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Departments of Health Research and Policy and Medicine, Stanford University School of Medicine, Stanford
Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA
Orentreich Foundation for the Advancement of Science, Inc., Cold Spring-on-Hudson, NY
Background.
An increase in the incidence of esophageal adenocarcinoma has coincided with a decrease in the prevalence of Helicobacter pylori infection. Whether these 2 phenomena are associated is unknown.
Methods.
We conducted a nested case-control study of 128,992 members of an integrated health care system who had participated in a multiphasic health checkup (MHC) during 19641969. During follow-up, 52 patients developed esophageal adenocarcinoma. Three randomly chosen control subjects from the MHC cohort were matched to each case subject, on the basis of age at the MHC, sex, race, and the date and site of the MHC. Data on cigarette smoking, alcohol consumption, body mass index (BMI), and education level were obtained at the MHC. Serum samples collected at the MHC were tested for IgG antibodies to H. pylori and to the H. pylori CagA protein.
Results.
Subjects with H. pylori infections were less likely than uninfected subjects to develop esophageal adenocarcinoma (odds ratio [OR], 0.37 [95% confidence interval (CI), 0.160.88]). This significant association was restricted to case subjects and control subjects <50 years old at the MHC (OR, 0.20 [95% CI, 0.060.68]). In patients with H. pylori infections, the OR for those who tested positive for IgG antibodies to the CagA protein was similar to that for those who tested negative for it. BMI 25 and cigarette smoking were strong independent risk factors for development of esophageal adenocarcinoma.
Conclusion.
The absence of H. pylori infection, independent of cigarette smoking and BMI, is associated with a markedly increased risk of development of esophageal adenocarcinoma.
The prevalence of Helicobacter pylori infection has been steadily decreasing in industrialized countries [1, 2]. Simultaneously, for reasons not fully understood, the incidence of esophageal adenocarcinoma has been increasing dramatically in North America, Europe, and Australia [3, 4]. This trend is particularly prominent in white males, who constitute >80% of all cases of esophageal adenocarcinoma in the United States [46].
Risk factors for development of esophageal adenocarcinoma include gastroesophageal reflux disease (GERD), Barrett esophagus [7, 8], obesity, smoking, and diet [9, 10]. Although H. pylori's role in GERD is controversial, a recent metaanalysis of 20 observational studies indicated a negative association between H. pylori infection and GERD (odds ratio [OR], 0.6 [95% confidence interval (CI), 0.470.78]) [11]. Investigators have speculated that H. pylori decreases gastric acidity in some infected hosts either by causing atrophic corpus gastritis or by directly affecting the amount of acid secreted, thereby reducing the risk of development of GERD, Barrett esophagus, and esophageal adenocarcinoma [12, 13].
To date, 4 studies have evaluated the relationship between H. pylori infection and esophageal adenocarcinoma. Two case-control studies found that H. pylori infection was not associated with a decreased risk of development of esophageal adenocarcinoma, although, in 1 study, being infected with the more-virulent, CagA proteinpositive strains of H. pylori was associated with a decreased risk of development of cancer [14, 15]. A third case-control study found a strong protective association between H. pylori infection and esophageal adenocarcinoma (OR, 0.3 [95% CI, 0.20.6]) [16]. In a nested case-control study, H. pylori infection was associated with a decreased risk of development of all types of esophageal neoplasm [17]. Of the 44 case subjects, 0 of the 7 who had esophageal adenocarcinoma were infected with H. pylori.
Risk factors for development of cancer, cardiovascular diseases, and other chronic conditions, including associations between H. pylori infection and either gastric cancer or gastric lymphoma [18, 19], have been identified through nested case-control studies of the multiphasic health checkup (MHC) cohort of the Kaiser Permanente Medical Care Program (KPMCP) [1822]. Using the same cohort and a similar study design, we assessed the association between H. pylori infection and the risk of development of esophageal adenocarcinoma.
SUBJECTS AND METHODS
Subjects.
