Introduction

Celiac disease (CD) is an autoimmune intestinal disorder affecting approximately 1% of the general population. The disease is produced by an immune-mediated enteropathy triggered by ingested prolamins present in wheat, barley, and rye (generically called gluten) occurring in predisposal individuals carrying the characteristic HLA haplotype DQ2 and/or DQ8. The disorder is characterized by almost invariable mucosal damage as a consequence of both the innate and adaptive immunologic response to the offensive proteins in the small intestine mucosa (1).

Celiac disease has been classified into a group of gluten-related disorders such as other autoimmune diseases (ADs) (gluten ataxia and dermatitis herpetiformis), wheat allergy (respiratory allergy, food allergy, wheat dependent exercise-induced anaphylaxis and contact urticaria) and non-autoimmune and non-allergic disease (gluten sensitivity) (2). Gluten comprises a broad group of prolamins (gliadins and glutenins) found in wheat. Other prolamins are also found in rye (secalins) and barley (hordeins) (3).

Due to lack of common definitions for the spectrum of terms and disorders related to CD, recently the different terms have been redefined. Therefore terms as “asymptomatic CD” or “silent CD” should be reclassified as “subclinical CD”. The terms typical, atypical and latent CD should no longer be used. Table 1 summarizes some related terms and some recommended terms (3).

Table 1

The Oslo definitions for celiac disease.

Epidemiology

Celiac disease is a common disorder that is very frequent in highly populated countries, where inhabitants have a white ancestry, mainly located in Europe and North America. However, CD has also been reported among people with Amerindian or African American origins (4,5). CD affects 0.6 to 1.0% of the population worldwide, the female-to-male ratio is 2.8:1 and the age distribution of onset shows a first peak between nine months and two years and a second peak during the fourth decade (6). Many epidemiological studies have shown that the prevalence of this disease varies according to the population (Table 2) (7–32).

Table 2

Prevalence of celiac disease in different populations.

The distribution of the CD has been associated with migratory patterns and changes in feeding habits over time. In the early days, man was not exposed to gluten-containing cereals. It was only 10 000 years ago in a small region called the “Fertile Crescent” of the Middle-East including Anatolia (Southern Turkey), Lebanon, Syria, Palestine and Iraq) where wild wheat and barley grains were successfully cultivated due to favorable environmental conditions. In this region some tribes settled, because the cultivation of the land allowed for storage of food. Then, people migrated to the Mediterranean area (Northern Africa and Southern Europe) and Central Europe searching for new lands for cultivation. The expansion continued from 9000 to 4000 BC to reach Northern Europe (Ireland, Denmark and the Scandinavian countries) (6).

The frequency of CD is likely to increase in many developing countries due to the progressing “westernization” of the diet, or by changes in wheat production or food elaboration. For instance, over the past 30 years, the prevalence of CD in the United States has increased five-fold, doubling approximately every 15 years (35).

Moreover, the prevalence of CD has increased among first-degree relatives of people affected with CD (10 to 15%), type 1 diabetes (3 to 16%), Hashimoto’s thyroiditis (5%) or other ADs (Sjögren’s syndrome, liver diseases, psoriasis and IgA nephropathy), IgA deficiency (9%), Down’s syndrome (5 to 19%), and Turner’s syndrome (3%) (35,36).

On the other hand, genetic susceptibility given mainly by HLA and other non-HLA genes are involved in the development of the disease. The HLA-DQ2 haplotype (DQA1*0501/DQB1*0201) is present in 90% of the patients with CD and this haplotype is also present in one third of the general population. The HLA-DQ8 haplotype (DQA1*0301/DQB1*0302) is present in 5% of patients and the remaining 5% of patients have at least one of two genes encoding DQ2 (DQA1-05-01 or DQB1*0201) (Chapter 17) (35).

