Autoantibodies Toward ATP4A and ATP4B Subunits of Gastric Proton Pump H+,K+-ATPase Are Reliable Serological Pre-endoscopic Markers of Corpus Atrophic Gastritis

Abstract

INTRODUCTION: Noninvasive assessment of corpus atrophic gastritis (CAG), a condition at increased risk of gastric cancer, is based on the measurement of pepsinogens, gastrin, and Helicobacter pylori antibodies. Parietal cell autoantibodies (PCAs) against the gastric proton pump (ATP4) are potential serological biomarkers of CAG. The purpose of this study was to compare the diagnostic performance of PCA and pepsinogen I tests in patients with clinical suspicion of CAG with the histopathological evaluation of gastric biopsies as reference standard. METHODS: A prospective case-finding study was performed on 218 naive adult patients (131 women, median age 65 years) who underwent gastric biopsies to confirm/exclude CAG. Patients with histopathological CAG were defined as cases, conversely as controls. Autoantibodies against the individual alpha (ATP4A) and beta (ATP4B) subunits of ATP4 were measured by luciferase immunoprecipitation, and global PCA and pepsinogen I by enzyme-linked immunosorbent assay. RESULTS: Histopathology classified 107 subjects (49%) as cases (CAG+, autoimmune 81.2%, and multifocal extensive 18.8%) and 111 subjects (51%) as controls (CAG−). In cases, ATP4A, ATP4B, and PCA titers were increased compared with controls, whereas pepsinogen I was reduced ( P < 0.0001 for all). ATP4B, ATP4A, and pepsinogen I tests showed sensitivities of 77%, 75%, and 73% and specificities of 88%, 88%, and 80%, respectively. The receiver operating characteristic (ROC) area under the ROC curve (AUC) of these serological biomarkers confirmed their ability to discriminate cases from controls (ATP4B = 0.838, ATP4A = 0.826, pepsinogen I = 0.775, and PCA = 0.805), whereas the partial ROC-pAUC 90 analysis showed that the ATP4B test had the best diagnostic performance ( P = 0.008 vs ATP4; P = 0.0002 vs pepsinogen I). The presence of autoimmune or extensive gastritis was not significantly different between ATP4B positive or negative cases ( P = 0.217). DISCUSSION: PCAs are promising serological biomarkers for the identification of CAG in high-risk individuals, particularly in an autoimmune pattern but also in an extensive-multifocal atrophy pattern.

Intrinsic factor autoantibodies by luminescent immuno-precipitation system in patients with corpus atrophic gastritis

“…In this cross-sectional study, we used archived sera from a prospective case-finding study of 215 consecutive adults presenting at our centre (May 2017–April 2018) with a clinical suspicion of CAG who matched the inclusion criteria [ 20 ]. Informed consent was provided by all participants and the study conducted with the approval of the local ethical committee (No.5390/2019).…”

“…The clinical suspicion of CAG mainly arose due to the presence of anemia (61.9%) or dyspepsia (31.2%), or less frequently for other reasons such as a family history of autoimmune disease or gastric malignancy (6.9%). Adult (>18 years) subjects with one of the following criteria underwent esophagogastroduodenoscopy with three biopsy samples taken from antrum and three from the corpus mucosa, following a standardized protocol for histopathological assessment (updated Sydney System) [ 11 , 20 , 22 ]. Diagnosis and grading of gastritis were based on the presence of focal or complete oxyntic glands loss and/or their replacement with intestinal or pseudo-pyloric glands [ 11 , 20 , 22 ].…”

“…Adult (>18 years) subjects with one of the following criteria underwent esophagogastroduodenoscopy with three biopsy samples taken from antrum and three from the corpus mucosa, following a standardized protocol for histopathological assessment (updated Sydney System) [ 11 , 20 , 22 ]. Diagnosis and grading of gastritis were based on the presence of focal or complete oxyntic glands loss and/or their replacement with intestinal or pseudo-pyloric glands [ 11 , 20 , 22 ]. The exclusion criteria were: 1) age<18 years, 2) a previous diagnosis of CAG, 3) previous inclusion in an endoscopic surveillance program for gastric malignant conditions.…”

“…All subjects were Caucasians, with no statistically significant difference in age or sex between cases (median age 64 years, range 18–88; 67.6% female) and controls (median age: 67 years, range 23–90; 53.6% female). Sera from these subjects were used previously in a study focusing on serological markers of CAG, including PCA against subunits A and B of the gastric parietal cell proton pump ATP4 [ 20 ]. In the current study these sera, preserved at −20 °C, were re-analyzed for IFA using the LIPS assay.…”

“…A previous study showed an overall IFA-positivity by ELISA in 27% of patients with CAG, and the combination of PCA and IFA increased diagnostic performance, particularly in CAG with PA [ 11 ]. An innovative liquid-phase method called LIPS (Luciferase Immuno-Precipitation System) has been used recently to determine circulating autoantibodies in a wide range of diseases including CAG [ [17] , [18] , [19] ]; for this condition, the diagnostic performance of LIPS-assayed PCA confirmed them as reliable markers of oxyntic mucosa damage [ 19 , 20 ]. Given this precedent, the current study aimed to assess the presence and diagnostic performance of IFA determined by LIPS in patients with CAG and controls.…”