A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways

Abstract

Background: Changing perspectives on the natural history of celiac disease (CD), new serology and genetic tests, and amended histological criteria for diagnosis cast doubt on past prevalence estimates for CD. We set out to establish a more accurate prevalence estimate for CD using a novel serogenetic approach.

Methods: The human leukocyte antigen (HLA)-DQ genotype was determined in 356 patients with 'biopsy-confirmed' CD, and in two age-stratified, randomly selected community cohorts of 1,390 women and 1,158 men. Sera were screened for CD-specific serology.

Results: Only five 'biopsy-confirmed' patients with CD did not possess the susceptibility alleles HLA-DQ2.5, DQ8, or DQ2.2, and four of these were misdiagnoses. HLA-DQ2.5, DQ8, or DQ2.2 was present in 56% of all women and men in the community cohorts. Transglutaminase (TG)-2 IgA and composite TG2/deamidated gliadin peptide (DGP) IgA/IgG were abnormal in 4.6% and 5.6%, respectively, of the community women and 6.9% and 6.9%, respectively, of the community men, but in the screen-positive group, only 71% and 75%, respectively, of women and 65% and 63%, respectively, of men possessed HLA-DQ2.5, DQ8, or DQ2.2. Medical review was possible for 41% of seropositive women and 50% of seropositive men, and led to biopsy-confirmed CD in 10 women (0.7%) and 6 men (0.5%), but based on relative risk for HLA-DQ2.5, DQ8, or DQ2.2 in all TG2 IgA or TG2/DGP IgA/IgG screen-positive subjects, CD affected 1.3% or 1.9%, respectively, of females and 1.3% or 1.2%, respectively, of men. Serogenetic data from these community cohorts indicated that testing screen positives for HLA-DQ, or carrying out HLA-DQ and further serology, could have reduced unnecessary gastroscopies due to false-positive serology by at least 40% and by over 70%, respectively.

Conclusions: Screening with TG2 IgA serology and requiring biopsy confirmation caused the community prevalence of CD to be substantially underestimated. Testing for HLA-DQ genes and confirmatory serology could reduce the numbers of unnecessary gastroscopies.

Figure 1

Human leukocyte antigen (HLA-DQ genetic status and celiac disease (CD)-specific serology. (A) HLA-DQ status of female (F) and male (M) community cohorts, and those who tested positive for anti-gliadin IgG (AGG) , anti-gliadin IgA (AGA), IgA specific for native human transglutaminase (TG)2, and composite TG2/DGP IgA/IgG (Comp.). Total numbers of subjects are in brackets. (B) HLA-DQ genotypes of women and men in the combined community cohorts classified by measured level of TG2 IgA and whether endomysial antibody (EMA) was also positive; or composite TG2/DGP IgA/IgG (Comp.) and whether all or at least one confirmatory serology (TG2 IgA, DGP IgA, or DGP IgG) was abnormal. Numbers of subjects are in brackets. DGP, Deamidated gliadin-derived peptide.

Figure 2

Community prevalence estimates for celiac disease (CD). Estimated prevalence of CD with 95% confidence intervals per 1,000 adult females (F) or male (M) subjects, based upon enrichment of human leukocyte antigen (HLA)-DQ2.5, DQ8, and DQ2.2 in subjects who were seropositive for transglutaminase (TG)2 IgA (TG2+), TG2 IgA+ and then endomysial antibody (EMA)+, composite TG2/DGP IgA/IgG (Comp+), Comp.+ and then TG2 IgA+, deamidated gliadin-derived peptide (DGP)-G+ or DGP-A+ (Comp + One+), and for Comp+ and then TG2 IgA+, DGP-G+ and DGP-A+ (Comp + All+).