Pathogenesis

Celiac Disease is determined by both genetic and environmental factors. The presence of gluten is necessary to develop an autoimmune response against the epithelium of the small intestine, HLA-DQ 2 or HLA-DQ 8 haplotypes, other non-HLA genes, and failures in both innate and adaptive immunity (Figure 1).

Figure 1

Steps involved in the development of celiac disease.

Alterations in the tight junction (TJ) system cause changes in the permeability and integrity of the intestinal epithelium. TJ are regulated by zonulin, this protein apparently alters epithelial permeability increasing the passage of gliadin and favoring the trigger of an autoimmune response (37). The passage of gliadin through the epithelium may also be accomplished by transcytosis (38) or by retrotrancytosis of secretory IgA (sIgA) by the transferrin receptor, denominated CD71. In active CD, CD71 expression is strongly upregulated at the apical surface of small intestinal enterocytes allowing the binding of intraluminal anti-gliadin IgA complexed to gliadin peptides and their subsequent retrotransport into lamina propria via the recycling endocytic pathway (39,40).

The gluten proteins have high content in glutamine (Q) and proline (P) residues assembled in related repetitive sequences. Proline-rich peptides are resistant to proteolysis by digestive enzymes (41). Peptides with Q and P rich motifs (notably Q-X-P sequence) are excellent substrates for the interaction with the tissular transglutaminase 2 (tTG2). This enzyme (78-kDa) is present in liver, heart, retina, intestine, placenta as well as erythrocytes, endothelial cells, immune cells and fibroblasts. tTG2 is involved in the stabilization and remodeling of the extracellular matrix, regulation of cell death, differentiation and apoptosis (42).

The tTG2 fulfills two key roles in the pathogenesis of the disease: as a deamidating enzyme, enhancing the immunostimulatory capacity of gluten, and as a target autoantigen in the immune response. The deamidation is a pH and calcium - dependent process (43,44). At low pH and in the absence of donor polyamines, tTG2 converts glutamine (neutral charge) to glutamate (negative charge), and thus, a more tightly binding of the negatively charged aminoacids to HLA-DQ2 and DQ8. This mechanism is similar to what occurs in rheumatoid arthritis by deamidation of arginine to citrulline mediated by peptidyl arginine deiminase (PAD) for recognition of HLA (45,46).

The positively charged pockets P4, P6, and P7 in HLA-DQ2 and P1 and P9 in HLA-DQ8 have a preference for negatively charged anchor residues. HLA-DQ2 and –DQ8 preferentially bind a glutamate residue of gluten peptide at positions 6 and 1/9 respectively (46).

In addition to being involved in the deamidation process, it is proposed that the binding of tTG2 to gliadin peptides can also induce gliadin-tTG crosslinking, resulting in the formation of a gliadin-tTG inmmunogenic complex and in increased production of anti-tTG IgA antibodies. An antibody-mediated inhibition of tTG functions by still unclear mechanisms, is involved in a decreased cell adhesion that decreases stabilizing matrix proteins and alters the wound repair (45). However, the presence of anti-tTG2 IgA is not sufficient to induce tissue damage in patients with subclinical CD (47).

Gluten-reactive CD4+T cells are activated by the presence of different epitopes with the 33-mer gliadin fragment LQLQPFPQPQLPYPQPLPYQPQLPYPQPQPF being this one the most immunogenic peptide (41). Activated T cells produce high levels of pro-inflammatory mediators with IFN- γ as the predominant cytokine, and display a characteristic T helper 1 (Th1) pattern of immune response (48).Interleukine (IL)-1β together with IL-1α, IL-18, and IL-33, has been associated with the inflammatory condition in CD patients. This cytokine has also been demonstrated to control the secretion of IL-23 that lead to Th1/Th17 immune pathways. Although Th17 cells participate in the pathogenesis of CD, the relative importance of each T cell response and their role in the initial events of the disease need further investigation (49). The dominant Th1 cytokines promotes inflammatory effects, including fibroblast or lamina propria mononuclear cell secretion of matrix metalloproteinases, which are responsible for tissue remodeling, resulting in villous atrophy and crypt hyperplasia (50). Other cytokines involved in this process of remodeling are TNF-α and IL-21,whose production is regulated by IL-15 (51).

