Negative predictive value of the repeated absence of gluten immunogenic peptides in the urine of treated celiac patients in predicting mucosal healing: new proposals for follow-up in celiac disease

Abstract

Background The treatment of celiac disease (CD) is a lifelong gluten-free diet (GFD). The current methods for monitoring GFD conformance, such as a dietary questionnaire or serology tests, may be inaccurate in detecting dietary transgressions, and duodenal biopsies are invasive, expensive, and not a routine monitoring technique. Objectives Our aim was to determine the clinical usefulness of urine gluten immunogenic peptides (GIP) as a biomarker monitoring GFD adherence in celiac patients and to evaluate the concordance of the results with the degree of mucosal damage. Methods A prospective observational study was conducted involving 22 de novo CD patients, 77 celiac patients consuming a GFD, and 13 nonceliac subjects. On 3 d of the week, urine samples were collected and the GIP concentrations were tested. Simultaneously, anti-tissue transglutaminase antibodies, questionnaire results, clinical manifestations, and histological findings were analyzed. Results Approximately 24% (18 of 76) of the celiac patients consuming a GFD exhibited Marsh II–III mucosal damage. Among this population, 94% (17 of 18) had detectable urine GIP; however, between 60% and 80% were asymptomatic and exhibited negative serology and appropriate GFD adherence based on the questionnaire. In contrast, 97% (31 of 32) of the celiac patients without duodenal damage had no detectable GIP. These results demonstrated the high sensitivity (94%) and negative predictive value (97%) of GIP measurements in relation to duodenal biopsy findings. In the de novo CD-diagnosed cohort, 82% (18 of 22) of patients had measurable amounts of GIP in the urine. Conclusions Determining GIP concentrations in several urine samples may be an especially convenient approach to assess recent gluten exposure in celiac patients and appears to accurately predict the absence of histological lesions. The introduction of GIP testing as an assessment technique for GFD adherence may help in ascertaining dietary compliance and to target the most suitable intervention during follow-up.

Poor Sensitivity of Fecal Gluten Immunogenic Peptides and Serum Antibodies to Detect Duodenal Mucosal Damage in Celiac Disease Monitoring

“…In our study, the main advantage of Liaison anti-tTG assay was the absence of false positives, as the two patients with positive concentrations had mucosal damage, while positive results in Quanta Flash assay were associated with lower adherence to a GFD measured by the CDAT questionnaire. In contrast, no association was observed between serum anti-tTG IgA concentrations and GIP results as also reported in previous studies [20,39], although others did find agreement between the two tests [40].…”

“…It should be noted that stool GIPs reflect gluten consumption 2-4 days before the sample is provided, so its use as a surrogate marker for mucosal damage, as suggested in some manufacturer-funded studies, needs to be evaluated carefully. Manufacturer-funded research assessing this issue showed good agreement (80-100%) between persistence of villous atrophy (Marsh types 2/3) and detectable GIPs in either urine [17,39] or both stool and urine [19]. However, our study found negative GIPs in 4 out of 6 patients with Marsh type 2/3 using a single determination in stool, overall providing remarkably low sensitivity (33.3%) and PPV (40.9%).…”

“…A single GIP determination displayed positive results in 22 patients (22.7%) and was associated with self-reported gluten consumption. Initial studies assessing urine or stool GIPs provided higher rates of 29.8% [16] and 46.5% [17], with positivity increasing further to between 58% to 89% when several samples were taken from the same patient over a period [20,39]. In these latest two studies, an increased span of testing, however, led to detecting patients with positive GIPs but no duodenal damage.…”

An efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease

“…Over 20 years ago, chromatographic analysis implied the existence of gluten-derived peptides in CeD patients' urine. This was confirmed more recently by antibody-based methods [24][25][26][27][28] . Indeed, most current gluten detection methods rely on monoclonal antibodies, which recognize amino acid motifs present in a subset of gluten proteins 29 .…”

“…Previous chromatographic and antibody-based detection methods suggested the presence of gluten-derived peptides in human urine but were incapable of directly elucidating their sequences [24][25][26][27][28] . To determine if an unbiased LC-MS/MS approach could be used for this purpose, we initially analyzed urine samples from volunteers who had consumed a meal rich in dietary gluten by following an extraction and analysis protocol typically used in LC-MS/MS-based proteomics studies (Supplementary Methods).…”