It has long been known that gastric atrophy is an indicator of increased risk of gastric cancer.29
In Pelayo Correa's model for the pathogenesis of intestinal-type gastric cancer, gastric atrophy is considered one of the precursor lesions of gastric cancer.4,29
Therefore, when low serum PGI and low serum PGI/II ratio were established as sensitive and specific markers for gastric fundic atrophy, a large number of studies examined the association between these markers and risk of gastric cancer, and they found a consistent association. However, the association between gastric atrophy or serum pepsinogens and other cancers, including ESCC, has not been studied until recently.
The first indication that gastric atrophy might be associated with ESCC came from a cohort study in Sweden that compared the risk of ESCC in pernicious anemia patients, who have severe gastric atrophy, with the risk of this tumor in the general population, and found a three-fold increased risk in the pernicious anemia patients.17,18
Then, in 2004, Ye and colleagues published the first evaluation of the association between serum pepsinogens and ESCC risk, in a Swedish case-control study, and found a four-fold increased risk of ESCC in patients with low serum PGI.9
Another recently published case-control study from Japan also found that gastric atrophy, diagnosed serologically or histologically, was associated with a four-fold or higher increased risk of superficial ESCC.19
Our study is the first that has examined the association between gastric atrophy, as measured by serum pepsinogens, and risk of ESD, the precursor lesion of ESCC. Our results show a continuous increase in risk of ESD associated with lower values of the serum PGI/II ratio, with a two-fold increased risk in the lowest compared to the highest quartile of this ratio. These results support the recent findings that suggest that gastric fundic atrophy increases the risk of ESCC. Gastric fundic atrophy results in reduced acid secretion, a higher luminal pH, and proliferation of bacteria in the stomach.4
These bacteria, in turn, may increase the production of carcinogens such as acetaldehyde and nitrosamines, which may underlie all of the observed associations between gastric atrophy and gastric and esophageal neoplasia.
We found a significant association in this study between ESD and low serum PGI/II ratio, but no association between ESD and low serum PGI, even though there was a strong correlation between PGI and PGII values (Pearson's r = 0.69). One possible reason for this apparent discrepancy is that the PGI/PGII ratio is a more sensitive and specific maker of gastric atrophy than PGI alone. Several previous studies suggest that the PGI/II ratio is a more accurate marker for both gastric atrophy 3
and future risk of cancer 5,10,11
than PGI alone. The superiority of the PGI/II ratio may be explained by the changes in the gastric mucosa during progression toward atrophy. In severe atrophy the fundic mucosa, which secretes both PGI and PGII, is replaced by antral-type mucosa, 30
which secretes only PGII. As a result, in subjects with severe atrophic gastritis, serum PGI levels are reduced, by up to one order of magnitude, while serum PGII levels remain constant or may even increase.3
Therefore, the PGI/II ratio may be a marker of atrophy (via its PGI component) that is adjusted for a person's total capacity of pepsinogen secretion (via its PGII component). While most studies have shown that PGI/II ratio is superior to PGI alone as a marker of atrophy, this is not a universal finding. For example, a recent study31
reported that serum PGI was more strongly correlated than PGI/II ratio with gastric maximal acid output, another functional measure of gastric fundic atrophy. Therefore, another possible explanation for the apparent discrepancy in PGI and PGI/II ratio results in this study is that the association between PGI:II and ESD is at least partly due to unknown mechanisms unrelated to atrophy.
The PGI and PGI/II ratio data were analyzed dichotomously, as quartiles, and as continuous variables. There are no universally accepted cutoff points for these two markers and, in fact, previous studies have used several different cutoff points.27
Because PGI and PGI/II ratio are indicators of gastric atrophy, one might assume that the best cutoff point might be determined by plotting Receiver Operating Characteristic (ROC) curves of these markers versus histologically confirmed gastric atrophy. However, this assumption may be misleading. Most gastric atrophy is endoscopically inapparent, and untargeted biopsies may fail to find patchy atrophic lesions, so there is no gold standard diagnostic method to which we can compare the serum markers. In fact, the serum markers may be more accurate than biopsies, because they integrate changes across the entire gastric mucosa. In our study, PGI was not associated with risk of ESD, regardless of the cutpoint used. For all but one cutpoint (4.0), the ORs found for the dichotomized PGI/II ratio values were close to 1.80. Indeed, fitting smoothed non-linear models to risk in our study suggested that risk of ESD increased continuously, and almost linearly, with lower PGI/II ratio levels. Therefore, our results support the hypothesis that progression toward gastric atrophy and increased risk of cancer is a continuous phenomenon; that using a continuous serological marker to diagnose atrophy may be more useful than using untargeted biopsies; and that using cutoff points for the PGI/II ratio, rather than continuous measurements, may reduce the power of this measurement to detect associations.
We cannot find obvious sources of bias or laboratory error that could lead to the observed associations. Ninety-eight percent of the subjects were asymptomatic at study enrollment, so it is unlikely that they changed their eating habits or other behaviors because of their disease prior to enrollment in this study. Studies with a cross-sectional design have some inherent limitations, such as evaluating temporal relationships, but these problems do not undermine our observed associations. The laboratory scientist who performed the assays was unaware of the patients’ clinical diagnoses, and calibration material suggested that the test kits functioned well. In addition, we found a correlation of 0.69 between PGI and PGII, which is similar to several previous studies, and this also suggests that the kits worked well. As always, chance findings and unknown confounders cannot be totally ruled out.
The strengths of this study include measurement of both PGI and PGII; modeling the associations multiple ways, using cutoff points, quartiles and continuous measures; the availability of data on potential confounders; and accurate classification of the ESD lesions. Limitations may include moderate sample size, the presence of unknown confounders, and imperfect correlation between PGI or PGI/II ratio and the true severity of gastric fundic atrophy.
In summary, this study showed an increased risk of moderate or severe ESD with lower levels of the serum PGI/II ratio, which is a marker of gastric fundic atrophy. This result supports recent findings that gastric fundic atrophy increases the risk of ESCC. The mechanisms by which gastric atrophy increases the risk of ESD and ESCC need to be explored further.