High-titre circulating tissue transglutaminase-2 antibodies predict small bowel villous atrophy, but decision cut-off limits must be locally validated

Abstract

SummaryNumerous studies suggest that high levels of circulating immunoglobulin (Ig)A tissue transglutaminase (TTG2) antibodies predict coeliac disease with high specificity. Accordingly, it has been suggested that duodenal biopsy may not be required routinely for diagnostic confirmation where quantitative serology identifies the presence of high antibody titres. However, defining a cut-off TTG2 threshold is problematic, as the multiple available assay methods are not harmonized and most studies have been focused on the paediatric population. Recent paediatric guidelines proposed a TTG2 antibody diagnostic cut-off at 10 × the upper limit of normal (ULN) for the method; however, concerns remain about errors of generalization, between both methods and laboratories. In this study, we used retrospective laboratory data to investigate the relationship between TTG2 antibody levels and Marsh 3 histology in the seropositive population of adults and children at a single centre. Among 202 seropositive patients with corresponding biopsies, it was possible to define a TTG2 antibody cut-off with 100% specificity for Marsh 3 histology, at just over 10 × ULN for the method. However, UK National External Quality Assurance Scheme returns during the study period showed a wide dispersion of results and poor consensus, both between methods and between laboratories using the same method. Our results support the view that high-titre TTG2 antibody levels have strong predictive value for villous atrophy in adults and children, but suggest that decision cut-offs to guide biopsy requirement will require local validation. TTG2 antibody assay harmonization is a priority, in order to meet the evolving requirements of laboratory users in this field.

Authors’ response: British Society of Gastroenterology guidelines on the diagnosis and management of coeliac disease

“…Studies continue to confirm our earlier paper7 showing that above such a threshold CD can be confidently diagnosed without recourse to a biopsy 3 5 6 8 9…”

Comparison of the Reliability of 17 Celiac Disease Associated Bio-Markers to Reflect Intestinal Damage

“…For the last 26 years, numerous studies evaluated only one serological marker in relation to intestinal pathology, mainly EMA and later on, tTg [8,9]. Fewer studies checked two antibodies, mainly IgA-tTg and IgA-EMA, the latest being in 2012-13 [10][11][12][13].…”

Harmonization in laboratory medicine: more than clinical chemistry?

“…After the discovery of the clinical value of immunoglobulin A (IgA) anti-tissue transglutaminase (tTG) antibody assay, which is the test of choice for detecting the disease, it was suggested that a histological assessment might be omitted in symptomatic children who have anti-tTG IgA levels 10-fold the upper reference limit (URL), as shown in data from some primary studies [50,51]. However, this is an arbitrary cutoff value, and a wide disparity of results and poor comparability, both between methods and between laboratories, has been reported [52]. Efforts to standardize and harmonize anti-tTG assays are therefore needed, particularly as the clinical goal, namely, the avoidance of an invasive examination, represents a major advantage for patients' safety and healthcare costs.…”