Abstract / Summary
This paper identifies a substantive misalignment between the experimental and epidemiologic literatures on the relationship between acid-suppressive therapy (AS) and esophageal adenocarcinoma (EAC). The experimental literature has proposed several hypotheses by which AS may increase the risk of EAC—either by altering the physicochemical properties of refluxate or proliferative signaling in reflux-injured tissue—and reviews of the in vivo literature have suggested that the positive association between AS and EAC may be causal. At the same time, clinical guidelines have long maintained that the AS–EAC association is an artifact of confounding by gastroesophageal reflux disease (GERD), a risk factor for EAC and a common indication for AS, and cite observational studies that either estimate the AS–EAC association among those without GERD or derive the treatment odds ratio upon adjusting for GERD as a main-effect covariate. This paper first outlines the causal hypotheses articulated in the in vivo literature and establishes that the patient's underlying reflux burden is an effect modifier under each of these hypotheses such that no causal effect would exist in the absence of reflux. It then argues that the epidemiologic findings presented in clinical guidelines as reassuring evidence against causality do not distinguish confounding by GERD from any of these hypotheses. The paper concludes by discussing the broader epidemiologic evidence base, focusing on the conditions under which evidence concerning the use of proton pump inhibitors among those with Barrett's esophagus, the precursor lesion to EAC, can adjudicate the source of the AS–EAC association observed in the general population.