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  • Jefferson Adams
    Jefferson Adams

    Mystery Molecule Identified: Key Role in Celiac Disease, Other Autoimmune Disorders

    Celiac.com 09/17/2009 - Just after the turn of this century, researchers at the University of Maryland School of Medicine discovered that a mysterious human protein called zonulin played a key role in celiac disease and other autoimmune disorders, such as multiple sclerosis and diabetes.

    The situation might be likened to sailors who've an island, but not explored it. Researchers knew Zonulin existed, and some of its influences, but little else about it. Recently, a team of scientists led by Alessio Fasano, M.D., set out to isolate and decode zonulin. Their results are in, and Fasano's research team has successfully identified zonulin as a molecule called haptoglobin 2 precursor.

    Understanding the exact biochemistry of zonulin, the exact make-up of the protein molecule, is crucial to a comprehensive study of zonulin and its relationship to numerous inflammatory disorders.

    Dr. Fasano is a professor of pediatrics, medicine and physiology and director of the Mucosal Biology Research Center and the Center for Celiac Research at the University of Maryland School of Medicine.

    Haptoglobin is a molecule that has been known to scientists for many years. It was identified as a marker of inflammation in the body. Haptoglobin 1 is the original form of the haptoglobin molecule, and scientists believe it evolved 800 million years ago. Haptoglobin 2 is a version found only in humans. Scientists believe the mutation occurred in India about 2 million years ago, spreading gradually among increasing numbers of people throughout the world.

    Dr. Fasano's study showed that zonulin is the precursor molecule for haptoglobin 2 — that is, it is an immature molecule that develops into haptoglobin 2. Scientists previously believed that such precursor molecules played no role in the body other than to develop into the molecules they were destined to become.

    But Dr. Fasano's study reveals precursor haptoglobin 2 as the first precursor molecule to serve another function altogether; that of opening a gateway in the gut, permitting gluten to pass through. People with celiac disease suffer from a sensitivity to gluten.

    "While apes, monkeys and chimpanzees do not have haptoglobin 2, 80 percent of human beings have it," says Dr. Fasano. "Apes, monkeys and chimpanzees rarely develop autoimmune disorders. Human beings suffer from more than 70 different kinds of such conditions. We believe the presence of this pre-haptoglobin 2 is responsible for this difference between species."

    According to Dr. Fasano, the haptoglobin 2 molecule "could be a critical missing piece of the puzzle to lead to a treatment for celiac disease, other autoimmune disorders and allergies and even cancer, all of which are related to an exaggerated production of zonulin/pre-haptoglobin 2 and to the loss of the protective barrier of cells lining the gut and other areas of the body, like the blood brain barrier."

    "The only current treatment for celiac disease is cutting gluten from the diet, but we have confidence Dr. Fasano's work will someday bring further relief to these patients. Zonulin, with its functions in health and disease as outlined in Dr. Fasano's paper, could be the molecule of the century," says E. Albert Reece, M.D., Ph.D., M.B.A., dean of the School of Medicine, vice president for medical affairs of the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor.

    Dr. Fasano published his findings in the online version of the Proceedings of the National Academy of Sciences, appearing the week of September 7, 2009.

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    Zonulin is the molecule that helps form tight junctions between cells in the gut (and other places like skin). The tight junctions form a barrier between gut contents and the body. If the tight junctions are damaged (as happens in inflammation), the body is exposed to the gut contents. So an inflammation marker turning out to be zonulin is interesting!

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  • About Me

    Jefferson Adams earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in biology, anatomy, medicine, science, and advanced research, and scientific methods. He previously served as Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

  • Related Articles

    Jefferson Adams
    Celiac.com 11/15/2007 - There’s a large body of evidence pointing to the importance of a life-long gluten-free diet for people with celiac disease. However, following a gluten-free diet is not always easy. Studies show that only 50% to 75% of all celiac patients are successful in faithfully following their gluten-free diets. But until now, very little has been published that indicates why this might be, or offers evidence as to the best way to succeed in faithfully maintaining a gluten-free diet.
    Recently, a team of doctors led by Dr. Daniel Leffler conducted a study of the factors that are most important in increasing the success rates for people trying to maintain a gluten-free diet. Dr. Leffler is a clinical fellow in gastroenterology at Boston’s Beth Israel Deaconess Medical Center. Dr. Leffler presented the results of that study recently at the 2007 American College of Gastroenterology’s Annual Scientific Meeting and Postgraduate Course. The results of the study indicate that support groups seem to have an important role to play.
    A team of doctors, dietitians, psychologists, and patients created a study questionnaire that included 155 questions designed to measure ten areas important to success in living with celiac disease, including the burden of the disease, knowledge specific to celiac, health care access, mood and stress factors, perceptions about adherence, reasons for adherence, social support, symptoms.
    Participants of the study were all found through biopsy to have celiac disease. A professional nutritionist assessed each of the participants for dietary adherence. Of the 154 participants, 76% were Caucasian women. Nearly 70% had at least a college-level education. The average age was 50, and they had followed gluten-free diets for an average of 5 years.
    Concerns over cost and changes in stress levels and shifts in mood were among the reasons that contributed not following a gluten-free diet. Being a member of a celiac support group (P=.008), the ease of eating gluten-free while traveling (P=.012), or while attending social functions were important factors in successfully following the gluten-free diet.
    Demographic factors like age, sex, and age at diagnosis had no bearing on successfully remaining on a gluten-free diet.


