Abstract
Background/Aims
The aim of this study was to evaluate the efficacy of serum pepsinogen (sPG) tests for gastritis, gastric adenoma (GA), and gastric cancer (GC) using the enzyme-linked immunosorbent assay-based GastroPanel kit and to investigate the correlation between GastroPanel- and Latex-enhanced Turbidimetric Immunoassay (L-TIA)-derived sPG results.
Methods
sPG I and II levels and PG I/II ratios were measured using both kits in 2,204 participants, including 1,109 controls, 316 GA, and 779 GC patients.
Results
The GastroPanel- and L-TIA-derived sPG results showed high concordance. An sPG I concentration of 70 ng/mL and a PG I/II ratio of 3 measured with the L-TIA kit corresponded to 100 ng/mL and 5.3 with the GastroPanel kit. sPG I decreased in the GA and GC groups, whereas sPG II was lower in the GA group, but higher in the GC group than that in control group. The PG I/II ratios significantly decreased in the GA and GC groups, especially for the intestinal type. The sensitivity and specificity of PG I/II ratio ≤5.3 using the GastroPanel kit for the detection of GA or GC were 51%–59% and 61%–66%, respectively, which were slightly higher than 51%–58% and 58%–63% using the L-TIA kit. The group with a PG I/II ratio ≤5.3 and Helicobacter pylori-negative status had the highest risk with an adjusted odds ratio of 3.36 for GA and 2.25 for GC, with more prominent increase in diffuse-type compared to intestinal-type.
Conclusions
The GastroPanel kit showed non-inferiority compared to the L-TIA kit.
Keywords: Pepsinogens, Helicobacter pylori, Stomach neoplasms, Early detection of cancer
INTRODUCTION
The risk of developing gastric cancer (GC) is high in East Asia, including Korea. Therefore, efforts to identify high-risk patients and diagnose GC early are ongoing.1 Although a health checkup program, including endoscopy, to detect GC has been implemented biennially by the Korean government for patients aged >40 years since 2001,2 there is still a need for cost-effective and less invasive screening modalities.
Serum pepsinogen (sPG) is a marker of gastric mucosal status, including mucosal atrophy, and is useful for identifying patients at a high risk of GC.1,3,4 That is, a low sPG I level with a low PG I/II ratio is associated with severe gastric atrophy, and is frequently found in GC,1,3,4 as PG I is produced primarily by the gastric fundic mucosa, whereas PG II is secreted by the fundic, antral, and duodenal mucosa.3 The measurement of sPG I and II levels has been studied since the 1980s,5 and some studies have been conducted in Japan, one of the countries with a high prevalence of GC. Although the 2014 edition of the Japanese Guidelines for Gastric Cancer Screening6 recommended that endoscopic screening be conducted in individuals aged ≥50 years every 2 years, the reported rate of endoscopy performed in 2016 was only 64%. A shortage of endoscopists/insufficient endoscopy processing capabilities, impossibility of creating a quality control system, and budget constraints were suggested as possible reasons.7
Against this background, there is high interest in studies on noninvasive GC screening to select patients who require endoscopy in Japan.8 For example, the ABC classification is a combined assay for serum anti-Helicobacter pylori antibody and sPG levels9,10 that classifies individuals who tested negative for both anti-H. pylori immunoglobulin G (HpIgG) antibody and sPG as group A; those who tested positive for HpIgG and negative for sPG as group B; those who tested positive for both HpIgG and sPG as group C; and those who tested negative for HpIgG and positive for sPG as group D. This method is based on two well-known risk factors for GC and H. pylori infections.11 The detection rate of H. pylori decreases in the presence of mucosal atrophy and metaplasia, especially at higher rates of atrophic gastritis (AG) and intestinal metaplasia (IM).12 The respective risks of developing GC among the groups were significantly different, and an elevated GC risk in groups C and D was observed in a previous meta-analysis.13 Therefore, serological testing is recommended as a noninvasive and straightforward method of mass screening for the detection of H. pylori infection14 and GC6 in Japan.
In Korea, with a higher prevalence of H. pylori and risk of GC similar to those in Japan, the circumstances are changing. The prevalence of H. pylori in South Korea has decreased in recent years,15 and the age-standardized incidence rate (per 100,000) significantly decreased between 2011 (43.0%) and 2019 (29.6%).16 Medical costs are rising due to rapid aging; therefore, it may be cost-effective when considering selective endoscopy for high-risk patients.17 Another problem is that adults aged <40 years are not included in the Korean National Health Check-up Program, mainly in terms of cost-benefits. Recently, GC was reported in young adults.18 In particular, GC commonly occurs in females than males aged <40 years, and the proportion of diffuse-type GC showing rapid progression and poor prognosis is high in young females,19 raising the need for targeted screening of this group. Given this situation, an efficient and effective screening test that can supplement the current national health checkup program based on endoscopy is required in Korea.
Previous studies have investigated the roles of sPG I, sPG II, and PG I/II ratio along with HpIgG and reported their effectiveness in diagnosing AG/IM, gastric adenoma (GA), and GC.4,20-22 A Korean study showed that the highest risk of GC was H. pylori positive, and the PG I/II ratio was <3.0, indicating that the ABC method in Japan does not fit Koreans.4 Furthermore, most studies measured sPG I and II using a Latex-enhanced Turbidimetric Immunoassay (L-TIA) kit and reported that a PG I/II ratio <3.0 was found to be a reliable marker for the detection of GA or GC.4 Meanwhile, studies measuring sPG levels using enzyme-linked immunosorbent assay (ELISA) have been conducted in Western countries.23,24 Recently, Asian25 and Korean26,27 studies have reported the diagnostic reliability of this kit for detecting atrophy or H. pylori infection. However, to date, there have been no large-scale studies in Koreans, and no study has investigated the superiority of this screening. Additionally, a concordance study between these two kits, L-TIA and GastroPanel, has not yet been performed.
