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Celiac Disease in the Clinical Spotlight -- What's New and What's the Path Forward?

Authors: Alessio Fasano, MDFaculty and Disclosures


Los Angeles, California; Wednesday, May 24, 2006 -- Celiac disease was one of the main topics featured during today's program at the 2006 Digestive Disease Week (DDW) meeting. For years neglected by the scientific and clinical communities, particularly in the United States, celiac disease is now enjoying much deserved attention. Celiac disease is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains (including wheat, rye, and barley) in genetically susceptible individuals. A packed "sunrise" session on the advances in celiac disease[1] was followed by a superb seminar on the multiple genes that lead to the disease,[2] and by more than 45 abstracts that shed light on new and exciting developments in the epidemiology, diagnosis, pathogenesis, management, and potential animal models of this disease entity.

Epidemiology of Celiac Disease

The general perception that celiac disease is rare in some countries, such as the United States, was unsubstantiated by any large epidemiologic study until recently. This controversy has been put to rest by a series of recent reports[3] suggesting that this disorder is as frequent in the United States (prevalence in the general population of 1:133)[4] as in Europe. This observation has been expanded to other regional areas, including North Africa, Asia, Oceania, and South America,[5,6] where celiac disease is now recognized as a frequent condition affecting approximately 0.5% to 1% of the general population.[3] Furthermore, the total prevalence of celiac disease seems to also be on the rise, as suggested by a study from Finland in which the prevalence of the disease doubled during the last 2 decades,[7] a trend similar to that observed for other autoimmune diseases. The bottom line is that if you search for it, you will find it.

Clinical Presentation -- How to Deal With a Clinical Chameleon (Think Out of the Box)

Celiac disease can manifest itself with a previously unappreciated range of clinical presentations, including the typical malabsorption syndrome (chronic diarrhea, weight loss, abdominal distension) affecting children, and a spectrum of symptoms potentially involving any organ system.[8] Given the low level of suspicion among healthcare professionals, particularly when the disease presents in an atypical manner, many cases of celiac disease remain undiagnosed and carry the risk for long-term complications, including osteoporosis,[9] infertility, psychiatric and behavioral disorders,[10] or cancer. One controversial topic addressed by 2 studies during this year's DDW meeting concerned the association between celiac disease and irritable bowel syndrome (IBS). A prospective multicenter study conducted in the United States suggested that more than 7% of IBS subjects enrolled tested positive for celiac disease antibodies.[11] Whether all of these patients were indeed affected by celiac disease remains to be established, as only a small number had the diagnosis confirmed by upper endoscopy. Conversely, a prospective observational study performed in The Netherlands established that screening patients with IBS for celiac disease is not cost-effective.[12]

Diagnosis -- From Educated Guess to Genomics and Proteomics

The mainstay for establishing the diagnosis of celiac disease remains a small intestinal biopsy showing the typical celiac enteropathy followed by clinical (and, in selected cases, histologic) remission after treatment with the gluten-free diet. Until the early 1980s, the diagnostic tools for celiac disease were rudimentary at best, being based on nonspecific tests. In the past 2 decades, however, a number of serologic tests have been developed (including antigliadin [AGA], antiendomysium [EMA], and human anti-tissue transglutaminase [tTG] antibody assays) that now have a definitive role in the diagnostic process. Although the AGA antibody assay has recently lost favor due to its poor specificity, new evidence presented during DDW 2006 seems to suggest that using novel antibody tests based on synthetic gliadin-related peptides may have a much better yield for the disease.[13] An intriguing report on a new noninvasive diagnostic algorithm based on the combination of 3 serologic tests (tTG, anti-actin antibodies, and serum zonulin levels) that yields a 100% positive predictive value in patients at risk for celiac disease was also presented during this meeting.[14]

It is the interplay between genes and gluten that leads to the generation of the antibodies and the histologic damage and symptoms that characterize the disease. Among the various genes, the HLA class II haplotypes DQ2 and/or DQ8 have been identified as absolutely necessary for the development of celiac disease. Because up to 30% of the healthy population also carries these HLA haplotypes, their presence is not diagnostic for celiac disease, although their absence practically rules it out. Therefore, this genetic test has its best indications in doubtful or mismanaged cases, or in the assessment of relatives of patients with celiac disease to decide whether they need to be followed over time. HLA typing for celiac disease has recently become commercially available; however, the test was costly, time-consuming, and not 100% accurate. Two studies presented during DDW 2006[15,16] reported on new generations of HLA typing tests that seem to be accurate, simple, and rapid and which can be useful in screening relatives and equivocal cases.

Management -- Follow-up and Treatment

Currently, total and lifelong abstinence from gluten ingestion remains the cornerstone of treatment for the disease. This diet requires an ongoing education of patients and their families, by both physicians and dieticians. The general understanding among celiac disease patients is that once diagnosed, a series of problems may be over, but many others will begin. Particularly frustrating is the limited information regarding what constitutes a gluten-free diet, what is safe and what is not, how to check for compliance, the potential complications of untreated celiac disease or of a delayed diagnosis, and how often it is necessary to follow up with the gastroenterologist, among other issues. Nevertheless, the "Holy Grail," the ultimate goal, is to find an alternative to the gluten-free diet, a task that requires additional information and/or tools to be achieved.