    Jefferson Adams
    Celiac.com 05/18/2009 - People with clinical irritable bowel syndrome (IBS) suffer from biopsy-proven celiac disease at rates that are more than four times higher than in non-IBS control subjects, according to the results of a recent systematic review and meta-analysis conducted by Alexander C. Ford, MBChB, MD, MRCP, from Health Sciences Centre, McMaster University, Hamilton, Ontario, Canada, and colleagues.
    Prior studies have indicated that people with IBS had higher rates of celiac disease, but evidence has not been clear, and medical guidelines do not always call for celiac screening in these individuals.
    To determine rates of celiac disease in random adults meeting clinical criteria for IBS, the research team reviewed MEDLINE from 1950 to May 31, 2008, and EMBASE from 1980 to May 31, 2008. They isolated case series and case-control studies that contained data for celiac disease blood screens. They found 14 such studies.
    From each study, they isolated and aggregated positive serologic test results for celiac disease and biopsy-proved celiac disease. They then compared the data to that for patients with IBS and control individuals, using an odds ratio (OR) and 95% confidence interval (CI).
    The team isolated 4204 suitable cases from the identified studies. Of those, 2278 met clinical criteria for IBS (54%). The overall rate of positive immunoglobulin A (IgA)–class antigliadin antibodies (AGA) was 4.0% (95% CI, 1.7% – 7.2%), the rate of positive endomysial antibodies (EMA) was 1.63% (95% CI, 0.7% – 3.0%), and the rate of tissue transglutaminase (tTGA) was 4.1% (95% CI, 1.9% – 7.0%). For biopsy-proven celiac disease, the overall rate was 4.1% (95% CI, 1.9% – 7.0%).
    In patients who met the clinical criteria for IBS compared with non-IBS control subjects, aggregate OR for positive IgA-class antigliadin antibodies was 3.40 (95% CI, 1.62 – 7.13), aggregate OR for either positive EMA or tTGA was 2.94 (95% CI, 1.36 – 6.35), and aggregate OR for biopsy-proved celiac disease was 4.34 (95% CI, 1.78 – 10.6).
    The study did have some weaknesses, including issues with the methodology governing study selection, possible spectrum bias in case-control studies, possible selection bias in studies based in secondary care, and, in some cases, results too limited to allow meaningful aggregation of data.
    Still the research team concludes that rates of biopsy-proven celiac disease are more than four times higher for IBS patients than for non-IBS controls. The team recommends that, if screening is undertaken, EMA or tTGA testing be used in lieu of IgA-AGA testing due to their higher positive predictive value, though they admitted that results will depend on celiac rates in the population being screened.  
    The study was supported by the American College of Gastroenterology.

    Arch Intern Med. 2009;169:651–658.

