Journal of Pediatric Gastroenterology & Nutrition:
Celiac Disease: An Emerging Global Problem
Lebenthal, Emanuel; Branski, David
Department of Pediatrics, Hadassah-Hebrew University Medical Center, Mount Scopus and Ein Kerem, Jerusalem, Israel.
Correspondence to Emanuel Lebenthal, International Institute of Infant Nutrition and Gastrointestinal Disease, Hadassah-Hebrew University, Mount Scopus Medical Center, POB 24035, Mount Scopus, Jerusalem, Israel 91240 (e-mail: firstname.lastname@example.org).
This editorial accompanies an article. Please see Celiac Disease in India: Are They True Cases of Celiac Disease? U Poddar, B Ram Thapa, C Kanwal Nain, A Prasad, and K Singh. J Pediatr Gastroenterol Nutr 2002;35:508–512.
Celiac Disease (CD) was considered primarily a disorder of the European and Western populations and those countries to which Europeans have immigrated (1,2). Currently there are more and more reports indicating that CD is relatively common in both Europe and North America. It is estimated that CD affects 1 of every 85 to 300 persons in populations of European descent (1–5). There were suggestions that CD occurs in other populations (3,4); however, loose criteria were used for diagnosis of CD. To answer these discrepancies we need strict criteria for diagnosis and elucidation of genetic components associated with CD in non-European populations worldwide.
CD has been reported from the wheat-eating areas of Bengal and the Punjab (6), as well as in children who immigrate from India and Pakistan to England (7). CD was found to occur in Blacks (8), Arabs, and Sudanese of mixed Arab-Black stock (9), Cuban, Mexicans, and Brazilians (10). Furthermore, it has been suggested that the incidence of CD in Asian children is as high as that in Caucasian children (11). Anecdotal evidence claims that CD can be seen in Chinese children (11).
A significant concern with the above studies is the possibility that other disorders may simulate clinical presentation of CD and even mimic the histopathologic findings in the small intestine. Such conditions include infectious enteritis, post-infectious diarrhea and protein malnutrition (12). Moreover, in some of the above-mentioned studies, the criteria used for the diagnosis of CD were possibly not strict enough. The revised diagnostic criteria of the European Society for Pediatric Gastroenterology and Nutrition (11) should be more workable for developing countries and could be used in future studies. The two requirements mandatory for the diagnosis of CD are characteristic small intestinal mucosal changes while eating an adequate amount of gluten and a full clinical remission following gluten-free diet. In addition, the determination of antibodies to gliadin, endomysium, and tissue transglutaminase at the time of the diagnosis and disappearance after a gluten-free diet should be added to the diagnostic workup for CD (13,14).
In this issue, Poddar et al. (15) suggest that by evaluating IgA Antigliadin (AGA) antibodies determination they can determine whether Indian children with small intestinal mucosal injury are true cases of CD. They showed that IgA AGA antibodies are detected in 88% of the children and report no false positively at a cutoff values of 10 units/ml. Poddar et al. (15) suggest that a cutoff value of 5 units/ml of AGA antibodies has 94% sensitivity and can be used as a screening test to select suspected cases for further workup.
In addition to AGA antibodies of isotypes IgA and IgG, Antiendomysial (EmA) antibodies of isotype IgA and anti tissue transglutaminase (tTG) antibodies of isotype IgA, were used as screening tests for CD (16,17). While the sensitivity of EmA and tTG antibodies was close to 100%, the sensitivity of AGA IgA and IgG was 89%. The specificity of EmA was 100%, anti tTG was 97%, while AGA IgA was 96% and AGA IgG was 78% (15). The most important predictive value was obtained using EmA antibodies—97%, and it was considerably lower for anti tTG and AGA IgA and IgG antibodies (16). It was demonstrated (17) that tTG enzyme-linked immunoabsorbent assay has a high frequency of false negative and false positive results (17). However, because the test is both simple and fast, it has been suggested that it should be used for large-scale CD screening programs (16). It is suggested that after an initial positive tTG, EmA antibodies should be performed provided that IgA deficiency was excluded (17).
The quest for improvement of the current tests for determination of EmA antibodies and tTG antibodies uses at least three methods based on different principles, all of which detect autoantibodies against the same antigen (18). One published study has found that, when compared to radioimmunoprecipitation assay using recombinant tTG, commercial enzyme immunoassay using guinea pig tTG (ELISA) and indirect immunofluorescence testing for EmA were less sensitive and specific (18). The results demonstrated a very high sensitivity and specificity for the radioimmunoprecipitation when compared to the other methods (18). The advantage of the radioimmunoprecipitation method is probably a result of using human recombinant tTG in the assay and the possible increased capacity of the method to detect low titers of autoantibodies. tTG is the autoantigen that elicits EmA antibodies, which are the serological hallmarks of CD. A simple, rapid immunochromatographic assay for IgA and IgG antibodies to tTG, claimed to be highly accurate for diagnosis of this disease (18).
Overall, an improved anti EmA or anti tTG of isotypes IgA and IgG might provide us with an ultimate tool to screen populations worldwide for CD.
