Pepsinogens to Distinguish Patients With Gastric Intestinal Metaplasia and Helicobacter pylori Infection Among Populations at Risk for Gastric Cancer

Valli De Re, Enrico Orzes, Vincenzo Canzonieri, Stefania Maiero, Mara Fornasarig, Lara Alessandrini, Silvia Cervo, Agostino Steffan, Giorgio Zanette, Cinzia Mazzon, Paolo De Paoli, Renato Cannizzaro, Valli De Re, Enrico Orzes, Vincenzo Canzonieri, Stefania Maiero, Mara Fornasarig, Lara Alessandrini, Silvia Cervo, Agostino Steffan, Giorgio Zanette, Cinzia Mazzon, Paolo De Paoli, Renato Cannizzaro

Abstract

Objectives: The objectives of this study were to investigate the serum pepsinogen test for the prediction of OLGIM (Operative Link on Gastric Intestinal Metaplasia Assessment) stages in first-degree relatives (FDR-GC) of patients with gastric cancer (GC) and autoimmune chronic atrophic gastritis (ACAG).

Methods: In 67 consecutive patients with ACAG, 82 FDR-GC, and 53 controls (CTRL) without gastric disease (confirmed by biopsy), serum levels of pepsinogen 1 (PG1), pepsinogen 2 (PG2), G17, and the PG1/2 ratio were assessed by enzyme-linked immunosorbent assay kit. All ACAG patients had positive antiparietal cell antibody levels, estimated by indirect immunofluorescence. Biopsies taken in duplicate from the antrum, corpus, and fundus were stained with Giemsa for Helicobacter pylori detection. Endoscopic detection of metaplasia was confirmed by histological diagnosis. Histological classification of OLGIM stages was applied by using the criteria of severity and topography of intestinal metaplasia (IM).

Results: The highest discrimination capacity for distinguishing ACAG from other groups of patients was the gastrin G17 test. The lowest mean for PG1 and PG2 serum levels was found in ACAG. In multivariate analysis by age, PG1 and PG1/PG2 were independent prognostic factors for metaplasia, and PG2 also for the presence of a histological H. pylori infection. The serum PG1 level was significantly lower in individuals with IM at OLGIM stage >2 than in those with IM at OLGIM stage <2, resulting in a useful method for the prediction of OLGIM stage. With the inclusion of patient age at diagnosis in the prediction of ≥2 vs. 0-1 OLGIM stages, the receiver operating characteristic (ROC) curve at 47.9 ng/ml PG1 level reached a significant area under the curve (AUC) value (0.978, P<0.001). We also observed a slight difference in PG2 serum levels between histological H. pylori-positive and H. pylori-negative subjects (ROC AUC: 0.599).

Conclusions: This study demonstrated an important increase in gastrin G17 serum level in autoimmune gastritis. PG1 serum level corrected by patient age can be used in the management of patients at risk for GC with a high predicted probability of having an OLGIM stage ≥2. Using a cutoff of 47.9 ng/ml, PG1 testing in FDR-GC and ACAG patients had a sensitivity of 95.83% and a specificity of 93.37. Although these results could be validated in a prospective study, the known importance of higher OLGIM stages in increasing the risk of GC development supports the rationale of proposing PG1 algorithm as a diagnostic tool for the selection of high-risk FDR-GC and ACAG patients at high-risk stages for subsequent detailed endoscopic examination to detect dysplasia and asymptomatic GC. In addition, serum PG1 and PG2 levels could stratify patients based on both H. pylori infection and OLGIM risk in consideration of the increased acknowledge regarding the role of H. pylori in the progression of gastritis to GC.

Conflict of interest statement

Guarantor of the article: Renato Cannizzaro, MD.

