Introduction

The serology, in terms of both positive anti-endomysial antibodies (EMA) and anti-tissue transglutaminases (a-tTG), plays a crucial role for coeliac disease (CD) diagnosis. More recently, deamidated anti-gliadin peptides (DGP) were added to the diagnostic work-up of CD in view of their accuracy. Strictly, EMA is an immunofluorescence-based tool, more expensive and operator-dependent than a-tTG and DGP (both based by ELISA).

Aims & Methods

Aim: To test the diagnostic accuracy of the a-tTG/DGP compared to the classical EMA/a-tTG combination for CD diagnosis.
Methods: From November 2020 to October 2022, we performed an observational prospective study including all consecutive adult patients with suspected CD. All subjects were tested for EMA (positive/negative), a-tTG (positive>7 U/mL) and DGP-IgA (positive>5.5 U/mL). CD diagnosis was made in presence of Marsh ≥2 at histilogy, and positive EMA. A ROC curve was constructed to establish the best specificity cut-off of a-tTG and DGP levels, which would predict the presence of Marsh ≥2 and Marsh 3 at histology. Furthermore, the diagnostic accuracy of the a-tTG/DG in comparison with EMA/a-tTG combination was performed. Also, a basic cost-analysis for the application of the two types of serological combination was effectuated.

Results

The study included 275 CD patients. Histology showed Marsh 1 in 9.9%, Marsh 2 in 4.5%, Marsh 3 in 85.6.%. The best cut-off value of a-tTG for predicting Marsh ≥2 was 42 U/mL (sensitivity 70%; specificity 100%; PPV 100%; NPV 24.1%) while it was 68.4 U/mL for atrophy (sensitivity 69%, specificity 100%; PPV 100%; NPV 31%). The best cut-off value of DGP for predicting Marsh ≥2 was 56 U/mL (sensitivity 59%, specificity 100%; PPV 100%; NPV 23%), being 78 U/mL for atrophy (sensitivity 68%; specificity 100%; PPV 100%; NPV 32.1%). When considering the diagnostic accuracy of the serological combination, a-tTG/EMA showed: sensitivity 97%; specificity 100%, PPV 100%; NPV 97%; the a-tTG/DGP combination presented: sensitivity 94%, specificity of 100%, PPV 100% and NPV 93% (p=N.S.). About cost-analysis, when including our entire population, the use of the a-tTG/DGP combination determined a saving of about 3790E respect to a-tTG/EMA association.

Conclusion

The serological ELISA diagnostic combination of a-aTG/DGP is accurate for the diagnosis of CD and could reduce the costs and the operator-dependency of the EMA procedure. DGP could substitute EMA in combination with a-tTG for diagnosis of CD.

Introduction

Anti-tissue transglutaminase IgA antibodies (tTG) are used in the follow-up of celiac disease (CD) to assess adherence to a gluten-free diet (GFD). Persistent positivity may indicate the need for histological reassessment. There is limited information about the rate of complete normalization of tTG and associated factors. Our objective was to evaluate the percentage, kinetics, and factors related to tTG normalization.

Aims & Methods

This was a retrospective observational study including patients with tTG testing at diagnosis and follow-up monitoring of these antibodies from 1991 to 2023 in a specialized unit dedicated to patients with CD. Inclusion criteria were: patients over 16 years of age at diagnosis, initially elevated tTG titres, and at least one serological follow-up after starting a GFD. Time to tTG normalization was estimated using the Kaplan-Meier method. Comparisons between groups were performed using the log-rank test. The association between demographic and clinicopathological characteristics at diagnosis and time to tTG normalization was assessed using Cox regression analysis.

Results

A total of 179 patients were included (75% female, mean age 40 ± 16 years). Duodenal atrophy was present in 81%, and 79% had symptoms. 83% strictly adhered to a GFD. Median follow-up was 3 years. The incidence rate of tTG normalization was 35% per patient-year. The cumulative tTG normalization rate was 38% (95% CI: 30-45) at 1 year, 61% (53-69) at 2 years, 70% (63-77) at 3 years, 80% (73-87) at 4 years, 81% (74-89) at 5 years, and 95% (88-100) at 10 years. The median time to tTG normalization was 24 months (95% CI: 20–28). Table 1 shows Kaplan–Meier estimates expressed as percentages of tTG normalization by adherece to GFD and baseline tTG. In the multivariable analysis, two factors were found to be significantly associated with the normalization of tTG: lower baseline tTG and good adherence to a GFD. Regarding baseline tTG level, patients with titres ≤ 286 U/ml (median) had 2.46 times higher likelihood of antibody normalization compared to those with higher titres (HR: 2.46; 95% CI: 1.69–3.56; p < 0.001). Regarding adherence to a GFD, patients who followed a strict GFD had 5.38 times higher likelihood of tTG normalization (HR: 5.38; 95% CI: 2.79–10.36; p < 0.001).

Table 1. Kaplan–Meier estimates expressed as percentages of normalization (with 95% CIs) after CD diagnosis, by adherece to GFD and baseline tGA titres.

Conclusion

1. The incidence rate of tTG normalization in CD patients after initiating a GFD was 35% per patient-year of follow-up.
2. In the long-term (10 years), 95% of CD patients achieved tTG normalization.
3. Lower tTG titres at diagnosis and good adherence to the GFD were predictive factors for tTG normalization.
4. Understanding the kinetics of tTG normalization according to various factors is essential before considering histological reassessment for suspected poor disease progression.

