This population-based study has shown that frequent symptoms of reflux are associated with increased risks of BE, and that these risks are substantially elevated by smoking and obesity. The strong association observed between symptoms of acid reflux and BE accords with hospital-based case-control studies 21-23
, although we are not aware of any population-based estimates of risk with which to compare these findings. Our data suggest that people who report experiencing at least weekly symptoms of acid reflux have substantially higher risks of BE than those with less frequent episodes. Moreover, we found that symptoms of acid reflux experienced at older ages conferred substantially higher risks of BE than symptoms at younger ages, despite the increasing prevalence of reflux episodes with increasing age among the control group. While all participants may have selectively recalled symptoms experienced at older ages in preference to early life, the progressively higher risks of BE associated with reflux at successively older ages suggest that biased recall is unlikely to explain all of this effect. It might also be argued that the association with acid reflux is explained by detection bias, in which people with frequent symptoms of acid reflux are more likely to undergo upper endoscopy and hence be diagnosed with BE than people without symptoms of acid reflux. This argument is difficult to sustain in the light of the universally larger associations with acid reflux we observed for BE with dysplasia than for BE without dysplasia.
Obesity has been shown to be a determinant of acid reflux 24-26
and has also been linked with esophageal adenocarcinoma 13,27
. In that context, our observation of modestly higher prevalence of obesity among BE patients is perhaps not surprising. One interpretation is that the association between obesity and BE is simply mediated by the effects of acid reflux, as suggested by the attenuated risk estimates for obesity after adjusting for the presence of reflux in the multivariate model. However, our finding that the presence of both self-reported history of acid reflux and obesity led to considerably higher risks than predicted under additive models of biologic interaction 20
suggests that obesity plays a further role in the development of BE, over and above its likely role in promoting acid reflux. Obesity has been associated with increased risks of many types of human cancer 28
, and various biologic mediators (such as steroid hormones, insulin and growth factors) have been proposed to explain the finding 29,30
. Similar mechanisms may also underlie esophageal metaplasia and neoplasia.
We found that smokers had higher risks of BE than non-smokers, although there was no evidence that longer duration or greater intensity of smoking materially altered the risk of disease. Similar patterns of association have been observed between smoking and adenocarcinoma of the esophagus 10,11
. In the absence of acid reflux symptoms, smokers were at no higher risk of BE than non-smokers, whereas when reflux was present, smoking substantially increased the risks of developing BE. These data suggest that smoking is neither necessary nor sufficient to induce BE, but rather potentiates the metaplastic changes initiated by acid reflux.
While regular use of NSAIDs has been associated with reduced risks of esophageal adenocarcinoma and BE 31-33
, we found little evidence to support this contention on univariate analysis. Rather, we found that whereas BE patients reported similar levels of NSAID use as population controls, they reported substantially higher levels of acetaminophen use. After mutual adjustment for other factors, the association with acetaminophen was no longer statistically significant, although patients with dysplastic BE remained considerably more likely than controls to report frequent use of acetaminophen. Despite this observation, we have no reason to believe the association with acetaminophen to be causal, and the most likely explanation for our finding is residual negative confounding due to acid reflux. If residual confounding does underlie this finding, it calls into question the previously observed protective effect of NSAIDs on BE and esophageal adenocarcinoma, particularly as such findings have provided a rationale for clinical trials 34,35
Several aspects of the study design lend credence to the findings. Patients newly diagnosed with BE were prospectively identified and ascertained from across an entire region and compared to controls sampled from a population register. We are not aware of any previous studies of BE that have sampled newly diagnosed cases and controls in such a way, hence these are likely to be the first population-based estimates of risk for this condition. Cases were rapidly recruited after their initial diagnosis, reducing the likelihood that their recall and reporting of past exposures was influenced by prolonged knowledge of their condition. Biased recall would also be unlikely to account for the interactions with smoking and obesity that we observed.
Ascertaining cases through pathology laboratories allowed us to systematically identify BE patients from the source population, and also ensured standard application of histologic inclusion criteria 15
. However we were unable to separately examine associations according to extent of involvement of the esophagus as length of BE (as opposed to biopsy site) was not routinely reported by the large number of community endoscopists in this population-based study. While there is some evidence that length of BE is an important determinant of prognosis, there is general consensus that “short” and “long” segment BE represent a continuum of the same pathologic process 36
. It is unlikely that these entities have sufficiently different causes to invalidate the strong associations observed here.
One potential limitation is that because control participants were sampled from the general population, we cannot exclude the possibility that some may have had undiagnosed BE. While this would lead to error in the risk estimates, the magnitude of the error will be small given that the most extreme upper estimates of the population prevalence of BE are no higher than 12% 1
. Moreover, such a bias would tend to make the control series, on average, more similar to the case series and thus would only serve to attenuate any observed associations.
A potentially more serious error for causal inference might arise if people who are diagnosed with BE because they have undergone endoscopy and biopsy do not represent all people with BE (diagnosed and undiagnosed). Thus, an association might be observed between acid reflux and BE simply because people with acid reflux are more likely to undergo endoscopy, and thus be more likely to be diagnosed with BE. Countering this conjecture are the observations that BE is rare in endoscopy series of healthy volunteers 37
and, in population studies, BE is diagnosed in less than 10% of patients with severe reflux who present for endoscopy 38
. These data mitigate the likelihood of a “bottom of the iceberg” pool of undiagnosed patients whose BE etiology differs from that of diagnosed BE patients 39
Rates of participation in population studies have been falling over time, leading to concerns about unrepresentative samples and potentially biased estimates of risk 40
. To address this issue, we compared self-reported prevalences of key exposures in our control series with those reported by the Australian National Health Survey conducted in 2001. We found very similar prevalences of smoking, obesity and use of medications and conclude that the control series was representative of the Australian community from which the cases arose 41
In summary, these data confirm the clinical impression that self-reported history of acid reflux is strongly associated with BE and BE with dysplasia, and suggest that smoking and obesity potentiate the effects of acid reflux. From a public health perspective, these data raise the prospect that quitting smoking and losing weight merit further investigation as potential adjuncts in the control of BE.