Risk Factors in the Development of Esophageal Adenocarcinoma

Heiko Pohl MD; Katharina Wrobel MD; Christian Bojarski MD; Winfried Voderholzer MD; Amnon Sonnenberg MD; Thomas Rösch MD; Daniel C Baumgart MD

Disclosures

Am J Gastroenterol. 2013;108(2):200-207. 

In This Article

Results

Patient Characteristics

A total of 1,338 patients were identified for all groups combined. Of these, 563 (42.1%) were included in the study (Figure 1), 113 patients into the no-GERD group, 188 patients into the GERD group, 162 patients into the Barrett group, and 100 patients into the cancer/HGD group. Inability to reach patients, unwillingness to participate, death, or meeting exclusion criteria were reasons for not including identified subjects. In the Barrett group, 11 (6.8%) had low-grade dysplasia and 67 (41.4%) had long-segment Barrett's esophagus ≥3 cm. Of the 100 patients in the cancer/HGD group, 75 had cancer and 25 HGD alone. All patients were of Caucasian ethnicity. Details of patient characteristics, endoscopy findings, and medications are summarized in Table 1 .

The no-GERD and GERD groups showed similar patient characteristics. Patients with Barrett's esophagus were older, more often men, heavier, ate less fruits and vegetables, and had reflux symptoms for more years than GERD patients. Patients with cancer/HGD and Barrett's esophagus were similar with respect to age, BMI at age 40, and duration of reflux symptoms. However, cancer/HGD patients were more likely to be male, to be current or former smokers, reported reflux symptoms more often, and had a lower intake of fruits and vegetables compared with Barrett patients.

Endoscopy showed a hiatal hernia more often in GERD than in no-GERD patients and in Barrett patients more often than in GERD patients. Non-significantly fewer patients with cancer/HGD had a hiatal hernia than Barrett patients. The length of Barrett's esophagus was available in 157 Barrett patients and 75 cancer/HGD patients. It was significantly longer in patients with cancer/HGD compared to patients with Barrett's esophagus alone. The prevalence of H. pylori infection was not significantly different among the four patient groups.

Proton-pump inhibitors/H2A use was more common in the GERD group compared with the no-GERD group and more common in the Barrett group compared with the GERD group or the cancer group. There were no differences among the four groups regarding their use of statins or non-steroidal anti-inflammatory drugs other than aspirin.

Risk Factors Associated With the Development of Esophageal Adenocarcinoma

Overall, male gender, history of smoking, and the presence and size of a hiatal hernia were strong risk factors for esophageal adenocarcinoma/HGD when compared with patients without reflux disease in the adjusted analysis. Increasing BMI at age 40 showed a small, but significant association with esophageal adenocarcinoma (P trend=0.034) with an OR of 1.21 for obese as compared with normal-weight patients (Figure 2; Supplementary Table 2a Appendix). A high intake of fruit and vegetables of at least four portions per day showed a strong protective effect (OR 0.25, 95% CI 0.07–0.83). Similarly, H. pylori infection appeared to be protective (OR 0.50, 95% CI 0.23–1.09). Duration of smoking, a history of diabetes, or timing of the largest meal during the day was not associated with esophageal adenocarcinoma/HGD.

Figure 2.

Effect of varying factors on the progression from the absence of reflux disease (no GERD) to reflux disease (GERD) to Barrett's esophagus to esophageal adenocarcinoma/high-grade dysplasia (cancer/HGD). Risks are expressed as odd ratios (OR) with 95% confidence interval (CI) adjusted for age, gender, history of smoking, and body mass index at age 40. BMI, body mass index; GERD, gastroesophageal reflux disease; HGD, high-grade dysplasia.

Risk Factors Associated With the Development of GERD in Patients Without GERD

Presence of a hiatal hernia was the only risk factor to be significantly associated with GERD (OR 3.62, 95% CI 2.15–6.09), and the OR increased with the size of the hernia (P trend<0.001). A large hiatal hernia increased the OR four times compared with patients without a hiatal hernia (OR 4.23, 95% CI 2.03–8.81). No other risk factors were identified (Figure 2; Supplementary Table 2b Appendix). Specifically, we did not find a high BMI or a low fruit and vegetable intake to be associated with an increased risk for reflux disease. Presence of H. pylori infection did not appear to protect against GERD.

Risk Factors Associated With the Development of Barrett's Esophagus in Patients With GERD

Age appeared to be a strong risk factor for the development of Barrett's esophagus among GERD patients (P trend=0.027) (Figure 2; Supplementary Table 2c Appendix). GERD patients older than 75 years were three times more likely to develop Barrett's esophagus than GERD patients younger than 55 years (OR 2.96, 95% CI 1.34–6.51). Male gender was also a strong risk factor. Men with GERD had a 2.7 higher OR of developing Barrett's esophagus than women (OR 2.71, 95% CI 1.70–4.32). Furthermore, there was a significant association between increasing BMI and Barrett's esophagus (P trend=0.014), with a non-significant doubling of the OR for obese compared with normal-weight patients (OR 1.99, 95% CI 0.88–4.50). Although high fruit and vegetable intake were protective in univariate analysis, the effect was not significant in the adjusted analysis. Heartburn duration was strongly associated with Barrett's esophagus (P trend=0.004). Heartburn duration of at least 20 years was associated with 2.4-fold higher OR of developing Barrett's esophagus than a heartburn duration of <10 years (OR 2.41, 95% CI 1.34–4.31). Frequency of heartburn was not associated with the development of Barrett's esophagus. Presence of a hiatal hernia was strongly associated with Barrett's esophagus (OR 2.43, 95% CI 1.50–3.94) among GERD patients, with a significant trend between size and effect (P trend=0.001). H. pylori infection was not associated with the development of Barrett's esophagus in patients with GERD.

Risk Factors Associated With the Development of Cancer/HGD in Patients With Barrett's Esophagus

Male gender, but not age was strongly associated with the development of cancer/HGD in Barrett patients (Figure 2; Supplementary Table 2d Appendix). Cancer/HGD patients were twice more likely to be male than patients with Barrett's esophagus alone (OR 2.29, 95% CI 1.15–4.59). Smoking also appeared to be a strong risk factor. Any history of smoking was associated with a 2.6-fold odds (OR 2.62, 95% CI 1.38–4.99), whereas duration of smoking or years since smoking cessation exerted no significant influence. A high fruit and vegetable intake appeared to be protective with a dose–response effect (P trend=0.051), although the OR among highest fruit and vegetable consumers were not significantly reduced in adjusted analysis (OR 0.60, 95% CI 0.19–1.91). Duration or frequency of reflux symptoms or the presence of a hiatal hernia was not associated with cancer/HGD. However, increasing Barrett length was associated with the development of cancer/HGD in Barrett patients. Patients with a long-segment Barrett's esophagus had a 2.7 higher OR of developing cancer/HGD than those with a short-segment Barrett's esophagus (OR 2.69, 95% CI 1.48–4.88). For every 1 cm increase in Barrett length, the OR increased by 19% (OR 1.19, 95% CI 1.09–1.30). H. pylori infection did not appear to significantly reduce the risk of progression to cancer/HGD.

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