I put an article that you can use to help start the research
Disease: Celiac Disease Disease: Celiac Disease Subtopic: Diagnosis: clinical and subclinical categorizations First Task is to create 4 page summary of your research. Essentially about the diagnosis and the clinical and subclinical categorization. (this info is to present to people so it needs to be detailed but easy to read when presenting) ● Make sure the summary is in order. I want you to talk about the diagnosis first and then clinical categories and finally subclinical Please have a reference list A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease1–3 Carlo Catassi, Elisabetta Fabiani, Giuseppe Iacono, Cinzia D’Agate, Ruggiero Francavilla, Federico Biagi, Umberto Volta, Salvatore Accomando, Antonio Picarelli, Italo De Vitis, Giovanna Pianelli, Rosaria Gesuita, Flavia Carle, Alessandra Mandolesi, Italo Bearzi, and Alessio Fasano ABSTRACT Background: Treatment of celiac disease (CD) is based on the avoidance of gluten-containing food. However, it is not known whether trace amounts of gluten are harmful to treated patients. Objective: The objective was to establish the safety threshold of prolonged exposure to trace amounts of gluten (ie, contaminating gluten). Design: This was a multicenter, double-blind, placebo-controlled, randomized trial in 49 adults with biopsy-proven CD who were being treated with a gluten-free diet (GFD) for �2 y. The back- ground daily gluten intake was maintained at �5 mg. After a baseline evaluation (t0), patients were assigned to ingest daily for 90 d a capsule containing 0, 10, or 50 mg gluten. Clinical, serologic, and histologic evaluations of the small intestine were performed at t0 and after the gluten microchallenge (t1). Results: At t0, the median villous height/crypt depth (Vh/Cd) in the small-intestinal mucosa was significantly lower and the intraepithe- lial lymphocyte (IEL) count (� 100 enterocytes) significantly higher in the CD patients (Vh/Cd: 2.20; 95% CI: 2.11, 2.89; IEL: 27; 95% CI: 23, 34) than in 20 non-CD control subjects (Vh/Cd: 2.87; 95% CI: 2.50, 3.09; IEL: 22; 95% CI: 18, 24). One patient (challenged with 10 mg gluten) developed a clinical relapse. At t1, the percentage change in Vh/Cd was 9% (95% CI: 3%, 15%) in the placebo group (n � 13), �1% (�18%, 68%) in the 10-mg group (n � 13), and �20% (�22%, �13%) in the 50-mg group (n � 13). No significant differ- ences in the IEL count were found between the 3 groups. Conclusions: The ingestion of contaminating gluten should be kept lower than 50 mg/d in the treatment of CD. Am J Clin Nutr 2007; 85:160–6. KEY WORDS Gastroenterology, celiac disease, gluten toxic- ity, small-intestinal morphometry, gluten-free diet, gluten threshold in gluten-free food INTRODUCTION Celiac disease (CD) is an immune-mediated enteropathy trig- gered by the ingestion of gluten—the major protein fraction contained in the cereals wheat, rye, and barley—in genetically susceptible persons. CD is a life-long disorder affecting 0.5–1% of the general population worldwide. The standard treatment of CD involves the consumption of a diet completely devoid of gluten proteins, a so-called gluten-free diet (GFD). In the long term (1–2 y), a GFD is associated with clinical, serologic, and histologic remission (1). However, it is almost impossible to maintain a diet with a zero gluten content because gluten con- tamination is very common in food. “Hidden” gluten (used as a protein filler) may be found in commercially available products, such as sausages, soups, soy sauces, and ice cream. Even prod- ucts specifically targeted to dietary treatment of CD may contain tiny amounts of gluten proteins, either because of the cross- contamination of originally gluten-free cereals during their mill- ing, storage, and manipulation or because of the presence of wheat starch as a major ingredient. The potential toxicity of trace amounts of gluten is still un- clear. We previously showed in treated CD patients that the 4-wk ingestion of 100–500 mg gliadin/d (roughly equivalent to 200– 1000 mg gluten) is able to cause measurable changes in the architecture of the small-intestinal mucosa (2). Only limited data are available on the toxicity of lower doses of gluten (3–6). This is an important issue because the daily ingestion of contaminat- ing gluten in apparently well-treated CD patients is most likely to range from 5 to 50 mg. Establishing a safe threshold of gluten consumption for CD patients is a matter of major public health importance, particu- larly in light of the recent reports concerning the high prevalence 1 From the Center For Celiac Research, University of Maryland School of Medicine, Baltimore, MD (CC and AF); the Department of Pediatrics, Uni- versità Politecnica delle Marche, Ancona, Italy (CC, EF, and GP); the De- partment of Gastroenterology, Children Hospital, Palermo, Italy (GI); the University Department of Gastroenterology, Catania, Italy (CD); the Uni- versity Department of Pediatrics, Bari, Italy (RF); the University Department of Gastroenterology, Pavia, Italy (FB); the University Department of Internal Medicine, Bologna, Italy (UV); the University Department of Pediatrics, Palermo, Italy (SA); the Department of Gastroenterology, “La Sapienza” University, Rome, Italy (AP); the Gastroenterology Unit, Catholic Univer- sity of Sacred Heart, Rome, Italy (ID); the Department of Biostatistics, Università Politecnica delle Marche, Ancona, Italy (RG and FC); the De- partment of Pathology, Università Politecnica delle Marche, Ancona, Italy (AM and IB). 2 Supported in part by the Italian Celiac Society. Purified gluten was kindly supplied by Bruno Jarry while working for the Tate & Lyle Group (United Kingdom). 3 Reprints not available. Address correspondence to A Fasano, Muco- sal Biology Research Center, University of Maryland School of Medi- cine, 20 Penn Street, Room 345, Baltimore, MD 21201. E-mail:
