towards the null (making the population controls more similar to the cases). Fourth, the number of cagA+ subjects was small in some analyses, decreasing the precision of these estimates, particularly the analyses of mediation by GORD symptoms.
In summary, in a community-based population, there were inverse associations between the presence of H. pylori antibodies and a first diagnosis of Barrett’s oesophagus. The associations for Barrett’s oesophagus were stronger for the cagA positive strain, but were present also for cagA negative strains. The attributable fraction analyses suggest that, if the associations are causal, a substantial portion of the risk for Barrett’s oesophagus may be associated with the absence of Helicobacter pylori. These data are consistent with the hypothesis that the absence of Helicobacter pylori infection may be linked to the risk of oesophageal adenocarcinoma, with Barrett’s oesophagus as a potential intermediary step. Future studies are needed to evaluate whether the absence of H. pylori infection is associated with an increased risk of Barrett’s oesophagus progressing to oesophageal adenocarcinoma and whether interventions that eradicate H. pylori infection modify the subsequent risk of developing oesophageal adenocarcinoma.
Acknowledgments
Funding Sources: United States National Institutes of Health RO1 DK63616 and K08 DK02697. The study sponsor reviewed the protocol, but did not participate in the collection, analysis, or interpretation of the data.
Abbreviations
- GORD
Gastroosophageal reflux disease
- BMI
body mass index
- KPNC
Kaiser Permanente, Northern California
- CI
confidence interval
- ICD-9
International Classification of Disease, 9th revision
- NSAID
nonsteroidal anti-inflammatory drug
Footnotes
Publisher's Disclaimer: The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Gut editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence (http://gut.bmjjournals.com/ifora/licence.dtl).
Statement of competing interests: none to declare
References
- 1.Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol. 1999;26(5 Suppl 15):2–8. [PubMed] [Google Scholar]
- 2.Bollschweiler E, Wolfgarten E, Gutschow C, et al. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer. 2001;92(3):549–55. doi: 10.1002/1097-0142(20010801)92:3<549::aid-cncr1354>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
- 3.Corley D, Buffler P. Oesophageal and gastric cardia adenocarcinomas: analysis of regional variation using the Cancer Incidence in Five Continents database. International Journal of Epidemiology. 2001;30:1415–25. doi: 10.1093/ije/30.6.1415. [DOI] [PubMed] [Google Scholar]
- 4.Kubo A, Corley DA. Marked regional variation in adenocarcinomas of the esophagus and the gastric cardia in the United States. Cancer. 2002;95(10):2096–102. doi: 10.1002/cncr.10940. [DOI] [PubMed] [Google Scholar]
- 5.Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett’s esophagus: the AGA Chicago Workshop. Gastroenterology. 2004;127(1):310–30. doi: 10.1053/j.gastro.2004.04.010. [DOI] [PubMed] [Google Scholar]
- 6.Huang JQ, Zheng GF, Sumanac K, et al. Meta-analysis of the relationship between cagA seropositivity and gastric cancer. Gastroenterology. 2003;125(6):1636–44. doi: 10.1053/j.gastro.2003.08.033. [DOI] [PubMed] [Google Scholar]
- 7.Ye W, Held M, Lagergren J, et al. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst. 2004;96(5):388–96. doi: 10.1093/jnci/djh057. [DOI] [PubMed] [Google Scholar]
- 8.Wu AH, Crabtree JE, Bernstein L, et al. Role of Helicobacter pylori CagA+ strains and risk of adenocarcinoma of the stomach and esophagus. Int J Cancer. 2003;103(6):815–21. doi: 10.1002/ijc.10887. [DOI] [PubMed] [Google Scholar]
- 9.de Martel C, Llosa AE, Farr SM, et al. Helicobacter pylori Infection and the Risk of Development of Esophageal Adenocarcinoma. J Infect Dis. 2005;191(5):761–7. doi: 10.1086/427659. [DOI] [PubMed] [Google Scholar]
- 10.Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res. 1998;58(4):588–90. [PubMed] [Google Scholar]
- 11.Go MF. Review article: natural history and epidemiology of Helicobacter pylori infection. Aliment Pharmacol Ther. 2002;16 (Suppl 1):3–15. doi: 10.1046/j.1365-2036.2002.0160s1003.x. [DOI] [PubMed] [Google Scholar]
