Celiac disease (Non tropical sprue, gluten senseitive enteropathy, Gee-Herter disease) is a unique autoimmune disorder, unique because the environmental precipitant is known.


The disorder was previously called celiac sprue, based on the Dutch word sprue, which was used to describe a disease similar to tropical sprue that is characterized by diarrhea, emaciation, aphthous stomatitis, and malabsorption.


Celiac disease is precipitated, in genetically predisposed persons, by the ingestion of gluten, the major storage protein of wheat and similar grains. Originally considered a rare malabsorption syndrome of childhood, celiac disease is now recognized as a common condition that may be diagnosed at any age and that affects many organ systems.


Celiac disease results from the interaction between gluten and immune, genetic, and environmental factors.

The Role of Gluten

Celiac disease is induced by the ingestion of gluten, which is derived from wheat, barley, and rye. It is comprised of hundreds of protein components, traditionally classified on the basis of their solubility in alcohol-water solutions, in prolamins (alcohol-soluble), and glutenins (alcohol insoluble) (Wieser, 2007).

Prolamins Glutenins

Gliadins, secalins, hordeins


A high content of glutamine and proline is a common feature of gliadins, secalins and hordeins, while prolamins of cereals considered to be non-toxic for persons with CD, such as rice and corn, have a lower content of these amino acids (Schuppan, 2000).

possibly during intestinal infections or when there is an increase in intestinal permeability. such as a peptide from an -gliadin fraction made up of 33 amino acids. are resistant to degradation by gastric. pancreatic. . and interact with antigen-presenting cells in the lamina propria. These peptides pass through the epithelial barrier of the intestine. and intestinal brush-border membrane proteases in the human intestine.Undigested molecules of gliadin.

. characterized by infiltration of the lamina propria and the epithelium with chronic inflammatory cells and villous atrophy. primarily in the upper small intestine. ´ This response is mediated by both the innate and the adaptive immune systems.MUCOSAL IMMUNE RESPONSES ´ In patients with celiac disease. immune responses to gliadin fractions promote an inflammatory reaction.

. the T cells subsequently produce proinflammatory cytokines.´ The adaptive response is mediated by gliadin-reactive CD4+ T cells in the lamina propria that recognize gliadin peptides. which are bound to HLA class II molecules DQ2 or DQ8 on antigen. The ensuing inflammatory cascade releases metalloproteinases and other tissue-damaging mediators. increasing their immunogenicity. . particularly interferon.presenting cells. ´ Tissue transglutaminase is an enzyme in the intestine that deamidates gliadin peptides.


15 by enterocytes. such as an infection. a cell-surface antigen induced by stress. ´ These activated cells become cytotoxic and kill enterocytes with surface expression of majorhistocompatibility-complex class I chainrelated A (MICA). . resulting in the activation of intraepithelial lymphocytes expressing the activating receptor NK-G2D. a natural-killer-cell marker.´ Gliadin peptides also activate an innate immune response in the intestinal epithelium that is characterized by increased expression of interleukin.

Celiac disease does not develop unless a person has alleles that encode for HLA-DQ2 or HLA-DQ8 proteins.GENETIC FACTORS ´ The genetic influence in the pathogenesis of celiac disease is indicated by its familial occurrence. ´ However. thus. Studies in siblings and identical twins suggest that the contribution of HLA genes to the genetic component of celiac disease is less than 50%. . many people. products of two of the HLA genes. carry these alleles. their presence is necessary but not sufficient for the development of the disease. most of whom do not have celiac disease.

However. also increases the risk of celiac disease in infancy . such as rotaviral infection. ´ The initial administration of gluten before 4 months of age is associated with an increased risk of disease development.ENVIRONMENTAL FACTORS ´ These include a protective effect of breast-feeding and the introduction of gluten in relation to weaning. The occurrence of certain gastrointestinal infections. and the introduction of gluten after 7 months is associated with a marginal risk. the overlap of gluten introduction with breast-feeding may be a more important protective factor in minimizing the risk of celiac disease.

irritability. and even constipation are also common. neurologic symptoms. Older children and adolescents often present with extraintestinal manifestations. abdominal distention. such as short stature. However. anorexia. vomiting. or anemia . Infants and young children generally present with diarrhea.CLINICAL MANIFESTATIONS ´ Clinical manifestations of celiac disease vary greatly according to age group. and failure to thrive.

