11/26/2010 Analysis of high risk factors for chronic atrophic gastritis Lin XK, Wang WL, - Saudi J Gastroenterol
Saudi Journal of Gastroenterology
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Analysis of high risk factors for chronic atrophic gastritis

1 Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
2 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province; Research Center of Diagnosis and Treatment Technology for Hepatocellular Carcinoma of Zhejiang Province; Clinical Medicine Innovation Center of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Disease of Zhejiang University; Clinical Research Center of Hepatobiliary and Pancreatic Diseases of Zhejiang Province; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China

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Date of Submission28-Aug-2022
Date of Acceptance16-Nov-2022
Date of Web Publication30-Dec-2022


Background: Screening for chronic atrophic gastritis (CAG) is crucial for the prevention and early detection of gastric cancer. Endoscopy is the main method of CAG diagnosis, with high training requirements and limited accuracy, making it difficult to popularize. The study attempts to improve the positive rate and accuracy of CAG screening through non-invasive testing.
Methods: A total of 2564 patients who underwent gastroscopy were included in this study. The results of gastroscopic evaluation, histological biopsy results (including H. pylori biopsy), urea breath test (UBT) results, serum pepsinogen, and testosterone were statistically analyzed.
Results: We found significant differences in the diagnosis of CAG between endoscopy and histological biopsy. Pepsinogen II and pepsinogen I/II ratio were more useful for the diagnosis of CAG compared with pepsinogen I. The risk of CAG was increased when pepsinogen II exceeded 11.05 μg/L, and the pepsinogen I/II ratio was less than 3.75. CAG positivity was higher in patients with positive H. pylori infection on UBT screening. In addition, higher levels of testosterone, SHBG and HSD17B2, and lower level of GNRH1 were found in CAG mucosa. Patients with high serum testosterone had a higher risk of CAG.
Conclusion: CAG screening should be combined with endoscopic evaluation, biopsy, and other non-invasive tests. Non-invasive tests include the combination of serum pepsinogen II protein and pepsinogen I/II ratio and high level of serum testosterone. UBT combined with serum pepsinogen testing may improve the positive rate of CAG and reduce gastric mucosal damage from multiple biopsies.

Keywords: Gastritis, helicobacter pylori, pepsinogen, testosterone, urea breath test

How to cite this URL:
Lin XK, Wang WL. Analysis of high risk factors for chronic atrophic gastritis. Saudi J Gastroenterol [Epub ahead of print] [cited 2023 Feb 2]. Available from: https://www.saudijgastro.com/preprintarticle.asp?id=366285

   Introduction Top

Chronic atrophic gastritis (CAG) is a specific type of chronic gastritis in which the gastric epithelium is atrophied, reduced or even lost with (or without) intestinal metaplasia (IM).[1] CAG may arise as a long-term consequence of superficial gastritis or in the context of gastric autoimmunity. H. pylori is considered the main etiology of the former. The latter is linked to autoantibodies toward the parietal cells and intrinsic factor and inflammatory destruction of oxyntic mucosa.[2]

The incidence of CAG increases with age, especially after the age of 40.[3] According to Correa's cascade theory, CAG is a precancerous state of gastric cancer (GC).[4] For early GC confined to the mucosal layer, the prognosis of endoscopic treatment is good and minimally invasive.[5] However, the radicality of endoscopic resection is compromised when GC invades the submucosa. Therefore, effective screening and gastroscopic follow-up of patients with CAG are essential to detect early GC and improve prognosis.

The diagnosis of CAG relies mainly on endoscopy combined with histological biopsy. However, the physical discomfort and high cost of endoscopy make it difficult to become a high-frequency screening modality for CAG. In addition, the accuracy of histologic biopsy depends on the accurate localization of the biopsy taken by the endoscopist and the expertise of the pathologist, which often requires multiple biopsies during a single gastroscopy, increasing the risk of bleeding and gastric ulcers. Although CAG can be diagnosed clinically according to the Kimura–Takemoto endoscopic classification,[6] strict training of endoscopists is required, and the accuracy remains to be verified. Therefore, effective and reliable non-invasive screening of CAG which improves the positivity and accuracy of gastroscopy is needed.[7]

Serological tests such as pepsinogen (PG) may help identify patients at risk for CAG with both high sensitivity and specificity.[8] Studies have shown a significantly increased risk of CAG when PG I is less than 70 μg/L and the PG I/II ratio (PGR) is less than 3.[9] H. pylori infection is closely associated with CAG. Due to the presence of false negatives, clinicians often prefer to use a combination of two or more testing methods to obtain reliable results of H. pylori infection.[10] The impact of different H. pylori detection methods on CAG screening remains unclear.

