Non-invasive diagnosis of gastroesophageal reflux disease using gastrin- and pepsinogen-based tests

Gastrin-17 (G-17), pepsinogen-1 (Pg1) and pepsinogen-2 (Pg2) reflect the functional state of gas-tric mucosa and are used for non-invasive diagnosis and screening of atrophic gastritis. The aimof the study was to clarify if erosive reflux disease (ERD) or non-ERD (NERD) can be distin-guished from other dyspeptic conditions in patients, in a non-invasive manner using specificbiomarkers. Levels of G-17, Pg1, and Pg2 were measured in 141 ERD patients (median age 48years, males — 68), 122 NERD patients (median age 45 years, males — 32) and 410 control pa-tients (median age 50 years, males — 97). Levels of biomarkers in ERD and NERD groups werecompared to controls. Median levels of G-17 (1.94 vs 2.92 pmol/L, p = 0.036) and Pg2 (6.70 vs7.79 μg/l,p= 0.046) were lower in the ERD group compared to control patients; no differencewith respect to the control was found for the NERD group. After exclusion of the patients havingat least one potential condition that might modify the levels of the biomarkers (gastric mucosa at-rophy, Helicobacter pylori colonisation), no difference in levels of biomarkers was observed withrespect to the control for both the ERD and NERD groups. G-17, Pg1, and Pg2 based tests can-not be used to distinguish ERD or NERD from other dyspeptic conditions in patients.publishersversionPeer reviewe

Higher CTX-M, TEM, and SHV extended-spectrum beta-lactamase plasmid gene combination frequency in ESBL producing Klebsiella pneumoniae compared with ESBL producing Escherichia coli

publishersversionPeer reviewe

The diagnostic value of anti-parietal cell and intrinsic factor antibodies, pepsinogens, and gastrin-17 in corpus-restricted atrophic gastritis

Raksta tekstā kļuda: afilācijai "Digestive Diseases Centre GASTRO Ltd", norādīta atrašanas vieta: Hong Kong, ChinapublishersversionPeer reviewe

Assessment of Serum Pepsinogens with and without Co-Testing with Gastrin-17 in Gastric Cancer Risk Assessment—Results from the GISTAR Pilot Study

Introduction-Serum pepsinogen tests for gastric cancer screening have been debated for decades. We assessed the performance of two pepsinogen assays with or without gastrin-17 for the detection of different precancerous lesions alone or as a composite endpoint in a Latvian cohort. Methods-Within the intervention arm of the GISTAR population-based study, participants with abnormal pepsinogen values by ELISA or latex-agglutination tests, or abnormal gastrin-17 by ELISA and a subset of subjects with all normal biomarker values were referred for upper endoscopy with biopsies. Performance of biomarkers, corrected by verification bias, to detect five composite outcomes based on atrophy, intestinal metaplasia, dysplasia or cancer was explored. Results-Data from 1045 subjects were analysed, of those 273 with normal biomarker results. Both pepsinogen assays showed high specificity (>93%) but poor sensitivity (range: 18.4-31.1%) that slightly improved when lesions were restricted to corpus location (40.5%) but decreased when dysplasia and prevalent cancer cases were included (23.8%). Adding gastrin-17 detection, sensitivity reached 33-45% while specificity decreased (range: 61.1-62%) and referral rate for upper endoscopy increased to 38.6%. Conclusions-Low sensitivity of pepsinogen assays is a limiting factor for their use in population-based primary gastric cancer screening, however their high specificity could be useful for triage

Who Could Be Blamed in the Case of Discrepant Histology and Serology Results for Helicobacter pylori Detection?

Funding Information: Acknowledgments: The study was funded in part by the Fundamental and Applied Research Project Program in Latvia, project No. lzp-2018/1-0135 “Research on implementation of a set of measures for prevention of gastric cancer mortality by eradication H. pylori and timely recognition of precancerous lesions”. We acknowledge the entire GISTAR study team as well as the infrastructure provided by the Digestive Diseases Centre GASTRO for endoscopy and the Academic Histology Laboratory for pathology infrastructures. Our acknowledgements also to Biohit Oyj, Finland, for their support with laboratory reagents. Funding Information: Funding: The work is funded by ERDF (European Regional Development Fund) within the frame-work of 2nd part of measure 1.1.1.1. ‘Practical Studies’, project ID Nr. 1.1.1.1/18/A/184. Funding Information: The work is funded by ERDF (European Regional Development Fund) within the framework of 2nd part of measure 1.1.1.1. ?Practical Studies?, project ID Nr. 1.1.1.1/18/A/184. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Background. Discrepancies between histology and serology results for Helicobacter pylori detection could be caused by a variety of factors, including a biopsy sampling error, expertise of the pathologist, natural loss of infection due to advanced atrophy, or a false-positive serology in the case of a previous infection, since antibodies may be present in blood following recovery from the infection. Aims. To identify true H. pylori-positive individuals in discrepant cases by serology and histology using real time polymerase chain reaction (RT-PCR) as a gold standard. Methods. Study subjects with discrepant histology and serology results were selected from the GISTAR pilot study data base in Latvia. Subjects having received previous H. pylori eradication therapy or reporting use of proton pump inhibitors, antibacterial medications, or bismuth containing drugs one month prior to upper endoscopy were excluded. We compared the discrepant cases to the corresponding results of RT-PCR performed on gastric biopsies. Results. In total, 97 individuals with discrepant results were identified: 81 subjects were serology-positive/histology-negative, while 16 were serologynegative/histology-positive. Among the serology-positive/histology-negative cases, 64/81 (79.0%) were false-positives by serology and, for the majority, inflammation was absent in all biopsies, while, in the serology-negative/histology-positive group, only 6.2% were proven false-positives by histology. Conclusions. Among this high H. pylori prevalent, middle-aged population, the majority of discrepant cases between serology and histology were due to false positive-serology, rather than false-negative histology. This confirms the available evidence that the choice of treatment should not be based solely on the serological results, but also after excluding previous, self-reported eradication therapy.publishersversionPeer reviewe

Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti–Helicobacter pylori IgG Titers

Funding Information: Funding The Rotterdam Study I-II was supported by the Netherlands Organization of Scientific Research (NWO; 175.010.2005.011, 911-03-012), Research Institute for Diseases in the Elderly (RIDE; 014-93-015), Genomics Initiative/NWO (project no. 050-060-810), Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), Ministry of Education, Culture, and Science and Ministry for Health, Welfare, and Sports, European Commission, and the Municipality of Rotterdam. GenerationR was supported by Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, ZonMw (907.00303, 916.10159), NWO, and the Ministry for Health, Welfare and Sports. The Study of Health in Pomerania (SHIP) and SHIP-TREND were supported by Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung (109102), Deutsche Forschungsgemeinschaft (DFG GRK840-D2/E3/E4, MA 4115/1-2/3), Federal Ministry of Education and Research (BMBF GANI-MED 03IS2061A and BMBF 0314107, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012), the European Union (EU-FP-7-EPCTM and EU-FP7-REGPOT-2010-1), AstraZeneca (unrestricted grant), the Federal Ministry of Education and Research, Siemens Healthcare, the Federal State of Mecklenburg–West Pomerania, and the University of Greifswald. The Framingham Heart Study was supported by National Institutes of Health grants N01-HC-25195, HHSN268201500001I, and 75N92019D00031 (to Boston University) and the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI). The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe projects were supported by the NHLBI (75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI grant N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Epidemiological Investigations on Chances of Preventing Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population were supported by the State Ministry of Science, Research and Arts, Baden-Württemberg, Federal Ministry of Education and Research, and Federal Ministry of Family Affairs, Senior Citizens, Women and Youth. LATVIA was supported by the European Regional Development Fund (ERDF; 009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016), National Program for Research in Latvia, Ministry of Health (6-1396-2016), and Fundamental and Applied Research Projects Program in Latvia (project no. lzp-2018/1-0135). Funding Information: Conceptualization: Linda Broer, Manon C.W. Spaander, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Ben Schöttker, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Raitis Peculis, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, André Uitterlinden, Ernst J. Kuipers, Maikel P. Peppelenbosch, and additional members of Rotterdam Study I-II, GenerationR, Study of Health in Pomerania, Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, Epidemiological Investigations on Chances of Preventing Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population, and LATVIA cohorts not directly involved in this manuscript. Methodology: all authors. Investigation: all authors. Formal analysis of discovery: Linda Broer, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, and Edmond K. Kabagambe. Formal analysis of replication: Yan Zhang, Hannah Stocker, Hermann Brenner, Marcis Leja, Janis Klovins, and Raitis Peculis. Formal analysis of meta-analysis: Linda Broer. Project administration: Suk Yee Lam and Gwenny M. Fuhler. Resources: Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, Ernst J. Kuipers, and Maikel P. Peppelenbosch. Supervision: Manon C.W. Spaander, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Gwenny M. Fuhler, Maikel P. Peppelenbosch, and André Uitterlinden. Visualization: Suk Yee Lam, Michiel C. Mommersteeg, Bingting Yu, Linda Broer, and Gwenny M. Fuhler. Writing—original draft: Suk Yee Lam, Michiel C. Mommersteeg, and Gwenny M. Fuhler. Writing—reviewing and editing: all authors. Publisher Copyright: © 2022 The Author(s)Background & Aims: A genome-wide significant association between anti–Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest anti–H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori–eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with anti–H pylori IgG titers (rs12233670; β = −0.267 ± SE 0.034; P = 4.42 × 10−15) presented with high heterogeneity and failed replication. Anti–H pylori IgG titers declined within 2–4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between anti–H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti–H pylori IgG titers on therapy, clearance, and antibody decay. H pylori–mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.publishersversionPeer reviewe

Factors Associated with False Negative Results in Serum Pepsinogen Testing for Precancerous Gastric Lesions in a European Population in the GISTAR Study