[email protected]. Received May 26, 2006. Accepted for publication August 28, 2006. 160 Am J Clin Nutr 2007;85:160–6. Printed in USA. © 2007 American Society for Nutrition D ow nloaded from https://academ ic.oup.com /ajcn/article/85/1/160/4649352 by U niversity of G uelph Library user on 02 February 2022 of the disease worldwide (7, 8). The recent National Institutes of Health Consensus Conference position on CD estimated that as many as 3 million people in the United States are affected by CD. These findings, together with the recently approved Food Aller- gen Labeling and Consumer Protection Act, created a vacuum in terms of health care policy, food safety, legislative guidelines, and industry-related legal liability that needs to be filled to allow the Food and Drug Administration’s governmental mandate to implement the new bill by 2006. The “gluten threshold” topic is currently under evaluation by the Codex Alimentarius, the WHO/FAO commission that is in charge of setting food stan- dards at the international level. To address the aforementioned issues we undertook a prospective, double-blind, placebo- controlled multicenter trial to investigate the toxicity of gluten traces in the celiac diet, with the cooperation and the sponsorship of the Italian Celiac Society (Associazione Italiana Celiachia; AIC). We report herein the final results of this study. SUBJECTS AND METHODS Study design This was a prospective, multicenter, placebo-controlled, double-blind, randomized trial performed between the years 2001 and 2004. The patients were adults with biopsy-proven CD who had consumed a GFD for �2 y and were in apparent good health. Patients were excluded if they 1) were younger than 18 y, 2) were poorly compliant with the GFD, 3) were positive for anti-tissue transglutaminase (tTG) antibodies or had a villous height/crypt depth (Vh/Cd) �1.5 at baseline (t0), or 4) associated conditions, such as selective immunoglobulin A (IgA) defi- ciency or other autoimmune diseases. Patients that qualified for the study were interviewed and gave their informed consent. Control subjects (only for comparison of the morphometric val- ues at t0) were adults who were negative for serologic CD mark- ers and for Helicobacter pylori (urea breath test) and were un- dergoing upper endoscopy for diagnostic purposes. The patients qualifying for the trial underwent a screening and a dietary interview (t�1). They were asked to maintain a strict GFD during the study period, ie, avoidance of any possible source of gluten contamination (such as restaurant meals). The only cereal-based food they were allowed to eat was the special GFD products on the market in Italy, which Italian law estab- lishes as having a gluten contamination of �20 ppm (20 ppm � 20 mg/kg product). After 1 mo the subjects returned for a baseline evaluation (t0), which involved 1) a clinical examination, 2) a dietary interview, 3) blood collection for serum anti-tTG anti- body and antigliadin antibody (AGA) measurements, and 4) an endoscopy and small-intestinal biopsy. While still adhering to a strict GFD, the patients were randomly assigned (by the coordi- nating center) to ingest daily and for 90 d a capsule containing either 10 mg purified gluten, 50 mg purified gluten, or 50 mg cornstarch as a placebo (double-blind microchallenge). After completing the 3-mo microchallenge (t1), the patients repeated the same clinical, serologic, and histologic tests as at t0. If any patient had symptoms suggestive of CD relapse during the mi- crochallenge, the protocol was stopped and the patient was asked to perform the t1 evaluation before dropping out of the study. From t�1 to t1, the adherence to both the GFD and the study protocol and clinical progress were checked weekly by telephone interview. The study protocol was approved by the Ethical Com- mittee of the Università Politecnica delle Marche, Ancona, Italy. Methods Purified gluten was used for the preparation of the capsules (Amygluten 110; Tate & Lyle PLC, London, United Kingdom). We used whole gluten rather than single gluten fractions because it has been shown that not only gliadins, but also glutenins (the other major component of gluten), contain toxic epitopes (9). Gelatin capsules that would quickly dissolve in the stomach were prepared by the pharmacy of the coordinating center. On a dry weight basis, the capsules contained 10 mg raw gluten, 50 mg raw gluten, or 50 mg cornstarch (placebo). All laboratory tests and analyses of biopsy specimens were centrally performed at the Università Politecnica delle Marche. Serum IgG class AGA and IgA class anti-tTG were measured by standard enzyme-linked immunosorbent assay methods (Alfa-Gliatest and h-TTG; Euro- spital Trieste, Trieste, Italy). Small-bowel biopsies (�4 specimens from each procedure) were taken from the second part of the duodenum. All biopsy specimens were oriented and fixed in 10% formalin, embedded in paraffin wax. The sections (5 �m) were stained with hema- toxylin and eosin and immunostained by using anti-human CD3 antibody (DAKO, Glostrup, Denmark) to enhance diagnostic accuracy in counting intraepithelial lymphocytes (IELs). Only well-oriented sections were examined; when necessary, the sam- ples were dissected again until they were of good quality. The specimens were examined in batches by 2 pathologists with long-standing experience in morphometric analysis (IB and AM), who were blinded to subject assignment. The morphomet- ric analysis of the sections was performed on �10 well-oriented