Meta-analyses of the effect of symptoms of gastroesophageal reflux on the risk of Barrett's esophagus

Abstract

Objectives: Esophageal adenocarcinoma (EAC) is a devastating disease that has risen in incidence over the past several decades. Barrett's esophagus (BE) is an associated premalignant lesion. Current preventative efforts rely on endoscopic screening of individuals with gastroesophageal reflux disease (GERD) symptoms and surveillance endoscopy for those with BE. However, some recent studies have found a high prevalence of BE in patients without GERD, and others have found little or no association with GERD. We hypothesized that studies of higher-quality design show weaker associations of GERD with BE, and that GERD is only weakly associated with short-segment Barrett's esophagus (SSBE).

Methods: We performed a systematic literature search in multiple online electronic databases regardless of language. Eligible studies required visualization of columnar mucosa and histological confirmation of intestinal metaplasia, and GERD symptoms ascertained by questionnaire or interview. The highest-quality sampling design was defined a priori by both cases and controls identified among unselected research volunteers ("research design") rather than by patients selected for endoscopy for clinical indications ("clinical design"), which introduces selection and ascertainment bias. A priori, heterogeneity was defined by Cochrane's Q P<0.20 and the inconsistency index (I(2); 25% low, 50% moderate, and 75% high). Heterogeneity of results can reflect significant differences in study design or effect modification by strata of outcomes.

Results: Systematic review identified 13,392 citations. Evaluation identified 108 potentially relevant journal articles, of which 26 met eligibility. Of these, 14 studies identified cases of BE and controls based on clinical indication ("clinical design"), and 6 used the "research design." The remaining six studies identified cases of BE from patients undergoing endoscopy for clinical indication and controls among patients without known BE ("cases clinical/controls research"). The summary odds ratio (OR) for the association of GERD with BE from all studies was 2.90 (95% confidence interval (CI), 1.86-4.54), but the results were very heterogeneous (P=0.0001; I(2)=89%). When stratified by BE length and sampling design, the studies with clinical design showed substantial, but heterogeneous, associations with SSBE (OR, 2.38; 95% CI, 1.21-4.70; P=0.02; I(2)=62%), and stronger and homogeneous association with long-segment BE (LSBE; fixed effects OR, 2.96; 95% CI, 1.69-5.19; P=0.25; I(2)=25%). In the research study design, stratifying by length of BE resolved the heterogeneity and showed a strong association between GERD and LSBE (fixed effects OR, 4.92; 95% CI, 2.01-12.0; P=0.30; I(2)=19%) and no association with SSBE (fixed effects OR, 1.15; 95% CI, 0.763-1.73; P=0.84; I(2)=0%). Funnel plots showed potential evidence for bias against dissemination of small negative studies.

Conclusions: In the highest-quality studies, GERD symptoms are not associated with SSBE, but increased the odds of LSBE by fivefold. GERD symptoms can serve as a reliable predictor of LSBE, but not SSBE. If SSBE is considered worthy of identification, then current screening practices do not select patients at risk for endoscopy, and alternative methods of selection for screening need to be developed.

Figure 1

Flow chart of study eligibility and classification. BE, Barrett's esophagus; GERD, gastroesophageal reflux disease; LSBE, long-segment Barrett's esophagus; SSBE, short-segment Barrett's esophagus.

Figure 2

Forest plots of studies with research design. The top panel represents results from studies for associations of gastroesophageal reflux disease (GERD) symptoms with short-segment Barrett's esophagus (SSBE), showing no association. The bottom panel represents the association with long-segment Barrett's esophagus (LSBE), showing a fivefold increased odds of LSBE with GERD symptoms. Note the scale is logarithmic. I², inconsistency index; OR, odds ratio.

Figure 3

Funnel plot for relation with short-segment Barrett's esophagus (SSBE). Two small, but strongly positive studies for the relation with SSBE, were identified (bottom right quadrant of plot), without balancing small studies showing no or inverse associations (none in bottom left quadrant). This suggests that such small studies may have been completed but were either never submitted for publication or rejected in the review process. CI, confidence interval.

Figure 4

Funnel plot for relation with long-segment Barrett's esophagus (LSBE). Studies were balanced across the summary odds ratio and size of the studies. Therefore, there was no evidence for dissemination bias among studies examining the relation with LSBE. CI, confidence interval.