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Review
. 2012 Nov 14;18(42):6036-59.
doi: 10.3748/wjg.v18.i42.6036.

Celiac disease: prevalence, diagnosis, pathogenesis and treatment

Naiyana Gujral  1 , Hugh J Freeman, Alan B R Thomson
Affiliations
Review

Celiac disease: prevalence, diagnosis, pathogenesis and treatment

Naiyana Gujral et al. World J Gastroenterol. .

Abstract

Celiac disease (CD) is one of the most common diseases, resulting from both environmental (gluten) and genetic factors [human leukocyte antigen (HLA) and non-HLA genes]. The prevalence of CD has been estimated to approximate 0.5%-1% in different parts of the world. However, the population with diabetes, autoimmune disorder or relatives of CD individuals have even higher risk for the development of CD, at least in part, because of shared HLA typing. Gliadin gains access to the basal surface of the epithelium, and interact directly with the immune system, via both trans- and para-cellular routes. From a diagnostic perspective, symptoms may be viewed as either "typical" or "atypical". In both positive serological screening results suggestive of CD, should lead to small bowel biopsy followed by a favourable clinical and serological response to the gluten-free diet (GFD) to confirm the diagnosis. Positive anti-tissue transglutaminase antibody or anti-endomysial antibody during the clinical course helps to confirm the diagnosis of CD because of their over 99% specificities when small bowel villous atrophy is present on biopsy. Currently, the only treatment available for CD individuals is a strict life-long GFD. A greater understanding of the pathogenesis of CD allows alternative future CD treatments to hydrolyse toxic gliadin peptide, prevent toxic gliadin peptide absorption, blockage of selective deamidation of specific glutamine residues by tissue, restore immune tolerance towards gluten, modulation of immune response to dietary gliadin, and restoration of intestinal architecture.

Keywords: Celiac disease; Demography; Diagnosis; Pathogenesis; Treatment.

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Figures

Figure 1
Figure 1
Prevalence of celiac disease worldwide. N/A: Not available.
Figure 2
Figure 2
Factors necessary for celiac disease development[96] (adapted). HLA: Human leukocyte antigen.
Figure 3
Figure 3
Mechanisms of mucosal damage in celiac disease[80] (adapted). Gliadin peptides crosses the enterocyte by paracellular tight junctions (TJ) as a consequence of increased release of zonulin leading to impaired mucosal integrity upon 19 mer gliadin binding to chemokine (C-X-C motif) receptor 3 (CXCR3) receptor, or via transcytosis, or retrotranscytosis of secretory immunoglobulin A (IgA) through transferrin receptor CD71. Tissue transglutaminase (tTG) deamidates or crosslinks 33 mer gliadin which is then recognized by human leukocyte antigen (HLA)-DQ2 or -DQ8 molecules of antigen presenting cell (APC). APC presents the toxic peptide to CD4+ T cells. Activated gluten-reactive CD4+ T-cells produce high levels of pro-inflammatory cytokines. T helper 1 (Th1) cytokines promote increased cytotoxicity of intraepithelial lymphocytes (IELs) and natural killer (NK) T cells which cause apoptotic death of enterocytes by the Fas/Fas ligand (FasL) system, or interleukin 15 (IL-15)-induced perforin/granzyme and homodimeric natural killer-activating receptor-major histocompatibility-classIchain-related gene A comple (NKG2D–MICA) signaling pathways. The production of T-helper2 (Th2) cytokines activate and induce clonal expansion of B cells, which differentiate into (antigliadin and anti-tTG) antibody secreting plasma cells. Interaction between with the extracellular tTG and anti-tTG-autoantibody may induce epithelial damage. TCR: T cell receptor.
Figure 4
Figure 4
CD71 receptor-mediated transport of immunoglobulin A-gliadin complexes in celiac disease[136] (adapted). Gliadin bound to apically expressed CD71 receptor in active celiac disease individual allows protected transport of gliadin into the lamina propria. SIgA: Secretory immunoglobulin A.
Figure 5
Figure 5
Proposed Zot intracellular signal mediated opening of intestinal tight junctions[146] (printed with permission). 1: Zot interacts with a specific Zot/Zonulin intestinal surface receptor; 2: Leading to protein internalization; 3: Activation of phospholipase C; 4: Hydrolyzes phosphatidyl inositol to release inositol 1,4,5-tris phosphate (PPI-3) and diacylglycerol (DAG), either via DAG or (4a) through the release of intracellular Ca2+ via PPI-3; 5: Protein kinase C alpha (PKCα) is then activated; 6: Membrane-associated, activated PKCα catalyzes the phosphorylation of _target protein(s); 7: With subsequent polymerization of soluble G-actin in F-actin; 8: This polymerization causes the rearrangement of the tight junctions (TJ) filaments and displacement of proteins [including zonula occludens-1 (ZO-1)]. As a result, intestinal TJ becomes loosened. IP3: Inositol trisphosphate.
Figure 6
Figure 6
Celiac disease diagnostic testing algorithm (adapted from Mayo Medical Laboratories, Mayo Foundation for Medical Education and Research). IgA: Immunoglobulin A; IgG: Immunoglobulin G; tTG: Tissue transglutaminase; EMA: Endomysial; HLA: Human leukocyte antigen; CD: Celiac disease.
Figure 7
Figure 7
A comparison between the Marsh classification for celiac disease. 1: Marsh-Oberhuber; 2: Grading system for celiac disease, and the new grading system; 3: Representative pictures of the grades A (original magnification, 20×; insert, 60×), B1 (20×), and B2 (20×), proposed in the new grading system. An alternative classification may simply describe “mild”, “moderate” or “severe (flat)” architectural changes[186] (printed with permission).
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