    Jefferson Adams
    Celiac.com 04/27/2010 - A team of clinicians recently assessed the diagnostic value of confocal endomicroscopy in celiac disease.
    Clinicians U. Günther, S. Daum, F. Heller, M. Schumann, C. Loddenkemper, M. Grünbaum, M. Zeitz, and C. Bojarski made up the research team. They are variously affiliated with the  Medical Clinic of Gastroenterology, Rheumatology and Infectious Diseases, and with the Department of Pathology, Charité of the Campus Benjamin Franklin of University Medicine Berlin, Germany.
    Studies by Gutschmidt, by Henker and others have shown that, even in the face of greater awareness and more widespread blood testing, a number of countries suffer from low rates of celiac disease detection.
    Patchiness of the mucosal and submucosal changes associated with celiac disease impedes proper celiac diagnosis, and contributes to a small, but important sampling error among those assessed.
    Some clinicians feel that the problem might be resolved somewhat by modifying the endoscopic screening process to include real-time assessment of the duodenal morphology. Better endoscopic and imaging procedures will mean better diagnostic accuracy of biopsy specimens.
    One early step toward improved gathering of targeted biopsies in celiac disease patients lies in using magnification endoscopy, either alone, or together with high-resolution narrow-band imaging. This method offers better ability to detect patchy villous atrophy sites in the duodenum.
    However, neither magnification, nor narrow-band imaging techniques can detect increased number of intraepithelial lymphocytes (IELs).
    Confocal endomicroscopy (CEM) permits live, real-time histology with a 1000x magnification during endoscopy. Recently, a prospective pilot study for the first time showed CEM to enable effective live, real-time diagnosis and evaluation of celiac disease.  Researchers compared endomicroscopic findings during live, real-time endoscopy with histological findings graded according to Marsh classification.
    The research team used CEM to examine twenty-four patients with celiac disease and six patients with refractory celiac disease, all following a gluten-free diet.
    The team evaluated duodenal mucosa by CEM and by conventional histological analysis for villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs > 40/100 enterocytes).
    They then compared the CEM to the histology results for sensitivity, specificity, and inter-observer variability using Marsh classification scores.
    As control subjects, the team used thirty patients without celiac disease, but who were undergoing routine upper gastrointestinal endoscopy.
    Using conventional histology on the 30 patients with celiac disease, the team found 23 cases with villous atrophy and crypt hyperplasia, and 27 cases of increased IELs.
    Using CEM, the team found 17 cases of villous atrophy, 12 cases of crypt hyperplasia, and 22 cases of increased IELs. The CEM results compared favorably to those of conventional histology for villous atrophy, for which CEM showed a sensitivity of 74%, and for increased numbers of IELs, for which CEM showed a sensitivity of 81%. However, the CEM results were lacking for detecting crypt hyperplasia, for which CEM showed a sensitivity of 52%. 
    The κ values for determination of inter-observer variability were 0.90 for villous atrophy, 1.00 for crypt hyperplasia, and 0.84 for IEL detection. For the 30 control patients, both traditional histology and CEM revealed normal duodenal architecture with overall specificity of 100%.
    From these results, the team concluded that the assessment of duodenal histology by CEM in patients with celiac disease is sensitive and specific in determining increased numbers of IELs and villous atrophy, but inadequate for detecting crypt hyperplasia. Until improvements are made, CEM is not suitable for use in diagnosing celiac disease.

    SOURCE: Endoscopy 2010; 42:197–202.


    Jefferson Adams
    Celiac.com 07/28/2010 - Most people with celiac disease keep themselves healthy by following a gluten free diet. More and more, doctors are recognizing the importance of confirming gut recovery through follow-up evaluation. Still, among clinicians, there is currently no standard for follow-up confirmation of gut healing in celiac disease treatment.
    Many guidelines recommend an initial follow-up biopsy at 4-6 months after the patient begins a gluten-free diet. However, the use of biopsy to confirm gut healing is still controversial, as it can yield enormously variable results.
    A group of researchers recently set out to establish the amount of time it takes for full gut recovery in patients with celiac disease.
    The research team was made up of J.M. Hutchinson, N.P. West, G.G. Robins and P.D. Howdle. They are variously affiliated with the Sections of Medicine, Surgery and Anesthesia, the Section of Pathology & Tumour Biology at the Leeds Institute of Molecular Medicine in Leeds, and with the Department of Gastroenterology of the York Foundation Hospitals Trust, York, UK.
    The team enrolled patients who attended a specialty celiac disease clinic prior to March 2009, and recorded various clinicopathological information into a database.
    The team reviewed histopathology reports for all duodenal biopsies, and scored each biopsy for histopathology based on a modified Marsh grade.
    The team indexed and performed at least one biopsy on two hundred and eighty-four patients.
    The team found marked gut improvement in two-hundred and twenty-seven patients (80%), and a complete return to normal histology in 100 patients (35%). Average recovery time was 1.9 years, with a range of 1.0–4.8 years.
    Patients with less serious celiac disease at the start showed a better overall response (r = 0.281, P < 0.0001), while older patients recovered more quickly (r = –0.200, P = 0.001).
    Patients who best followed a gluten-free diet showed the best biopsy scores (r = –0.134, P = 0.040) and the greatest degree of histological recovery (r = 0.161, P = 0.014).
    Current guidelines for treatment of celiac disease recommend timing repeat biopsy 4-6 months after commencing a gluten free diet.
    These results shows histological recovery generally takes longer than traditionally thought, and that doctors looking to conduct such follow-ups might do well to factor in the patient’s age at diagnosis, the initial disease score, as well as the level of compliance with a gluten free diet.
    Source:

    QJM 2010 103(7):511-517

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