J Clin Med. 2023 Sep 23;12(19):6152. doi: 10.3390/jcm12196152.
* Strongest known risk factor for GC development is infection with the bacterium Helicobacter pylori (H. pylori)
* Endoscopic surveillance of gastric precancerous lesions (GPL) such as atrophic gastritis (AG) or intestinal metaplasia (IM) decreases the risk of developing invasive GC.
* Another cause of chronic gastritis is autoimmune gastritis (AIG), an immune-mediated disorder characterized with the destruction of gastric parietal cells.
* We investigated the prevalence of AIG in a prospectively followed cohort of patients with GPL.
* Clinical characteristics of AIG-associated IM and attempted to determine the diagnostic efficiency of gastric function biomarkers to optimize the detection of AIG in patients with GPL.
2. Materials and Methods
2.1. Study Population
* Prospective, multicenter study
* AIG-associated pathological features were re-evaluated in APCA-positive patients to confirm the diagnosis of AIG.
PROREGAL (Progression and Regression of Precancerous Gastric Lesions) 연구는 현재 진행 중인 전향적 다기관 연구입니다 [21].
- 2009년에 시작되었으며, 네덜란드의 6개 병원(1개 대학병원, 5개 지역병원)과 노르웨이의 1개 지역병원이 참여하고 있습니다.
연구 대상 및 제외 기준
✅ 포함 기준
- 18세 이상 환자
- 이전 위축성 위염(AG), 장상피화생(IM), 또는 위 점막 이형성증을 진단받은 환자
❌ 제외 기준
- 상부 위장관 수술을 받은 병력이 있는 경우
- 위암 병력이 있는 경우
- 기대 수명이 2년 미만인 중증 동반질환이 있는 경우
연구 참여자 및 데이터 수집
- 이번 연구에서는 PROREGAL 코호트에서 256명의 환자를 포함, 혈청 샘플을 활용하였습니다.
- 기본 인구학적 정보 및 비타민 보충제 사용 여부는 설문지를 통해 수집되었습니다.
- APCA(항위벽세포항체) 양성 환자의 경우, 다른 자가면역 질환 동반 여부도 조사되었습니다.
대조군 설정 및 H. pylori 관련성 고려
- H. pylori가 AIG(자가면역성 위염)와 관련이 있으며 [22,23], 심지어 AIG를 유발할 가능성이 제기된 바 있습니다 [24,25]. 이를 고려하여, H. pylori 유병률이 유사한 대조군을 설정하였습니다.
- 대조군:
- 18세 이상 환자 70명으로 구성
- H. pylori 감염이 의심되어 요소호기검사(UBT)를 시행한 연속적인 환자군
윤리 승인 및 동의 절차
- Erasmus MC 의학 윤리 검토 위원회(MEC-2009-090, MEC-2017-528)의 승인을 받았으며,
- 모든 연구 참여자로부터 사전 동의를 획득하였습니다.
2.2. Serological Tests
PROREGAL 연구에서 혈청 샘플 수집 및 분석
- PROREGAL 연구에 등록된 환자의 혈청 샘플은 기본 검사 시점(baseline) 및 내시경 추적검사 시점에 수집되었습니다.
- 대조군의 혈청 샘플은 요소호기검사(UBT) 당일에 수집되었습니다.
- 모든 샘플은 -80°C에서 보관되었습니다.