The accuracy of plasma pepsinogen (Pg) as a marker for precancerous gastric lesions (PGL) has shown variable results. We aimed to identify factors associated with false negative (FN) cases in Pg testing and to adjust cut-off values for these factors in order to improve Pg yield. Plasma Pg was measured and upper endoscopy with biopsy was performed within the “Multicentric randomized study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality: the GISTAR study”. A multivariable logistic model was built for FN and multiple factors. Values of Pg were compared and sensitivity and specificity were calculated using pre-existing Pg cut-offs for factors showing strong associations with FN. New cut-offs were calculated for factors that showed substantially lower sensitivity. Of 1210 participants, 364 (30.1%) had histologically confirmed PGL, of which 160 (44.0%) were FN. Current smokers, men, and H. pylori positives were more likely FN. Smoking in H. pylori negatives was associated with a higher Pg I/II ratio and substantially lower sensitivity of Pg testing than in other groups. Adjusting Pg cut-offs for current smokers by H. pylori presence improved sensitivity for detecting PGL in this group. Our study suggests that adjusting Pg cut-offs for current smokers by H. pylori status could improve Pg test performance

Pepsinogen testing for evaluation of the success of Helicobacter pylori eradication at 4 weeks after completion of therapy

Funding Information: This study was supported in part from the European Fund for Regional Development project No. 2010/0302/2DP/2.1.1.1.0/10/APIA/VIAA/158 entitled “Development of a Genetic/Serological Biomarker Diagnostic Method for Early Identification of Autoimmune Gastrointestinal Lesions With Increased Malignancy Risk in Patients With Autoimmune Disease.” Publisher Copyright: © 2014 Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.Background and objective: Pepsinogen levels in plasma are increased by inflammation in the gastric mucosa, including inflammation resulting from Helicobacter pylori infection. A decrease in pepsinogen II level has been suggested as a reliable marker to confirm the successful eradication of infection. The aim of our study was to evaluate the potential role of pepsinogens I and II, gastrin-17 and H. pylori antibodies in confirming successful eradication. Material and methods: Altogether 42 patients (25 women, 17 men), mean age 45 years (range 23-74), were enrolled. Pepsinogens I and II, gastrin-17 and H. pylori IgG antibodies were measured in plasma samples using an ELISA test (Biohit, Oyj., Finland) before the eradication and 4 weeks after completing the treatment. The success of eradication was determined by a urea breath test. Results: Eradication was successful in 31 patients (74%) and unsuccessful in 11 patients (26%). Pepsinogen II decreased significantly in both the successful (P = 0.029) and unsuccessful (P = 0.042) eradication groups. Pepsinogen I decreased significantly in the successful (P = 0.025) but not the unsuccessful (P = 0.29) eradication group. The pepsinogen I/II ratio increased in the successful eradication group (P = 0.0018) but not in the group in which treatment failed (P = 0.12). There were no differences in gastrin-17 or H. pylori antibody values. Conclusions: A decrease in pepsinogen II levels cannot be used as a reliable marker for the successful eradication of H. pylori 4 weeks after the completion of treatment. The increase in pepsinogen I/II ratio reflects differences in pepsinogen production following the eradication irrespective of improvement in atrophy.publishersversionPeer reviewe

Accuracy of two plasma antibody tests and faecal antigen test for non-invasive detection of <i>H. pylori</i> in middle-aged Caucasian general population sample

<p><b>Objective:</b> The aim of the study was to assess the accuracy of two plasma <i>Helicobacter pylori (H. pylori)</i> antibody test-systems and a stool antigen test (SAT) system in a general population sample in Latvia.</p> <p><b>Materials and methods:</b> Blood and faecal samples were analysed in healthy individuals (40–64 years), referred for upper gastrointestinal endoscopy according to pilot study protocol within a population-based study investigating gastric cancer prevention strategies (GISTAR pilot study). Antibodies to <i>H. pylori</i> were assessed in plasma by latex-agglutination test and enzyme-linked immunosorbent assay (ELISA). <i>H. pylori</i> antigen in faecal samples was detected by a monoclonal enzyme immunoassay-based SAT. Histological assessment of <i>H. pylori</i> based on a modified Giemsa staining method was used as the gold standard. Individuals having received <i>H. pylori</i> eradication within one year prior to enrolment were excluded. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy were calculated. Receiver-operating characteristic curves were designed to estimate the optimal diagnostic cut-off value of tests.</p> <p><b>Results:</b> The analysis included 779 participants for latex-agglutination test, 1002 for ELISA and 672 individual samples for SAT. The sensitivity, specificity, PPV, NPV and overall accuracy were as follows: latex-agglutination test (86;81;87;80;84%), ELISA (97;72;83;94;86%) and SAT (87;81;87;81;85%), respectively. The optimal diagnostic cut-off value for ELISA test was ≥50.26 g/L.</p> <p><b>Conclusions:</b> Although the performance of the three tests was comparable to each other, the three test systems showed suboptimal accuracy, with important implications for public health programs based on <i>‘test-and-treat’</i> strategy.</p