Despite the well-known male predominance of gastric cancer, there is no gender difference in the prevalence of CAG in most studies.[11] Some scholars believe that older age and male sex were independently associated with gastric IM.[12] The gender differences in GC may be related to sex steroid hormones.[13],[14] As a precancerous state of GC,[4] the relationship between CAG and sex hormones has not been reported and needs to be further studied.

In this study, we compared different diagnostic methods for CAG and analyzed the effects of serum PG, different H. pylori detection methods, and serum testosterone on CAG, in an attempt to improve the positive rate and accuracy of CAG screening.

   Materials and Methods Top

Patient information

A total of 2564 gastroscopy patients (1486 men and 1078 women), who completed gastroscopy and pathological biopsy (including H. pylori biopsy) from November 2019 to March 2021, were included in this study. None of them were pathologically diagnosed with autoimmune chronic atrophic gastritis. In this cohort, 1680 patients completed 13C urea breath test (UBT), 965 patients completed serum PG testing (PG I, PG II, and PGR), and 321 patients completed serum testosterone testing. This study was approved by the ethical committee of the First Affiliated Hospital, Medical College, Zhejiang University (Hangzhou; Ethical number: 2022249). Written informed consent was obtained from all participants included in the study.

Diagnostic criteria for CAG

The diagnosis of CAG includes on gastric mucosal atrophy assessed by endoscopy (endoscopic CAG) or glandular atrophy or IM confirmed by histological biopsy (pathological CAG). Endoscopic CAG is mainly based on the Japanese Kimura–Takemoto endoscopic classification criteria.

Statistical methods

Differences in the expression of PG, testosterone, sex hormone-binding globulin (SHBG), hydroxysteroid 17-β dehydrogenase 2 (HSD17B2), and gonadotropin-releasing hormone 1 (GNRH1) between different groups were analyzed mainly by t-test (unpaired t-test if the variance was homogeneous; Welch-corrected unpaired t-test if the variance was unequal). The Chi-square test was used in the following comparisons: 1. comparison of CAG positivity rates in men and women; 2. comparison of endoscopic CAG and pathological CAG; 3. comparison of CAG positivity rates between groups at each PG optimal cut-off value; 4. differences in sensitivity and specificity of CAG screening with different PG criteria; and 5. comparison of CAG positivity rates between H. pylori positive and negative groups with different detection methods. ROC curves and Youden's index were used to analyze and determine the optimal cut-off values for PG and testosterone. Analysis was performed using GraphPad Prism 9.02 (GraphPad Software, San Diego, CA, USA) software. A P value < 0.05 was considered to indicate statistical significance.

CAG dataset

The CAG dataset was obtained from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/). A total of 18 samples (6 CAG mucosal samples and 12 normal gastric mucosal samples) were included in the dataset GSE27411, based on array expression profiles (GPL6255 Illumina humanRef-8 v2.0 expression bead slice).

   Results Top

Significant differences in the diagnosis of endoscopic CAG and pathological CAG

Among the 2564 patients, there were 500 male CAG patients (33.6%) and 397 female CAG patients (36.8%), with no gender difference in CAG positivity (P = 0.1019). After excluding all cases of pathologically definite H. pylori infection, there remained no statistical difference in CAG positivity rates between males and females (367/1136, 32.3% vs. 291/855, 34.0%; P = 0.4413). Among the 897 patients with CAG, 285 patients were endoscopic CAG and 781 patients were pathological CAG, the latter including 166 patients with pathologically confirmed glandular atrophy and 707 patients with pathologically confirmed IM ([Supplementary Figure 1]a[Additional file 1]). Pathological biopsy results of glandular atrophy and IM were inconsistent (P < 0.0001). Only 169 of the 897 patients with CAG were diagnosed with both endoscopic CAG and pathologic CAG ([Supplementary Figure 1]b), with a significant statistical difference in the concordance between endoscopic CAG and pathological CAG (P < 0.0001).