Gluten-reactive CD4+Tcells may participate in the activation of intraepithelial lymphocytes (IELs) via cross-priming or via the production of IL-21 that synergizes with IL-15 produced by enterocytes, DCs and macrophages present in the lamina propria (52).

Additionally, gluten-reactive CD4⁺ Tcells may differentiate into Th2 cells that are capable of triggering activation and clonal expansion of B cells that lead to the production of anti-gliadin and anti tTG- autoantibodies. By interacting with the extracellular membrane-bound tTG, tTG-autoantibody deposits in the basement membrane region might induce changes in the enterocyte cytoskeleton with actin redistribution and epithelial damage (53).

Genetic factors

The HLA DQ2 and HLA DQ8 are the most important genes associated with CD; however, HLADQ2/8 is necessary but no sufficient to explain CD development. Some polymorphisms in non-HLA genes are also necessary for disease development. Celiac disease has been associated with more than thirty non-HLA genes (55).The majority of these genes have also been reported to be related to other autoimmune diseases. These genes are involved in T cell and B cell functions such as antigen presentation and production of cytokines (46).These genes are involved in the differentiation (RUNX3, THEMIS, ETS1, SH2B3, IL12A, IL18R1, IL18RAP, IL1RL1, IL1RL2), survival (FASLG, TNFSF18), migration (RGS1) and activation (CTLA4, ICOS, CD28, CD80, PTPN 2, IL2, FASLG, CD247, SH2B3, UBASH3A, PRKCQ, TAGAP, ARHGAP31) of T cells or in antigen presentation (CD80, TNFSF4, CIITA, ELM01, NFIA) (46,52). Genes associated with activation and migration of T cells such as MAP3K7, IL-21, CCR9 and RGS1 and genes associated with the activation and maturation of B cells such as ICOSLG, RGS1, BACH2, POU2AF1, TNFAIP3 and ZFP36L1 are also included (46,52).

Accordingly with the involvement of cytokines as IFN-γ and IL-21 in tissue damage, polymorphisms in genes involved in the synthesis of these cytokines such as STAT4, TNFRSF9, RUNX3, SOCS1, PTPN2 for IFN-γ synthesis, or IRF4 and ICOS for IL-21 synthesis have also been described to be associated with CD (52). (Chapter 18)

Environmental factors

Gluten coming from the diet is the most critical environmental antigenic factor recognized so far. Celiac disease is considered as an outstanding example of the loss of tolerance to a food protein in humans. To induce uncontrolled activation of the adaptive immune system this should be recognized in the context of “danger signals”. Indeed several infectious agents have been associated with the development of CD such as Campylobacter jejuni (56), Giardia lamblia (57), rotavirus (58), hepatitis C virus (59,60), adenovirus type 12 (61,62) and enterovirus (63). It has been observed that that the treatment with IFN α of patients having hepatitis C virus might contribute to induction of the disease (64).

The composition of the intestinal microbiota has also been related to CD. Changes of its composition due to the treatment of patients with a gluten-free diet suggest that intestinal microbiota may play a role in the manifestation of the disease (65). Alterations in the microbiota have also been associated with other ADs where a loss of tolerance and uncontrolled induction of the immune system does occur (Chapter 19).

Other environmental factors that have been attributed to the development of CD are the timing of gluten ingestion, breast feeding cessation (23) and cigarette smoking (66).