Specific author contributions: Valli De Re analyzed and interpreted data and wrote the paper; Enrico Orzes analyzed and interpreted data; Vincenzo Canzonieri and Paolo De Paoli planned the study; Stefania Maiero, Mara Fornasarig, Silvia Cervo, Agostino Steffan, Giorgio Zanette, and Cinzia Mazzon conducted the study; Lara Alessandrini conducted the study and analyzed and interpreted data; Renato Cannizzaro planned and conducted the study, and analyzed and interpreted data. All authors have approved the final draft submitted.

Financial support: This study was funded by an CRO intramural 5x000 research grant. The study is independent of the funding.

Potential competing interests: None.

Figures

Figure 1
Figure 1
Box-and-whisker plots of age- and gender-adjusted means of pepsinogens 1 and 2 (PG1 and PG2), PG1/PG2 ratio, and gastrin G17 for comparison of patients and control groups. Mean and s.e. are reported in more detail in the graph below. Median PG1 level and PG1/PG2 ratio were found significantly decreased in individuals at risk for GC (i.e., ACAG and FDR-GC) compared with controls. Gastrin G17 showed the highest mean level associated with ACAG status. ACAG, autoimmune chronic atrophic gastritis; CTRL, general population; FDR-GC, first-degree relatives of patient with gastric cancer. Pc: Bonferroni corrected value of analysis of variance (ANOVA) for age and gender.
Figure 2
Figure 2
Box plot data of PG1 serum level based on OLGIM stages (a). Area under the PG1 serum value ROC curve (AUC) for the diagnosis of OLGIM stage >2 (b). Box plot analysis of gastritis by using the OLGIM stage system with PG1 level indicated a decrease in the PG1 level that was associated with worsening of the OLGIM stage. ROC curve analysis of PG1 level corrected for age of patients at diagnosis predicts the presence of an OLGIM stage ≥2. AUC, area under the ROC curve; OLGIM, Operative Link on Gastric Intestinal Metaplasia Assessment; PG1, pepsinogen 1; ROC, receiver operating characteristics.
Figure 3
Figure 3
ROC curve analysis of PG2 levels for discriminating individuals with Helicobacter pylori (HP) infection. ROC curve analysis of PG2 levels discriminates individuals with H. pylori infection from those without a proven histological presence of the bacteria. PG2 values were corrected for age and gender covariables. AUC, area under the ROC curve; PG2, pepsinogen 2; ROC, receiver operating characteristic.
Figure 4
Figure 4
Predictive risk stratification model for advanced OLGIM stages. A combination of gastrin G17 and PG1 serum levels was used to define a model for predicting OLGIM stage ≥2. The number of patients resulting in each category is indicated (N). **Linear logistic regression was used to assess the impact of age on PG1 serum level. To this aim we select the optimal G17 cutoff value obtained by ROC curves; the obtained equation was PG1=23 −0.01006 × for G17 value >66 pmol/l and PG1=−12+1.6636 × for G17 <66 pmol/l, respectively. Risk stratification based on these factors stratified patients with a good performance: 24 of the 202 cases who were tested by pathologists showed an OLGIM stage ≥2 (18 with stage 2 and 6 with stage 3); 22 cases (16 cases with stage 2 and all of the 6 cases with stage 3) were correctly predicted using the proposed model. ACAG, autoimmune chronic atrophic gastritis; OLGIM, Operative Link on Gastric Intestinal Metaplasia Assessment; PG1, pepsinogen 1.
Figure 5
Figure 5
Images of representative OLGIM score 1 and score 3 diagnostic histological biopsies. In the gastric mucosa, atrophy is defined as the “loss of appropriate glands.” Intestinal metaplasia (IM) is defined as replacement of gastric glands by glands with a different (intestinal) commitment. (a) Scattered glands showing that IM changes (OLGIM score 1) are evident in this antrum biopsy (active chronic gastritis is also present throughout the biopsy) (insert: higher magnification image of metaplastic glands showing goblet cells). (b) Diffuse metaplastic changes involving nearly 80% of all gastric glands could be identified in this antrum biopsy (OLGIM score 3). OLGIM, Operative Link on Gastric Intestinal Metaplasia Assessment.

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