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HeatherAdministrator

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Celiac Disease: Where We Are and Where We Are Going
      06/27/04 01:58 PM

Celiac Disease: Where We Are and Where We Are Going

Alessio Fasano, MD

New Orleans, Tuesday, May 18, 2004 --

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains (including wheat, rye, and barley) in genetically susceptible individuals. CD is associated with HLA molecules DQ2 (90%-95%) and DQ8 (5%-10%), and in the continued presence of gluten the disease is self-perpetuating. CD is one of the most common lifelong disorders worldwide. This condition can manifest with a previously unsuspected range of clinical presentations. These include the typical malabsorption syndrome (chronic diarrhea, weight loss, bloating) and a spectrum of symptoms potentially affecting any organ or body system. Because CD is often atypical or even silent on clinical grounds, many cases remain undiagnosed and become exposed to the risk of long-term complications, such as osteoporosis, infertility, or cancer. There is also a growing interest in the social dimension of CD, because the burden of illness related to this condition is doubtless higher than previously thought.

Many aspects of CD were discussed during this year's Digestive Disease Week (DDW) meeting that may help pave the way for future breakthroughs concerning the pathogenesis, diagnosis, and, most important, alternative treatment options.

The Genetics
The major component of the genetic predisposition to CD resides in the HLA region of chromosome 6. CD is strongly associated with HLA class II antigens, and approximately 90% of cases show a particular DQ2 alpha/beta heterodimer, with the remaining cases being HLA DQ8-positive. Therefore, the presence of HLA DQ2 and/or DQ8 is considered absolutely essential and their absence essentially rules out CD. The latter already has applications in clinical practice, particularly in those cases in which the diagnosis has not been validated by the currently recommended diagnostic algorithm. However, the HLA alleles explain only part of the genetic susceptibility to CD. In most European and North American populations, the frequency of DQ2 is high (15%-30%), but only a minority of DQ2-positive subjects develop CD. In the absence of strong functional candidate genes, several genome-wide scans in families with affected sib-pairs have been conducted. Although no additional susceptibility loci have been clearly identified thus far, there is some evidence of a genetic risk factor on chromosomes 5q and 11p11.[1]

The Immunopathology
The celiac enteropathy is the result of immune-mediated damage to the small intestinal mucosa. The cascade of pathophysiologic events most likely starts with an alteration in the barrier function and/or increased transcellular passage of gluten through the small intestinal mucosa. In the lamina propria, the tissue transglutaminase (tTG), a ubiquitous enzyme that catalyzes the cross-linking of proteins, deamidates gliadin peptides, strongly increasing their affinity for the HLA molecules located on the membrane of antigen-presenting cells (APC; eg, the macrophages). The HLA molecule forms a "groove" where short peptides (eg, a product of gliadin digestion) can be specifically linked. Among these fragments, the recently described 33-mer seems to be the most intriguing gliadin fragment, given its exceptional resistance to intraluminal as well as surface digestion and its immunodominant motifs particularly suited to bind to T lymphocytes either directly or following manipulation by APC.[2] Ultimately, the interaction between gliadin peptides and HLA molecules activates intestinal T cells. The release of proinflammatory cytokines (eg, interferon-gamma) by activated T cells could determine the damage to the enterocyte, increased proliferation in the intestinal crypts, and, finally, severe damage to the intestinal mucosa architecture.

The Epidemiology
Traditionally, CD was perceived as a rare disorder typical of infancy, with wide incidence fluctuation in space and time, and confined to the European population. Both evolutionary and epidemiologic observations suggested an inverse relationship between CD frequency and the introduction of wheat with agriculture. However, this theory is now challenged by recent epidemiologic studies showing that, beside being frequently found in countries where individuals are mostly of European origin, CD is a common disorder in many areas of the developing world where agriculture started 10,000 years ago.

It is interesting to note that the highest frequency of CD in the world has actually been reported among the Saharawi refugees, an inbred population of Berber-Arabic origin. These results raise an interesting question: Why is a disease that is associated with a high rate of morbidity and increased mortality, if left untreated, not segregated out by genetic evolution? The disease has remained one of the most frequent genetically based disorders of humankind. One possible explanation is that gluten, a protein introduced in large quantities in the human diet only after the advent of agriculture, activates "by mistake of evolution" mechanisms of innate immunity that are too important for human survival to be eliminated.

Treatment
One of the most innovative aspects of today's session on CD was discussion of the possible alternatives to the gluten-free diet that can be developed based on the new pathophysiologic findings discussed above. Inhibition of the gliadin-induced increased permeability of the intestinal barrier is a strategy already applied in the setting of type-1 diabetes, a disease that shares a leaky gut pathology with CD.[3] The digestion of the proteolytic-resistant gliadin peptides (33-mer) using bacterial-derived prolyl endopeptidase is another attractive therapeutic strategy. This enzyme has already been used to predigest gliadin with interesting preliminary results in human trials that need to be confirmed on a larger scale.[4] The inhibition of the tTG deamidating activity is another theoretical strategy for treatment; however, the caveat of affecting other important functions of the enzyme, such as wound repair, requires further scrutiny. Finally, the recently reported crystallographic data on gliadin binding on the T-lymphocyte groove offer the possibility to block the receptor using synthetic peptide inhibitors.

Concluding Remarks
CD is a common disorder in children as well as adults. At any age, the spectrum of clinical presentations is wide, and at present, extraintestinal manifestations (eg, anemia or short stature) are more common than the classical malabsorption symptoms. A high degree of awareness among healthcare professionals and a "liberal" use of serologic CD tests (case findings) can help to identify many of the atypical cases. Although the gluten-free diet currently remains the cornerstone of treatment for CD, new perspectives are on the horizon that may help disclose a better future for all individuals affected with this condition.

References
Fasano A. Prevalence and genetics. In: AGA Clinical Symposium -- Celiac Disease Clinical Symposium. Program and abstracts of Digestive Disease Week 2004; May 15-20, 2004; New Orleans, Louisiana. [Sp418]
Sollid LM. Immunology. In: AGA Clinical Symposium -- Celiac Disease Clinical Symposium. Program and abstracts of Digestive Disease Week 2004; May 15-20, 2004; New Orleans, Louisiana. [Sp 419]
Sapone A, Warrs T, Counts D, et al. Inhibition of the zonulin-dependent increased intestinal permeability prevents the onset of type 1 diabetes in BB/Wor rats. Gastroenterology. 2004;126(suppl 2):A-518. [T1820]
Gray GM. Treatment. In: AGA Clinical Symposium -- Celiac Disease Clinical Symposium. Program and abstracts of Digestive Disease Week 2004; May 15-20, 2004; New Orleans, Louisiana. [Sp 419]




Copyright © 2004 Medscape.

http://www.medscape.com/viewarticle/478293


--------------------
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