항위벽세포항체(APCA) 검사 방법
예비 검사 (Pre-screening)
- 간접 면역형광 항체검사(IFT)를 사용하여 정성적(qualitative) 검사를 실시
- 상업용 조직 슬라이드(ImmuGlo™ Rat stomach slides, Immco Diagnostics, Buffalo, NY, USA) 사용
- 환자 혈청(1:10 희석)과 반응 후, 항-인간 IgG-FITC(Inova Diagnostics Inc., San Diego, CA, USA)로 염색
정량 검사 (Quantitative analysis)
- IFT 검사에서 양성 반응을 보인 샘플에 대해 H⁺/K⁺ ATPase 특이적 ELiA™ 자동 효소형광면역분석 실시
- Phadia 250 시스템(Thermo Fischer Scientific, Freiburg, Germany) 사용
- APCA 농도를 U/mL 단위로 정량 분석
GastroPanel 분석
- GastroPanel(Biohit Qyi, Helsinki, Finland)을 이용하여 혈청 내 Pepsinogen I(PGI), Pepsinogen II(PGII), Gastrin-17(G17), 및 항-H. pylori 항체 수치를 측정 (제조업체의 지침(manufacturer instructions)에 따라 실험 진행)
- 광학 밀도(OD) 측정 (450 nm 파장에서 OD[optical density] 값 측정)
- Infinite 200 Pro ELISA 리더(TECAN, Mannedorf, Switzerland) 사용
정상 참고 범위 (검사항목 정상 범위)
|
| APCA | > 10 U/mL |
| PGI | 30–160 µg/L |
| PGII | 3–15 µg/L |
| PGI/PGII 비율 | 3–20 |
| G17 | 1–75 pmol/L |
| 항-H. pylori 항체 | < 30 EIU |
H. pylori 감염 상태 해석
- 항-H. pylori 항체 ≥ 30 EIU:
- 과거에 H. pylori 감염 이력이 있으며 현재 박멸된 경우
- 또는 현재 활성 H. pylori 감염 상태(박멸되지 않음)
<Results>
1. Prevalence of AIG Is Increased in Patients with Gastric Premalignant Lesions
* APCA positivity was seen for 51 individuals, 36 of whom were women.
* A significantly higher prevalence of APCA positivity was seen in the GPL group as compared to the control cohort (18% vs. 7%, p = 0.033).
* The multivariable logistic regression analysis showed that APCA positivity (adjusted OR = 3.76, 95% CI = −1.31 to 10.79; p = 0.013), age (adjusted OR = 1.07, 95% CI = −1.04 to 1.09; p < 0.001) and male gender (adjusted OR = 0.47, 95% CI = −0.26 to 0.86; p = 0.015) were independently associated with IM.
연구 대상 및 주요 결과
총 326명의 대상자가 연구에 포함되었으며,
- 256명은 GPL(위 전암성 병변, gastric premalignant lesions) 환자군, 70명은 대조군이었습니다.
두 그룹의 기본 특성은 Table 1에 제시되었습니다.
- GPL 환자군은 대조군보다 남성 비율이 높았으며
- 남성 비율: 50% vs. 34% (p = 0.024)
- 연령이 유의미하게 더 높았습니다.
- GPL 환자군: 64세 (중앙값, 범위 55–71세)
- 대조군: 51세 (중앙값, 범위 43–60세) (p < 0.001)
- H. pylori 감염(현재 또는 과거)의 비율은 두 그룹 간에 유의한 차이가 없었습니다.
APCA(항위벽세포항체) 양성률
- 총 51명(36명 여성)이 APCA 양성이었으며,
- GPL 환자군에서 APCA 양성률이 대조군보다 유의미하게 높았습니다.
다변수 로지스틱 회귀 분석 결과
장상피화생(IM, intestinal metaplasia)과 독립적으로 연관된 변수는 다음과 같았습니다.
- APCA 양성
- 보정된 OR = 3.76 (95% CI: −1.31~10.79, p = 0.013) → APCA 양성자는 IM 발생 위험이 약 3.76배 증가
- 연령
- 보정된 OR = 1.07 (95% CI: −1.04~1.09, p < 0.001) → 연령이 증가할수록 IM 발생 위험 증가
- 남성
- 보정된 OR = 0.47 (95% CI: −0.26~0.86, p = 0.015) → 남성은 IM 발생 위험이 여성보다 낮음
Table 1. Baseline characteristics of study population and association between age, gender, APCA positivity, H. pylori infection history and GPL.
* Only three of the APCA-positive GPL cases were previously identified with AIG. (AIG may go underdiagnosed in patients with GPL)
* More than half of patients presented with low vitamin B12 levels (54.3%).
* Concomitant autoimmune disease was observed in 23.7% of cases (ATD: 19.5%).
* 19 presented with limited AG/IM lesions (44.2%, under surveillance according to the MAPSII guidelines )
APCA 양성 GPL 환자에서의 AIG 특징 확인
APCA(항위벽세포항체) 양성 GPL(위 전암성 병변) 사례 중 이전에 AIG(자가면역성 위염)로 진단된 경우는 3건뿐이었습니다.