Changes in PG II and PGR are more pronounced in patients with CAG

A total of 965 patients underwent gastroscopy, histological biopsy, and serum PG testing (including PG I, PG II, and PGR) all at the same time. Of these 965 patients, a total of 329 patients were diagnosed with CAG, including 119 endoscopic CAGs and 275 pathological CAGs. There was no difference in PG I between the CAG-positive and negative groups (P = 0.9223), but CAG patients had higher PG II (P = 0.0272) and lower PGR (P = 0.0092; [Figure 1]a). In subgroup analysis, PG I in the endoscopic CAG-positive group was not different from the negative group (P = 0.8158), but the PG II was higher (P = 0.0052) and PGR was lower (P = 0.0131; [Figure 1]b). In patients with pathological CAG, there was no statistical difference in PG I, PG II, or PGR between the positive and negative groups (P = 0.9603, 0.1029, and 0.1118, respectively). Considering that only IM without significant glandular atrophy was seen in biopsy samples from some patients with pathological CAG, the pathological CAG group was further divided into atrophy group and IM group for analysis. There was no difference in PG I relative to negative patients in the atrophic subgroup (P = 0.9655), but higher PG II (P = 0.0128) and lower PGR were observed in atrophic subgroup (P = 0.0016; [Figure 1]c). In the IM subgroup, there was no significant difference for either PG I, PG II, or PGR (P = 0.9313, 0.2629, 0.3454, respectively).
Figure 1: Differences of PG I, PG II, and PGR in CAG patients. (a) There was no difference in PG I levels between the CAG positive and negative groups (61.88 vs. 62.09 ± 2.204; P = 0.9223), but PG II levels were higher in CAG patients (14.03 vs. 13.01 ± 0. 4579; P = 0.0272) and PGR was lower (4.667 vs. 4.917 ± 0.0957; P = 0.0092). (b) There was no difference in PG I levels between the endoscopic CAG and negative groups (62.67 vs. 61.93 ± 3.177; P = 0. 8158), but PG II levels were higher in patients with endoscopic CAG (14.98 vs. 13.13 ± 0.6591; P = 0.0052) and PGR was lower (4.531 vs. 4.874 ± 0.1380; P = 0.0131). (c) There was no difference in PG I levels between the atrophic and negative groups (61. 86 vs. 62.03 ± 3.926; P = 0.9655), but the atrophic patients had higher PG II levels (15.24 vs. 13.20 ± 0.8152; P = 0.0128) and lower PGR (4.334 vs. 4.873 ± 0.1702; P = 0.0016). (d) PG I has no diagnostic value for CAG (P = 0.6567). PG II and PGR have diagnostic significance (P = 0.0386, 0.0061, respectively)

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PG II >11.05 μg/L and PGR <3.75 are associated with a higher risk of CAG

According to the ROC curves of PG I, PG II, and PGR [Figure 1]d, PG I had no diagnostic value for CAG (P = 0.6567), while PG II and PGR were useful for diagnosis (P = 0.0386, 0.0061, respectively). Further calculations based on the Youden index [Table 1] showed a sensitivity of 60.18% and a specificity of 35.53% when PG I is <62.15 μg/L, a sensitivity of 59.87% and a specificity of 49.37% when PG II > is 11.05 μg/L, and a sensitivity of 27.05% and a specificity of 83.18% when PGR is <3.75. There was no difference in the CAG positivity rate even when patients were grouped by PG I <62.15 μg/L (P = 0.2056), whereas when patients were grouped by PG II >11.05 μg/L or PGR <3.75, there was a more significant difference in the CAG positivity rate between the two groups (P = 0.0065; 0.0003, respectively).
Table 1: Cut-off value of PG and testosterone with their specificity and sensitivity

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According to previous criteria, patients with PG I ≤70 ug/L and PGR ≤3 were defined as a high-risk group for CAG. Our data confirmed that the high-risk group had a higher positive rate of CAG and endoscopic CAG (P = 0.0023, 0.0082; respectively), but there was no statistical difference of pathological CAG (P = 0.0801). Although with a high specificity, the sensitivity of previous criteria was low [Table 2]. In this study, we used PG II >11.05 ug/L and PGR value <3.75 as the new high-risk criteria. More patients with CAG (either endoscopic CAG or pathological CAG) belonged to the high-risk group (P = 0.0004, 0.0073, 0.0036, respectively). The new criteria had a higher sensitivity and was superior to the previous one.
Table 2: Differences in sensitivity and specificity of different CAG screening standard based on PG

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Diagnostic rate of CAG in UBT positive patients is higher than in biopsy positive patients

