Diagnostic performance of three serologic tests in childhood celiac disease

Abstract

Background: IgA- and IgG-antibodies against deamidated gliadin peptides (DGP) specifically bind the disease-inducing antigen and might be superior to transglutaminase type 2 (TG2) IgA in monitoring patients on a gluten-free diet (GFD). The aim of this study was to compare the performance of DGP-IgG and DGP-IgA with TG2-IgA of four manufacturers in pediatric celiac patients at diagnosis and during follow-up under a GFD.

Patients and Methods: In total 411 sera of 91 IgA competent children with biopsy proven celiac disease were analyzed at diagnosis and during follow-up on a GFD. Ninety-eight children with normal duodenal histology served as controls. The tests (TheBindingSite, Euroimmun, Phadia, part of Thermo Fisher Scientific, INOVA) for detection of TG2-IgA, DGP-IgG and DGP-IgA were used according to the manufacturers’ instructions.

Results: Sensitivity to diagnose CD was high for TG2-IgA (100 %) and DGP-IgG (90 − 100 %), but lower for DGP-IgA (67 − 86 %). Specificity was high for all tests (97 – 100 %). The frequency of TG2-IgA titers > 10 × upper limit of normal at diagnosis ranged from 47 − 90 %. Under a GFD DGP-IgA became negative more rapidly than DGP-IgG and TG2-IgA. Non-adherence to GFD was best indicated by positive TG2-IgA.

Conclusions: Combined testing for TG2-IgA and DGP-IgG does not increase the detection rate of CD in IgA competent children compared to TG2-IgA only. There are significant differences with respect to proportions of celiac children with titers > 10 × ULN between the manufacturers. This calls for harmonization of tests. TG2-IgA showed the highest titer rise with non-adherence to the GFD, independent of the manufacturer.

Zusammenfassung

Hintergrund: IgA- und IgG-Antikörper gegen deaminierte Gliadin-Peptide (DGP) binden das krankheitsauslösende Antigen und könnten deshalb bei Patienten mit Zöliakie besser zur Verlaufskontrolle unter Gluten-freier Diät (GFD) geeignet sein als Gewebs-Transglutaminase 2 (TG2)-IgA. Ziel dieser Studie war der Vergleich von DGP-IgG und DGP-IgA mit TG2-IgA 4 verschiedener Hersteller zur Diagnostik und Verlaufskontrolle von Kindern mit Zöliakie.

Patienten und Methodik: Es wurden 411 Seren von 91 IgA-kompetenten Kindern mit Biopsie-gesicherter Zöliakie zum Zeitpunkt der Diagnosestellung sowie unter GFD untersucht und mit Seren von 98 Kontrollpatienten verglichen. Die Tests (TheBindingSite, Euroimmun, Phadia/Thermo Fisher Scientific, INOVA) zur Detektion von TG2-IgA, DGP-IgG und DGP-IgA wurden entsprechend der Herstellerangaben durchgeführt.

Ergebnisse: TG2-IgA und DGP-IgG hatten eine signifikant höhere Sensitivität (100 % und 90 − 100 %) für die Diagnose Zöliakie als DGP-IgA (67 − 86 %). Alle Tests hatten eine vergleichbar hohe Spezifität (97 – 100 %). Die Häufigkeit von TG2-IgA > 10 × des oberen Normwerts (ULN) zum Zeitpunkt der Diagnosestellung lag zwischen 47 und 90 %. Unter GFD normalisierte sich DGP-IgA früher als DGP-IgG und TG2-IgA. Bei Diätfehlern hatten TG2-IgA die deutlichsten Titeranstiege.

Schlussfolgerung: Die kombinierte Messung von TG2-IgA und DGP-IgG hat im Vergleich zur alleinigen Bestimmung von TG2-IgA bei IgA-kompetenten Kindern mit Zöliakie keinen diagnostischen Vorteil. Die hohe Variabilität der TG2-IgA > 10 × ULN zeigt, dass eine Harmonisierung der kommerziellen Tests anzustreben ist. Diätfehler unter GFD werden am besten durch einen Anstieg der TG2-IgA diagnostiziert.

Schlüsselwörter

Sprue - Nahrungsmittelintoleranz - Malabsorption - anti-deaminierte Gliadin-Peptide - anti-Gewebs-Transglutaminase 2 - Gluten-freie Diät

Key words

celiac disease - food intolerance - malabsorption - anti-deamidated gliadinpeptide antibody - anti-tissue transglutaminase 2 - gluten-free diet (GFD)