´ Among adults. for unknown reasons. the prevalence of autoimmune diseases is higher in women than in men. are more often diagnosed in women. two to three times as many women have the disease as men. each of which prompts an assessment for celiac disease. In general. and iron deficiency and osteoporosis. The predominance of the disease in women diminishes somewhat after the age of 65 years .

constipation. which may be accompanied by abdominal pain or discomfort.´ The classic presentation in adults is diarrhea. ´ Patients often have symptoms for a long time and undergo multiple hospitalizations and surgical procedures before celiac disease is diagnosed . weight loss. hypoproteinemia. silent presentations in adults include iron-deficiency anemia. Less common presentations include abdominal pain. dermatitis herpetiformis. hypocalcemia. Other. neurologic symptoms. and elevated liver enzyme levels. osteoporosis etc.


Turner¶s syndrome.´ Some cases are diagnosed because of increased surveillance for celiac disease among people who have a family history of the disease and among those with Down syndrome. all of which are associated with celiac disease. ´ Persons with celiac disease have an increased risk of autoimmune disorders as compared with the general population . or type 1 diabetes.

based on their very high diagnostic accuracy. 2005). .Diagnosis ´ Case-finding in persons with clinical conditions known to be associated with CD is currently considered the most appropriate way to detect atypical cases (Fasano. serologic IgA EMA and IgA anti-tTG tests are the best available tests for the screening of at-risk individuals (Rostom et al.. 2003).

. and villous atrophy and a positive response to a gluten-free diet. although histologic improvement on a gluten-free diet is frequently sought and is recommended in adults because villous atrophy may persist despite a clinical response to the diet. ´ The diagnostic criteria developed by the European Society for Pediatric Gastroenterology and Nutrition require only clinical improvement with the diet. crypt hyperplasia.´ The diagnosis of celiac disease requires both a duodenal biopsy that shows the characteristic findings of intraepithelial lymphocytosis.

g. Chronic diarrhea.. folate deficiency and irondeficiency anemia). with or without malabsorption Or the irritable bowel syndrome. ´ First-degree relatives with celiac disease .SEROLOGIC TESTING Indications for serologic testing include: ´ ´ ´ ´ Unexplained bloating or abdominal distress. Abnormalities on laboratory tests that might be caused by malabsorption (e.

connective-tissue antibodies (antireticulin and antiendomysial antibodies). . except in children younger than 18 months of age. the enzyme responsible for the deamidation of gliadin in the lamina propria.´ The most sensitive antibody tests for the diagnosis of celiac disease are of the IgA class. ´ The available tests include those for antigliadin antibodies. and antibodies directed against tissue transglutaminase. The antigliadin antibodies are no longer considered sensitive enough or specific enough to be used for the detection of celiac disease.

they are highly specific markers for celiac disease. the sensitivity of the tests for both endomysial antibodies and anti±tissue transglutaminase antibodies is greater than 90%. and a test for either marker is considered the best means of screening for celiac disease .´ The diagnostic standard in celiac serologies remains the endomysial IgA antibodies. Overall. approaching 100% accuracy.

BIOPSY ´ Biopsy of the small intestine remains the standard for diagnosing celiac disease. given the lifelong nature of the disease and the attendant need for an expensive and socially inconvenient diet. Biopsy confirmation is crucial. . and it should always be performed when clinical suspicion is high. irrespective of the results of serologic testing.

absent or reduced duodenal folds. or weight loss should undergo duodenal biopsy. such as scalloping of mucosal folds.´ Who ´ should undergo endoscopic biopsy? In addition to patients whose serologic tests are positive. ´ The recognition of endoscopic signs of villous atrophy. any patient who has chronic diarrhea. . should prompt biopsy. irrespective of whether serologic testing for celiac disease has been performed. iron deficiency. or a mosaic pattern of the mucosa.

.CAUSES OF VILLOUS ATROPHY OTHER THAN CELIAC DISEASE. chicken. soy. Giardiasis Common-variable immunodeficiency Autoimmune enteropathy Radiation enteritis Tuberculosis Tropical sprue Eosinophilic gastroenteritis Human immunodeficiency virus enteropathy Intestinal lymphoma Zollinger²Ellison syndrome Crohn·s disease Intolerance of foods other than gluten (e. tuna) ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ . milk.g.

