Celiac disease is a gluten-sensitive enteropathy

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1 Original Communication Prospective Study of Clinical and Histological Safety of Pure and Uncontaminated Canadian Oats in the Management of Celiac Disease Journal of Parenteral and Enteral Nutrition Volume Number July - American Society for Parenteral and Enteral Nutrition./ hosted at Michael Sai Lai Sey, MD ; Jeremy Parfitt, MD, FRCPC ; and Jamie Gregor, MD, FRCPC Financial disclosure: The study was supported by a Gastroenterology Division grant from the University of Western Ontario. Oats were donated free of charge from Cream Hill Estates. Background: Pure oats are safe for most patients with celiac disease, but concerns regarding contamination by other grains limit their consumption. The Canadian Celiac Association recently released guidelines governing the production of pure oats. The objective was to test the safety of a product manufactured under these guidelines. Methods: Fifteen adults with established, biopsy-confirmed celiac disease of year duration were challenged with g/wk of pure oats for weeks. Symptom scores, weight, hemoglobin, ferritin, albumin, and tissue transglutaminase (ttg) were assessed at weeks,, and. Duodenal biopsies were obtained before and after oat challenge and assessed based on the modified Marsh Oberhuber score. Compliance with a gluten-free diet was monitored with Clinical Relevancy Statement Pure oats are safe for consumption by patients with celiac disease. However, contamination with wheat, barley, and rye has been an ongoing concern limiting oat consumption. Pure, uncontaminated oats manufactured under guidelines established by the Canadian Celiac Association are now commercially available. Our study supports the clinical and histological safety of these oats. However, given the limitations of our study, clinical follow-up is still warranted in this population. From the Department of Medicine, Division of Gastroenterology, and Department of Pathology, University of Western Ontario, London, Ontario, Canada. Received for publication July, ; accepted for publication September,. Address correspondence to: Michael Sey, MD, London Health Sciences Centre University Campus, Department of Medicine, University of Western Ontario, Windermere Rd, Room ALL-, London, ON, Canada NA A; msey@uwo.ca. random food diaries. Results: Fifteen patients completed the study and were analyzed in intention-to-treat and per-protocol analyses. There were no significant changes in symptom scores, weight, hemoglobin, ferritin, or albumin during oat consumption. The ttg remained negative in all patients, and the histology scores did not significantly change during oat challenge. The only relapse occurred in a patient who became noncompliant with her gluten-free diet. Conclusion: The findings support the safety of pure, uncontaminated oats manufactured under Canadian Celiac Association guidelines for patients with celiac disease. (JPEN J Parenter Enteral Nutr. ;:-) Keywords: celiac disease; oats; safety Celiac disease is a gluten-sensitive enteropathy characterized by small bowel injury when exposed to wheat, barley, or rye., Treatment consists of a lifelong adherence to a strict gluten-free diet (GFD). Oats were also excluded in the GFD until recently, when the pioneering work of Janatuinen et al, demonstrated the safety of pure, uncontaminated oats in celiac disease. Since then, several other studies have also found no harm with the addition of pure oats to the GFD. - The common oat, Avena sativa, has a multitude of nutrition benefits. As a rich source of fiber, which is often deficient in the traditional GFD, oat helps to promote bowel regularity through its effect on fecal bulking. Several studies have also demonstrated attenuated postprandial glycemic response in diabetic patients, improved lipid profiles, and possibly even cardiovascular risk reduction in those who consume oats. Despite its nutrition benefits, reports of oat contamination with other grains have raised concern within the celiac community and limited its consumption. In a recent study examining the purity of commercially available oat products in the United States, Canada, and Europe, % were found to be contaminated with wheat, barley, or rye. Furthermore, most studies of oat safety