Therefore, this study aimed to evaluate the efficacy of sPG testing for AG, IM, GA, and GC using the GastroPanel kit. Additionally, these results were compared with those of an existing L-TIA kit to determine the correlation between the two kits. Another aim was to investigate whether the ABC method was suitable for the Koreans in this cohort.
MATERIALS AND METHODS
1. Patients
A total of 2,204 patients who visited the Seoul National University Bundang Hospital for upper endoscopy between June 2003 and May 2023 were prospectively enrolled. The study participants were classified into three groups, according to their endoscopic and histological diagnoses: control, GA, and GC. Participants whose endoscopic findings were normal or who were diagnosed with non-dysplastic benign lesions, such as gastritis or peptic ulcer diseases, were classified as the control group. The medical histories of the participants were reviewed using electronic medical records, and those with systemic diseases requiring continuous medication were excluded. The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-2403-889-303), and written informed consent was obtained from all the participants (B-0602-030-001, B-0903-071-001, B-1012-117-013, and B-1103-123-004).
2. Endoscopy, histology, and H. pylori tests
An existing study by our team was referred to for the acquisition of blood and tissue samples and measurement methods.4,20 First, HpIgG levels were determined qualitatively using an ELISA (Genedia H. pylori ELISA; Green Cross Medical Science Corp., Seoul, Korea; and GastroPanel ELISA; Biohit Oyj, Helsinki, Finland). A cutoff optical density of 450 nm was used for HpIgG, according to the manufacturer’s instructions. Additionally, history of H. pylori eradication was investigated through medical history taking. Those who were positive for any of these tests or had a history of H. pylori eradication were classified as a positive group, and those who did not correspond to any of these were classified as a negative group.
Additionally, three diagnostic methods were performed to confirm H. pylori infection using 10 biopsy specimens were obtained from the antrum and the corpus during upper endoscopy. Of the 10, four specimens, which were fixed in 10% neutral-buffered formalin and paraffin-embedded, were stained with modified Giemsa, hematoxylin and eosin to evaluate the presence of H. pylori and the stage of operating link for gastritis assessment and operating link for gastric IM. The histological features of the gastric mucosa were recorded using the updated Sydney system scores (0=none, 1=slight, 2=moderate, and 3=marked). All biopsies were examined independently by two experienced pathologists who were blinded to the patient details. In the event of a disagreement, biopsies were re-examined by both pathologists until a consensus was reached. The other four specimens were cultured for H. pylori at 37°C under microaerobic conditions for 3 to 5 days. The last two specimens were subjected to a rapid urease test (CLOtest; Delta West, Bentley, WA, Australia).
3. Serologic testing for pepsinogen
Fasting serum samples were collected from all the participants upon entry into the study. The samples were centrifuged immediately at 4°C and stored at −70°C until required. sPG I and II levels were measured using L-TIA (HBi Corp, Seoul, Korea, imported from Shima Laboratories, Tokyo, Japan) and GastroPanel ELISA (GastroPanel ELISA; Biohit Oyj) kits, respectively, and the sPG I to sPG II ratios (PG I/II) were calculated. The cutoff values for measurements using the L-TIA kit were sPG I ≤70 ng/mL and a PG I/II ratio ≤3.28 The cutoff values for measurements using GastroPanel kit were sPG I <30 μg/L or sPG I <50 μg/L with PG I/II ratio <3 using GastroSoft algorithm,29 but the corresponding cutoff values for the GastroPanel kit were calculated using receiver operating characteristic (ROC) curve analysis.
4. Outcome assessment and statistical analysis
The primary objective of this study was to evaluate the sensitivity and specificity of sPG testing for AG, IM, GA, and GC using the GastroPanel kit. The secondary objective was to compare the diagnostic accuracy of the GastroPanel kit with that of the existing L-TIA kit to determine the correlation between them.
All statistical analyses were performed using SPSS software (version 25.0; IBM Corp., Armonk, NY, USA). The Student t-test or a paired t-test was used to compare the two groups, and analysis of variance was used to compare multiple groups. Correlations between the histological and serological features and between the two kits were analyzed using the Spearman correlation test. The sensitivities and specificities of the two kits were calculated and compared using ROC curves. The effects of H. pylori infection and PG I/II ratio on the risk of GC were calculated using multivariate logistic regression, and expressed as odds ratio (ORs) and 95% confidence interval (CI). Statistical significance was set at p-values of <0.05.
RESULTS
1. Patient characteristics
Baseline characteristics of the enrolled patients are shown in Table 1. There were 1,250 (56.7%) males and 954 (43.3%) females, with a mean age of 57.4 years. The study participants included 1,109 (50.3) normal controls without dysplastic lesions, and 316 (14.3%) and 779 (35.3%) with histologically confirmed GA or GC, respectively. Among patients with cancer, 57.1% had intestinal-type cancer and 35.4% had diffuse-type cancer. A total of 81.2% of the participants were positive for H. pylori, as determined by a positive result on the urea breath test, rapid urease test, HpIgG, histology, culture, or a previous history of eradication treatment, while 18.8% tested negative on all methods (Supplementary Fig. 1).
Table 1.
