REVIEW URRENT C OPINION
Risk factors for Barrett’s esophagus Joel H. Rubenstein a,b
Purpose of review To summarize the emerging data on the risk factors for Barrett’s esophagus and risk stratification tools. Recent findings Obesity, particularly abdominal obesity, is associated with Barrett’s esophagus, likely because of both mechanical effects promoting gastroesophageal reflux and nonmechanical effects. Circulating peptides related to obesity alter the risk of Barrett’s esophagus and may work synergistically with gastroesophageal reflux. Tobacco use is an underappreciated risk for Barrett’s esophagus. A number of genetic variants have been associated with Barrett’s esophagus, involving pathways in esophageal development. Risk stratification tools are becoming available that have modest discriminatory capability and good calibration. Summary The developing understanding of risk factors for Barrett’s esophagus is shifting the clinical guidelines to a nuanced approach incorporating multiple risk factors to select patients for screening for Barrett’s esophagus. Keywords adipokines, esophageal neoplasms, genetic loci, obesity, risk assessment
INTRODUCTION
obesity. In a meta-analysis of 15 studies, Singh et al. [4 ] reported a summary odds ratio (OR) of 1.98 [95% confidence interval (CI) ¼ 1.52, 2.57] for the greatest vs. lowest category of abdominal obesity for Barrett’s esophagus. In contrast, there was only a weak association of Barrett’s esophagus with total body obesity as measured by the BMI (OR for greatest vs. lowest category ¼ 1.24; 95% CI ¼ 1.02, 1.52). A leading hypothesis explaining the association of abdominal obesity with Barrett’s esophagus has been that the increased intra-abdominal pressure leads to GERD. But the relationship between obesity and the pressure dynamics across the esophagogastric junction are rather complex. Derakhshan et al. [5] found that BMI was not only positively associated with intra-abdominal pressure, but also with intra-thoracic pressure. During inspiration, BMI was not only moderately positively correlated with the pressure gradient across the esophagogastric &&
The cause of esophageal adenocarcinoma remains largely unknown. It is well accepted that gastroesophageal reflux disease (GERD) promotes development of the associated precancerous lesion, Barrett’s esophagus. However, most individuals with GERD will never develop esophageal adenocarcinoma [1]. Furthermore, the majority of individuals with esophageal adenocarcinoma deny prior substantial symptoms of GERD (Fig. 1) [2]. A better understanding of the cause of Barrett’s esophagus and esophageal adenocarcinoma might be leveraged to control the burden of the cancer. There seem to be tantalizing clues to the cause within the epidemiologic evidence. The incidence of esophageal adenocarcinoma rose six-fold between 1975 and 2001, suggesting a strong environmental effect [3]. The male-to-female ratio for esophageal adenocarcinoma is greater than nearly every other cancer, and there is a similar, albeit somewhat weaker predilection of men for Barrett’s esophagus. Recent evidence of risk factors for Barrett’s esophagus are reviewed.
Veterans Affairs Center for Clinical Management Research and bDivision of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
ABDOMINAL OBESITY
Correspondence to Joel H. Rubenstein, MD, MSc, VA Medical Center, 111-D, 2215 Fuller Road, Ann Arbor, MI 48105, USA. Tel: +1 734 845 5865; fax: +1 734 845 3237; e-mail: [email protected]
Obesity has been associated with Barrett’s esophagus, and the effect seems to be specific to abdominal www.co-gastroenterology.com
a
Curr Opin Gastroenterol 2014, 30:408–414 DOI:10.1097/MOG.0000000000000084 Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risk factors for Barrett’s esophagus Rubenstein
KEY POINTS Important risk factors for Barrett’s esophagus include GERD symptoms, abdominal obesity, tobacco use, and male sex. The strong effect of abdominal obesity is likely mediated by the synergistic effects on GERD and alterations in circulating peptides. Clinical tools predicting the presence of Barrett’s esophagus have been developed. Major known risk factors for Barrett’s esophagus and esophageal adenocarcinoma do not appear to explain the trends in the changing incidence of the cancer.
