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From Cornell University and Columbia University, New York, New York.
Requests for Single Reprints: Armin Alaedini, PhD, Department of Neurology and Neuroscience, LC-807, Cornell University, 1300 York Avenue, New York, NY 10021; e-mail, firstname.lastname@example.org.
Potential Financial Conflicts of Interest: Consultancies and Honoraria: P.H.R. Green (Prometheus Laboratory).
Current Author Addresses: Dr. Alaedini: Department of Neurology and Neuroscience, LC-807, Cornell University, 1300 York Avenue, New York, NY 10021.
Dr. Green: Department of Medicine, Room 645, Columbia University, 161 Fort Washington Avenue, New York, NY 10032.
Celiac disease is a common autoimmune disorder that has genetic, environmental, and immunologic components. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy, and crypt hyperplasia in the intestine. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8. Transglutaminase 2 appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Sensitive and specific serologic tests, including those for antiâ€“transglutaminase antibody, are facilitating fast and noninvasive screening for celiac disease. Thus, they are contributing to a more accurate estimate of the prevalence of the disease and its association with other disorders. Celiac disease is associated with increased rates of anemia, osteoporosis, cancer, neurologic deficits, and additional autoimmune disorders. A gluten-free diet is the mainstay of safe and effective treatment of celiac disease, although its effect on some of the extraintestinal manifestations of the disease remains to be determined.
Confirmation of characteristic mucosal abnormalities by intestinal biopsy and clear clinical or histologic improvement after institution of a gluten-free diet are required for a positive diagnosis. The algorithm is based on the criteria of the European Society for Paediatric Gastroenterology and Nutrition and recommendations of the National Institutes of Health Consensus Development Conference on Celiac Disease. TG2 = transglutaminase 2.
Gluten peptides that are resistant to digestive enzymes reach the lamina propria after intestinal permeability increases B. Intruding peptides are deamidated by enzymatic activity of transglutaminase 2 (TG2 ), creating epitopes with increased immunostimulatory potential. The gluten peptides may also become covalently linked to transglutaminase 2 C. Deamidated gluten peptides are presented in complex with HLA-DQ2 or HLA-DQ8 molecules of antigen-presenting cells (APC ), such as dendritic cells, macrophages, or B cells, to CD4 T cells D. Gluten-specific B cells receive help from gluten-specific T cells, leading to B-cell clonal expansion and release of antibodies against gluten. Transglutaminase 2–specific B cells can also receive help from gluten-specific T cells when they take up gluten–transglutaminase 2 complexes and specifically present gluten peptides to the T cells. This hypothetical mechanism of intermolecular help has been proposed to account for release of anti–transglutaminase 2 antibodies in the absence of transglutaminase 2–specific T cells E. Expression of proinflammatory cytokines by activated T cells promotes the release of matrix metalloproteinases that cause epithelial cell damage and tissue remodeling. The resulting tissue injury leads to further release of transglutaminase 2. TCR = T-cell receptor.
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TO THE EDITOR: In their review (1), Alaedini and Green, among the disorders associated with celiac disease, do not mention anorexia nervosa. Although data in literature are based only on case reports (2), the association between anorexia nervosa and celiac disease should deserve attention: the dietary restriction associated with a gluten-free diet could initiate an eating disorder; furthermore, in patients with a defined diagnosis of anorexia nervosa, the onset of celiac disease could increase the medical complications associated with anorexia. Thus, celiac disease should be considered in the differential diagnosis of eating disorders (3) but physicians should also be extremely vigilant for the diagnosis of anorexia nervosa in patients with celiac disease.
Luca Mascitelli, MD Comando Brigata alpina "Julia" Udine, Italy 33100
Francesca Pezzetta, MD Ospedale di San Vito al Tagliamento San Vito al Tagliamento, Italy 33078
1. Alaedini A, Green PH. Narrative review: celiac disease: understanding a complex autoimmune disorder. Ann Intern Med. 2005;142:289- 98.
2. Ricca V, Mannucci E, CalabrÃ² A, Bernardo MD, Cabras PL, Rotella CM. Anorexia nervosa and celiac disease: two case reports. Int J Eat Disord. 2000;27:119-22.
3. Levine RL. Endocrine aspects of eating disoredrs in adolescents. Adolesc Med. 2002;13:129-43.
TO THE EDITOR: Arthritis should be added to the group of disorders associated with celiac disease in the review by Alaedini and Green (1). Lubrano et al. (2) reported that arthritis was found in 52 out of 200 patients with celiac disease compared to 7 out of 40 control patients with irritable bowel syndrome. The most common patterns of arthritis included asymmetrical oligo/polyarthritis, spondyloarthritis, or an overlap of these two patterns. The arthritis is non-erosive and typically involves the shoulders, elbows, wrists, and knees (2). Other reports have supported the association of both synovitis (3) and sacroiliitis (4) with celiac disease. A more recent review by Slot and Locht (5) suggests that arthritis may be the presenting manifestation of celiac disease, even in the absence of typical gastro-intestinal symptoms. As with other manifestations of the celiac disease, the arthritis often remits with a gluten-free diet, although relapse may occur with dietary indiscretion (5).
2. Lubrano E, Ciacci C, Ames PRJ, Mazzacca G, Oriente P, Scarpa R. Clinical review: the arthritis of coeliac disease: prevalence and pattern in 200 adult patients. Br J Rheumatol 1996;35:1314-18.
3. Bourne JT, Kumar P, Huskisson EC, Mageed R, Unworth DJ, Wojtulewski JA. Arthritis and coeliac disease. Ann Rheum Dis 1985;44:592- 8.
4. Usai P, Boi MF, Piga M, Cacace E, Lai MA, Beccaris A et al. Adult celiac disease is frequently associated with sacroiliitis. Dig Dis Sci 1995;40:1906-8.
5. Slot O, Locht H. Arthritis as presenting symptom in slient adult celiac disease: two cases and review of the literature. Scand J Rheumatol 2000;29:260-3.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
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