Baseline Characteristics
| Characteristics | Total | Control | Gastric adenoma |
GC | p-value | Intestinal-type GC | Diffuse-type GC | Mixed-type GC or unknown | p-value |
|---|---|---|---|---|---|---|---|---|---|
| Number | 2,204 (100.0) | 1,109 (50.3) | 316 (14.3) | 779 (35.3) | 445 (57.1) | 276 (35.4) | 58 (7.5) | ||
| Sex | <0.001 | <0.001 | |||||||
| Male | 1,250 (56.7) | 513 (46.3) | 201 (63.6) | 536 (68.8) | 344 (77.3) | 154 (55.8) | 38 (65.5) | ||
| Female | 954 (43.3) | 596 (53.7) | 115 (36.4) | 243 (31.2) | 101 (22.7) | 122 (44.2) | 20 (34.5) | ||
| Age, mean±SD, yr | 57.4±12.8 | 53.7±13.2 | 62.6±9.7 | 60.6±11.8 | <0.001 | 63.5±9.8 | 55.7±13.2 | 61.7±10.6 | <0.001 |
| Age category | <0.001 | <0.001 | |||||||
| <40 yr | 212 (9.6) | 174 (15.7) | 4 (1.3) | 34 (4.4) | 3 (0.7) | 30 (10.9) | 1 (1.7) | ||
| 40–69 yr | 1,598 (72.5) | 818 (73.8) | 229 (72.5) | 551 (70.7) | 314 (70.6) | 195 (70.6) | 42 (72.4) | ||
| ≥70 yr | 394 (17.9) | 117 (10.5) | 83 (26.2) | 194 (24.9) | 128 (28.7) | 51 (18.5) | 15 (25.9) | ||
| Smoking | <0.001 | 0.010 | |||||||
| Never | 1,085 (49.6) | 656 (59.9) | 138 (43.8) | 291 (37.5) | 148 (33.4) | 123 (44.9) | 20 (34.6) | ||
| Ex | 430 (19.7) | 203 (18.5) | 61 (19.4) | 166 (21.4) | 93 (21.0) | 54 (19.7) | 19 (32.7) | ||
| Current | 671 (30.7) | 237 (21.6) | 116 (36.8) | 318 (41.1) | 202 (45.6) | 97 (35.4) | 19 (32.7) | ||
| Alcohol drinking | <0.001 | 0.003 | |||||||
| Never | 1,219 (55.8) | 673 (61.5) | 171 (54.3) | 375 (48.5) | 194 (43.9) | 150 (54.8) | 31 (54.4) | ||
| Ex | 704 (32.2) | 311 (28.4) | 113 (35.9) | 280 (36.2) | 168 (38.0) | 93 (33.9) | 19 (33.3) | ||
| Current | 260 (11.9) | 111 (10.1) | 31 (9.8) | 118 (15.3) | 80 (18.1) | 31 (11.3) | 7 (12.3) | ||
| Family history of GC | 0.007 | ||||||||
| No | 1,674 (76.5) | 810 (73.7) | 248 (78.5) | 616 (79.7) | 353 (79.5) | 218 (80.4) | 45 (77.6) | ||
| Yes | 514 (23.5) | 289 (26.3) | 68 (21.5) | 157 (20.3) | 91 (20.5) | 53 (19.6) | 13 (22.4) | ||
| HP status | <0.001 | <0.001 | |||||||
| Negative | 415 (18.8) | 256 (23.1) | 37 (11.7) | 122 (15.7) | 75 (16.9) | 30 (10.9) | 17 (29.3) | ||
| Positive | 1,789 (81.2) | 853 (76.9) | 279 (88.3) | 657 (84.3) | 370 (83.1) | 246 (89.1) | 41 (70.7) |
Data are presented as number (%) unless indicated otherwise.
GC, gastric cancer; HP, Helicobacter pylori.
In a comparison between each disease group, the normal control group had a significantly high proportion of females, while the adenoma and cancer groups had a high proportion of males. The mean age of the normal control group was the lowest, and that of the adenoma group was the highest. In the adenoma and cancer groups, the ratio of smoking and alcohol consumption (present or past) was higher than that in the normal control group, and the positive rate of H. pylori infection was also significantly higher. In the histological classification of the GC group, the proportion of males was high in the intestinal-type cancer group, whereas the proportion of females was higher in the diffuse-type cancer group. The mean age of patients in the diffuse-type cancer group was significantly lower than that of patients in the intestinal-type cancer group. The positive rate of H. pylori infection was higher in the diffuse-type cancer group than in the intestinal cancer group.
2. Correlations between GastroPanel and L-TIA kits
Correlations between GastroPanel and L-TIA kits were analyzed using Spearman’s correlation and linear regression analyses, and the results are presented in Table 2. sPG I measured using the GastroPanel and L-TIA kits were 86.26±78.38 and 65.63±119.08 ng/mL, respectively, and sPG II measured using the two kits were 14.58±12.08 and 22.48±25.59 ng/mL, respectively. In general, sPG I measured using the GastroPanel kit was higher than that measured using the L-TIA kit, whereas sPG II measured using the GastroPanel kit was lower than that measured using the L-TIA kit. As a result, the PG I/II ratios calculated using the two kits were 7.03±5.48 and 3.68±3.18, respectively, and the values measured using the GastroPanel kit showed higher results (Spearman’s rho was 0.830 for sPG I, 0.757 for sPG II, and 0.753 for PG I/II ratio) (Table 2). In general, sPG I and II levels and PG I/II ratios showed strong correlations between the two kits. Subgroup analysis according to the diagnosis also showed an evenly high concordance (Spearman’s rho was 0.799–0.842 for sPG I, 0.701–0.823 for sPG II, and 0.706–0.834 for the PG I/II ratio).
Table 2.