We conducted a nested case-control study of the MHC cohort of the KPMCP, which serves a large, socioeconomically and ethnically diverse population in northern California. At KPMCP's Oakland and San Francisco facilities, during 19641969, a total of 128,992 ambulatory patients received an MHC at which information on height, weight, sex, age, race, cigarette smoking, alcohol consumption, and education level were recorded. Serum samples were also obtained and initially were stored at -23°C; since 1980, they have been stored at -40°C by the Orentreich Foundation for the Advancement of Science, Inc. (OFAS) (Cold Spring-on-Hudson, NY) [23].
During 1973, the KPMCP began to report cases of cancer diagnosed in 10 of its subregions to the Surveillance, Epidemiology, and End Results (SEER) program, whose team members reviewed the patients' medical records and confirmed the cancer diagnoses. Since 1973, SEER coverage has been expanding in California, and in 2001 the entire state was included in the program. Twenty-five incident cases of esophageal adenocarcinoma diagnosed during 19642000 were identified in the MHC cohort and were confirmed by information in the SEER database. An additional 61 cases of esophageal adenocarcinoma in the MHC cohort were diagnosed outside the time period or region of SEER reporting and were identified through information in the KPMCP database; reviewing the medical charts and pathology reports for these 61 patients, to confirm the diagnosis of cancer and the primary location of the tumor, we confirmed 27 cases of esophageal adenocarcinoma, which brought the total number of case subjects in the present study to 52.
Three randomly chosen control subjects from the MHC cohort were matched to each case subject on the basis of age at MHC (same birth year), sex, race (Asian, black, white, or other), site of MHC (Oakland or San Francisco), and date of MHC (same calendar year). If the 2-tailed type 1 error is assumed to be 5%, 52 cases and 156 controls have 92% power to detect an OR of 0.30 [24].
Serologic assays.
Stored serum samples from case subjects and control subjects were coded, blinded, and shipped on dry ice to Stanford University. Twenty-seven serum samples were submitted, in a blinded fashion, by the OFAS, as quality controls. Serum samples were tested for IgG antibodies to H. pylori, by use of an in-house ELISA. Compared with those of histopathologic diagnosis, the sensitivity and specificity of this assay when used on serum samples from 77 persons from a variety of racial and ethnic groups were 94% and 91%, respectively. Twenty-three control subjects who died before their respective matched case subjects were diagnosed with esophageal adenocarcinoma and 2 control subjects whose serum samples were no longer stored were replaced with new control subjects who were matched to the case subjects. For quality control, all serum samples from these newly matched case subjects and control subjects were simultaneously tested for IgG antibodies.
Serum samples from all subjects (those positive or negative for IgG antibodies to H. pylori) were also tested by ELISA (OraVax) for IgG antibodies to the H. pylori CagA protein, as described elsewhere [25]. Quality-control samples were also tested for IgG antibodies to the CagA protein.
Statistical analysis.
Statistical analysis was performed with SAS software (version 9.0; SAS). Univariate comparisons were made with the t test and Fisher exact test. Data on the unadjusted effects of the variables of interest were obtained by fitting a univariable conditional logistic regression model for each of the covariates. The body mass index (BMI)calculated as weight (kg)/[height (m)]2was categorized by use of clinically meaningful cutoffs (25 for overweight and 30 for obese) [26]. For age, the median value was used for categorization. Interaction among selected variables was explored by adding cross-product interaction terms to the logistic model. The attributable risk percentage (and 95% CI) for the MHC cohort (i.e., the proportion of cancers theoretically attributable to the presence or absence of H. pylori infection in this cohort) was estimated by use of adjusted measures from unconditional logistic regression (Stata version 8; StataCorp). This model incorporated the matching factors and the 4 independent covariates from the primary logistic model. The standard error (and 95% CI) for the attributable risk was based on asymptotic approximations using maximum likelihood estimation [27]. All P values were 2-tailed.
RESULTS
The mean time interval between each case subject's MHC and diagnosis of esophageal adenocarcinoma was 19.7 years (SD, 7.7 years). The mean age at diagnosis was 67.6 years (SD, 10.1 years). Concordant with the literature, 75% of case subjects were white males; in contrast, the proportion of white males in the entire MHC cohort was 36%.
Because 1 case subject and 7 control subjects had indeterminate results when tested for IgG antibodies to H. pylori, they were excluded from the study, which left 51 case subjects and 149 control subjects in the analysis. Results of testing the 27 quality-control serum samples for IgG antibodies to H. pylori and to the CagA protein corresponded with those that were expected by the OFAS.