Natural history

Potential CD (PCD) is applied to people with normal small intestinal mucosa who are at increased risk of developing CD as indicated by positive CD serology (Table 1). It can evolve into flat, active CD but this evolution is, however, uncertain. A recent retrospective study has compared PCD and active CD during a 12 year period in order to understand the natural history of adult patients with potential CD. Interestingly, age at diagnosis, laboratory data, and prevalence of symptoms, associated diseases, and familiarity for CD did not differ between patients with PCD and those with active CD. Furthermore, some patients with PCD maintained a normal duodenal mucosa for many years and their symptoms spontaneously improved despite maintaining a gluten containing diet. These observations suggest that PCD is not a prodrome of CD but is a separate entity that can only subsequently evolve into active CD (67). In other study, children with PCD were advised to remain on a gluten-containing diet and prospectively investigated form birth for a 2-years period. In that study, the prevalence of PCD and the percentage of negativisation of CD-related serology in the short-term were high. These results led to the conclusion that children without symptoms and with positive celiac serology, the decision of performing an intestinal biopsy should be preceded by positive serology results in more than one occasion (68).

Clinical manifestations

Celiac disease is recognized as a systemic disease that may affect various systems; mainly gastrointestinal but only 40% to 50% of patients have symptoms and signs as diarrhea, weight loss, recurrent abdominal pain and abdominal distention. CD affects people of any age and ethnic groups. Associated clinical manifestations include iron deficiency with or without anemia, aphthous stomatitis, short stature, neurological symptoms, chronic fatigue, hypertransaminasemia, hypoproteinemia, hypocalcemia and reduced bone mineral density, among others (Table 3) (69).

Table 3

Clinical manifestations of celiac disease.

Most patients are asymptomatic or have mild clinical manifestations, which makes diagnosis much more complicated. In some cases the disease is diagnosed in at-risk individuals (familiarity or association with other diseases such as genetic or autoimmune diseases) (Table 3–4) (70).

Table 4

Populations at-risk of developing celiac disease.

Celiac crisis is a life-threatening syndrome present in patients with untreated CD and is frequently observed in children. It is characterized by severe diarrhea, hypoproteinemia, and metabolic and electrolyte alterations (71).

Diagnosis

Diagnosis of CD is based on small bowel histopathology in biopsies of the duodenum and accurate serological tests. Due to the wide variety of clinical manifestations of the disease, diagnostic criteria have been defined (Table 5) (72) and an algorithm has been proposed for the diagnosis and to identify asymptomatic patients but with positive serology (PCD or subclinical CD) (Figure 2).

Table 5

Diagnostic Criteria for celiac disease.

Figure 2

Diagnosis of celiac disease. Adapted from from Bai et al. (70).

Serological tests

Autoantibodies are fundamental for screening. Antibodies can be used with two purposes: initial testing in persons with clinical suspicion or to confirm the diagnosis in cases in which an enteropathy has been detected (Table 6) (35,73).

Table 6

Serological tests for the diagnosis of celiac disease.

In the past, serological tests consisted of the detection of autoantibodies against gliadin and reticulin but nowdays they are considered obsolete for the diagnosis because of the low sensitivity and specificity (74). In the recent years these antibodies have been replaced by IgG or IgA anti-tissue transglutaminase (anti-tTG), IgA and IgG anti-endomysium (IgA and IgG EMA), and IgA or IgG anti- deaminated gliadin peptides (IgG DGP).

The initial screening is done with IgA anti-tTG in persons who do not have concomitant IgA deficiency because this test has high sensitivity (94%) and high specificity (97%) (75). In patients with IgA deficiency, the detection of IgG anti-TG is particularly useful. Measurement of IgA EMA has nearly 100% of specificity for active CD, but it should be used only as a confirmatory test in the cases of borderline or possibly false positive results with anti-tTG, as occurs in other autoimmune diseases (type 1 diabetes, primary biliary cirrhosis, Sjogren´s syndrome, psoriasis and systemic lupus erythematosus). Low levels of anti-tTG have also been associated with infections, tumors, liver disorders and myocardial damage (76–79). Performing IgA anti-tTG and IgA EMA has a sensitivity and specificity of 100% (76). IgG DGP is other antibody used for the diagnosis of CD, but this test alone has not a better performance than the other two (73), except in the cases of IgA deficiency, in which it has proven to be more suitable (80). The DGP/tTG Screen assay could be considered as the best initial test for CD. Combinations of two tests, including a DGP/tTG Screen, might be able to diagnose CD accurately in different clinical scenarios making biopsy avoidable in a high proportion of subjects (81)