Comparison of GastroPanel and L-TIA
| Group | Mean±SD | Spearman’s rho | p-value | ||
|---|---|---|---|---|---|
| GastroPanel | L-TIA | ||||
| Total | sPG I, ng/mL | 86.26±78.38 | 65.63±119.08 | 0.830 | <0.001 |
| sPG II, ng/mL | 14.58±12.08 | 22.48±25.59 | 0.757 | <0.001 | |
| PG I/II ratio | 7.03±5.48 | 3.68±3.18 | 0.753 | <0.001 | |
| Control | sPG I, ng/mL | 79.38±52.78 | 56.11±33.93 | 0.842 | <0.001 |
| sPG II, ng/mL | 12.47±9.46 | 20.83±25.21 | 0.754 | <0.001 | |
| PG I/II ratio | 7.92±4.83 | 4.13±4.12 | 0.711 | <0.001 | |
| Gastric adenoma | sPG I, ng/mL | 60.91±49.42 | 48.51±40.25 | 0.858 | <0.001 |
| sPG II, ng/mL | 12.69±9.46 | 18.77±17.71 | 0.823 | <0.001 | |
| PG I/II ratio | 5.51±4.41 | 2.93±1.73 | 0.834 | <0.001 | |
| Gastric cancer | sPG I, ng/mL | 82.54±77.89 | 70.48±184.61 | 0.799 | <0.001 |
| sPG II, ng/mL | 15.49±12.55 | 25.11±28.20 | 0.721 | <0.001 | |
| PG I/II ratio | 6.29±5.96 | 3.26±3.06 | 0.733 | <0.001 | |
| Intestinal type | sPG I, ng/mL | 74.43±61.21 | 58.53±42.90 | 0.817 | <0.001 |
| sPG II, ng/mL | 14.17±10.91 | 22.21±22.57 | 0.701 | <0.001 | |
| PG I/II ratio | 5.96±3.49 | 3.23±2.44 | 0.750 | <0.001 | |
| Diffuse type | sPG I, ng/mL | 99.37±96.91 | 94.76±305.08 | 0.754 | <0.001 |
| sPG II, ng/mL | 18.10±14.10 | 30.69±33.84 | 0.707 | <0.001 | |
| PG I/II ratio | 6.82±8.41 | 3.36±4.05 | 0.706 | <0.001 | |
L-TIA, Latex-enhanced Turbidimetric Immunoassay; sPG, serum pepsinogen; PG I/I ratio, sPG I to sPG II ratio.
3. Comparisons of sPG levels in controls and patients with gastric dysplasia
The PG levels in the control, GA, and GC groups measured using the GastroPanel kit are presented in Fig. 1. Among the three groups, sPG I was highest in the control group and decreased in the GA and GC groups. There was no statistically significant difference in the PG I level of the total cancer group compared to that in the normal control group; however, a significant decrease in the intestinal-type cancer group compared to the diffuse-type cancer was observed in the subgroup analysis according to histologic types (Fig. 1A). In the case of sPG II, levels decreased in the adenoma group compared to the controls, though not significantly, whereas they increased in the cancer group. Classification according to histologic type showed that sPG II was significantly decreased in the intestinal-type cancer group compared to that in the diffuse-type cancer group (Fig. 1B). The PG I/II ratios were significantly lower in the GA and GC groups, especially the intestinal-type cancer group compared to that in the control group (Fig. 1C).
Fig. 1.
(A) sPG I, (B) sPG II, and (C) PG I/II ratio of participants according to histologic diagnosis. sPG, serum pepsinogen.
4. Sensitivities and specificities of sPG levels for the detection of GA or GC
The ROC curves and quartiles were calculated by measuring the sPG I and II using each of the two kits in the sample of the same participants. This was to determine the optimal cutoff value of the GastroPanel kit corresponding to PG I of ≤70 ng/mL and PG I/II ratio ≤3 for the L-TIA kit (Fig. 2). In our calculations, PG I value of 70 ng/mL for the L-TIA kit corresponded to 100 ng/mL for the GastroPanel, and PG I/II ratio of 3 corresponded to 5.3.
Fig. 2.
Receiver operating characteristic curve of sPG levels for diagnosing GA with (A-C) GastroPanel and (D-F) L-TIA. sPG, serum pepsinogen; L-TIA, Latex-enhanced Turbidimetric Immunoassay; ROC, receiver operating characteristic; AUC, area under the curve.
The diagnostic sensitivity and specificity of histological AG, IM, GA, and GC were calculated using these levels of 100 ng/mL for PG I and 5.0 PG I/II ratio (Table 3). In terms of diagnosing histological AG and IM in the antrum and corpus, the sensitivity of sPG I was relatively high, whereas its specificity was relatively low. That is, the sensitivity of sPG I ≤100 ng/mL was found to be 75%–86%, with a specificity of 32%–35% for the histologic atrophy and metaplasia in the antrum and corpus. However, the sensitivity and specificity of PG I/II ratio of ≤5.3 were 50%–69% and 70%–74%, respectively, and the specificity was relatively higher than that of PG I. In case of GA, the sensitivity and specificity of sPG I ≤100 ng/mL were found to be 85% and 31%, while those of PG I/II ratio of ≤5.3 were 59% and 63%, respectively. In case of GC, the sensitivity and specificity of sPG I ≤100 ng/mL were found to be 72% and 29%, while those of PG I/II ratio ≤5.3 were 51% and 66%, respectively. The sensitivity and specificity of the diagnosis tended to be lower than those of adenoma diagnosis. The sensitivity and specificity in the intestinal-type cancer group were higher than those in the diffuse-type group (Table 3).
Table 3.