2 Journal of Parenteral and Enteral Nutrition / Vol., No., July celiac patients considered Asymptomatic GFD year Normal ttg patients declined patients compliant with GFD PER-PROTOCOL ANALYSIS patients had study entry Mod-Marsh score patients enrolled INTENTION-TO-TREAT ANALYSIS Figure. Enrollment of patients into the study. GFD, gluten-free diet. Mod-Marsh, modified Marsh Oberhuber; ttg, tissue transglutaminase level. Table. Canadian Celiac Association Guidelines for the Production of Pure Oats Seed purity Foundation # Canada Seed Act ( wheat, barley, or rye seed per kg of oat groat) Production Dedicated fields, harvesting, processing, storage, and transportation equipment strictly for oats Confirmation Purity confirmed by R enzyme-linked immunosorbent assay, which is able to detect parts per million (ppm) gluten contamination (gluten-free diet ppm) have been conducted in Europe, resulting in a paucity of evidence for the safety of oats manufactured in North America. To address this issue, the Canadian Celiac Association has developed guidelines for the production of pure, uncontaminated oats for the first time in Canada (Table ). Our objective was to assess the safety of oats manufactured under these guidelines. Study Participants Methods Nineteen adult patients with biopsy-confirmed celiac disease who were followed at the London Health Sciences Centre were contacted between November and April (Figure ). Fifteen patients consented for the study. Inclusion criteria included being asymptomatic on a GFD for at least year and having a normal tissue transglutaminase (ttg) level. For the purposes of our study, we defined asymptomatic as the resolution of the original symptoms that led to the diagnosis of celiac disease. Exclusion criteria included anyone with an uncertain diagnosis of celiac disease (eg, those with other causes of villous atrophy), noncompliance to GFD, contraindication to endoscopy, and not being in remission on study entry biopsy (modified Marsh-Oberhuber score >). Ethics approval was obtained from the University of Western Ontario Research Ethics Board, and informed consent was obtained from all participants. Clinical Challenge Patients were challenged with g/wk of pure, uncontaminated oats for weeks duration. Although previous studies have typically used -g/d challenges, we decided to use a weekly target to offer more dietary flexibility that better simulates real-life conditions. Oats were donated by Cream Hill Estates, a Canadian company that manufactures pure, uncontaminated oats and is adherent to the Canadian Celiac Association guidelines. Other than the donation of oats, the company was otherwise uninvolved in the design, implementation, or analysis of the study. The oats were tested with an R enzyme-linked immunosorbent assay (ELISA) and verified to have parts per million gluten content.

3 Safety of Canadian Oats in Celiac Disease / Sey et al Table. Modified Marsh Oberhuber Classification Score IEL Crypts Villi < Normal Normal > Normal Normal > Hypertrophic Normal a > Hypertrophic Mild atrophy b > Hypertrophic Marked atrophy c > Hypertrophic Absent IEL, intraepithelial lymphocytes, expressed as number of IEL/ epithelial cells. Oat samples were provided in, -g bags with instructions to consume bag per week. Patients started oat consumption immediately following study entry biopsy and continued for weeks. Unfinished bags of oats were returned to study investigators for weighing to determine how much oats were consumed. Patients were asked to adhere to an otherwise GFD. Monitoring Patients were assessed at weeks,, and. Symptom scores, weight, nutrition markers (hemoglobin, ferritin, albumin), and ttg (Celikey Varelisa assay) were assessed at each visit. Symptoms were assessed on a -cm visual analog scale for pain, diarrhea, flatulence, and abdominal distension, with and representing no and maximal symptoms, respectively. Esophagogastroduodenoscopy (EGD) with duodenal biopsies was obtained before oat challenge (week ) and after oat challenge (week ). All patients were given topical anesthetic spray (% lidocaine) and conscious sedation with midazolam. Six biopsies at baseline and after weeks of oat consumption were obtained from each patient, taken from the second part of the duodenum and fixed in % formalin. Histology was scored at the end of the study by one pathologist (JP), using the modified Marsh Oberhuber score (Table ). Random food diaries were completed for days between weeks and and weeks and to monitor for GFD compliance. Pathological Analysis Formalin-fixed, paraffin-embedded tissue was used to prepare hematoxylin and eosin stained slides using standard techniques. Biopsies were reviewed histologically by a gastrointestinal pathologist unblinded (JP), using a modified Marsh score as follows: = normal; = increased intraepithelial lymphocytes (IELs) only; = increased IELs with crypt hyperplasia; and a c = increased IELs with mild (a), marked (b), or complete (c) villous atrophy (Table ). Statistical Analysis A priori sample size calculation determined that participants were required to predict, with a P value of. and a power of., that % of celiac patients could safely tolerate weeks of oat consumption. Symptom scores, weight, and laboratory parameters were analyzed for all patients as an intention-to-treat (ITT) analysis. A separate per-protocol (PP) analysis was also performed with the exclusion of patients who met exclusion criteria. Changes in mean values at weeks and were analyzed using paired t tests. A P value of. was accepted as being statistically significant. Histology scores were compared before and after oat challenge to assess for relapse. A relapse was defined as an increase in the modified Marsh score from at week (in remission) to a score > at week. Results Fifteen patients enrolled in and completed our study. Despite a normal ttg, patients were found to not be in remission on study entry biopsy with a modified Marsh score > (Figure ). Three patients had modified Marsh a lesions on study entry biopsy, and had modified Marsh lesions. Among these patients, had the same histology score on study exit biopsy. One patient with a score of a on study entry had a score of b on study exit. Another patient who was initially in remission at the start of the study (modified Marsh score, ) had multiple lapses in her GFD due to prolonged travel during the study period. Her modified Marsh score, increased from to at study exit. An ITT analysis was used for all patients, but a separate PP analysis was also used for the remaining patients who did not meet our exclusion criteria. Baseline patient demographics are presented in Table. Overall, there were no symptomatic recurrences or serological relapses in the ITT or PP groups (Table ). The ITT group had cases of histological deterioration: one occurred in the patient with multiple lapses in her GFD, and the other occurred in the patient who was not in remission at the start of the study (modified Marsh a b). There were no cases of histological worsening in the PP analysis. Patients were largely asymptomatic throughout the study (Figure ). There were no statistically significant changes in mean pain, diarrhea, flatulence, or abdominal distension scores during the study in the ITT or PP groups. Mean weight and laboratory parameters remained stable throughout the study (Table ). Mean hemoglobin, ferritin, albumin, and ttg levels did not change significantly after the oat challenge. ttg remained negative for all patients at all time points.

