Serological Investigation of Persistent Villous Atrophy in Celiac Disease

Abstract Introduction: Persistent villous atrophy (VA) is not uncommon in celiac disease (CeD) while patients take a gluten-free diet (GFD). Methods: We conducted a retrospective study with 122 serum samples collected from controls and CeD patients either at the initial diagnosis or follow-up during endoscopy. These samples were assigned to three groups: non-celiac control, non-VA CeD (Marsh score 0-2), and VA CeD (Marsh score 3a-3c). We established an in-house multiplex assay to identify potential serological biomarkers for villous atrophy. We assessed autoantibodies reported to affect the small intestine, including IgA and IgG antibodies against tissue transglutaminase (tTG), interferons, villin, actin, autoimmune enteropathy-related 75 kDa antigen (AIE-75), and tryptophan hydroxylase (TPH)-1, as well as 27 cytokines. The apolipoproteins quantified included apo A1, apo B-100, and apo A4, which were produced predominantly by the intestinal epithelium or expressed specifically in villi. Results: Autoantibody levels were high only for tTG antibodies, which performed well in initial CeD diagnosis, but suboptimally for VA prediction during follow-up, as 14.6% of the follow-up patients with VA had low tTG-IgA. Increasing dilution improved tTG-IgA quantification, particularly when the antibody levels were extremely high, but did not significantly improve VA detection. Among those with low tTG-IgA and persistent VA, high proinflammatory cytokines were observed in two patients. Median LDL-C levels were significantly lower in the VA CeD group ( P = 0.03). Apolipoprotein levels were similar in patients with and without VA, but diverged between those on a gluten-free diet (GFD) or not. Conclusions: tTG-IgA as a biomarker is suboptimal for villous atrophy prediction while on a GFD. Persistent villous atrophy is associated with low LDL-C levels, and partially related to persistent high proinflammatory cytokines.