Case subjects and control subjects were well matched (table 1). Univariate comparisons showed that case subjects were more likely than control subjects to be heavy smokers or to be obese (P = .003, for each variable, by 2 test). Case subjects were somewhat more likely than control subjects to be heavy drinkers, whereas control subjects were more likely than case subjects to have had a college education. Case subjects were infected with H. pylori less often than were control subjects, although IgG antibodies to the CagA protein were prevalent at similar rates in infected case subjects and infected control subjects (table 2).
The final conditional multivariate logistic regression model included H. pylori serology, BMI, cigarette smoking (ever vs. never), and education level (<3 vs. 3 years of college). Because data on their risk factors were unavailable, 5 case subjects and 19 control subjects were excluded from this model. Subjects with H. pylori infections were less likely than uninfected subjects to develop esophageal adenocarcinoma (OR, 0.37 [95% CI, .16.88]; P = .02, by conditional logistic regression) (table 3).
Of subjects <50 years old at the MHC, those who tested positive for IgG antibodies to H. pylori were 5 times less likely than those who tested negative for IgG antibodies to H. pylori to develop esophageal adenocarcinoma (OR, 0.20 [95% CI, 0.060.68]). On the basis of this OR, 69.1% (95% CI, 29.4%86.4%) of the esophageal adenocarcinomas that developed in subjects <50 years old were attributable to the absence of H. pylori infection [27]; in contrast, in subjects 50 years old at the MHC, H. pylori infection was not significantly associated with esophageal adenocarcinoma (table 4) (OR, 1.99 [95% CI, 0.3511.42]; P = .01, for interaction between age and H. pylori infection, by conditional logistic regression), although the wide CI limited the precision of this estimate. H. pylori infection was significantly associated with esophageal adenocarcinoma only in the subset of subjects with a >20-year interval between the MHC and the diagnosis of this cancer (table 4). Because the age at diagnosis, the interval between donation of serum and diagnosis of this cancer, and the age at the MHC were correlated, it was impossible to assess them jointly in multivariate models. Analyses on the basis of sex and race were unrevealing, although the small sample sizes limited the power to detect differences (table 4).
Both a BMI 25 and cigarette smoking were strong independent risk factors for development of esophageal adenocarcinoma (OR, 2.38 and 3.04, respectively) (table 3). Obesity (BMI, 30) increased this risk further (OR, 50 [95% CI, 4614]), although the small sample size (8 case subjects and 4 control subjects) rendered these results unstable.
The risk of development of esophageal adenocarcinoma in subjects who tested positive for IgG antibodies to the H. pylori CagA protein was similar to that in those who tested negative for it (5 control subjects and 1 case subject who had indeterminate results when tested for IgG antibodies to the H. pylori CagA protein were excluded) (table 5), and the results were similar when 2 subjects who tested negative for IgG antibodies to H. pylori but positive for IgG antibodies to the CagA protein were included in this analysis.
DISCUSSION
We found a strong negative association between H. pylori infection and esophageal adenocarcinoma. Subjects <50 years old who were infected with H. pylori were only 20% as likely as uninfected subjects <50 years old to develop this cancer during the subsequent 535 years. If the connection is causal, then the negative association between H. pylori infection and esophageal adenocarcinoma may at least partly explain the recent increase of esophageal adenocarcinoma in Western countries, where the prevalence of gastric colonization with H. pylori is decreasing.
That H. pylori infection protects against the development of esophageal adenocarcinoma is plausible in terms of physiology. Esophageal damage caused by acid reflux has been linked to esophageal adenocarcinoma, possibly through the development of Barrett esophagus [7, 8, 28]. H. pylori may mitigate against carcinogenesis by reducing the secretion of acid, either through the inhibition of parietal cells by bacterial products and cytokines or through mucosal atrophy resulting from chronic inflammation [12, 13, 29].