Introduction

Gluten free diet (GFD) is the one therapy for patients affected by celiac disease (CD). Dietary products are considered safe (“without” gluten) when containing less of 20 ppm (20 mg/kg). CD diagnosis is quite simple in most cases, however some patients start GFD before the serological and histological approach, so significantly complicating the CD diagnostic work-up. In these cases, the Oslo guidelines for CD suggest a 14-day gluten intake > 3 gr (about 2 slices of bread/day) to induce serological and histological changes in most CD patients; though, many subjects refuse this method being fearful for symptoms reviving (1). In 2007, Catassi showed that the intake of a daily dose of 50 mg/day of gluten for 3 months was able to determine villous atrophy and serological positivity in most CD patients (2).

Aims & Methods

Aims: Starting from these considerations, we performed a pilot dietary study administering a daily low-dose of gluten in form of a package of “crackers” (2-4 crackers/day; about 60-120 mg of gluten/day) for 3 months, in order to detect serological/histological activation in subjects with doubt CD already on “self-prescribed” GFD.
Methods: From May 2019 to September 2022, all DQ2/DQ8+ adult patients with a doubt of CD who had started a self-prescribed GFD before the diagnostic work-up and that had refused the traditional gluten challenge. All patients were recruited at Gastroenterology Unit of University of Naples and Salerno. All subjects were invited to continue their GFD by adding a half (or full) package of crackers containing gluten for a 3-months period. At the end of 3 months, all patients were analysed for the presence of Ab anti-transglutaminases (a-tTG), anti-endomisyal antibodies (EMA) and deamidated gluten peptited (DGP). All patients with positive serology underwent endoscopic/histological evaluation. The diagnosis of CD was made by histology in accordance with Marsh-Oberhuber classification. Furthermore, the grade of satisfaction for this kind of challenge diet and the possible onset of adverse events were recorded. Patient’s satisfaction about this kind of challenge was evaluated by a simple VAS (1-10).

Results

At the end, we enrolled 120 patients (M/F 42/78; mean age 38 years). All patients could terminate the study without relevant adverse events. Serological positivity/activation was detected in 54 patients (45%): positive a-tTG: 51 patients; EMA (slight/full) positivity: 49 patients; DGP positivity: 48 patients. At histology, 47 (88%) were atrophic, while 7 subjects showed a Marsh 1-2 grade. The remaining 66 patients continued the trial for further 3 months without substantial serological modifications and, finally, were considered as not CD patients. Regarding patient’s satisfaction, 99 patients (83%) resulted to be satisfied and reassured by this dietary approach. About adverse events, 15 patients (12%) recorded bloating, 12 (10%) mild pain and 8 (6%) mild diarrhoea.

Conclusion

Low-dose gluten diet by using “crackers” could be a very simple, useful, and safe diagnostic approach in subject with doubt of CD who had start a GFD before the regular diagnostic work-up for CD.

References

1) Ludvigsson JF et. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014;63:1210-28.
2) Catassi C et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr 2007 Jan;85(1):160-6.

Introduction

Current international guidelines recommend duodenal biopsies to confirm the diagnosis of coeliac disease in adult patients. However, growing evidence suggests that IgA anti-tissue transglutaminase (tTg) antibody levels ≥10 times the upper limit of normal (ULN) can accurately predict coeliac disease, eliminating the need for biopsy. We performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of the no-biopsy approach for the diagnosis of coeliac disease in adults.

Aims & Methods

We systematically searched MEDLINE, EMBASE, Cochrane Library and Web of Science from January 1998 to April 2023 for studies reporting the sensitivity and specificity of IgA-tTG ≥10×ULN against duodenal biopsies (Marsh grade ≥2) in adults with suspected coeliac disease. We used a bivariate random-effects model to calculate the summary estimates of sensitivity, specificity, positive and negative likelihood ratios. The positive and negative likelihood ratios were used to calculate the positive predictive value (PPV) of the no-biopsy approach across different pre-test probabilities of coeliac disease. This study was registered with PROSPERO, number CRD42023398812.

Results

Thirteen studies comprising 10,078 participants from 11 countries were included. The pooled prevalence of biopsy-proven coeliac disease in the included studies was 60% (95% CI, 36% - 84%). The summary sensitivity of IgA-tTG ≥10×ULN was 52% (95% CI, 41% - 62%), and the summary specificity was 100% (95% CI, 98% - 100%). The area under the summary receiver operator characteristic curve was 0.84 (95% CI, 0.77 – 0.89). The PPV of the no-biopsy approach to identify patients with coeliac disease was 68%, 90%, 96%, and 99% if coeliac disease prevalence was 1%, 4%, 10% and 30%, respectively. Between-study heterogeneity was moderate (I²=25%), and additional sensitivity analyses did not significantly alter our findings.

Conclusion

The results of this meta-analysis support the adoption of the no-biopsy approach to diagnose adult patients with coeliac disease in secondary care settings, where the pre-test probability of coeliac disease is high. Biopsy could be avoided in almost one-in-three patients referred to gastroenterology with suspected coeliac disease. Our findings may inform future guidelines for the diagnosis of coeliac disease in adults.