The Sensitivity and Specificity of the sPG Test for the Detection of Histologic Gastritis, Adenoma, and Cancer
| Group | GastroPanel | L-TIA | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| sPG I ≤100 ng/mL | PG I/II ratio ≤5.3 | sPG I ≤70 ng/mL | PG I/II ratio ≤3.0 | |||||||||
| Sensitivity, % | Specificity, % | Sensitivity, % | Specificity, % | Sensitivity, % | Specificity, % | Sensitivity, % | Specificity, % | |||||
| AG | Antrum | 75 | 32 | 50 | 71 | 71 | 32 | 50 | 63 | |||
| Corpus | 84 | 35 | 69 | 74 | 83 | 35 | 69 | 67 | ||||
| IM | Antrum | 76 | 34 | 53 | 71 | 73 | 34 | 51 | 64 | |||
| Corpus | 86 | 35 | 65 | 70 | 83 | 36 | 65 | 66 | ||||
| Adenoma | 85 | 31 | 59 | 63 | 80 | 31 | 58 | 59 | ||||
| Cancer | Total | 72 | 29 | 51 | 66 | 68 | 29 | 54 | 63 | |||
| Intestinal | 75 | 29 | 51 | 62 | 71 | 30 | 54 | 60 | ||||
| Diffuse | 65 | 27 | 51 | 61 | 60 | 28 | 51 | 58 | ||||
sPG, serum pepsinogen; PG I/I ratio, sPG I to sPG II ratio; L-TIA, Latex-enhanced Turbidimetric Immunoassay; AG, atrophic gastritis; IM, intestinal metaplasia.
Comparison of the GastroPanel and L-TIA kits showed that the sum of the sensitivity and specificity calculated using GastroPanel was slightly higher for the diagnosis of AG, IM, and GA than that calculated using L-TIA, although there was no significant difference in the diagnosis of GC.
5. Proportion with GA and GC according to H. pylori status and PG I/II Ratio
As mentioned above, individuals who tested positive on any of the following—urea breath test, rapid urease test, histology, culture, or HpIgG—or had a history of H. pylori eradication were classified as the positive group, and those who did not correspond to any of these were classified as the negative group. When this method was applied, 1,789 (81.2%) of the enrolled participants were positive and 415 (18.8%) were negative for H. pylori (Supplementary Fig. 1). The study participants were classified into four groups, according to their H. pylori infection status and PG I/II ratio.
There were differences in the sPG levels among the groups. sPG I was the lowest in the PG I/II ratio ≤5.3 and H. pylori-negative group, and highest in PG I/II ratio >5.3 and H. pylori-positive group, although sPG II was lowest in the PG I/II ratio >5.3 and H. pylori-negative group and highest in the PG I/II ratio ≤5.3 and H. pylori-positive group. Consequently, PG I/II ratio was lowest in the PG I/II ratio ≤5.3 and H. pylori-negative group, and highest in the PG I/II ratio >5.3 and H. pylori-negative group (Table 4).
Table 4.
Serum Levels of Pepsinogen According to Helicobacter pylori Status and Pepsinogen I/II Ratio
| HP negative PG I/II ratio >5.3 (n=357) |
HP negative PG I/II ratio ≤5.3 (n=58) |
HP positive PG I/II ratio >5.3 (n=961) |
HP positive PG I/II ratio ≤5.3 (n=826) |
p-value | |
|---|---|---|---|---|---|
| sPG I, ng/mL | 84.70±61.72 | 31.90±40.05 | 105.36±96.61 | 68.72±53.20 | <0.001 |
| sPG II, ng/mL | 8.67±6.42 | 10.78±9.16 | 13.62±12.97 | 18.56±11.70 | <0.001 |
| PG I/II ratio | 10.40±4.14 | 2.54±1.43 | 9.06±6.41 | 3.53±1.22 | <0.001 |
Data are presented as mean±SD.
HP, Helicobacter pylori; sPG, serum pepsinogen; PG I/I ratio, sPG I to sPG II ratio.
The risk of GA and GC in each group was calculated and compared to the PG I/II ratio >5.3 in the H. pylori-negative group, and the risk adjusted for confounding factors, including sex, age, smoking, alcohol consumption, and family history of GC was additionally calculated. The risk of having GA was highest in the PG I/II ratio ≤5.3 and H. pylori-negative group (OR, 3.62 [95% CI, 2.32 to 5.67], p<0.001; adjusted OR [aOR], 3.36 [95% CI, 2.14 to 5.29], p<0.001), was second highest in the PG I/II ratio ≤5.3 and H. pylori-positive group (OR, 2.06 [95% CI, 1.59 to 2.68], p<0.001; aOR, 1.81 [95% CI, 1.38 to 2.37], p<0.001), and was relatively low in PG I/II ratio >5.3 and H. pylori-positive group (OR, 0.90 [95% CI, 0.48 to 1.71], p=0.756; aOR, 1.11 [95% CI, 0.58 to 2.14], p=0.748). The risk of having GC was also highest in the PG I/II ratio ≤5.3 and H. pylori-negative group (OR, 2.37 [95%, 1.80 to 3.13], p<0.001; aOR, 2.25 [95% CI, 1.68 to 3.00], p<0.001), was second highest in the PG I/II ratio ≤5.3 and H. pylori-positive group (OR, 1.80 [95% CI, 1.48 to 2.18], p<0.001; aOR, 1.65 [95% CI, 1.35 to 2.03], p<0.001), and was relatively low in the PG I/II ratio >5.3 and H. pylori-positive group (OR, 0.60 [95% CI, 0.35 to 1.02], p=0.060; aOR, 0.72 [95% CI, 0.41 to 1.26], p=0.243). In the histological classification of GC, the risk of having intestinal- and diffuse-type GC was also highest in the PG I/II ratio ≤5.3 and H. pylori-negative group (for intestinal-type GC: OR, 1.74 [95% CI, 1.26 to 2.40], p=0.001; aOR, 1.54 [95% CI, 1.09 to 2.17], p=0.014, and for diffuse-type GC: OR, 2.92 [95% CI, 1.83 to 4.67], p<0.001; aOR, 3.41 [95% CI, 2.09 to 5.55], p<0.001) (Table 5).
Table 5.