.´ In this paper. and (2) the possibility of using salivary CD-associated antibodies as screening tests for the disease. they have reviewed studies that evaluated: (1) the possibility of using oral mucosa for the initial diagnosis of CD or for local gluten challenge.

ORAL MUCOSA FOR INITIAL DIAGNOSIS OF CD OR FOR LOCAL GLUTEN CHALLENGE ´ Differences in histological features of the oral mucosa of persons both with and without CD were demonstrated in a study that involved persons with GFD-treated CD. and healthy control individuals (Lähteenoja et al. those with newly diagnosed CD. . 1998). Moderate to severe lymphocytic inflammation was observed in 42.7% of the oral biopsy specimens from persons with treated CD.. as compared with 10% of control individuals.

´ The authors concluded that the oral mucosa cannot be used for the initial diagnosis of CD. in which the T-cell count in the epithelium of treated persons was higher than that in untreated persons and control individuals.´ These results were confirmed in another study by the same investigators (Lähteenoja et al. 2000). In contrast. since persons with untreated CD did not differ from healthy control individuals with regard to oral mucosal infiltration. persons with treated CD showed significantly increased numbers of Tcell subsets in their oral mucosa . and the mast cell count in the lamina propria of treated persons was higher than that of untreated persons..

an immunological µmemory¶ for gluten hypersensitivity is perpetuated prompted the authors to evaluate the reaction of the oral mucosa to a local gluten challenge. ´ A solution of an a-gliadin-related synthetic peptide was injected into the buccal submucosa of persons with GFD-treated CD and healthy control individuals (Lähteenoja et al. 2000b). in the oral mucosa of persons with GFD-treated CD.´ The observation that. ..

similarly. . The numbers of CD3+ and CD4+ cells were significantly higher after than before peptide challenge in persons with CD. the expression of the T-cell activation marker CD25 was also observed in the lamina propria of these persons after the challenge. ´ The oral challenge induced no statistically significant difference in the cell counts of the control individuals.´ The peptide significantly increased the T-cell counts in the lamina propria of persons with CD. results of the serum EMA test remained negative after the challenge in all participants. neither the persons with CD nor the control individuals had any oral complaints or visible changes after the challenge. Importantly.

the same group performed the oral gluten challenge both at supramucosal (gliadin powder applied with an oral adhesive bandage) and submucosal (injection of gliadin solution) sites (Lähteenoja et al.. Also.6% and 73% of cases. the number of intraepithelial CD4+ and CD8+ T-cells increased in 67. respectively. . ´ After a supramucosal challenge on the oral mucosa of persons with CD and on GFD.´ In another study. there was a significant increase in the number of CD4+ cells in the lamina propria of persons with CD. 2000c).

the mean numbers of total T-cells and CD4+ T-cells were significantly increased in the lamina propria of persons with CD. and the negative predictive value was 44%. There were no differences in the mean cell counts of the healthy control individuals after submucosal challenge. . and a specificity of 80%. the positive predictive value was 93%.´ After a submucosal gliadin challenge. ´ Based on these results. the authors reported a 73% sensitivity of the submucosal gliadin challenge in persons with treated CD.

2% of cultured oral biopsies. respectively.. One of the groups (Carroccio et al. 2007) found IgA EMA and antitTG in 53. 2007).´ Recently. Vetrano et al... 2007. results from two groups of investigators have demonstrated that in vitro culture media of oral mucosa biopsies from persons with untreated CD can release IgA-class EMA and anti-tTG (Carroccio et al. IgA EMA and anti-tTG assayed on culture media of duodenal biopsies were positive in all persons with CD .6% and 57.

and accuracy were 57. For the anti-tTG test. sensitivity specificity. and the diagnostic accuracy was 79%.´ The sensitivity of the EMA test on oral mucosa media was 53. 100%.6%. .2%. the specificity was 100%. and 79%. respectively.

with a reported diagnostic accuracy of 100% (alBayaty et al. 1989). 1992). . ´ In 1989.SALIVARY CD-ASSOCIATED ANTIBODIES AS SCREENING TESTS ´ Conflicting results have been reported regarding the usefulness of measuring CD-associated antibodies in saliva to screen for CD... A similar result was obtained in a study where a sensitivity of 100% was assumed. IgA-class AGA levels in whole unstimulated saliva of persons with untreated CD were significantly higher than those of both persons with GFD-treated CD and individuals without CD. and the salivary test for IgA AGA had a 90% specificity (Hakeem et al.