A total of 1679 patients in this study underwent both 13C UBT and H. pylori gastroscopic biopsy and 829 of them completed PG tests. H. pylori infection was diagnosed in 591 cases, including 561 UBT-positive patients (33.41%) and 395 biopsy-positive patients (23.53%). Between two H. pylori detection methods, the positive rate of H. pylori infection by UBT was higher than by biopsy (P < 0.0001). Of these 591 positive patients, only 365 were double positive by UBT and H. pylori biopsy ([Supplementary Figure 1]c). PG I and PG II were higher, and PGR was lower in H. pylori-positive patients, regardless by UBT or biopsy [Figure 2], P < 0.0001). The CAG positive rates (both endoscopic CAG and pathological CAG) were higher in H. pylori-positive patients, regardless by UBT or biopsy [Table 3]. Meanwhile, patients who tested positive for H. pylori by UBT had a higher CAG diagnosis rate than those by biopsy ([Supplementary Table][Additional file 2]).
Figure 2: Differences of PG I, PG II, and PGR under different H. pylori detection methods. Regardless of UBT or histological biopsy, PG I and PG II levels were higher and PGR was lower in H. pylori-positive patients (P < 0.0001)

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Table 3: Differences in CAG between H. pylori positive and negative groups

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High serum testosterone is associated with a high risk of CAG

A total of 321 women underwent gastroscopy, UBT, H. pylori biopsy, and serum testosterone testing at the same time. Considering the influence of age and H. pylori infection, 169 H. pylori-negative (both by UBT and biopsy) women aged ≥40 years were finally analyzed. Serum testosterone levels were significantly higher in the CAG group than in the negative group, both in the endoscopic CAG and pathological CAG groups (P = 0.0030, 0.0333, 0.0076, respectively, [Figure 3]a), with no difference in age (P = 0.3487, 0.2738, 0.5075, respectively). Serum testosterone levels were useful in the diagnosis of CAG in women over 40 years of age (P = 0.0075; [Figure 3]b). The diagnosis of CAG had a high specificity (55.56%) and sensitivity (69.81%) when testosterone was > 28.84 ng/dL. According to the cut-off value (28.84 ng/dL), the positive rate of CAG in the high testosterone group was higher than that in the low testosterone group (P = 0.0019; [Table 1]). We further analyzed the expression levels of testosterone transport and metabolism related genes in 6 CAG gastric mucosa and 12 normal gastric mucosa (GSE27411), and found higher expression of SHBG and HSD17B2 and lower expression of GNRH1 in CAG mucosa, with a statistically significant difference (P = 0.0071, 0.0010, 0.0180, respectively; [Figure 3]c).
Figure 3: Differences in the expression of serum testosterone and related proteins and the ROC curve of serum testosterone. (a) Among 169 women aged ≥40 years with negative 13C UBT and H. pylori biopsy, serum testosterone levels were significantly higher in the CAG patients than in the negative group, including the endoscopic CAG and pathological CAG groups (P = 0.0030, 0.0333, 0.0076, respectively). (b) The ROC curve showed that high serum testosterone level was diagnostic of CAG in women over 40 years of age. (c) Expression of SHBG, HSD17B2 and GNRH1 in CAG patients. The CAG dataset was obtained from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/). Differences in the expression of SHBG, HSD17B2, and GNRH1 in CAG mucosa and normal gastric mucosa were analyzed, respectively

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   Discussion Top

Accurate pathological diagnosis of CAG requires specialized endoscopists and pathologists, but even then, false negative diagnoses can occur. To improve the positivity rate, multiple random biopsies during one single gastroscopy are often the first choice of endoscopists. To avoid the risks of biopsies, the endoscopic classification of Kimura–Takemoto is widely used clinically as a diagnostic criterion for CAG in Asia.[15] Although both endoscopists and pathologists in this study were professionally trained and were from a large clinical center in China, there were significant differences between the endoscopic diagnosis of CAG and the pathological biopsy-based diagnosis of CAG. Therefore, effective and reliable non-invasive screening methods are important to improve the accuracy of CAG diagnosis.

Theoretically, both serum PG I and PG II are increased in gastritis, but both decrease as gastric mucosal atrophy progresses. Usually, the decrease in PG I is more pronounced, leading to a decrease in PGR.[16] Therefore, the decrease in PG I and PGR contributes to the identification of CAG.[17] In this study, PG changes were more pronounced in patients with endoscopic CAG than in the pathological CAG group, which may be related to the fact that endoscopically observable CAG tends to have more severe atrophy. In addition, patients with glandular atrophy in biopsies had more pronounced PG changes relative to those with IM only, suggesting that IM may have less effect on gastric secretion function, but more data are needed to prove this concept.

When atrophy is combined with gastritis, changes of PG I may be of lower magnitude than of PG II. In this study, serum PG II and PGR in CAG patients were significantly altered and had a higher diagnostic value for CAG, which was different from the results of some studies in Western countries.[18] This may be related to the high incidence of H. pylori infection and superficial gastritis in China. A Korean study showed that increased serum pepsinogen II concentration correlates well with active H. pylori infection.[19] High level of PG II after H. pylori eradication was a marker of the presence of atrophic corpus gastritis.[20] In this study, a new screening criterion based on PG II and PGR improved the positive rate of CAG, implying that the value of PG II and PGR should be noteworthy for CAG diagnosis.