Odd Ratios for Gastric Cancer and Adenoma According to Helicobacter pylori Status and Pepsinogen I/II Ratio
| Group | HP status | PG I/II ratio | No. | OR (95% CI) | p-value | aOR* | p-value |
|---|---|---|---|---|---|---|---|
| Gastric adenoma | Negative | >5.3 | 24/357 | Ref | Ref | ||
| Negative | ≤5.3 | 13/58 | 3.62 (2.32–5.67) | <0.001 | 3.36 (2.14–5.29) | <0.001 | |
| Positive | >5.3 | 108/961 | 0.90 (0.48–1.71) | 0.756 | 1.11 (0.58–2.14) | 0.748 | |
| Positive | ≤5.3 | 171/826 | 2.06 (1.59–2.68) | <0.001 | 1.81 (1.38–2.37) | <0.001 | |
| GC | Negative | >5.3 | 89/357 | Ref | |||
| Negative | ≤5.3 | 33/58 | 2.37 (1.80–3.13) | <0.001 | 2.25 (1.68–3.00) | <0.001 | |
| Positive | >5.3 | 293/961 | 0.60 (0.35–1.02) | 0.060 | 0.72 (0.41–1.26) | 0.243 | |
| Positive | ≤5.3 | 364/826 | 1.80 (1.48–2.18) | <0.001 | 1.65 (1.35–2.03) | <0.001 | |
| Intestinal-type GC | Negative | >5.3 | 58/357 | Ref | Ref | ||
| Negative | ≤5.3 | 17/58 | 1.74 (1.26–2.40) | 0.001 | 1.54 (1.09–2.17) | 0.014 | |
| Positive | >5.3 | 162/961 | 0.81 (0.45–1.46) | 0.486 | 1.05 (0.56–1.96) | 0.884 | |
| Positive | ≤5.3 | 208/826 | 1.66 (1.32–2.09) | <0.001 | 1.39 (1.09–1.78) | 0.009 | |
| Diffuse-type GC | Negative | >5.3 | 22/357 | Ref | Ref | ||
| Negative | ≤5.3 | 8/58 | 2.92 (1.83–4.67) | <0.001 | 3.41 (2.09–5.55) | <0.001 | |
| Positive | >5.3 | 113/961 | 1.20 (0.56–2.59) | 0.643 | 1.08 (0.50–2.36) | 0.844 | |
| Positive | ≤5.3 | 133/826 | 1.44 (1.10–1.89) | 0.008 | 1.56 (1.18–2.07) | 0.002 |
HP, Helicobacter pylori; PG I/I ratio, serum pepsinogen (sPG) I to sPG II ratio; OR, odds ratio; CI, confidence interval; aOR, adjusted OR; GC, gastric cancer; Ref, reference.
*Adjusted for sex, age, smoking, alcohol drinking, and family history of GC
The results of additional analyses using a different definition of H. pylori infection also showed similar results. First, when H. pylori infection was defined as positive if at least one of the following tests—urea breath test, rapid urease test, histology, or culture—yielded a positive result, the risk of having GA and GC was highest in the PG I/II ratio ≤5.3 and H. pylori-negative group (for GA: OR, 2.61 [95% CI, 1.74 to 3.93], p<0.001; aOR, 2.11 [95% CI, 1.39 to 3.22], p=0.001, and for GC: OR, 2.95 [95% CI, 2.12 to 4.11], p<0.001; aOR, 2.28 [95% CI, 1.61 to 3.23], p<0.001) (Supplementary Tables 1, 2). Second, when H. pylori infection was defined as positive if either at least one of the aforementioned four tests or HpIgG was positive, the risk of having GA and GC was generally highest in the PG I/II ratio ≤5.3 and H. pylori-negative group (for GA: OR, 2.28 [95% CI, 1.24 to 4.19], p=0.008; aOR, 1.81 [95% CI, 0.97 to 3.38], p=0.062, and for GC: OR, 3.33 [95% CI, 2.06 to 5.40], p<0.001; aOR, 2.73 [95% CI, 1.65 to 4.53], p<0.001) (Supplementary Tables 3, 4).
In addition, we applied the L-TIA kit results (using a PG I/II ratio cutoff value of 3.0) and analyzed the data using the same approach as in Table 4 to facilitate the comparison of the two kits. The results were slightly different, that the risk of having GA and GC was generally highest in the PG I/II ratio ≤3.0 and H. pylori-positive group (for GA: OR, 3.11 [95% CI, 1.99 to 4.87], p<0.001; aOR, 2.93 [95% CI, 1.86 to 4.63], p<0.001, and for GC: OR, 2.29 [95% CI, 1.72 to 3.04], p<0.001; aOR, 2.21 [95% CI, 1.64 to 2.97], p<0.001) (Supplementary Table 5).
6. Results of duplication test
To confirm the reliability of the test, the same sample from 40 participants was analyzed twice using the GastroPanel kit (Supplementary Table 6). These results were consistent, suggesting the high reliability of the GastroPanel kit.