It is known that not all of the patients with CD have positive serological tests; these patients are characterized by clinical, genetic and histological changes. Seronegativity in patients with CD is associated with IgA deficiency (72). The sensitivity of the serological tests is dependent on the gluten-containing diet; patients with gluten-free diet decrease the tests performance.

Intestinal biopsy

An intestinal biopsy together with positive serology represents the gold standard in the diagnosis. The histological diagnosis of CD consists of an integrated assessment of IEL counts, mucosal architecture and intracytoplasmic alterations. Villous atrophy is defined by a decrease in villous height, alteration of normal crypt/villous ratio (3:1) to total disappearance of villi. Crypt hyperplasia reflects the regeneration of epithelial crypts associated with changes and the presence of more than 1 mitotic cell per crypt (82).

Histological classification of CD of Marsh, Marsh-Oberhuber and Corazza-Villanacci are commonly used (Table 7). Intestinal biopsy should be taken from the first and second portion of the duodenum. As in the case of serological testing, for the histological diagnosis, it is required that the patient has a normal gluten-containing diet at the time of the biopsy (82). It should be borne in mind that other pathologies may have similar histological characteristics to those found in CD (Table 8) (72). For these cases or for patients with negative serology the detection of subepithelial anti-tTG IgA depots by immunofluorescence is recommended (83).

Table 7

Histopathological classification.

Table 8

Causes of villous atrophy other than celiac disease.

The European Society for Pediatric Gastroenterology and Hepatology and Nutrition (ESPGHAN) recommends that the diagnosis in patients with signs or symptoms suggestive of CD and high anti-tTG levels (higher than 10 times the upper limit of the normal range) might be made without biopsy (76).

Treatment

The main treatment for CD is a strict gluten-free diet for the lifetime. Foods containing gluten from wheat, rye or barley must be completely eliminated from the diet (Table 9). Oat is not toxic in more than 95% of patients with CD, but there is in <5% in whom this cereal grain is not safe. In addition, in some countries there is reluctance to advise liberal use of oat, because of difficulties in guaranteeing that commercially available oat are free of contamination with other grains (87, 88). This contamination is difficult to avoid, therefore the new Codex Alimentarius regulation endorses a maximum gluten contamination of 20 ppm in gluten-free products (89). The lowest amount of daily gluten that causes damage to the intestinal mucosa over time is 10 to 50 mg per day (a 25-g slice of bread contains approximately 1.6 g of gluten) (90).

Table 9

Fundamentals of the gluten-free diet.

Complete removal of gluten from the diet will result in symptomatic, serological, and histologic remission in most patients (91). The healing of the intestinal damage occurs within 6 to 24 months after initiation of diet. However, complete normalization of mucosal damage is rare in adult patients, despite negativisation of serological tests and disappearance of symptoms(92).

In addition, growth and development in children returns to normal with adherence to the gluten-free diet and many disease complications in adults are avoided, with an improvement in the life quality (93–95).

Approximately 70% of patients present an amelioration of symptoms within 2 weeks after starting the gluten-free diet (91).

However, patients with poor adherence to the gluten-free diet or with RCD should have alternative treatments. These treatments may alternatively involve hydrolysis of toxic gliadin, prevention of gliadin absorption, blockage of selective deamination of specific glutamine residues by a tTG2 inhibitor, peptide vaccination, modulation of immune response to dietary gliadin (HLA-DQ blocker, interleukin blocker and NKG2D antagonists) and restoration of intestinal architecture (6).

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