Celiac disease: a comprehensive current review

Abstract

Background: Celiac disease remains a challenging condition because of a steady increase in knowledge tackling its pathophysiology, diagnosis, management, and possible therapeutic options.

Main body: A major milestone in the history of celiac disease was the identification of tissue transglutaminase as the autoantigen, thereby confirming the autoimmune nature of this disorder. A genetic background (HLA-DQ2/DQ8 positivity and non-HLA genes) is a mandatory determinant of the development of the disease, which occurs with the contribution of environmental factors (e.g., viral infections and dysbiosis of gut microbiota). Its prevalence in the general population is of approximately 1%, with female predominance. The disease can occur at any age, with a variety of symptoms/manifestations. This multifaceted clinical presentation leads to several phenotypes, i.e., gastrointestinal, extraintestinal, subclinical, potential, seronegative, non-responsive, and refractory. Although small intestinal biopsy remains the diagnostic 'gold standard', highly sensitive and specific serological tests, such as tissue transglutaminase, endomysial and deamidated gliadin peptide antibodies, have become gradually more important in the diagnostic work-up of celiac disease. Currently, the only treatment for celiac disease is a life-long, strict gluten-free diet leading to improvement in quality of life, ameliorating symptoms, and preventing the occurrence of refractory celiac disease, ulcerative jejunoileitis, and small intestinal adenocarcinoma and lymphoma.

Conclusions: The present review is timely and provides a thorough appraisal of various aspects characterizing celiac disease. Remaining challenges include obtaining a better understanding of still-unclear phenotypes such as slow-responsive, potential (minimal lesions) and seronegative celiac disease. The identification of alternative or complementary treatments to the gluten-free diet brings hope for patients unavoidably burdened by diet restrictions.

Keywords: Alternative treatment; Clinical phenotypes; Epidemiology; Genetics; Gluten-free diet; Histopathological findings; Pathogenesis; Serological markers.

Fig. 1

Celiac disease pathogenesis. Partially digested gliadin fragments interact with chemokine receptor 3 on the apical side of epithelium (1) inducing a myeloid differentiation primary response 88-dependent release of zonulin (2). Zonulin interacts with the intestinal epithelium and triggers increased intestinal permeability (3). Functional loss of the gut barrier facilitates gliadin peptide translocation from lumen to the lamina propria (4). Gliadin peptides trigger release of IL-15, keratinocyte growth factor, and IL-8 (5), with consequent recruitment of neutrophils in the lamina propria (6). Simultaneously, alpha-amylase/trypsin inhibitors engage the Toll like receptor 4–MD2–CD14 complex with subsequent up-regulation of maturation markers and release of proinflammatory cytokines (7). Following innate immune-mediated apoptosis of intestinal cells with subsequent release of intracellular tissue transglutaminase, gliadin peptides are partially deamidated (8). Deamidated gliadin is recognized by DQ2/8⁺ antigen presenting cells (9) and then presented to T helper cells (10). T helper cells trigger activation and maturation of B cells, producing IgM, IgG, and IgA antibodies against tissue transglutaminase (11). T helper cells also produce pro-inflammatory cytokines (interferon γ and tumor necrosis factor α) (12), which in turn further increase gut permeability and, together with T killer cells, initiate the enteropathy. Damaged enterocytes express CD71 transporter also on their apical side, resulting in retrotranscytosis of secretory IgA-gliadin complexes (13), thus potentiating gluten trafficking from gut lumen to lamina propria. Ultimately, the interaction between CD4⁺ T cells in the lamina propria with gliadin induces their activation and proliferation, with production of proinflammatory cytokines, metalloproteases, and keratinocyte growth factor by stromal cells, which induces crypt hyperplasia and villous blunting secondary to intestinal epithelial cell death induced by intraepithelial lymphocytes. The hyperplastic crypts (14) are characterized by an expansion of the immature progenitor cells compartment (WNT) and downregulation of the Hedgehog signaling cascade. An increased number of stromal cells known to be part of the intestinal stem cell niche and increased levels of bone morphogenetic protein antagonists, like Gremlin-1 and Gremlin-2, may further contribute to the crypt hyperplasia present in celiac disease

Fig. 2

Prevalence of clinical phenotypes of adult celiac disease in our experience

Fig. 3

Causes of ongoing signs and/or symptoms of celiac disease (CD) despite a gluten-free diet (formerly referred to as ‘non-responsive’ CD). In this review, two clinical phenotypes have been proposed – ongoing active celiac disease (OACD), related to three main causes, and associated celiac disease conditions (ACDC), encompassing a wide array of diseases

Fig. 4

Diagnostic algorithm for celiac disease diagnosis

Fig. 5

Comparison between the two classifications for the duodenal biopsy

Fig. 6

Diagnostic algorithm for seronegative villous atrophy. SIBO small intestinal bacterial overgrowth