DISCUSSION
In this study, sPG I and II levels and PG I/II ratios were measured in 2,204 patients using the GastroPanel kit, and the results were compared with those measured using the L-TIA kit. The measurements using the two kits showed high concordance, and the sPG I and PG I/II ratios measured using the GastroPanel kit were higher, whereas sPG II was lower than that measured using the L-TIA kit. In the comparison between the control, GA, and GC groups, sPG I decreased in the GA and GC groups compared with the control group. sPG II was lower in the GA group, but was higher in the cancer group than in the control group. Consequently, the PG I/II ratios were significantly lower in the GA and GC groups, especially in the intestinal-type cancer group than in the control group. The sPG I of 70 ng/mL and PG I/II ratio 3 of the L-TIA kit corresponded to 100 ng/mL and 5.3 of the GastroPanel kit, respectively, and the diagnostic accuracy calculated using the GastroPanel kit showed non-inferiority compared to the L-TIA kit. The sensitivity and specificity were slightly higher in the diagnosis of AG, IM, and GA, although there was no significant difference in the diagnosis of GC compared to that calculated using the L-TIA kit. The risk of having GA and GC differed according to the PG I/II ratio and H. pylori infection status, in that the risks of GA and GC compared to PG I/II ratio >5.3 and H. pylori-negative group were highest in the PG I/II ratio ≤5.3 and H. pylori-negative group. This was supported by the lowest sPG I and PG I/II ratios in this cohort, which were different from those in a previous Korean report.4
sPG testing is being used worldwide for the early detection of high-risk patients. First, the Japanese guidelines recommend that the ABC classification is a widely recognized modality involving a combined assay for HpIgG and sPG levels.8 Another publication stated that the ratio of PG I/II is known to decrease upon inflammation of the gastric mucosa, and proposed different cutoff values for the test have been proposed for gastritis before eradication treatment and at diagnosis of gastritis after eradication treatment as sPG I and sPG II decrease and the PG I/II ratio increases as inflammation improves after successful H. pylori eradication. However, it was stated that it is necessary to note that a serum H. pylori antibody test and pepsinogen test may yield false‐negative results at the high GC risk stage (age ≥50 years) (Recommendation: 1, Evidence level: B).6 Meanwhile, European guidelines also address the utility of the sPG test, stating that sPG levels can predict extensive AG. That is, low sPG I or/and a low PG I/II ratio identify patients with advanced stages of AG, and endoscopy is recommended for these patients, particularly if H. pylori serology is negative. They also pointed out that there is great heterogeneity among existing studies (moderate quality evidence, strong recommendation, 88% agree).30 In the recently published Maastricht VI, serum PG testing—including the calculation of the PG I/II ratio and the analysis of HpIgG—was stated as the best option for a noninvasive test to diagnose preneoplastic changes in the gastric mucosa (grade A1, agreement 98%).31 Overall, serum PG testing is recognized for its utility as a noninvasive method to evaluate the condition of the gastric mucosa and to screen high-risk patients; however, a limitation is that its performance may vary depending on the target population. As mentioned in the introduction, interest in serum PG testing is relatively low in Korea, where GC screening via endoscopy is highly active. Nonetheless, continuous research on the application of noninvasive testing methods is needed for individuals under 40—who are not included in the national screening program—as well as for elderly or high-risk patients who may have difficulty undergoing endoscopy.
Consistent with the results of this study, previous studies have verified the relationship between a low PG I/II ratio and high risk of GA and GC.3,32-34 As PG I is produced primarily by the gastric fundic mucosa, whereas PG II is secreted by the fundic, antral, and duodenal mucosa,3 the decrease in sPG I is noticeable, and the PG I/II ratio also decreases as AG and IM, which are precursor lesions of GA and GC, develop and progress. Various cutoff values for GC screening have been proposed, but a sPG I of ≤70 ng/mL and PG I/II ratio of ≤3 are well known and have been used most commonly.3,28,32,34 However, It should be noted that the existing studies that suggested these cutoff values used radioimmunoassay or enzyme immunoassay methods,28 which are different from the ELISA method.
To discuss the ELISA method, there are a number of previous studies that report the results of analyses using the GastroPanel kit for diagnosis of H. pylori infection,35 AG,23,24,3, and GC, mostly conducted in northern Europe. In the case of studies using GastroPanel, various cutoff values have been presented. For example, in a recent meta-analysis, sPG I from 25.0–75.07 and PG I/II ratio between 3.0–6.25 were used as cutoff values, and the sensitivity and specificity were reported as 39.9%–80% and 48.8%–95.6%, respectively. In other words, the optimal cutoff value and diagnostic accuracy of GastroPanel vary greatly, depending on the characteristics of the population group and enrolled study participants, and appropriate validation in the country and region is considered essential. Meanwhile, in a study of a cohort of the Caucasian population in Western Siberia using the GastroPanel kit, a decrease in the PG I/II ratio well predicted the risk of GC (OR, 2.9; 95% CI, 1.01 to 8.00) when sPG I 30.0 and PG I/II ratio 3.0 were set as cutoff values. However, this study involved a relatively small number of patients (52 patients with GC and 104 matched controls).
There are not many studies directly comparing the measurement results of latex-based kits and ELISA-based kits. First, a European study showed good correlations between the different measurement methods.39 However, the measurements of sPG I and the PG I/II ratio using ELISA-based kits (Biohit and Vector Best) were higher than those obtained using the latex-based kit (Eiken). Furthermore, the optimal cutoff values for Biohit and Vector Best were relatively higher, 6.9 and 4.1, respectively, while the optimal cutoff value for Eiken was 2.7. Second, a recent study from Korea reported that the PG I measurement results using the ELISA-based GastroPanel kit were approximately twice as high as those obtained using the latex-based kit, similar to our study.25 The reason for the difference is likely due to different laboratory principles or technical matter due to the difference between the measurement methods of the two kits.
Based on these results, we determined that it would be difficult to directly apply the cutoff values of sPG I of 70 ng/mL and PG I/II ratio of 5.3 to the GastroPanel and aimed to calculate the corresponding optimal cutoff values using the ROC curve. As a result, sPG I of 70 ng/mL for the L-TIA kit corresponded to 100 ng/mL for the GastroPanel kit, and a PG I/II ratio of 3 for the L-TIA kit corresponded to 5.3 for the GastroPanel kit in the analyses comparing the ROC curves of each of the two kits. As a result of the analysis using these cutoff values, GastroPanel showed diagnostic accuracy that corresponded to existing study results. Furthermore, the sensitivity and specificity of the GastroPanel kit for diagnosing AG, IM, GA, and GC were higher than those for the L-TIA kit when the measurement results of the same sample were compared, except for the sensitivity of the PG I/II ratio for GC. Thus, sPG I of ≤100 ng/mL and PG I/II ratio of ≤5.3 for the GastroPanel kit are thought to be reliable cutoff values.
