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Celiac Disease

Celiac disease a chronic disease with a characteristic small bowel lesion but not diagnostic, which impairs absorption in response to gluten withdrawal celiac disease, celeac, seliac. Gluten is the major storage protein of wheat and it consists of a mixture of gliadins and glutenins. Itís actually the gliadin fraction, which is an alcohol soluble component of gluten, which is the factor.

Now there are four different electrophoretic sub-fractions, alpha, beta, gamma and omega, and actually beyond that there are about 40 characteristic kinds of gliadin in each fraction of gluten. And which specific amino acid sequence brings on the disease is unknown. Now prolamins are the gliadin equivalents in barley and rye.

When we look at prevalence data for celiac sprue, if you read the text youíll see quotations from 0.05% to 0.2% in the general population, with high risk groups in Western Ireland up to 0.3%. It is infrequent in African-Americans, Chinese and Japanese. But these statistics are probably old. There was a recent trial in the U.S. blood donor population where they used serologies -again, serologies as we will see are not perfect - and identified a frequency of 0.4%. So you will see the sprue in increasing numbers.

When you look at the etiology or the pathogenesis and you have several proposed mechanisms, that means one of two things. Either we donít fully understand it, or as is the case in sprue, there is probably a combination of mechanisms which leads to the disease entity; genetic, immune-mediated and environmental. Now there is a fair amount of evidence for a genetic association. Celiac sprue or celiac disease is a strongly associated with HLA class 2-D molecules. Specifically, subregion alleles DQA-10501 and DQA-B10201. And these two comprise a specific molecule, the HLA-DQ2 molecule, which we see in up to 95% of sprue patients. Those that are negative for DQ-2 are typically positive for DQ-8. About 5-20% first degree relatives of celiac sprue patients will be positive as well, and there is a 70% concordance in identical twins. Now there is about a 30% concordance in HLA matched siblings which suggests that not only are HLA genes a factor but there are probably non-HLA genes.

Immune mediating mechanisms are important and these include humoral immune responses, the gliadin antibody may form an antigen antibody complex that can stimulate complement, or through antibody mediated cytotoxicity it can stimulate the release of cytokines. But gliadin is seen in normal patients and not every patient with sprue has an antigliadin antibody, so more than likely cell-mediated immune responses are more important. In this sense you have an increased density of lymphocytes within the epithelium and within the lamina propria and there is evidence to suggest that these lymphocytes are activated. Itís through the activated lymphocytes and the release of cytokines, such as TNF and interferon gamma, that this immune response is elicited. There is probably a role of direct toxicity of gliadin.

Again, without wheat you donít have the disease. There was an interesting trial done in Naples done recently using in vitro organ cultures. And what they found was when they added gliadin to the culture media for the susceptible mucosa, they had an immediate inflammatory response.

The issue of oats is somewhat controversial. Now this was a nice study by Janet Tonnin and colleagues and published in the New England Journal in 1995. They took 92 patients with celiac disease who were on a gluten-free diet. Forty of the patients were newly diagnosed and 52 were in remission on a gluten-free diet. They randomly assigned the group to a gluten-free diet plus 50-70 grams of oats per day, versus the standard gluten-free diet without oats and they followed them for 12 months. What they found was that the addition of oats had no difference whatsoever, both in terms of maintenance

What is refractory sprue? Refractory sprue is either patients who donít respond to a gluten-free diet or temporarily respond and then remit and have their disease symptoms recur. In the majority of these patients it is related to dietary non-compliance. And as I mentioned earlier, an antigliadin antibody or an antiendomysial antibody in this setting may be beneficial. Obviously we have to think about intestinal lymphoma and Iíll come back to that point in a little bit. But there are other concerns. There was a nice review by Fine and colleagues in Gastroenterology just about two years ago, that looked at patients with celiac sprue. And he found in his population that there were 17% of patients who were diagnosed with sprue, maintained on a gluten-free diet theoretically, and still had persistent diarrhea. In that group of 17% he did find a few patients

Sources of gluten: I think these are things that we all need to be concerned about. Medications contain gluten as a filler, airborne flour, communion wafers on Sunday morning, grain-derived alcohol drinks, and cross contamination where flour is milled, it may not be necessarily the cleanest circumstances and you may have some mixing of the flours.

So what are the complications of sprue? The biggest concerns related to sprue is that there is a increased rate of mortality, about two-fold above the general matched population. And unfortunately, the majority of these patients that have mortality, the mortality relates specifically to malignancy. Lymphoma comprises about 50% of that group. Squamous cell carcinoma of the esophagus, adenocarcinoma of the small bowel, squamous cell carcinoma of the oropharynx are all at increased risk, plus a slew of non-GI tumors. We have to be concerned about the development of collagenous colitis. This is a condition, again a component of sprue, where they develop a thick collagen band under the mucosal surface in the involved portion of the bowel, and this can lead to a refractory condition. One of the more dreaded consequences of sprue is also jejunitis. In this setting these patients developed profuse ulcerations of the proximal jejunum, which may extend distally into

The final point I would like to make is that we do have to consider lymphoma. And lymphoma may be a patient who doesnít respond to gluten-free diet, in fact it may not be sprue at all but it may be lymphoma as the initial diagnosis, or lymphoma may develop as a consequence of long standing sprue. We have to be suspicious for that in any patient who has diarrhea in this setting. The encouraging fact, as was mentioned yesterday with hepatoma, is that the treatment is prevention and

We do know now that if patients maintain themselves on a gluten-free diet for an extended period of time and their compliance is good, they will reduce their incidence of developing lymphoma. Now this is an interesting lymphoma in that it often presents, when it does present, it often presents widely metastatic. As opposed to typical small bowel lymphoma, itís T-cell instead of being a