´ Both IgA and IgG salivary AGA has been measured in persons with treated and untreated CD. two studies that tested stimulated parotid secretion. 1996). and not unstimulated whole saliva.. . 61. reported only little (O¶Mahony et al.2% for IgA) (Rujner et al. sensitivities were poor (50% for IgG.. 1991) elevation of IgA AGA levels in persons with untreated CD. although specificities were relatively high (93. 1991) or no (Gibney and Brady.´ In addition.3% for both IgA and IgG).

´ In contrast.. an enzyme-linked immunosorbent assay (ELISA) test detected IgA anti-tTG antibodies in saliva from persons with CD and with low sensitivity (Baldas et al. 2004). . while none of the saliva samples from healthy control individuals was found to be IgA anti-tTG-positive (Bonamico et al. IgA anti-tTG was detected in saliva from 97. their presence in saliva was evaluated in four studies.7% (Ocmant and Mascart. 2007).. By means of a fluidphase radio-immunoassay. A recent study that used a commercial solid-phase ELISA test has reported a sensitivity of 90% and a specificity of 96.´ As to tTG antibodies.4% of persons with untreated CD. 2004). with different results.

BONAMICO. F. STRAPPINI & C. NENNA. LUPARIA. PERRICONE. (M.A. M. MURA . MONTUORI. P. TIBERTI 2008) . CASTRONOVO. LUCANTONI. R. P. A. C. L. R. but also during GFD. S. This study demonstrates that it is possible to detect salivary tTGAbs with high sensitivity not only at CD diagnosis.´ Serum radioimmunoassay (RIA) tissue transglutaminase autoantibodies (tTG-Abs) proved to be a sensitive test during coeliac disease (CD) follow-up. TURCHETTI .

. the recent demonstration that the oral mucosa of persons with untreated CD can produce IgA-class EMA and anti-tTG in culture media (Carroccio et al.. 2000a).DISCUSSION ´ Histological examination of the oral mucosa of persons with untreated CD did not show any significant alteration (Lähteenoja et al. 2007.. ´ Nevertheless. 2007) offers a new approach for using the oral mucosa to diagnose CD. the oral mucosa cannot be used for an initial diagnosis of CD. although there are conflicting results regarding the sensitivity of the tests . Vetrano et al. consequently.

the presence of CD-associated antibodies in saliva would seem plausible . 2007a). and IgA-producing gliadin-specific lymphocytes have been detected in the peripheral blood of children with CD (Hansson et al.. In view of this µplasmablast¶ trafficking throughout the body. 1997).´ Evidence exists that activated B-cells can migrate from gut-associated lymphoid tissue (GALT) to salivary glands (Brandtzaeg.

. . Johansen et al. the inductive sites of the mucosal immune system consist of organized mucosaassociated lymphoid tissue (MALT) (Johansen et al. ´ Although GALT is the largest and most important part of MALT.´ Oral mucosa and salivary glands are effector sites of the mucosal immune system. and primed lymphocytes can migrate from GALT to salivary glands (Brandtzaeg. 2007).. 2007). 2007a). there is now compelling evidence that supports the compartmentalization of the mucosal immune system (Brandtzaeg and Johansen. 2005.

1986. It is accessible to oral antigens by retrograde passage through salivary ducts. 2007b). 2004).. a duct associated lymphoid tissue (DALT) of the salivary glands has been described (Nair and Schroeder. . Ciccone et al. nasopharynx-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) may be more important than GALT in inducing an immune response in the upper aerodigestive tract. activated immune cells seem to home preferentially to the sites where they were originally primed (Brandtzaeg. DALT could have an independent role in the gluten-related immune response in the oral cavity (Baldas et al. 1998).´ Therefore. thus.. In this view. ´ Moreover.


rye. .TREATMENT ´ Nutritional therapy. involves the lifelong elimination of wheat. and barley from the diet. the only accepted treatment for celiac disease.