- 12.Devesa SS, Blot WJ, Fraumeni JF., Jr Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer. 1998;83(10):2049–53. [PubMed] [Google Scholar]
- 13.Kubo A, Corley DA. Marked multi-ethnic variation of esophageal and gastric cardia carcinomas within the United States. Am J Gastroenterol. 2004;99(4):582–8. doi: 10.1111/j.1572-0241.2004.04131.x. [DOI] [PubMed] [Google Scholar]
- 14.el-Serag HB, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease. Gut. 1998;43(3):327–33. doi: 10.1136/gut.43.3.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Moayyedi P. Should we test for Helicobacter pylori before treating gastroesophageal reflux disease? Can J Gastroenterol. 2005;19(7):425–7. doi: 10.1155/2005/261835. [DOI] [PubMed] [Google Scholar]
- 16.Johansson J, Hakansson HO, Mellblom L, et al. Risk factors for Barrett’s oesophagus: a population-based approach. Scand J Gastroenterol. 2007;42(2):148–56. doi: 10.1080/00365520600881037. [DOI] [PubMed] [Google Scholar]
- 17.Ferrandez A, Benito R, Arenas J, et al. CagA-positive Helicobacter pylori infection is not associated with decreased risk of Barrett’s esophagus in a population with high H. pylori infection rate. BMC Gastroenterol. 2006;6:7. doi: 10.1186/1471-230X-6-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Wong A, Fitzgerald RC. Epidemiologic risk factors for Barrett’s esophagus and associated adenocarcinoma. Clin Gastroenterol Hepatol. 2005;3(1):1–10. doi: 10.1016/s1542-3565(04)00602-0. [DOI] [PubMed] [Google Scholar]
- 19.Zhang J, Chen XL, Wang KM, et al. Relationship of gastric Helicobacter pylori infection to Barrett’s esophagus and gastro-esophageal reflux disease in Chinese. World J Gastroenterol. 2004;10(5):672–5. doi: 10.3748/wjg.v10.i5.672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Weston AP, Badr AS, Topalovski M, et al. Prospective evaluation of the prevalence of gastric Helicobacter pylori infection in patients with GERD, Barrett’s esophagus, Barrett’s dysplasia, and Barrett’s adenocarcinoma. Am J Gastroenterol. 2000;95(2):387–94. doi: 10.1111/j.1572-0241.2000.01758.x. [DOI] [PubMed] [Google Scholar]
- 21.Vaezi MF, Falk GW, Peek RM, et al. CagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. Am J Gastroenterol. 2000;95(9):2206–11. doi: 10.1111/j.1572-0241.2000.02305.x. [DOI] [PubMed] [Google Scholar]
- 22.Lord RV, Frommer DJ, Inder S, et al. Prevalence of Helicobacter pylori infection in 160 patients with Barrett’s oesophagus or Barrett’s adenocarcinoma. Report No.: 70. 2000 doi: 10.1046/j.1440-1622.2000.01737.x. [DOI] [PubMed] [Google Scholar]
- 23.Vicari JJ, Peek RM, Falk GW, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology. 1998;115(1):50–7. doi: 10.1016/s0016-5085(98)70364-6. [DOI] [PubMed] [Google Scholar]
- 24.Csendes A, Smok G, Cerda G, et al. Prevalence of Helicobacter pylori infection in 190 control subjects and in 236 patients with gastroesophageal reflux, erosive esophagitis or Barrett’s esophagus. Dis Esophagus. 1997;10(1):38–42. doi: 10.1093/dote/10.1.38. [DOI] [PubMed] [Google Scholar]
- 25.Nelson DB, Murdoch M, Sandozi IK, et al. Dyspepsia is associated with CagA-positive Helicobacter pylori. Am J Gastroenterol. 2000;95(12):3412–7. doi: 10.1111/j.1572-0241.2000.03354.x. [DOI] [PubMed] [Google Scholar]
- 26.Danesh J, Lawrence M, Murphy M, et al. Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia. Arch Intern Med. 2000;160(8):1192–8. doi: 10.1001/archinte.160.8.1192. [DOI] [PubMed] [Google Scholar]
- 27.Graham DY, Lew GM, Klein PD, et al. Effect of treatment of Helicobacter pylori infection on the long-term recurrence of gastric or duodenal ulcer. A randomized, controlled study. Ann Intern Med. 1992;116(9):705–8. doi: 10.7326/0003-4819-116-9-705. [DOI] [PubMed] [Google Scholar]
- 28.Cutler AF, Prasad VM, Santogade P. Four-year trends in Helicobacter pylori IgG serology following successful eradication. Am J Med. 1998;105(1):18–20. doi: 10.1016/s0002-9343(98)00134-x. [DOI] [PubMed] [Google Scholar]