The Quest for This Ultimate Goal in Celiac Disease

In this quest to find an alternative to the gluten-free diet, a major effort has been aimed at developing an animal model of celiac disease. One report presented at DDW 2006 described a triple NOD mouse model transgenic for human HLA-DR4, -DQ8, and human CD4, that showed an immune response when challenged with gliadin similar to that detected in patients with celiac disease.[17] However, no intestinal tissue damage was observed. Conversely, a spontaneous baboon model of enteropathy was described in which, besides the typical autoimmune repertoire of celiac disease, intestinal mucosal damage resembling that described in patients with celiac disease was detected.[18]

However, the search for genes other than the HLA haplotypes remains the cornerstone to paving the way to treatment alternatives to the gluten-free diet. A comprehensive overview of this mission was presented by Dr. Wijmenga, who shared her studies that led to the identification of myosin IXB, a molecule involved in the regulation of intestinal permeability, as an additional gene linked to celiac disease.[2] This finding, along with the identification by her group of 3 additional genes related to intestinal tight junctions (structures that govern intestinal permeability), seem to support the notion that besides the 2 classical "ingredients" (genetic predisposition and exposure to the environmental factor gluten), a third element, ie, loss of the intestinal barrier function, is necessary for the celiac disease "recipe." These findings offer the prospect of treatment alternatives to the gluten-free diet that will certainly help increase the quality of life in patients with celiac disease and reduce the chance for long-term complications for those in whom the disease is not properly managed.


  1. Semrad C, Anderson R. Advances in celiac disease. In: AGA Sunrise Session -- Celiac Disease. Program and abstracts of Digestive Disease Week; May 20-25, 2006; Los Angeles, California. [Sp716a]
  2. Wijmenga C. Multiple classes of genes leading to celiac disease. In AGA State-of-the-Art Lecture -- Multiple Classes of Genes Leading to Celiac Disease. Program and abstracts of Digestive Disease Week; May 20-25, 2006; Los Angeles, California. [Sp738]
  3. Catassi C, Fasano A., Corazza GR, eds. The Global Village of Celiac Disease. Basel, Switzerland: Karger Press; 2005.
  4. Fasano A, Berti I, Gerarduzzi T, et al. A multicenter study on the sero-prevalence of celiac disease in the United States among both at risk and not at risk groups. Arch Int Med. 2003;163:286-292.
  5. Alencar ML, Ortiz-Aghostino CL, Nishitokukado I, et al. Prevalence of celiac disease among blood donors in Sao Paulo City -- the most populated and multi-ethnic center of Brazil. Gastroenterology. 2006;130:A-668. [#S1110]
  6. Mendez-Sanchez N, Zamora-Valdes D, Sanchez-Giron F, et al. Seroprevalence of anti-gliadin and anti-endomysium antibodies in Mexican adults. Gastroenterology. 2006;130:A-155. [#W1257]
  7. Lohi S, Mustalahti K, Kaukinen K, et al. The prevalence of celiac disease is increasing in process of time. Gastroenterology. 2006;130:A-665. [#W1242]
  8. Fasano A. Celiac disease: How to handle a clinical chameleon. N Eng J Med. 2003;348:2568-2570.
  9. Duerksen D, Wilhelm-Boyles C, Parry D. Risk factors for osteoporosis and effect of gluten free diet on bone density in patients with celiac disease. Gastroenterology. 2006;130:A-667. [#W1255]
  10. Sfoggia S, Nachman F, Maurino E, et al. Psychiatric alterations, depression, and symptomatic dimensions in patients with celiac disease at diagnosis. The impact of quality on life. Gastroenterology. 2006;130:A-667. [#W1251]
  11. Cash BD, Andrews AH, Lee DH, et al. Yield of diagnostic testing in patients with suspected irritable bowel syndrome (IBS): A prospective, US multi-center trial. Gastroenterology. 2006;130:A-111. [Abstract #771]
  12. van der Woulden E, Nelis E, Vecht J. Screening for celiac disease (CS) in patients fulfilling the Rome II criteria for irritable bowel disease (IBS) in a secondary care hospital in the Netherlands: a prospective observational study. Gastroenterology. 2006;130:A-111. [Abstract #772]
  13. Bai JC, Vazquez H, Nachman F, et al. Novel antibody tests based on synthetic gliadin-related peptides have a great yield for celiac disease. Gastroenterology. 2006;130:A-70. [Abstract #484]
  14. Niveloni S, Kryszak D, Moreno ML, et al. Positive and negative predicted values of a combination of celiac disease serology tests as compared to intestinal histology damage. Gastroenterology. 2006;130:A-664. [ #W1236]
  15. Oh E, Barry M. High resolution SSOP typing of celiac disease-associated HLA DQ haplotypes. Gastroenterology. 2006;130:A-668. [W#1259]
  16. Teresi S, Drago S, Gucciardino E, et al. Evaluation of a new simple and fast assay for HLA typing of the celiac disease-associated alleles. Gastroenterology. 2006;130:A-70. [W#1232]
  17. Freitag T, Sonderstrup G, Schuppan D. Challenge of HLA-DR4, -DQ8, human CD4 triple transgenic NOD mice with gliadin in complete Freund's adjuvant, followed by oral gluten. Gastroenterology. 2006;130:A-95. [Abstract #660]
  18. Fasano A, Kryszak D, Leland M, et al. Baboons affected by hereditary chronic diarrhea as a possible non-human primate model of celiac disease. Gastroenterology. 2006;130:A-665. [#W1243]
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