This is the first retrospective cohort study to investigate the association of RE and H. pylori with the progression from endoscopic SSBE to LSBE referring to changes in RE and H. pylori status. Progression to LSBE is comparatively rare in Japanese individuals. RE and non-H. pylori infection were associated with a higher rate of progression to LSBE, considering the changes in exposures. In addition, H. pylori eradication may not increase the rate of progression to LSBE.
Time-dependent Cox models may have accurately estimated the relationship between time-varying RE and H. pylori status and the progression to LSBE. To date, a few studies have investigated the natural history of endoscopic or histological SSBE [9, 21, 28]. Among them, two studies reported the association between H. pylori infection/AG and SSBE elongation within 2- or 5.7-year periods [9, 21]. One study revealed that shortening of endoscopic SSBE tended to be associated with H. pylori and AG, although this was statistically nonsignificant . Another study showed that the absence of AG was associated with the elongation of endoscopic SSBE . These past studies were well designed; however, they did not take into account both the change in RE status and H. pylori eradication. These analyses may have underestimated the association between RE and H. pylori status and progression to LSBE. In our analysis, Cox models with baseline time-fixed covariates provided the attenuated hazard ratios of RE and non-H. pylori infection for the progression to LSBE compared to time-dependent Cox models. In addition, the hazard ratio of smoking for the progression to LSBE was underestimated in Cox models by baseline time-fixed covariate. These results suggest that time-dependent Cox models were useful to accurately estimate the effects of time-varying exposures such as RE, H. pylori status, and smoking.
The association between RE and non-H. pylori was affected by changes in exposure. Our study revealed that RE and non-H. pylori were the highest risk group for progression to LSBE (OR: 7.17, 95% CI: 2.48–20.73). Additionally, H. pylori suppressed the progression to LSBE (OR: 0.48, 95% CI: 0.22–1.07). These associations are, at least in part, biologically plausible with respect to a decrease in gastric acid secretion. H. pylori infection causes gastric atrophy, decreasing gastric acid secretion . The decrease in gastric acid secretion prevents RE, leading to the prevention of the development of LSBE.
H. pylori eradication may not increase the rate of progression to LSBE. Past studies have shown that H. pylori eradication increases gastric acid secretion, leading to an increased prevalence of RE [14, 29, 30]. This suggests that H. pylori eradication may also increase the rate of endoscopic SSBE elongation. Our study, however, failed to show such a tendency. However, the results should be interpreted with caution. First, it was uncertain whether the follow-up period was sufficient to assess the association between H. pylori eradication and progression to LSBE. Past studies have shown that the risk of developing RE increases as the period after H. pylori eradication is extended . Because in many cases, SSBE extends to LSBE after developing RE, H. pylori eradication may promote the progression to LSBE with longer follow-up. Furthermore, the association between H. pylori eradication and progression to LSBE may differ depending on the degree of AG before eradication. Only among subjects with mild AG, H. pylori eradication may increase gastric acid secretion, leading to progression to LSBE. Long-term prospective cohort studies are expected that take into account the degree of AG at the time of H. pylori eradication.
Progression from endoscopic SSBE to LSBE is comparatively rare in Japanese individuals. A major reason for the low incidence of developing LSBE may be the different clinical criteria of SSBE. In the United States and Europe, intestinal metaplasia is needed for the diagnosis of SSBE; however, SSBE is diagnosed without histological confirmation of intestinal metaplasia in Japan and the United Kingdom [4, 31]. Endoscopic SSBE in Japan may include more cases that are not diagnosed with BE according to the criteria of other countries. Indeed, there are far more subjects endoscopically diagnosed with SSBE in Japan than those histopathologically diagnosed with SSBE in other countries . A substantial proportion of endoscopic SSBE cases in Japan may have lower malignant potential. In fact, in our study, only 34 subjects developed LSBE (1.0 per 1000 person-years). This result suggests that not all subjects with endoscopic SSBE should be followed-up closely. In particular, subjects with H. pylori infection and without RE had a low risk of progression to LSBE (0.4 per 1000 person-years). Long-term follow-up studies are needed to investigate the natural history of endoscopic SSBE.
There were several limitations. First, the exact endoscopic assessment of the elongation of SSBE is difficult and therefore unreliable . To minimize this problem, we evaluated only whether the length of circumferential Barrett epithelium was more than 3 cm or not (LSBE or SSBE). Additionally, all cases initially diagnosed with LSBE by endoscopy experts were reconfirmed by the most experienced endoscopy specialist. Second, the criteria of SSBE in Japan are different from those in the United States and Europe. It remains unclear whether our results may be extrapolated into other populations. Third, all subjects in our study voluntarily took these medical surveys. Most subjects were men with medium and high socioeconomic status. Additionally, subjects who did not undergo an additional health-check program after being diagnosed with SSBE were excluded. These may have led to a selection bias. Fourth, the frequency of medical surveys varied from subject to subject. Finally, the number of subjects who experienced the progression to LSBE was rather small. A large long-term study is expected in the future.
In conclusion, we showed that progression to LSBE is comparatively rare in Japanese individuals. Non-RE and H. pylori infection was associated with a lower rate of progression to LSBE in a Japanese population, considering the changes in exposure. H. pylori eradication may not increase the rate of progression to LSBE.