junction, but also weakly positively correlated with the lower esophageal sphincter pressure which might protect against reflux. During expiration, BMI correlated not only weakly with the pressure gradient, but also inversely with the lower esophageal pressure, the combination of which might
promote reflux. In a meta-analysis restricted to studies that controlled for GERD symptoms, the effect of abdominal obesity on the risk of Barrett’s esophagus appeared to be independent of GERD (OR ¼ 2.04; 95% CI ¼ 1.44, 2.90) [4 ]. All of the studies in the meta-analysis are prone to residual confounding by GERD status as many obese patients with GERD may be asymptomatic. Nonetheless, the absence of any attenuation of the effect of abdominal obesity by GERD symptoms suggests that non-GERD-related mechanisms are likely at least partly responsible for the effect of abdominal obesity on Barrett’s esophagus. Further supporting a nonmechanical effect of obesity was the finding in a case–control study that gluteofemoral obesity was inversely associated with erosive esophagitis and Barrett’s esophagus; for each 5 cm increment of hip circumference, the adjusted odds ratio (OR) for either erosive esophagitis or Barrett’s esophagus decreased, adjusted for abdominal obesity and other factors (OR ¼ 0.872; 95% CI ¼ 0.766, 0.995) [6 ]. Thus, obesity measures comparing abdominal to lower extremity obesity &&
&
Author (year) Proportion (CI)
Lagergren (1999)
60% (53%; 67%)
Farrow (2000)
34% (27%; 41%)
Wu (2003)
49% (42%; 56%)
Anderson (2007) 48% (42%; 55%)
Whiteman (2008)
42% (37%; 47%)
Synthesis
47% (39%; 54%)
0%
20%
40%
60%
80%
100%
FIGURE 1. A meta-analysis of the proportion of esophageal adenocarcinoma patients reporting prior GERD symptoms. A previously published systematic review and meta-analysis presented data on the summary odds ratio of the effect of prior GERD symptoms on the odds of esophageal adenocarcinoma [2]. Using the same studies identified in that systematic review, this figure displays the point estimates and confidence intervals of the proportion of patients with esophageal adenocarcinoma who reported experiencing GERD symptoms at least weekly prior to the cancer. The summary estimate and confidence interval using a random effects model is displayed by the diamond (46.5%, 95% CI ¼ 38.7%, 54.4%). The results were heterogeneous (Cochrane’s Q P-value
Risk factors for Barrett’s esophagus Joel H. Rubenstein a,b
Purpose of review To summarize the emerging data on the risk factors for Barrett’s esophagus and risk stratification tools. Recent findings Obesity, particularly abdominal obesity, is associated with Barrett’s esophagus, likely because of both mechanical effects promoting gastroesophageal reflux and nonmechanical effects. Circulating peptides related to obesity alter the risk of Barrett’s esophagus and may work synergistically with gastroesophageal reflux. Tobacco use is an underappreciated risk for Barrett’s esophagus. A number of genetic variants have been associated with Barrett’s esophagus, involving pathways in esophageal development. Risk stratification tools are becoming available that have modest discriminatory capability and good calibration. Summary The developing understanding of risk factors for Barrett’s esophagus is shifting the clinical guidelines to a nuanced approach incorporating multiple risk factors to select patients for screening for Barrett’s esophagus. Keywords adipokines, esophageal neoplasms, genetic loci, obesity, risk assessment
INTRODUCTION
obesity. In a meta-analysis of 15 studies, Singh et al. [4 ] reported a summary odds ratio (OR) of 1.98 [95% confidence interval (CI) ¼ 1.52, 2.57] for the greatest vs. lowest category of abdominal obesity for Barrett’s esophagus. In contrast, there was only a weak association of Barrett’s esophagus with total body obesity as measured by the BMI (OR for greatest vs. lowest category ¼ 1.24; 95% CI ¼ 1.02, 1.52). A leading hypothesis explaining the association of abdominal obesity with Barrett’s esophagus has been that the increased intra-abdominal pressure leads to GERD. But the relationship between obesity and the pressure dynamics across the esophagogastric junction are rather complex. Derakhshan et al. [5] found that BMI was not only positively associated with intra-abdominal pressure, but also with intra-thoracic pressure. During inspiration, BMI was not only moderately positively correlated with the pressure gradient across the esophagogastric &&
The cause of esophageal adenocarcinoma remains largely unknown. It is well accepted that gastroesophageal reflux disease (GERD) promotes development of the associated precancerous lesion, Barrett’s esophagus. However, most individuals with GERD will never develop esophageal adenocarcinoma [1]. Furthermore, the majority of individuals with esophageal adenocarcinoma deny prior substantial symptoms of GERD (Fig. 1) [2]. A better understanding of the cause of Barrett’s esophagus and esophageal adenocarcinoma might be leveraged to control the burden of the cancer. There seem to be tantalizing clues to the cause within the epidemiologic evidence. The incidence of esophageal adenocarcinoma rose six-fold between 1975 and 2001, suggesting a strong environmental effect [3]. The male-to-female ratio for esophageal adenocarcinoma is greater than nearly every other cancer, and there is a similar, albeit somewhat weaker predilection of men for Barrett’s esophagus. Recent evidence of risk factors for Barrett’s esophagus are reviewed.
