Seronegative Celiac Disease and Immunoglobulin Deficiency: Where to Look in the Submerged Iceberg?

Abstract

In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten “challenge” are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs’ range of 15–25/100 enterocytes, suggesting that there may be a “grey zone” of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association.

Intraepithelial lymphocytes, scores, mimickers and challenges in diagnosing gluten-sensitive enteropathy (celiac disease)

“…Common variable immunodeficiency (CVID) may also manifest with gastrointestinal symptoms, being the second most common primary immunodeficiency, and its diagnosis relies on recurrent infections, decreased IgG levels at least 2-standard deviations below normal with at least decreased levels of one other immunoglobulin subclass, exclusion of other causes of immunodeficiency, and a failure to mount a response to vaccination. In 2/3 patients with CVID undergoing endoscopy, the duodenal biopsy shows IEL with or without villous architectural changes and 2 CVID characteristic clues are the paucity or absence of plasma cells with prominent crypt apoptosis in CVID[ 29 , 111 - 113 ].…”

Value of routine duodenal mucosal biopsies in the evaluation of anemia in a large Australian referral centre

“…The absence of either of these haplotypes virtually excludes the diagnosis of celiac disease (NPV > 99%) . The limiting feature of genetic testing is the low specificity, with these HLA subtypes present in 20–30% of the population . However, by testing for HLA‐DQ2/8 only in a subgroup of female patients with confirmed iron deficiency, biopsies could be limited to only 20–30% of this population.…”

Role of capsule endoscopy in suspected celiac disease: A European multi-centre study

“…In patients with seronegative CD (Group-I), the absence of antibodies could be associated with fluctuating antibodies, advanced age or a GFD[ 4 ]. The negative serology is inversely related to the degree of atrophy because this entity includes initial states (latent and potential atypical CD)[ 21 ], reducing the benefits of CE[ 22 ]. However, in our study, CE is very beneficial in these cases because CE has a high global diagnosis effect, providing a diagnosis of villous atrophy in almost half of the patients and in a significant proportion of the patients who had complicated CD.…”