이에 APCA 양성 GPL 환자에서 AIG의 특징이 있는지 확인하기 위해,
- HE(헤마톡실린-에오신) 염색된 슬라이드를 재평가한 결과,
- 46명 중 19명에서 ECL(Enterochromaffin-like) 세포 과형성이 관찰되었습니다.
또한,
- 절반 이상의 환자에서 비타민 B12 수치가 낮았으며,
- 23.7%의 환자가 동반성 자가면역 질환을 가지고 있었습니다(보충자료 Table S1 참고).
PROREGAL 연구 내에서의 추적 관찰
PROREGAL 연구의 전향적(prospective) 코호트에서는 AG(위축성 위염)/IM(장상피화생)의 범위와 관계없이 연구 프로토콜에 따라 환자들을 정기적으로 추적 관찰하였습니다. 이는 MAPSII 가이드라인에 비해 더 빈번한 추적 관찰을 의미합니다. 그러나, 46명의 APCA 양성 환자 중 19명은 제한적인 AG/IM 병변을 보였으며, MAPSII 가이드라인에 따르면 추가적인 추적 관찰에서 제외될 가능성이 있었습니다. 즉, AIG 진단이 직접적으로 확인되지 않은 경우,추적 관찰에서 제외될 가능성이 있었던 43명의 환자 중 44.2% (19명)은 AIG가 존재했음에도 불구하고 지속적인 관리에서 배제될 위험이 있었습니다.
2. AIG in GPL Patients Is Associated with Gastric Location, but Not Severity of GPL
* 51.2% (24/43) of APCA-positive patients have extended GPL, which is significantly more than in APCA-negative patients.
* Corpus involvement was more frequently identified in APCA-positive patients
* Antrum involvement was more frequently identified in APCA-negative subjects
Table 2. Distribution of precancerous lesion in the gastric mucosa of patients with or without anti-parietal-cell antibodies.
* OLGIM score was not affected by either APCA status (p = 0.16) or concentration of APCA (r = −0.06; p = 0.62; Figure 1A, C).
* OLGA score was lower in patients without APCA (p < 0.001).
* APCA levels did not correlate to severity of atrophy (r = 0.14; p = 0.31; Figure 1B,D).
Figure 1. Association between anti-parietal cell antibodies and severity of intestinal metaplasia and gastric atrophy. (A) No differences in Operative Link for Gastric Intestinal Metaplasia Assessment (OLGIM) stage were seen for cases with GPL positivity for anti-parietal cell antibodies (APCA) and those negative for APCA (p = 0.16). (B) Operative Link of Gastritis Assessment (OLGA) score of zero was more often seen for GPL cases without APCA (p < 0.001). (C) Serum concentration of APCA did not correlate with OLGIM score (r = −0.06; p = 0.62). (D) Serum concentration of APCA did not correlate with OLGA score (r = 0.14; p = 0.31).
* APCA was also compared to the worst OLGIM and OLGA score seen at any time during follow up, with similar results
Supplementary Figure S1. Serum concentration of APCA did not correlate with the worst OLGIM score detected during longitudinal follow-up (A, r=-0.1; p=0.39) or the worst OLGA stage (B, r=0.01; p=0.96).
3. AIG in the Context of Precancerous Gastric Lesions Is Associated with Serum Markers Indicative of Parietal Cell Loss
* In APCA-positive GPL cases, respectively of which PGI and the PGI/II ratio were significantly lower as compared to APCA-negative subjects.
* In APCA-positive GPL cases, the median G17 levels were significantly higher than in APCA-negative cases .
Table 3. Results of GastroPanel testing in patients with or without anti-parietal-cell antibodies.
* Divided the GPL patients into four groups, based on their history of H. pylori infection and APCA status (Figure 2A).
* G17, PGI and PGII levels are dependent on APCA positivity rather than the history of H. pylori infection.
* Investigated the diagnostic accuracy of GastroPanel in predicting AIG with an ROC analysis (Figure 2B & C)
* Diagnostic ability of PGII and H. pylori IgG was low, but PGI, the PG I/II ratio and G17 showed good diagnostic accuracy.