Another issue which requires clarification is the diagnostic accuracy of histologic findings to the diagnosis of celiac disease. Of particular concern are the jejunal biopsies with an apparent normal architecture but with increased numbers of intraepithelial lymphocytes (Marsh type I) (19). A distinct pattern of abnormalities has been observed in the small intestine which includes partial, subtotal, or total villous atrophy, elongated crypts, increased mitotic index in the crypts, increased intraepithelial lymphocytes, infiltration of plasma cells, lymphocytes, mast cells, eosinophils, and basophils in the lamina propria, loss of nuclear polarity with pseudostratification of the epithelial cells, and absence of the epithelial brush border transformation of the epithelial cell shape from columnar to cuboidal (19). However, these changes are not pathognomonic of CD, and most of them may be seen in other entities (19) Hence, it is crucial to establish the gluten dependence of the jejunal lesion. Asian populations suffer from high prevalence of diarrhea and small intestinal mucosal damage attributed to recurrent infections of the gastrointestinal tract (2,20).
It has been suggested that infection with adenovirus 12 might precipitate the clinical and histologic appearance of CD (20). Kagnoff et al. reported that 89% of untreated CD patients had evidence of past adenovirus 12 infection (20). Thus, there is a question as to whether the high incidence of infectious mucosal damage in developing countries might be a precipitating factor for the appearance of CD in genetically susceptible subjects.
On the other hand, it is now accepted that gluten-dependent enteropathy is not restricted to patients with flat mucosa during gluten-containing diet (21). There are patients who have a high count of intraepithelial lymphocytes in an otherwise normal-looking jejunal mucosa. The intraepithelial cells decreases during gluten free diet and increase during gluten reintroduction (22). This presents another group of patients who might have latent CD.
Currently, as the Asian diet shifts to contain more wheat, barley, rye, and oats, rather than the traditional rice, perhaps more cases of CD will appear (23). It is not clear whether Asian populations actually have a genetic risk for CD. Celiac disease has been shown to be associated with a genetic component of an HLA DQ 2 (or DQ8) autoimmune disorder of the human small intestine (24).
HLA genes along with non-HLA genes predispose to the disease. Linkage studies have identified chromosomal regions other than the HLA region which might have modest effects, suggesting the existence of multiple non-HLA predisposing genes with modest effects (25). Association studies have shown that CTLA4 or a closely located gene is one of these genes (25).
The primary HLA association in the majority of CD patients is with DQ2 (DQA1*0501/DQB1*0201) and in the minority of patients with DQ8 (DQA1*0301/DQB1*0302) (26). Gluten reactive CD4+ T cells can be isolated from small intestinal biopsies of CD patients but not from controls. DQ2 or DQ8, but not other HLA molecules carried by patients, present peptides to these T cells. It is suggested that a number of distinct T cell gluten epitopes exist, most of them post translationally modified by deamidation by tTG (27). DQ2 and DQ8 bind subsequently the epitopes at the glutamic acid residues (27). Overall, the results point to control of the immune response to gluten by intestinal T cells restricted by the DQ2 or DQ8 molecules. This is likely to be a critical checkpoint for the development of CD and could explain the significant genetic role of HLA in the disorder (27). However, this genetic susceptibility is not entirely explained by HLA associations. Two previous genome wide linkage studies have been performed to identify additional loci outside this region. These studies both used a sib-pair design and produced conflicting results. A main concern is whether it is possible to identify non-MHC genetic loci contributing to CD. Linkage analysis performed using lod score and model free methods showed two new potential susceptibility loci with lod scores of 1.9, at 10q23.1 and 16q23.3. Significant, but lower lod scores were found for 6q14 (1.2), 11p11 (1.5), and 19q13.4 (0.9) areas implicated in a previous genome wide study. Lod scores of 0.9 were obtained for both D78507, which is close to the gamma T-cell receptor gene, and for D2S364, which lies 12cM from the CTLA4 gene (22).
If we are to determine the prevalence and incidence of CD worldwide, we need first to define the simplest and least costly test with acceptable specificity and sensitivity. The new EmA enzyme linked immunoabsorbent assay (ELISA) that is replacing the cumbersome immunofluorescent technique might be the recommended test (18), or, alternatively, the one-step immunochromatographic assay for IgA and IgG antibodies to tTG (13). Second, we suggest that more attention be paid to intraepithelial lymphocytes in the jejunal mucosa as part of the histologic criteria for the diagnosis of CD. It would be very helpful if a uniform standard for the evaluation of intraepithelial lymphocytes could be developed. Third, the genetic susceptibility to develop CD that is currently associated with the human leukocyte antigen region on chromosome 6, especially DQ alpha/beta heterodimer encoded by the DQA1*0501 and the DQB 1*0201 genes should be defined in worldwide populations. It is mandatory to know if Asian and other non-European populations have this genetic susceptibility, or a different genetic susceptibility.
Last but not least, it will be important to study the clinical presentations and associated disorders in the non-European populations with CD to determine whether there is a unique clinical spectrum in these populations different from the European spectrum.
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