Bacterial culture from the gastric biopsy is the gold standard technique for H. pylori infection.[21] However, some patients with focal infections may have false negative results. UBT is a common non-invasive screening method for H. pylori infection.[22] Although UBT may also give false negatives, it is still considered the most useful non-invasive test because it is rapid, inexpensive, and widely available.[10],[23]

In this study, the positive results of H. pylori infection by UBT and biopsy partially overlapped but were not equivalent. Based on the higher positive rate for UBT, we recommend UBT as the preferred screening strategy for H. pylori. Especially for CAG patients, UBT testing is still necessary even if the biopsy result is negative. Since eradication of H. pylori is beneficial to the treatment of CAG and prevention of GC,[24] it is necessary to perform multiple UBT tests in CAG patients after anti-H. pylori treatment, to avoid false negatives.

In this study, gastric mucosal secretory function was significantly affected in H. pylori-positive patients, and the CAG positivity rate was significantly higher, especially in patients who tested positive for H. pylori by UBT. Therefore, we suggest that patients with positive UBT results and abnormal serum PG (PG II >11.05 μg/L and PGR <3.75) should be considered as high risk for CAG. For these patients, biopsy can be performed only at the suspected cancerous site instead of the traditional multi-point biopsy and H. pylori biopsy, to avoid unnecessary damage to the gastric mucosa from biopsy at gastroscopic follow-up.

Gender differences in the incidence of gastric cancer may be related to sex steroid hormones.[13],[14] Camargo et al.[25] found that exposure to estrogen decreases the risk of GC. Epidemiological data from a sizable prospective study showed a link between the incidence of GC and frontal baldness (androgenic alopecia).[26] As a precancerous state of GC, we found that women aged ≥40 years with CAG have higher serum testosterone. The relationship between testosterone and CAG is unclear, but an experimental model in rats documented that testosterone delays the healing of gastric ulcer potentially through a rise in systemic levels of pro-inflammatory cytokines and an increase in gastric acid secretion.[27]

Testosterone is transported in the blood by SHBG, which is often used to estimate the amounts of testosterone in the blood.[28] HSD17B2 catalyzes the oxidation of testosterone to androstenedione with lower binding affinity,[29] which is thought to play a protective role against sex hormone overload states.[30] GNRH1, a tropic peptide hormone synthesized and released by GNRH neurons in the hypothalamus, promotes testosterone secretion.[31] We found that SHBG was higher in the gastric mucosa of CAG patients, which suggests that CAG patients may suffer from higher serum testosterone levels. Also, CAG patients had higher HSD17B2 expression and lower GNRH1 expression, which may be related to the negative feedback regulation of androgen overload status.

More molecular biological studies about testosterone and CAG need to be further conducted to arrive at an affirmative conclusion. In addition, as a single-center study, all above results need to be verified by more data from other centers. In further research, we intend to include more non-invasive indicators and to differentiate between H. pylori-associated atrophic gastritis and autoimmune gastritis in terms of non-invasive screening. Meanwhile, as a one-time cross-sectional study, longitudinal data will be collected in further studies.

The aim of this study was to improve the diagnostic accuracy of CAG through non-invasive testing. Endoscopic diagnosis of CAG and biopsy-based diagnosis of CAG are very different, and both may have false negatives. For the diagnosis of CAG, it is important to refer not only to endoscopic evaluation combined with biopsy, but also to other CAG-related indicators. The screening value of the combination of PG II and PGR is of more concern than that of PG I. At the same time, UBT should be the preferred and necessary screening strategy for H. pylori due to its high positivity rate. Patients with positive UBT results and serum PG suggesting impaired gastric mucosal secretion, should be followed up with gastroscopy as a high-risk group for CAG. For these patients, the interval of gastroscopy can be appropriately shortened to improve the detection rate of early GC. Considering the significant effect of H. pylori on CAG, UBT should be tested several times after anti-H. pylori treatment. In addition, high serum testosterone levels and corresponding sex hormone changes may be associated with CAG and may be a high-risk factor requiring gastroscopy.

Financial support and sponsorship

Supported by the National Natural Science Foundation of China (No. 81773096 and 82072650) and Key Research and Development Program of Zhejiang Province (No. 2018C03085 and 2021C03121).

Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Wei-Lin Wang,
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, Zhejiang - 310009
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/sjg.sjg_383_22


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]


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