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This article appeared in the Spring 2007 edition of Celiac.coms Scott-Free Newsletter. Celiac.com 08/29/2007 - The XII International Celiac Disease Symposium, proudly hosted by the Celiac Disease Center at Columbia University, featured presentations from researchers from all over the globe. The last session of the scientific portion of the symposium, entitled “Non-Dietary Therapies”, was full of controversy and fireworks. Talks given by Drs. Khosla, Gray, Paterson, Anderson and Mitea all revealed that potential alternatives to the gluten free diet are now being aggressively pursued. Several groups have even spun off from pharmaceutical companies to raise funds to test these alternatives in patient trials. However, several questions remain. How close are we to a “pill” or “vaccine” to treat or prevent celiac disease? And do we even need, or more importantly, WANT them, given that the diet is safe and effective? Any alternative therapy for celiac disease must be at least as safe as the gluten-free diet, which, if done correctly, has NO side-effects. So the bar is raised very high. An alternative must offer great medical benefit to celiac patients without causing any medical harm. It is also unclear how, exactly, these new therapies will be implemented. Can they treat existing celiac disease? Will they prevent those at increased risk for the disease (such as siblings) from having symptoms? Will these medications allow celiac patients to ingest as much gluten as they want, or will they just take away the fear of contamination when eating questionable foods? What follows is a summary of several important points raised by some of these speakers in regard to the research that their center is doing in this area of “alternative therapies for celiac disease. Two groups discussed their research on what has commonly become known as “the celiac pill”. The idea behind the “pill” is somewhat similar to the idea of taking a lactase enzyme supplement to digest the milk sugar lactose (if you are lactose intolerant). However, digesting the proteins that trigger the immune reaction in celiac disease is much more complex than digesting the simple sugar found in dairy products. The small fragments of the gluten proteins from wheat, rye and barley, which stimulate the immune system in someone with celiac disease, contain a large quantity of an amino acid called proline. The stomach and pancreatic enzymes in humans have difficulty digesting the fractions where these prolines are located, making the gluten highly resistant to complete digestion. The idea behind the “celiac pill” is to provide enzymes to break down the gluten into smaller fragments which will not be recognized by a celiac patient’s immune system. Therefore, theoretically, gluten would not cause an immune reaction and could be safely eaten. Dr. Gary Gray, an adult gastroenterologist working at Stanford University in California, addressed this issue in his presentation “Oral Enzyme Therapy”. Their study looked at 20 biopsy-proven celiacs in remission (without symptoms) who received orange juice with either gluten or gluten pre-treated with a special enzyme (abbreviated PEP, for prolyl endopeptidase). Each patient consumed a low dose of gluten daily, 5 grams, which is equivalent to one slice of bread. The patients completed a daily symptom questionnaire, and had urine and stool tests of to measure intestinal damage. The researchers concluded that pretreatment of gluten with PEP avoided the development of fat or carbohydrate malabsorption in the majority of those patients who, after a 2-week gluten challenge, developed fat or carbohydrate malabsorption. The PEP enzyme needs to be investigated further in larger trials of celiac patients. Cristina Mitea, working with Dr. Fritz Koning at Leiden University in The Netherlands, also presented some data using similar technology, entitled “Enzymatic degradation of gluten in a GI-tract model”. This group published in 2006 that the above described PEP enzyme may not work optimally in the celiac patient, since it is not active at low stomach pH. The PEP enzyme may also be broken down by pepsin, a digestive enzyme in the stomach, before it reaches the small bowel where gluten causes the most damage. Given these facts, this group of researchers characterized a prolyl endoprotease enzyme, derived from the fungus Aspergillus niger, abbreviated AN-PEP. The AN-PEP enzyme, according to some publications, has been shown to work at stomach pH while resisting pepsin digestion. In the lab, the AN-PEP was able to degrade intact gluten as well as small fragments of gluten, including those that stimulate the immune system in patients with celiac disease. It also appeared to act within minutes, which is 60 times faster than PEP. This is particularly important, as ingested gluten will leave the stomach to enter the small bowel within 1 to 4 hours after being eaten. These researchers state that this enzyme is very stable, and could be produced at low cost at food-grade quality in an industrial setting. However, it has not yet been tested in human clinical studies. In summary, some of these future potential treatments include: The development of genetically detoxified grains Oral or intranasal celiac vaccines to induce tolerance Inhibitors to the effects of zonulin on intestinal permeability Detoxification of immunogenic gliadin peptides (or gluten proteolysis) via oral peptidase supplementation Inhibitors of tissue transglutaminase Dr. Michelle Pietzak, “The Gluten Free MD” is an Assistant Professor of Clinical Pediatrics at the University of Southern California Keck School of Medicine. She sees patients at Childrens Hospital Los Angeles and Los Angeles County Women’s and Children’s Hospital. With New Era Productions, she has recently released an audio celiac disease set as well as a 2 disc DVD set about celiac disease and the gluten free diet, available at www.glutenfreemd.com.