* Combining the PGI/II ratio and G17 : AUC increased to 0.884 (95% CI = 0.838–0.920) / sensitivity of 80.4% (95% CI = 66.1–90.6) and a specificity of 94.2% (95% CI = 90.2–97.0) - valuable supplementary tool in the detection of AIG among patients with GPL (Figure 2C)
Figure 2. Biomarker analysis for detection of autoimmune gastritis. (A) Serum level of PGI, PGII, PGI/II ratio, G17 and H. pylori IgG in patients with only autoimmune gastritis (AIG), patients with AIG and previous or active H. pylori infection, patients with only H. pylori infection and patients with no H. pylori infection or AIG. (B,C) Receiver operating characteristic (ROC) curve analysis of PGI, PGII, PGI/PGII ratio, G17 and H. pylori IgG for discrimination of patients with and without AIG.
<Discussion>
PG1, PGII and G17 measurement might be a reliable tool to help to identify AIG in patients with precancerous gastric lesions.
This study has real strengths. First, by prospectively following our cohort of patients with premalignant lesions, we were able to accurately link the presence of APCA to the course of disease. Secondly, this cohort is one of the largest prospective cohorts of patients with GPL to date and currently has a follow-up time of over 10 years.
Our data show that the prevalence of AIG is increased in patients presenting with GPL and may be subject to underdiagnoses. Awareness for AIG testing should be raised among both pathologists and gastroenterologists in order to optimize surveillance strategies.
<Abstract>
Background: Autoimmune gastritis (AIG), characterized with the presence of anti-parietal cell antibodies (APCA), is a risk factor for gastric cancer. However, AIG may go underdiagnosed, especially in the case of H. pylori infection and the presence of gastric precancerous lesions (GPL), due to the ambiguous pathology and delayed symptom onset.
Aim: Investigate the prevalence and characteristics of AIG in GPL patients.
Methods: Prevalence of AIG was determined with the presence of APCA in patients with GPL (n = 256) and the control group (n = 70). Pathological characteristics and levels of gastrin 17 (G17), pepsinogen (PG) I and II and anti-Helicobacter pylori IgG were assessed in GPL cases, and the severity of intestinal metaplasia and gastric atrophy was scored by expert pathologists.
Results: APCA positivity was observed in 18% of cases vs. 7% of controls (p = 0.033). Only 3/256 patients were previously diagnosed with AIG. The presence of APCA was associated with corpus-limited and extended GPL. A receiver operating curve analysis demonstrated that the G17 and PGI/II ratio could identify APCA-positive patients within GPL cases (AUC: 0.884).
Conclusions: The prevalence of AIG is higher in patients with GPL but goes undiagnosed. Using G17 and PG I/II as diagnostic markers can help to identify patients with AIG and improve surveillance programs for patients with GPL.
Keywords: autoimmune gastritis; gastric precancerous lesions; gastrin 17; pepsinogen
J Clin Med. 2023 Sep 23;12(19):6152. doi: 10.3390/jcm12196152.
* Strongest known risk factor for GC development is infection with the bacterium Helicobacter pylori (H. pylori)
* Endoscopic surveillance of gastric precancerous lesions (GPL) such as atrophic gastritis (AG) or intestinal metaplasia (IM) decreases the risk of developing invasive GC.
* Another cause of chronic gastritis is autoimmune gastritis (AIG), an immune-mediated disorder characterized with the destruction of gastric parietal cells.
* We investigated the prevalence of AIG in a prospectively followed cohort of patients with GPL.
* Clinical characteristics of AIG-associated IM and attempted to determine the diagnostic efficiency of gastric function biomarkers to optimize the detection of AIG in patients with GPL.
2. Materials and Methods
2.1. Study Population
* Prospective, multicenter study
* AIG-associated pathological features were re-evaluated in APCA-positive patients to confirm the diagnosis of AIG.
PROREGAL (Progression and Regression of Precancerous Gastric Lesions) 연구는 현재 진행 중인 전향적 다기관 연구입니다 [21].
연구 대상 및 제외 기준
✅ 포함 기준
❌ 제외 기준
연구 참여자 및 데이터 수집
대조군 설정 및 H. pylori 관련성 고려
윤리 승인 및 동의 절차
2.2. Serological Tests
PROREGAL 연구에서 혈청 샘플 수집 및 분석
항위벽세포항체(APCA) 검사 방법
예비 검사 (Pre-screening)
정량 검사 (Quantitative analysis)
GastroPanel 분석
정상 참고 범위 (검사항목 정상 범위)
H. pylori 감염 상태 해석
<Results>
1. Prevalence of AIG Is Increased in Patients with Gastric Premalignant Lesions
* APCA positivity was seen for 51 individuals, 36 of whom were women.
