Recently, serum pepsinogen I (sPG I) and PG II (sPG II), serum gastrin-17 (sG-17), and immunoglobulin G anti-Helicobacter pylori antibodies were proposed as non-invasive markers to assess the status of the gastric mucosa in patients with dyspeptic symptoms [1,2]. Both pepsinogen I (PG I) and PG II are precursors of pepsin. PG II is produced by all gastric glands (namely, oxyntic, cardiac, and pyloric) as well as duodenal (Brunner’s) glands, but PG I is secreted exclusively by oxyntic glands, which reflects its corpus secretion capacity [3]. Previous studies have shown that the sPG I level and/or I/II ratio reflect the morphological [4,5] and functional status of the gastric mucosa [6-8]. Several studies have reported the relationship between the sPG level and gastric mucosal changes [9,10]. Measuring the sPG I and sPG II levels offered a non-invasive and straightforward means of mass screening for gastric cancer in Japan when compared with endoscopy [11,12]. Moreover, recent studies have reported that advanced gastric atrophy is associated with high-fasting intragastric pH [13,14].

As in Japan, the prevalence of H. pylori (59.6% among adults aged ≥ 16 years in 2005) is high in Korea [15], but the efficacy of the sPG level and intragastric pH as a non-invasive marker for gastric atrophy in neoplastic lesions remains to be evaluated in Korea.

This study determined whether the sPG level and intragastric pH are related with the existence of gastric atrophy in gastric neoplastic lesions before endoscopic submucosal dissection (ESD). In addition, the relationships among the clinicopathological characteristics of gastric neoplasm, age, and sPG level in patients with gastric atrophy were investigated.

Gastric cancer is one of the major cancers in the world, especially in East Asian countries such as Korea and Japan. The incidence and mortality of gastric cancer have decreased in several regions, including Korea, owing to advancements in diagnosis and treatment. However, with the rapid aging of the population, the absolute numbers of new cases and deaths from gastric cancer are expected to increase [17].

Correa’s hypothesis that “the intestinal type of gastric cancer develops from chronic inflammation leading to atrophic gastritis, intestinal metaplasia, dysplasia and cancer” has been widely accepted, and this pathogenesis may be caused by H. pylori infection [18]. A previous study revealed that chronic atrophic gastritis carries an 18-fold increased risk of gastric cancer in antral-predominant atrophic gastritis and a 4.6-fold risk in corpus atrophic gastritis [19]. Currently, gastric cancer and atrophic gastritis are screened and diagnosed mainly by endoscopy and biopsy. However, due to the associated discomfort and cost-effectiveness, several non-invasive tests have recently been proposed as alternatives. As the severity of atrophic gastritis increases, normal gland function is lost and enzyme production is affected. Therefore, sPG produced by the gastric mucosa has been found to act as a marker of gastric mucosal status [4-8], and a low sPG I level and a low PG I/II ratio have been associated with severe gastric atrophy [4,5,20].

As the oxyntic gland’s atrophy progresses, the sPG I level decreases. In addition, when pyloric gland metaplasia of the proximal stomach occurs, the sPG II level increases. However, in severe atrophic gastritis, the sPG II level generally decreases to normal. Thus, the levels of sPG I and sPG II and the sPG I/II ratio reflect the morphological and functional status of the gastric mucosa. Based on several previous studies, a low sPG I level and a low sPG I/II ratio are reliable biomarkers for atrophic gastritis of the gastric fundus and are related with the severity of atrophy [4,21].

Although various cut-off values have been suggested for atrophic gastritis and gastric cancer, a sPG I level ≤ 70 ng/mL and a sPG I/II ratio ≤ 3 have frequently been used with a sensitivity of 73.2% to 84.6% and a specificity of 70% to 73.5%, respectively [11,22-24]. In the present study, we also defined serologic gastric atrophy as a sPG I level ≤ 70 ng/mL and a sPG I/II ratio ≤ 3. Patients who matched this criteria of serologic atrophy were more common in the severe atrophy group (61%) than in the mild atrophy group (18%) (p = 0.000). In addition, patients with severe atrophy showed a lower serum level of sPG I and a lower sPG I/II ratio than those with mild atrophy (p = 0.000). The mean sPG II level decreased slightly in the severe atrophy group than in the mild atrophy group, although the levels were comparable (17.1 ± 11.6 vs. 21.1 ± 15.3, respectively; p = 0.058). These results revealed the same tendency as reported by previous studies.