- 29.Gisbert JP, Blanco M, Benito LM, et al. Value of quantitative serology for confirmation of Helicobacter pylori eradication: an 18-month follow-up study. Clin Infect Dis. 2000;30(6):976–80. doi: 10.1086/313820. [DOI] [PubMed] [Google Scholar]
- 30.Kokkola A, Kosunen TU, Puolakkainen P, et al. Spontaneous disappearance of Helicobacter pylori antibodies in patients with advanced atrophic corpus gastritis. Apmis. 2003;111(6):619–24. doi: 10.1034/j.1600-0463.2003.1110604.x. [DOI] [PubMed] [Google Scholar]
- 31.Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut. 2001;49(3):347–53. doi: 10.1136/gut.49.3.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. American Journal of Public Health. 1992;82(5):703–10. doi: 10.2105/ajph.82.5.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Rothman KJ, Greenland S. Modern Epidemiology. 2. Philadelphia: Lippincott-Raven; 1998. [Google Scholar]
- 34.Locke GR, Talley NJ, Weaver AL, et al. A new questionnaire for gastroesophageal reflux disease. Mayo Clin Proc. 1994;69(6):539–47. doi: 10.1016/s0025-6196(12)62245-9. [DOI] [PubMed] [Google Scholar]
- 35.Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med. 1994;330(18):1267–71. doi: 10.1056/NEJM199405053301803. [DOI] [PubMed] [Google Scholar]
- 36.Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991;325(16):1127–31. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
- 37.Parsonnet J, Replogle M, Yang S, et al. Seroprevalence of CagA-positive strains among Helicobacter pylori-infected, healthy young adults. J Infect Dis. 1997;175(5):1240–2. doi: 10.1086/593680. [DOI] [PubMed] [Google Scholar]
- 38.Parsonnet J, Friedman GD, Orentreich N, et al. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut. 1997;40(3):297–301. doi: 10.1136/gut.40.3.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Zhao Y, Ash AS, Ellis RP, et al. Predicting pharmacy costs and other medical costs using diagnoses and drug claims. Med Care. 2005;43(1):34–43. [PubMed] [Google Scholar]
- 40.Zhao Y, Ellis RP, Ash AS, et al. Measuring population health risks using inpatient diagnoses and outpatient pharmacy data. Health Serv Res. 2001;36(6 Pt 2):180–93. [PMC free article] [PubMed] [Google Scholar]
- 41.Breslow NE, Day NE. Statistical methods in cancer research. Volume 1 - The analysis of case-control studies. Lyon: International Agency for Research on Cancer; 1980. [PubMed] [Google Scholar]
- 42.Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research. Principles and Quantitative Methods. New York: Van Nostrand Reinhold; 1982. [Google Scholar]
- 43.Hosmer DW, Lemeshow S. Applied Logistic Regression. 2. New York: John Wiley & Sons; 2000. [Google Scholar]
- 44.Greenland S, Drescher K. Maximum likelihood estimation of the attributable fraction from logistic models. Biometrics. 1993;49(3):865–72. [PubMed] [Google Scholar]
- 45.Wu JC, Sung JJ, Chan FK, et al. Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2000;14(4):427–32. doi: 10.1046/j.1365-2036.2000.00714.x. [DOI] [PubMed] [Google Scholar]
- 46.Labenz J, Jaspersen D, Kulig M, et al. Risk factors for erosive esophagitis: a multivariate analysis based on the ProGERD study initiative. Am J Gastroenterol. 2004;99(9):1652–6. doi: 10.1111/j.1572-0241.2004.30390.x. [DOI] [PubMed] [Google Scholar]
- 47.Koike T, Ohara S, Sekine H, et al. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut. 2001;49(3):330–4. doi: 10.1136/gut.49.3.330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Webb PM, Crabtree JE, Forman D. Gastric cancer, cytotoxin-associated gene A-positive Helicobacter pylori, and serum pepsinogens: an international study. The Eurogst Study Group. Gastroenterology. 1999;116(2):269–76. doi: 10.1016/s0016-5085(99)70122-8. [DOI] [PubMed] [Google Scholar]
- 49.Oksanen A, Sipponen P, Karttunen R, et al. Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy. Gut. 2000;46(4):460–3. doi: 10.1136/gut.46.4.460. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.McColl KE. Review article: Helicobacter pylori and gastro-oesophageal reflux disease--the European perspective. Aliment Pharmacol Ther. 2004;20 (Suppl 8):36–9. doi: 10.1111/j.1365-2036.2004.02227.x. [DOI] [PubMed] [Google Scholar]