* A significantly higher prevalence of APCA positivity was seen in the GPL group as compared to the control cohort (18% vs. 7%, p = 0.033).
* The multivariable logistic regression analysis showed that APCA positivity (adjusted OR = 3.76, 95% CI = −1.31 to 10.79; p = 0.013), age (adjusted OR = 1.07, 95% CI = −1.04 to 1.09; p < 0.001) and male gender (adjusted OR = 0.47, 95% CI = −0.26 to 0.86; p = 0.015) were independently associated with IM.
연구 대상 및 주요 결과
총 326명의 대상자가 연구에 포함되었으며,
두 그룹의 기본 특성은 Table 1에 제시되었습니다.
APCA(항위벽세포항체) 양성률
다변수 로지스틱 회귀 분석 결과
장상피화생(IM, intestinal metaplasia)과 독립적으로 연관된 변수는 다음과 같았습니다.
Table 1. Baseline characteristics of study population and association between age, gender, APCA positivity, H. pylori infection history and GPL.
* Only three of the APCA-positive GPL cases were previously identified with AIG. (AIG may go underdiagnosed in patients with GPL)
* More than half of patients presented with low vitamin B12 levels (54.3%).
* Concomitant autoimmune disease was observed in 23.7% of cases (ATD: 19.5%).
* 19 presented with limited AG/IM lesions (44.2%, under surveillance according to the MAPSII guidelines )
APCA 양성 GPL 환자에서의 AIG 특징 확인
APCA(항위벽세포항체) 양성 GPL(위 전암성 병변) 사례 중 이전에 AIG(자가면역성 위염)로 진단된 경우는 3건뿐이었습니다.
이에 APCA 양성 GPL 환자에서 AIG의 특징이 있는지 확인하기 위해,
또한,
PROREGAL 연구 내에서의 추적 관찰
PROREGAL 연구의 전향적(prospective) 코호트에서는 AG(위축성 위염)/IM(장상피화생)의 범위와 관계없이 연구 프로토콜에 따라 환자들을 정기적으로 추적 관찰하였습니다. 이는 MAPSII 가이드라인에 비해 더 빈번한 추적 관찰을 의미합니다. 그러나, 46명의 APCA 양성 환자 중 19명은 제한적인 AG/IM 병변을 보였으며, MAPSII 가이드라인에 따르면 추가적인 추적 관찰에서 제외될 가능성이 있었습니다. 즉, AIG 진단이 직접적으로 확인되지 않은 경우,추적 관찰에서 제외될 가능성이 있었던 43명의 환자 중 44.2% (19명)은 AIG가 존재했음에도 불구하고 지속적인 관리에서 배제될 위험이 있었습니다.
2. AIG in GPL Patients Is Associated with Gastric Location, but Not Severity of GPL
* 51.2% (24/43) of APCA-positive patients have extended GPL, which is significantly more than in APCA-negative patients.
* Corpus involvement was more frequently identified in APCA-positive patients
* Antrum involvement was more frequently identified in APCA-negative subjects
Table 2. Distribution of precancerous lesion in the gastric mucosa of patients with or without anti-parietal-cell antibodies.
* OLGIM score was not affected by either APCA status (p = 0.16) or concentration of APCA (r = −0.06; p = 0.62; Figure 1A, C).
* OLGA score was lower in patients without APCA (p < 0.001).
* APCA levels did not correlate to severity of atrophy (r = 0.14; p = 0.31; Figure 1B,D).
Figure 1. Association between anti-parietal cell antibodies and severity of intestinal metaplasia and gastric atrophy. (A) No differences in Operative Link for Gastric Intestinal Metaplasia Assessment (OLGIM) stage were seen for cases with GPL positivity for anti-parietal cell antibodies (APCA) and those negative for APCA (p = 0.16). (B) Operative Link of Gastritis Assessment (OLGA) score of zero was more often seen for GPL cases without APCA (p < 0.001). (C) Serum concentration of APCA did not correlate with OLGIM score (r = −0.06; p = 0.62). (D) Serum concentration of APCA did not correlate with OLGA score (r = 0.14; p = 0.31).
