Add-On: Celiac Profile

Tissue transglutaminase is a calcium-dependent enzyme that cross-links glutamine residues in gluten peptides to lysine residues in extracellular matrix proteins, creating immunogenic epitopes in the small intestinal mucosa. In genetically susceptible individuals, this process triggers an adaptive immune response that generates IgA antibodies against both gluten peptides and tissue transglutaminase itself. Circulating tTG-IgA antibodies correlate closely with active small bowel mucosal injury and fall with strict adherence to a gluten-free diet.

tTG-IgA is the single most sensitive and specific serological marker for coeliac disease, recommended as the first-line test in both symptomatic and at-risk populations. Sensitivity exceeds 90 per cent in patients with villous atrophy, though it may be lower in mild enteropathy. A positive result in the appropriate clinical or genetic context prompts referral for small bowel biopsy, the diagnostic gold standard, while a negative result in an IgA-sufficient individual makes active coeliac disease unlikely.

Immunoglobulin A is the dominant antibody isotype at mucosal surfaces and in external secretions, where it provides first-line adaptive immune defence. Selective IgA deficiency, the most common primary immunodeficiency, affects approximately 1 in 300–700 individuals and is more prevalent in coeliac disease populations. When total IgA is low or absent, IgA-based serological tests for coeliac disease will be falsely negative regardless of disease activity.

Total IgA is measured alongside tTG-IgA to identify IgA deficiency, which would invalidate an IgA-based coeliac screen. In IgA-deficient patients, IgG-based tests—tissue transglutaminase IgG, deamidated gliadin peptide IgG, or endomysial IgG—must be used instead.

Gliadin, a prolamin component of wheat gluten, is resistant to complete proteolysis by gastrointestinal enzymes. Tissue transglutaminase deamidates specific glutamine residues in gliadin fragments to glutamic acid, enhancing binding to HLA-DQ2 or HLA-DQ8 and triggering T-cell activation. Antibodies to deamidated gliadin peptides reflect this adaptive immune response and correlate with mucosal inflammation, though less closely than tTG-IgA.

DGP-IgA adds incremental sensitivity in young children (under two years) and in patients with mild enteropathy or Marsh I/II histology, where tTG-IgA may be weakly positive or negative. It is less specific than tTG-IgA and is not recommended as a standalone first-line test, but its inclusion in a panel can reduce false-negative results in select populations.

IgG antibodies to deamidated gliadin peptides are produced in parallel with IgA responses but do not depend on mucosal IgA secretion. Their clinical utility is primarily as a surrogate marker when IgA-based tests are unreliable.

DGP-IgG is essential in IgA-deficient individuals, where it serves as the primary serological marker for coeliac disease. It also adds value in very young children, where the IgG response may mature earlier than IgA. In IgA-sufficient patients it is less specific than tTG-IgA and should not replace it as the first-line test.