In addition, older patients and those with more atrophic changes at the upper gastric body (atrophic lesions located in the upper region) demonstrated a lower sPG I level and a lower sPG I/II ratio, but more severe endoscopic atrophy. In these patients, serologic and endoscopic atrophy was more severe.

Using histology and the CLO test, H. pylori infection was detected in 58 of 186 patients (31.2%), with 18 patients (36.7%) showing mild atrophy and 40 (29.2%) showing severe atrophy. However, these results do not suggest a lesser association between H. pylori infection and gastric atrophy. Although the CLO test has a high sensitivity and specificity of 85% to 97% and 92%, respectively, it also has the possibility of a false negative result in atrophic gastritis or intestinal metaplasia due to uneven mucosal distribution of the bacteria [25,26]. Moreover, in the advanced stage of the disease, due to disease-related clearance of the infection, there is a possibility of underestimating H. pylori infection [27].

Kikuchi et al. [28] observed a lower level of sPG I and a lower sPG I/II ratio in the H. pylori-positive group. Ito et al. [29] reported improvements in gastric atrophy and intestinal metaplasia and increases in the sPG I level and in the sPG I/II ratio after H. pylori eradication in patients with atrophic gastritis, as explained by the pathophysiology of H. pylori infection. In a past study, a polypeptide secreted by H. pylori stimulated the chief cells directly and promoted the synthesis and secretion of pepsinogens, mainly PG II [30]. However, long-term persistent infection may cause PG gene mutation and glandular cell damage, which may result in corpus atrophy, decrease in the capability of PG I secretion, and increased gastric pH. PG II is secreted extensively, including in the metaplastic pyloric gland. Therefore, the sPG II level is almost constant and the sPG I/II ratio is correspondingly decreased [3-7]. In the present study, the mean sPG I/II ratio was the highest in the serologic atrophy (−)/H. pylori (−) group (4.8 ± 1.8) and the lowest in the serologic atrophy (+)/H. pylori (−) group (2.0 ± 0.7). Furthermore, severe endoscopic atrophy type was more common in the serologic atrophy group than in the serologic non-atrophy group, irrespective of H. pylori infection, although the difference was not statistically significant.

In our study, gastric neoplastic lesions were classified into LGD, HGD, and EGC by our endoscopic pathology findings. The value of the sPG I/II ratio was the lowest in the LGD group than in the HGD and EGC groups (p = 0.015). Chang et al. [31] reported that the sPG I/II ratio was significantly lower in patients with LGD than in those with functional dyspepsia and that the ratio was not further decreased in patients with HGD, EGC, and AGC. These results of severe serologic atrophy in LGD comprehensively imply that LGD can be considered as a serious precancerous lesion that rationalizes the endoscopic resection of the lesion.

There are several limitations in our study. First, it was conducted at a single center and included a small sample size. Second, as we conducted the survey of patients with precancerous lesions and EGC before ESD, no normal control group or advanced gastric cancer group existed in our study. Third, we defined “serologic atrophy” using cut-off values of sPG I level ≤ 70 ng/mL and the sPG I/II ratio ≤ 3.0 with high sensitivity and specificity, respectively, based on previous studies. However, these cut-off values may not be suitable in Korea, because they may vary with regard to ethnicity, diet, environment, and disease epidemiology, thus necessitating further studies on the appropriate sPG cut-off value for gastric atrophy among Korean patients. Forth, the serum H. pylori antibody status was not evaluated in this study.

In conclusion, a low sPG I level and a low sPG I/II ratio are closely related to the severity of gastric atrophy and dysplasia, but intragastric pH was not relevant. The age and location of atrophic lesions are related to the severity of gastric atrophy. We concluded that the sPG test is useful as a marker of gastric precancerous lesions and EGC; therefore, it is helpful not only in diagnosing a benign disease status with a high malignancy risk or early stage of gastric malignancy but also in improving the patient’s compliance and cost-effectiveness of screening. This test may also help in the primary selection of high-risk patients with premalignant gastric lesions who need endoscopic examination and biopsy.