To compare pure H. pylori-negative individuals with those who had at least one H. pylori infection, we categorized subjects with a history of eradication therapy as H. pylori-positive. In cases of severe atrophy or metaplasia, the numbers of H. pylori become few and sometimes they cannot survive, and finally adenomas or GC occur.40 Furthermore, the results of the HpIgG test may not be entirely reliable if there is a history of H. pylori eradication therapy.41 Taking these into account, we designated individuals who had negative results on all H. pylori infection tests and no history of eradication therapy as the negative control group for our analysis, while aiming to diagnose the current H. pylori infection as accurately as possible through culture. This allowed us to investigate the impact of H. pylori infection on GC development. In a previous Korean study in 2008, individuals positive for H. pylori and with a PG I/II ratio of ≤3 were reported to be at the highest risk of having GC.4 However, Japanese studies around the same period reported contradictory results; individuals with a PG I/II ratio of ≤3 and negative for H. pylori infection were the highest-risk group.42-44 These studies showed that advanced gastric atrophy due to H. pylori infection occurred, after which the H. pylori burden decreased and H. pylori antibodies spontaneously disappeared.43,45
These results are also relatively consistent in recent studies; first, groups B, C, and D, according to the ABC method, were independent risk factors for GC, and hazard ratios of the incidence of GC were highest in groups C and D (being positive for sPG) in a large-scale study with 20,000 participants.46 Another recent Korean study reported that groups D (negative for HpIgG and positive for sPG; OR, 5.862 [95% CI, 2.427 to 14.155]) and C (positive for both HpIgG and sPG; OR, 3.807 [95% CI, 2.382 to 6.085]) were high-risk groups for gastric neoplasms.11 Additionally, the aforementioned meta-analysis also reported an increased risk of developing GC in groups D and C compared with that in group A.13
In our study, individuals who were H. pylori-negative with a PG I/II ratio ≤5.3 had the highest risk of GC, aligning with findings from most prior studies. This outcome differs from our earlier study;4 however, the reason for this is unclear. We hypothesized that the number of participants in the previous study was relatively small because of age and sex-matched for this calculation. To address this, we recalculated the sPG levels in all four groups (based on H. pylori infection status and PG I/II ratio). As expected, the most severe gastric atrophy pattern was observed in the H. pylori-negative and low PG I/II ratio group. Given the widespread health checkup programs in South Korea, including endoscopy for adults over 40, measuring sPG levels could further improve early GC diagnosis. It would be particularly beneficial for high-risk individuals not included in national health checkup programs or those unable to undergo endoscopy.
This study has some limitations. First, this study was conducted in a gastroenterology outpatient-based cohort instead of in a large health screening cohort. Of note, the fact that approximately half of the patients have GA or GC would be a factor influencing diagnostic accuracy, considering the sensitivity and specificity of the diagnostic method depend on the prevalence of the disease and characteristics of the group. Although most subjects (about 70%) in the control group underwent an endoscopy for screening purposes and showed normal results, a larger-scale, unbiased follow-up study targeting the general population will be necessary to validate this diagnostic kit and the ABC method in the Korean population. Second, we tried to exclude some conditions which could influence PG levels such as autoimmune gastritis. However, we did not use specific measurements of anti-parietal antibody. Nevertheless, autoimmune gastritis is quite rare in Korea and other identifiable factors including gastrectomy or proton pump inhibitor use were excluded. Third, this study included a large number of >2,200 participants, but the number of participants in the H. pylori-negative and PG I/II ≤5.3 group was still relatively small in the subgroup analysis.
Despite these limitations, this study has several advantages. To our knowledge, this is the first large-scale study to evaluate the diagnostic efficacy of PG testing using the GastroPanel kit. Furthermore, no previous study in South Korea has compared the measurement results with those of the L-TIA kit, which is more commonly used in South Korea. We confirmed a high concordance between the values measured using the two kits, and calculated the optimal cutoff value for conversion. The non-inferiority of the GastroPanel kit was confirmed, which generally showed better sensitivity and specificity for the diagnosis of gastritis and GA, although the difference was not statistically significant. Furthermore, the analysis results considering the PG I/II ratio with H. pylori infection status confirmed that participants with a low PG I/II ratio, especially H. pylori-negative patients, are at high risk of having GC; therefore, individuals in this group would benefit from serologic screening tests. The effort to improve diagnostic accuracy for the current H. pylori infection by performing culture is also one of the strengths of this study. Finally, we found a high reproducibility of the GastroPanel kit through repeated measurements.
In conclusion, the GastroPanel kit showed non-inferiority compared to the L-TIA kit. In addition, PG I/II ratio of ≤5.3 for the GastroPanel kit could be a reliable biomarker for the detection of GA and GC in combination with H. pylori infection status.
ACKNOWLEDGEMENTS
This work was supported by Seoul National University Bundang Hospital Research Fund (06-2024-0143). In addition, the clinical study was supported by Dow Biomedica.
SUPPLEMENTARY MATERIALS
Supplementary materials can be accessed at https://doi.org/10.5009/gnl250055.
Footnotes
CONFLICTS OF INTEREST
This clinical study was supported by Dow Biomedica. However, funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
AUTHOR CONTRIBUTIONS
Study concept and design: Y.C., N.K. Data acquisition: Y.C., J.H.P. Data analysis and interpretation: Y.C. Drafting of the manuscript: Y.C. Critical revision of the manuscript for important intellectual content: N.K., J.H.L., Y.K., H.K.L., Y.K.J., H.Y., C.M.S., Y.S.P. Study Supervision: N.K, D.H.L. Statistical analysis: Y.C. Obtained funding: N.K. Approval of final manuscript: all authors.
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