• References

• 1 Husby S, Koletzko S, Korponay-Szabo IR et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 2012; 54: 136-160
• 2 Leffler DA, Schuppan D. Update on serologic testing in celiac disease. Am J Gastroenterol 2010; 105: 2520-2524
• 3 Prince HE. Evaluation of the INOVA diagnostics enzyme-linked immunosorbent assay kits for measuring serum immunoglobulin G (IgG) and IgA to deamidated gliadin peptides. Clin Vaccine Immunol 2006; 13: 150-151
• 4 Sugai E, Vazquez H, Nachman F et al. Accuracy of testing for antibodies to synthetic gliadin-related peptides in celiac disease. Clin Gastroenterol Hepatol 2006; 4: 1112-1117
• 5 Prause C, Ritter M, Probst C et al. Antibodies against deamidated gliadin as new and accurate biomarkers of childhood coeliac disease. J Pediatr Gastroenterol Nutr 2009; 49: 52-58
• 6 Niveloni S, Sugai E, Cabanne A et al. Antibodies against synthetic deamidated gliadin peptides as predictors of celiac disease: prospective assessment in an adult population with a high pretest probability of disease. Clin Chem 2007; 53: 2186-2192
• 7 Giersiepen K, Lelgemann M, Stuhldreher N et al. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J Pediatr Gastroenterol Nutr 2012; 54: 229-241
• 8 Olen O, Gudjonsdottir AH, Browaldh L et al. Antibodies against deamidated gliadin peptides and tissue transglutaminase for diagnosis of pediatric celiac disease – diagnostic performance and cost in clinical practice. J Pediatr Gastroenterol Nutr 2012; 55: 695-700
• 9 Monzani A, Rapa A, Fonio P et al. Use of deamidated gliadin peptide antibodies to monitor diet compliance in childhood celiac disease. J Pediatr Gastroenterol Nutr 2011; 53: 55-60
• 10 Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999; 11: 1185-1194
• 11 Pellegrino S, Villanacci V, Sansotta N et al. Redefining the intraepithelial lymphocytes threshold to diagnose gluten sensitivity in patients with architecturally normal duodenal histology. Aliment Pharmacol Ther 2011; 33: 697-706
• 12 Walker MM, Murray JA, Ronkainen J et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010; 139: 112-119
• 13 Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65: 909-911
• 14 Rashtak S, Ettore MW, Homburger HA et al. Comparative usefulness of deamidated gliadin antibodies in the diagnosis of celiac disease. Clin Gastroenterol Hepatol 2008; 6: 426-432 ; quiz 370
• 15 Vermeersch P, Geboes K, Marien G et al. Diagnostic performance of IgG anti-deamidated gliadin peptide antibody assays is comparable to IgA anti-tTG in celiac disease. Clin Chim Acta 2010; 411: 931-935
• 16 Simell S, Kupila A, Hoppu S et al. Natural history of transglutaminase autoantibodies and mucosal changes in children carrying HLA-conferred celiac disease susceptibility. Scand J Gastroenterol 2005; 40: 1182-1191
• 17 Vermeersch P, Geboes K, Marien G et al. Defining thresholds of antibody levels improves diagnosis of celiac disease. Clin Gastroenterol Hepatol 2013; 11: 398-403
• 18 Egner W, Shrimpton A, Sargur R et al. ESPGHAN guidance on coeliac disease 2012: multiples of ULN for decision making do not harmonise assay performance across centres. J Pediatr Gastroenterol Nutr 2012; 55: 733-735
• 19 Liu E, Li M, Emery L et al. Natural history of antibodies to deamidated gliadin peptides and transglutaminase in early childhood celiac disease. J Pediatr Gastroenterol Nutr 2007; 45: 293-300
• 20 Basso D, Guariso G, Fogar P et al. Antibodies against synthetic deamidated gliadin peptides for celiac disease diagnosis and follow-up in children. Clin Chem 2009; 55: 150-157
• 21 Nachman F, Sugai E, Vazquez H et al. Serological tests for celiac disease as indicators of long-term compliance with the gluten-free diet. Eur J Gastroenterol Hepatol 2011; 23: 473-480
• 22 Lahdeaho ML, Maki M, Laurila K et al. Small-bowel mucosal changes and antibody responses after low- and moderate-dose gluten challenge in celiac disease. BMC Gastroenterology 2011; 11: 129
• 23 Leffler D, Schuppan D, Pallav K et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 2012;
• 24 Vecsei E, Steinwendner S, Kogler H et al. Follow-up of pediatric celiac disease: value of antibodies in predicting mucosal healing, a prospective cohort study. BMC Gastroenterology 2014; 14: 28
• 25 Hopper AD, Hadjivassiliou M, Hurlstone DP et al. What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis. Clin Gastroenterol Hepatol 2008; 6: 314-320
• 26 Sharkey LM, Corbett G, Currie E et al. Optimising delivery of care in coeliac disease – comparison of the benefits of repeat biopsy and serological follow-up. Aliment Pharmacol Ther 2013; 38: 1278-1291
• 27 Li M, Yu L, Tiberti C et al. A report on the International Transglutaminase Autoantibody Workshop for Celiac Disease. Am J Gastroenterol 2009; 104: 154-163