Celiac.com 09/01/2002 - Patients with celiac disease are 20 times more likely than the general population to have epilepsy and often have associated cerebral and cerebellar calcifications imaged by CT and MRI. Depression, dementia, and schizophrenia are all also common in persons with untreated celiac disease. Cerebellar degeneration with resulting ataxia (gluten-associated ataxia) is a known entity in Europe, and the National Institutes of Health (NIH) is currently recruiting subjects with ataxia to examine them for gluten sensitivity and celiac disease. Focal white matter lesions in the brain recently have been reported to occur in children with celiac disease and are thought to be either ischemic in origin as a result of vasculitis or caused by inflammatory demyelination. Parents of children with celiac disease have reported behavioral changes such as irritability, separation anxiety, emotional withdrawal, and autistic-like behaviors that all seemed to improve on a GFD. Although not scientifically validated, the GFD is now also being advocated for children with autism by several groups. Whether or not children with autism are at a higher risk for celiac disease or celiac children have a higher incidence of autism remains to be proven. However, children with Down syndrome, who often have autistic-like behaviors, are at higher risk for celiac disease. It has been hypothesized that gluten may be broken down into small peptides that may cross the blood-brain barrier and interact with morphine receptors, leading to alterations in conduct and perceptions of reality. The serologic tests can be divided into 4 different types of antibodies: antigliadin (AGA), antireticulin, antiendomysium (AEA), and antitissue transglutaminase (tTG). Each antibody varies widely in its sensitivity, specificity, and positive and negative predictive values (Table 2). Table 2 (from Pietzak et al, 2001, compiled data from multiple studies) Test Sensitivity Specificity PPV NPD AGA IgG 57-100 42-98 20-95 41-88 AGA IgA 53-100 65-100 28-100 65-100 AEA IgA* 75-98 96-100 98-100 80-95 Guinea pig tTG† 90.2 95 Human tTG† 98.5 98 * Patients older than 2 years of age. † IgG +IgA antibodies. The AEA IgA immunofluorecent antibody is an excellent screening test for celiac disease, with both a high sensitivity and specificity. This antibody was discovered in the early 1980s and rapidly gained use as part of a screening celiac panel by commercial laboratories in combination with AGA IgG and AGA IgA. Its major drawbacks are that it may be falsely negative in children under the age of 2 years, in patients with IgA deficiency, and in the hands of an inexperienced laboratory. Also, the substrate for this antibody was initially monkey esophagus, making it expensive and unsuitable for screening large numbers of people. Recently, the human umbilical cord has been used as an alternative to monkey esophagus. However, the subjective nature of the AEA assay may lead to false-negative values and unacceptable variability between laboratories. Because tTG had been first described as the autoantigen of celiac disease in 1997, it has been used to develop innovative diagnostic tools. The tTG IgA ELISA test is highly sensitive and specific, using either the commercially available guinea pig tTG or human recombinant tTG. The tTG assay correlates well with AEA-IgA and biopsy. However, it represents an improvement over the AEA assay because it is inexpensive and rapid (30 minutes), is not a subjective test, and can be performed on a single drop of blood using a dot-blot technique. Therefore, this test is ideally suited for mass screenings and in the future could be performed in the general practitioners office, much like the now routine finger-stick hematocrit. For the reasons outlined above, the IgA class human anti-tTg antibody, coupled with the determination of total serum IgA, currently seems to be the most cost-effective way to screen for celiac disease. AEA should be used as a confirmatory, pre-biopsy test, whereas AGA determinations should be restricted to the diagnostic work-up of younger children and patients with IgA deficiency, using the guidelines in Table 3. Table 3 Probability of celiac disease based on three antibodies in combination AEA IgA AGA IgA AGA IgG Interpretation + + + Celiac disease 99% probable + - + probable + + - Celiac disease probable + - - Celiac disease probable - + + Celiac disease less likely* - - + Celiac disease less likely* - + - Celiac disease less likely - - - Celiac disease very unlikely+ * If patient is IgA sufficient: AGA IgG > 100 warrants work-up of enteropathy. + If patient is on a gluten-containing diet. Celiac disease: AEA, antiendomysium antibodies: AGA, antigliadin antibodies.