kidney beans. rye. teff (an Ethiopian cereal grain). navy beans. sorghum. pumpkin . buckwheat. basmati. sorghum. corn (polenta). oats Sources of gluten-free starches that can be used as flour alternatives ´ Cereal grains: amaranth. quinoa. jicama. rice (white. jasmine). wild. chestnuts. millet. walnuts. cashews ´ Seeds: sunflower. barley (including malt) ´ Safe grains (gluten-free) ´ Rice. manioc. buckwheat. pea beans. teff. taro. corn. brown. peanuts. quinoa. Grains that should be avoided ´ Wheat. montina (Indian rice grass) ´ Tubers: arrowroot. tapioca (cassava. potato. hazelnuts.Fundamentals of the Gluten-free Diet. yucca) ´ Legumes: chickpeas. lentils. flax. millet.soybeans ´ Nuts: almonds.

or Internet Dining out of the home Social.PROBLEMS OF DIETARY ADHERENCE ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ High cost Poor availability of gluten-free products (in developing countries) Poor palatability Absence of symptoms when dietary restrictions not observed Inadequate information on gluten content of food or drugs Inadequate dietary counseling Inadequate initial information supplied by diagnosing physician Inadequate medical or nutritional follow-up Lack of participation in a support group Inaccurate information from physicians. or peer pressures Transition to adolescence Inadequate medical follow-up after childhood . cultural. support groups. dietitians.

milk.g.. soy) Inflammatory bowel disease Irritable bowel syndrome Anal incontinence Autoimmune enteropathy Refractory celiac disease (with or without clonal T cells) Enteropathy-associated T-cell lymphoma .CAUSES OF POORLY RESPONSIVE CELIAC DISEASE ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ ´ Incorrect diagnosis Gluten ingestion (intentional or unintentional) Microscopical colitis Lactose intolerance Pancreatic insufficiency Bacterial overgrowth Intolerance of foods other than gluten (e. fructose.

which in turn will lead to greater availability of gluten-free foods and efforts to develop drug therapies that relieve patients of the burden of a glutenfree diet. Increasing awareness of the epidemiology and diverse manifestations of the disease. as well as the availability of sensitive and specific serologic tests. especially among primary care physicians. will lead to more widespread screening and diagnosis. .CONCLUSION ´ Celiac disease occurs in nearly 1% of the population in many countries.

The latter would have important implications not only for diagnostics.´ There is no consensus regarding the accuracy of a salivary CD-associated antibody test in screening for CD. ´ Further studies should also investigate whether the oral gluten-sensitized lymphocytes do originate exclusively from homing of cells primed in gut-associated lymphoid tissue. but also for the understanding of CD in general. and analysis methods seems to affect the reliability and reproducibility of the reported results. handling. or. . whether they could also be primed directly in the oral cavity. storage. Lack of standardized collection. rather.

G. D. No. Daniela Santon. M. Gabriella Clarich. Tania Gerarduzzi. Ph. Fiorella Florian. 2008. Peter H. and Alessandro Ventura Testing for Anti-Human Transglutaminase Antibodies in Saliva Is Not Useful for Diagnosis of Celiac Disease Clinical Chemistry 50. Pastore.. and L.REFERENCES 1. Roberto Marzari.D. 2.D. Green. Daniele Sblattero. Campisi. Tarcisio Not. Review article Celiac Disease N Engl J Med 2007. M. Alberto Tommasini. . 3. and Christophe Cellier. Stefano Martellossi. L.357:1731-43. Valentina Baldas. 2004.D. Compilato. Lo Muzio Orally Based Diagnosis of Celiac Disease: Current Perspectives J Dent Res 87(12):1100-1107.. 1.R.

2006. . 6. 5. A.4. R. mura . C. M. P. 364±370. Shafer¶s textbook of oral pathology 5th edition. R. A. tiberti Radioimmunological detection of anti-transglutaminase autoantibodies in human saliva: a useful test to monitor coeliac disease follow-up. montuori. turchetti . F. M. Volume 73² August. 28. strappini & C. L. P. luparia. lucantoni. S. bonamico. Aliment Pharmacol Ther 2008. castronovo. nenna. perricone.Shinjini Bhatnagar and Nitya Tandon Diagnosis of Celiac Disease Indian Journal of Pediatrics.

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