4 Journal of Parenteral and Enteral Nutrition / Vol., No., July Table. Baseline Patient Characteristics (n = ) Average age, y ± Gender, male/female / (% female) Duration of disease, y. ±. Mean oat consumption, g/wk ± Study entry modified Marsh score (number of patients) Marsh : Marsh : Marsh : Marsh a: Marsh b: Marsh c: Values are mean ± standard deviation, unless otherwise specified. Discussion We did not find any injurious effects of pure, uncontaminated oats manufactured under Canadian Celiac Association guidelines in our study. There were no significant changes in symptoms, biochemistry, or histology after oat challenge. Our study is the first to provide clinical evidence for the safety of oats manufactured under these guidelines. Given the concerns regarding contamination of commercial oats with other gluten-containing grains, it is reassuring to know that oat producers working under these strict guidelines are now providing a muchneeded supply of pure, uncontaminated oats for North America. Although our inclusion criteria of being asymptomatic, being on a stable GFD for at least year, and having a negative ttg were designed to recruit celiac patients in remission for our study, we were surprised to have enrolled patients who were not in remission (ie, study entry modified Marsh score >). This was a similar observation in studies that aimed to recruit celiac patients in remission for oat challenges. In the first study, Størsrud et al found that of patients had partial villous atrophy at baseline, which corresponds to a Marsh a or higher histology score. In the second study, Lundin and colleagues found that of the patients they recruited had Marsh a lesions at study entry. This observation likely reflects the poor correlation between symptoms/ serology and histology, thus highlighting the importance of duodenal biopsies in celiac studies. Although the sensitivity of ttg generally exceeds % for the diagnosis of celiac disease, its sensitivity for detecting relapses is likely much lower. In one study, the sensitivity of ttg in this situation was only %. Despite the unexpected enrollment of these patients into our study, the lack of a difference between our ITT and PP analyses suggests against there being a significant effect on our study. One patient in our study had numerous lapses in her GFD as a result of months of travel during the study. Table. Clinical and Histological Safety Intention-to-Treat (n = ) Per-Protocol (n = ) Symptomatic recurrence Serological relapse Histological deterioration a a One patient had multiple documented lapses in gluten-free diet; patient progressed from Marsh a to b. Her histology worsened from modified Marsh to, and this was likely a result of her noncompliance with the GFD. Another patient who began the study with a modified Marsh score of a completed the study with a score of b. This slight increase in histology score is not considered significant and most likely represents sampling variability, especially given the lack of change in other clinical parameters for this patient. Previous oat challenge studies in celiac disease have been plagued with patient withdrawals due to increased gastrointestinal symptoms, presumably because of its high fiber content. -, In our case, we did not have any patient withdrawals. Rather, patients in our study were largely asymptomatic at baseline, which was likely a result of our inclusion criteria, and remained so during the study. One limitation of our study is the use of random food diaries to monitor for compliance to a GFD. Since this method uses self-reporting, the potential for bias exists, as patients may be more GFD compliant on days they record their food diaries. Another limitation of our study is its length of follow-up. We chose a follow-up period of weeks, as we felt this was sufficient time to allow a histological response to our oat challenge. This is supported by previous studies that have demonstrated significant histological changes within weeks, with a % relapse rate being reported in one study., Although these studies were performed with wheat gliadin rather than oat avenin, they are the closest comparisons available in the literature. Small sample size was another limitation of our study. Patient recruitment has been a persistent challenge in oat safety studies because of the need for invasive procedures. Since all studies require a minimum of endoscopies, before and after oat challenge, these research-driven procedures serve as a deterrent to patient recruitment. In fact, the landmark randomized, placebo-controlled clinical trial demonstrating the safety of oats involved only patients, of whom only received oats, and withdrew from the study ( from the oat group). Since then, several non placebo-controlled safety studies have emerged with sample sizes comparable to our study (n < )., Although our results support the safety of oats manufactured under these guidelines, future studies with larger sample sizes are needed to prove beyond % certainty that these products are indeed safe in patients with celiac disease.