* APCA was also compared to the worst OLGIM and OLGA score seen at any time during follow up, with similar results
Supplementary Figure S1. Serum concentration of APCA did not correlate with the worst OLGIM score detected during longitudinal follow-up (A, r=-0.1; p=0.39) or the worst OLGA stage (B, r=0.01; p=0.96).
3. AIG in the Context of Precancerous Gastric Lesions Is Associated with Serum Markers Indicative of Parietal Cell Loss
* In APCA-positive GPL cases, respectively of which PGI and the PGI/II ratio were significantly lower as compared to APCA-negative subjects.
* In APCA-positive GPL cases, the median G17 levels were significantly higher than in APCA-negative cases .
Table 3. Results of GastroPanel testing in patients with or without anti-parietal-cell antibodies.
* Divided the GPL patients into four groups, based on their history of H. pylori infection and APCA status (Figure 2A).
* G17, PGI and PGII levels are dependent on APCA positivity rather than the history of H. pylori infection.
* Investigated the diagnostic accuracy of GastroPanel in predicting AIG with an ROC analysis (Figure 2B & C)
* Diagnostic ability of PGII and H. pylori IgG was low, but PGI, the PG I/II ratio and G17 showed good diagnostic accuracy.
* Combining the PGI/II ratio and G17 : AUC increased to 0.884 (95% CI = 0.838–0.920) / sensitivity of 80.4% (95% CI = 66.1–90.6) and a specificity of 94.2% (95% CI = 90.2–97.0) - valuable supplementary tool in the detection of AIG among patients with GPL (Figure 2C)
Figure 2. Biomarker analysis for detection of autoimmune gastritis. (A) Serum level of PGI, PGII, PGI/II ratio, G17 and H. pylori IgG in patients with only autoimmune gastritis (AIG), patients with AIG and previous or active H. pylori infection, patients with only H. pylori infection and patients with no H. pylori infection or AIG. (B,C) Receiver operating characteristic (ROC) curve analysis of PGI, PGII, PGI/PGII ratio, G17 and H. pylori IgG for discrimination of patients with and without AIG.
<Discussion>
PG1, PGII and G17 measurement might be a reliable tool to help to identify AIG in patients with precancerous gastric lesions.
This study has real strengths. First, by prospectively following our cohort of patients with premalignant lesions, we were able to accurately link the presence of APCA to the course of disease. Secondly, this cohort is one of the largest prospective cohorts of patients with GPL to date and currently has a follow-up time of over 10 years.
Our data show that the prevalence of AIG is increased in patients presenting with GPL and may be subject to underdiagnoses. Awareness for AIG testing should be raised among both pathologists and gastroenterologists in order to optimize surveillance strategies.
<Abstract>
Background: Autoimmune gastritis (AIG), characterized with the presence of anti-parietal cell antibodies (APCA), is a risk factor for gastric cancer. However, AIG may go underdiagnosed, especially in the case of H. pylori infection and the presence of gastric precancerous lesions (GPL), due to the ambiguous pathology and delayed symptom onset.
Aim: Investigate the prevalence and characteristics of AIG in GPL patients.
Methods: Prevalence of AIG was determined with the presence of APCA in patients with GPL (n = 256) and the control group (n = 70). Pathological characteristics and levels of gastrin 17 (G17), pepsinogen (PG) I and II and anti-Helicobacter pylori IgG were assessed in GPL cases, and the severity of intestinal metaplasia and gastric atrophy was scored by expert pathologists.
Results: APCA positivity was observed in 18% of cases vs. 7% of controls (p = 0.033). Only 3/256 patients were previously diagnosed with AIG. The presence of APCA was associated with corpus-limited and extended GPL. A receiver operating curve analysis demonstrated that the G17 and PGI/II ratio could identify APCA-positive patients within GPL cases (AUC: 0.884).
Conclusions: The prevalence of AIG is higher in patients with GPL but goes undiagnosed. Using G17 and PG I/II as diagnostic markers can help to identify patients with AIG and improve surveillance programs for patients with GPL.
Keywords: autoimmune gastritis; gastric precancerous lesions; gastrin 17; pepsinogen