The present study showed a much stronger protective association between H. pylori infection and esophageal adenocarcinoma than did 2 retrospective case-control studies [14, 15]. Protection, however, was limited to case subjects and control subjects <50 years old at the MHC. Given that previous case-control studies evaluated older subjects, a possible explanation for this discrepancy is that, in infected control subjects, a loss of antibodies to H. pylori with increasing age or advancing gastritis masked a true association between H. pylori infection and esophageal adenocarcinoma [30]. The stronger association between H. pylori infection and esophageal adenocarcinoma in subjects who had a longer interval between the MHC and the diagnosis of this cancer is probably mostly explained by the high correlation between age at serology and the interval between the MHC and the diagnosis of cancer. ORs calculated for serum samples drawn from young subjects may more accurately reflect the true lifetime impact of H. pylori infection.
In contrast to the results of 2 prior case-control studies, we did not observe a specific association between the presence of IgG antibodies to the H. pylori CagA protein and esophageal adenocarcinoma [15, 16]. Studies of the association between either GERD or Barrett esophagus and infection with CagA proteinpositive H. pylori strains have shown conflicting results [3138]. Compared with CagA proteinnegative H. pylori strains, CagA proteinpositive strains have been associated with more mucosal atrophy and reduced secretion of acid, in the setting of corpus gastritis, and with increased secretion of acid, in the setting of antral gastritis and duodenal ulceration [12, 13]. These differences in results may therefore reflect the inclusion or exclusion of patients with peptic ulcer disease [31, 32, 37]; exclusion of such patients would tend to increase the association between esophageal diseases and infection with CagA proteinpositive H. pylori strains.
Cigarette smoking and alcohol consumption are known risk factors for development of squamous cell carcinoma of the esophagus, and cigarette smoking is also associated with esophageal adenocarcinoma [3, 10]. Our study confirmed that alcohol consumption did not affect the risk of development of esophageal adenocarcinoma, whereas cigarette smoking was associated with a 3-fold increased risk. Moreover, because cigarette smoking was documented many years before the diagnoses of this cancer and because the risk of development of esophageal adenocarcinoma was increased in both former and current smokers, cigarette smoking may be an early event in esophageal carcinogenesis. Other researchers have reported that the risk of development of esophageal adenocarcinoma did not decrease until many years after cessation of smoking [10]. Our finding that a BMI 25 is associated with a 2.4-fold increase in the risk of development of esophageal adenocarcinoma is also consistent with findings in previous studies [9, 39].
The strengths of our study are its powerful, nested case-control design; its exhaustive search for case subjects; its use of control subjects individually matched to case subjects on the basis of characteristics such as age, race, and sex; and the consistency of its results with those of our group's previous pilot study, which used the same case subjects and several different groups of control subjects [40]. Our study also has limitations. First, the measured risk factorsincluding H. pylori infection statuswere assessed only at the MHC and may have changed over time; and such changes could influence the observed associations, in unpredictable ways. Second, we cannot eliminate all possible confounding effects: the protective association between H. pylori infection and esophageal adenocarcinoma that was observed in our study could be due to another factor strongly correlated with H. pylori infection; for example, H. pylori infection is closely linked to low socioeconomic status, and it is possible that a factor linked to low socioeconomic status is the true cause of the associations observed, although, in our study, 2 potential markers of low socioeconomic statusH. pylori infection and educationhad opposite effects on the risk of development of esophageal adenocarcinoma.
In conclusion, we have confirmed a strong negative association between H. pylori infection and esophageal adenocarcinoma. If this association is causal, then an individual with H. pylori infection may be, simultaneously, at increased risk of development of gastric cancer and at decreased risk of development of esophageal adenocarcinoma. The present study does not address whether eradication of H. pylori is deleterious, nor do these results lead us to recommend against treatment of H. pylori infections in individuals with ulcers or a history of gastric malignancy. Rather, these data merely corroborate the complexity of our coexistence with the microbial world. H. pylori is one of myriad organisms that chronically inhabit the human body, but this single organism may simultaneously increase the risk of development of ulcers, gastric cancer, and gastric lymphoma and decrease the risk of development of esophageal adenocarcinoma and GERD. Future longitudinal studies and cost-benefit analyses will ultimately identify the healthiest balance between humans and H. pylori.
Acknowledgments
We gratefully acknowledge Natalia Udaltsova and Shufang Yang, for data management and serum testing, respectively. We also thank Rita Popat and Alice Whittemore, for their insights on data analysis, and Nancy P. Durr of OFAS, for editorial assistance.
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