5 Safety of Canadian Oats in Celiac Disease / Sey et al Pain Pain Flatulence Flatulence Diarrhea Abdominal Distension Diarrhea Abdominal Distension Figure. Symptom scores at weeks,, and in the per-protocol group. Symptoms were reported on a visual analog scale from cm (no symptoms) to cm (maximal intensity). P values were not significant in all cases. Intention-to-treat analysis produced similar results. Table. Mean Weight and Laboratory Parameters Intention-to-treat Weight, kg. ±.. ±. Hemoglobin, g/l. ±.. ±. Ferritin, µg/l. ±.. ±. Albumin, g/l. ±.. ±. ttg, U/mL. ±.. ±. Per-protocol Weight, kg. ±.. ±. Hemoglobin, g/l. ±.. ±. Ferritin, µg/l. ±.. ±. Albumin, g/l. ±.. ±. ttg, U/mL. ±.. ±. Values are mean ± standard deviation. No P values were statistically significant. Conclusion Our findings support the safety of pure, uncontaminated oats manufactured under the Canadian Celiac Association guidelines. Oat products manufactured under these strict guidelines are a safe source of pure oats for North America. Although we did not detect any symptomatic, biochemical, or histological relapses with oat ingestion, clinical followup is still warranted until larger oat safety studies can be conducted. References. Rostom A, Murray JA, Kagnoff MF. American Gastroenterology Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. ;:-.. Gregor J, Sey M. Celiac disease. In: McDonald JWD, Burroughs AK, Feagan BG, Fennerty BM, eds. Evidence Based Gastroenterology and Hepatology. rd ed. West Sussex, UK: BMJ Books; :-.. Janatuinen EK, Pikkarainen PH, Kemppainen TA, et al. A comparison of diets with and without oats in adult with celiac disease. N Engl J Med. ;:-.. Janatuinen EK, Kemppainen TA, Julkunen RJ, et al. No harm from five year ingestion of oats in coeliac disease. Gut. ;:-.. Peraaho M, Kaukinen K, Mustalahti K, et al. Effect of an oats containing gluten free diet on symptom and quality of life in celiac disease: a randomized study. Scand J Gastroenterol. ;:-.. Størsrud S, Olsson M, Arvidsson Lenner R, Nilsson LA, Nilsson O, Kilander A. Adult coeliac patients do tolerate large amounts of oats. Eur J Clin Nutr. ;:-.. Lundin KE, Nilsen EM, Scott HG, et al. Oats induced villous atrophy in coeliac disease. Gut. ;:-.. Sadiq Butt M, Tahir-Nadeem M, Khan MKI, Shabir R, Butt MS. Oat: unique among the cereals. Eur J Nutr. ;:-.

6 Journal of Parenteral and Enteral Nutrition / Vol., No., July. Hernando A, Mujico JR, Mena MC, Lombardia M, Mendez E. Measurement of wheat gluten and barley hordeins in contaminated oats from Europe, the United States, and Canada by sandwich R ELISA. Eur J Gastroenterol Hepatol. ;:-.. Rashid M, Butzner D, Burrows V, et al. Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association. Can J Gastroenterol. ;:-.. Kemppainen TA, Heikkinen MT, Ristikankare MT, et al. Unkilned and large amounts of oats in the celiac disease diet: a randomized, controlled study. Scand J Gastroenterol. ;:-.. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of celiac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. ;:-.. Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective biopsy-confirmed study with economic analysis. Clin Gastroenterol Hepatol. ;: -.. Størsrud S, Hulthén LR, Ragnhild AL. Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms, and subjective experiences. Br J Nutr. ;: -.. Catassi C, Rossini M, Rätsch IM, et al. Dose dependent effects of protracted ingestion of small amounts of gliadin in coeliac disease children: a clinical and jejunal morphometric study. Gut. ;: -.. Jansson UH, Gudjónsdóttir AH, Ryd W, Kristiansson B. Two different doses of gluten show a dose-dependent response of enteropathy but not of serological markers during gluten challenge in children with coeliac disease. Acta Paediatr. ;: -.

Diagnosis Diagnostic principles Confirm diagnosis before treating

Diagnosis 1 1 Diagnosis Diagnostic principles Confirm diagnosis before treating Diagnosis of Celiac Disease mandates a strict gluten-free diet for life following the diet is not easy QOL implications Failure