Veterans Affairs Center for Clinical Management Research and bDivision of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA
ABDOMINAL OBESITY
Correspondence to Joel H. Rubenstein, MD, MSc, VA Medical Center, 111-D, 2215 Fuller Road, Ann Arbor, MI 48105, USA. Tel: +1 734 845 5865; fax: +1 734 845 3237; e-mail: [email protected]
Obesity has been associated with Barrett’s esophagus, and the effect seems to be specific to abdominal www.co-gastroenterology.com
a
Curr Opin Gastroenterol 2014, 30:408–414 DOI:10.1097/MOG.0000000000000084 Volume 30 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Risk factors for Barrett’s esophagus Rubenstein
KEY POINTS Important risk factors for Barrett’s esophagus include GERD symptoms, abdominal obesity, tobacco use, and male sex. The strong effect of abdominal obesity is likely mediated by the synergistic effects on GERD and alterations in circulating peptides. Clinical tools predicting the presence of Barrett’s esophagus have been developed. Major known risk factors for Barrett’s esophagus and esophageal adenocarcinoma do not appear to explain the trends in the changing incidence of the cancer.
junction, but also weakly positively correlated with the lower esophageal sphincter pressure which might protect against reflux. During expiration, BMI correlated not only weakly with the pressure gradient, but also inversely with the lower esophageal pressure, the combination of which might
promote reflux. In a meta-analysis restricted to studies that controlled for GERD symptoms, the effect of abdominal obesity on the risk of Barrett’s esophagus appeared to be independent of GERD (OR ¼ 2.04; 95% CI ¼ 1.44, 2.90) [4 ]. All of the studies in the meta-analysis are prone to residual confounding by GERD status as many obese patients with GERD may be asymptomatic. Nonetheless, the absence of any attenuation of the effect of abdominal obesity by GERD symptoms suggests that non-GERD-related mechanisms are likely at least partly responsible for the effect of abdominal obesity on Barrett’s esophagus. Further supporting a nonmechanical effect of obesity was the finding in a case–control study that gluteofemoral obesity was inversely associated with erosive esophagitis and Barrett’s esophagus; for each 5 cm increment of hip circumference, the adjusted odds ratio (OR) for either erosive esophagitis or Barrett’s esophagus decreased, adjusted for abdominal obesity and other factors (OR ¼ 0.872; 95% CI ¼ 0.766, 0.995) [6 ]. Thus, obesity measures comparing abdominal to lower extremity obesity &&
&
Author (year) Proportion (CI)
Lagergren (1999)
60% (53%; 67%)
Farrow (2000)
34% (27%; 41%)
Wu (2003)
49% (42%; 56%)
Anderson (2007) 48% (42%; 55%)
Whiteman (2008)
42% (37%; 47%)
Synthesis
47% (39%; 54%)
0%
20%
40%
60%
80%
100%
FIGURE 1. A meta-analysis of the proportion of esophageal adenocarcinoma patients reporting prior GERD symptoms. A previously published systematic review and meta-analysis presented data on the summary odds ratio of the effect of prior GERD symptoms on the odds of esophageal adenocarcinoma [2]. Using the same studies identified in that systematic review, this figure displays the point estimates and confidence intervals of the proportion of patients with esophageal adenocarcinoma who reported experiencing GERD symptoms at least weekly prior to the cancer. The summary estimate and confidence interval using a random effects model is displayed by the diamond (46.5%, 95% CI ¼ 38.7%, 54.4%). The results were heterogeneous (Cochrane’s Q P-value