- 51.Cremonini F, Di Caro S, Delgado-Aros S, et al. Meta-analysis: the relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2003;18(3):279–89. doi: 10.1046/j.1365-2036.2003.01665.x. [DOI] [PubMed] [Google Scholar]
- 52.Cremonini F, Di Caro S, Delgado-Aros S, et al. Meta-analysis: the relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2004;19(1):145. doi: 10.1111/j.1365-2036.2004.01870.x. [DOI] [PubMed] [Google Scholar]
- 53.Laine L, Sugg J. Effect of Helicobacter pylori eradication on development of erosive esophagitis and gastroesophageal reflux disease symptoms: a post hoc analysis of eight double blind prospective studies. Am J Gastroenterol. 2002;97(12):2992–7. doi: 10.1111/j.1572-0241.2002.07116.x. [DOI] [PubMed] [Google Scholar]
- 54.Rowland M, Daly L, Vaughan M, et al. Age-specific incidence of Helicobacter pylori. Gastroenterology. 2006;130(1):65–72. doi: 10.1053/j.gastro.2005.11.004. quiz 211. [DOI] [PubMed] [Google Scholar]
- 55.Fennerty MB. Is nonulcer dyspepsia related to Helicobacter pylori infection? Semin Gastrointest Dis. 2001;12(3):180–5. [PubMed] [Google Scholar]
- 56.El-Serag HB, Petersen NJ, Carter J, et al. Gastroesophageal reflux among different racial groups in the United States. Gastroenterology. 2004;126(7):1692–9. doi: 10.1053/j.gastro.2004.03.077. [DOI] [PubMed] [Google Scholar]
- 57.Rex DK, Cummings OW, Shaw M, et al. Screening for Barrett’s esophagus in colonoscopy patients with and without heartburn. Gastroenterology. 2003;125(6):1670–7. doi: 10.1053/j.gastro.2003.09.030. [DOI] [PubMed] [Google Scholar]
- 58.Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett’s esophagus in asymptomatic individuals. Gastroenterology. 2002;123(2):461–7. doi: 10.1053/gast.2002.34748. [DOI] [PubMed] [Google Scholar]
- 59.Farrow DC, Vaughan TL, Sweeney C, et al. Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer. Cancer Causes Control. 2000;11(3):231–8. doi: 10.1023/a:1008913828105. [DOI] [PubMed] [Google Scholar]
- 60.Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340(11):825–31. doi: 10.1056/NEJM199903183401101. [DOI] [PubMed] [Google Scholar]
- 61.Sykora J, Malan A, Zahlava J, et al. Gastric emptying of solids in children with H. pylori-positive and H. pylori-negative non-ulcer dyspepsia. J Pediatr Gastroenterol Nutr. 2004;39(3):246–52. doi: 10.1097/00005176-200409000-00004. [DOI] [PubMed] [Google Scholar]
- 62.Lee J, O’Morain C. Who should be treated for Helicobacter pylori infection? A review of consensus conferences and guidelines. Gastroenterology. 1997;113(6 Suppl):S99–106. doi: 10.1016/s0016-5085(97)80021-2. [DOI] [PubMed] [Google Scholar]
- 63.Shiotani A, Miyanishi T, Uedo N, et al. Helicobacter pylori infection is associated with reduced circulating ghrelin levels independent of body mass index. Helicobacter. 2005;10(5):373–8. doi: 10.1111/j.1523-5378.2005.00343.x. [DOI] [PubMed] [Google Scholar]
- 64.Tatsuguchi A, Miyake K, Gudis K, et al. Effect of Helicobacter pylori infection on ghrelin expression in human gastric mucosa. Am J Gastroenterol. 2004;99(11):2121–7. doi: 10.1111/j.1572-0241.2004.30291.x. [DOI] [PubMed] [Google Scholar]
- 65.Nwokolo CU, Freshwater DA, O’Hare P, et al. Plasma ghrelin following cure of Helicobacter pylori. Gut. 2003;52(5):637–40. doi: 10.1136/gut.52.5.637. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Azuma T, Suto H, Ito Y, et al. Eradication of Helicobacter pylori infection induces an increase in body mass index. Aliment Pharmacol Ther. 2002;16 (Suppl 2):240–4. doi: 10.1046/j.1365-2036.16.s2.31.x. [DOI] [PubMed] [Google Scholar]
- 67.Kubo A, Corley DA. Body mass index and adenocarcinomas of the esophagus or gastric cardia: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15(5):872–8. doi: 10.1158/1055-9965.EPI-05-0860. [DOI] [PubMed] [Google Scholar]
- 68.Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications. Ann Intern Med. 2005;143(3):199–211. doi: 10.7326/0003-4819-143-3-200508020-00006. [DOI] [PubMed] [Google Scholar]
- 69.Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. J Natl Cancer Inst. 2006;98(20):1445–52. doi: 10.1093/jnci/djj393. [DOI] [PubMed] [Google Scholar]
- 70.Morrison AS. Screening in Chronic Disease. 2. New York: Oxford University Press; 1992. [Google Scholar]