Celiac disease
CME update for family physicians
Shane M. Devlin, MD, FRCPC Christopher N. Andrews, MD, FRCPC Paul L. Beck, MD, PHD, FRCPC
ABSTRACT
OBJECTIVE
To review current understanding of the epidemiology, pathophysiology, diagnosis, and management of celiac disease.
QUALITY OF EVIDENCE
Few recent randomized controlled trials (level I evidence) have studied treatments for celiac disease. There are recent comparative studies (level II evidence) and there is well established consensus (level III evidence) on diagnosis and treatment of celiac disease.
MAIN MESSAGE
Celiac disease is an immune-mediated small bowel enteropathy caused by exposure to wheat gluten protein. The disease can be insidious and often presents with only subtle extraintestinal manifestations in a variety of organ systems. Recent epidemiologic surveys suggest celiac disease is much more common in North America than previously thought. Advances in immunology and screening have made diagnosis more reliable than in the past.
Removing gluten from the diet is eff ective in most cases.
CONCLUSION
Celiac disease manifests subtly and is an easy diagnosis to miss. Good laboratory screening tests and eff ective treatment are available. Family practitioners should consider celiac disease in patients who present with confounding symptoms.
RÉSUMÉ
OBJECTIF
Faire le point sur l’épidémiologie, la pathophysiologie, le diagnostic et le traitement de la maladie cœliaque.
QUALITÉ DES PREUVES
Peu d’essais randomisés récents (preuves de niveau I) ont abordé le traitement de la maladie cœliaque. Récemment, toutefois, des études comparatives (preuves de niveau II) et des déclarations consensuelles solides (preuves de niveau III) ont porté sur le diagnostic et le traitement de cette maladie.
PRINCIPAL MESSAGE
La maladie cœliaque est une maladie du grêle d’origine immunitaire causée par le gluten, une protéine du blé. Elle apparaît souvent de façon insidieuse, avec comme seules manifestations des troubles discrets de diff érents organes extra-intestinaux. Les études épidémiologiques récentes suggèrent que sa fréquence en Amérique du Nord est plus grande qu’on ne le croyait. Les progrès de l’immunologie et du dépistage permettent maintenant un diagnostic plus sûr. Un régime sans gluten est effi cace dans la plupart des cas.
CONCLUSION
Comme ses manifestations sont plutôt discrètes, la maladie cœliaque peut facilement passer inaperçue.
On dispose maintenant de tests de dépistage et de traitements effi caces. Le médecin de famille doit penser à ce diagnostic en présence de symptômes peu spécifi ques.
This article has been peer reviewed.
Cet article a fait l’objet d’une évaluation externe.
Can Fam Physician 2004;50:719-725.
eliac disease (also known as celiac sprue or gluten-sensitive enteropathy) is a small- intestine enteropathy characterized by an infl ammatory response to gluten protein found in wheat and related grains. Celiac disease might be much more common in North America than pre- viously thought. Symptoms can be subtle and pose a diagnostic quandary for primary care physicians.
Th is paper reviews the epidemiology, pathophysiol- ogy, diagnosis, and treatment of celiac disease, with a focus on new research on diagnostic testing.
Quality of evidence
A MEDLINE search from 1966 to 2003 using the search terms “celiac” or “coeliac” and “trial” produced only one randomized controlled trial (level I evi- dence) focused on aspects of treatment. Some well conducted open-label and comparative studies (level II evidence) provided new information about disease epidemiology and diagnostic screening. Recent tech- nical reviews and consensus statements on diagno- sis and management of celiac disease1-4 complement established textbook reviews (level III evidence).
Epidemiology
Celiac disease principally affects people of European heritage, with an estimated prevalence of 1/300 in the United Kingdom and a similar preva- lence reported in Italy, Sweden, and Austria.5 Th e highest prevalence is reported in Northern Ireland at 1/1501; prevalence in the rest of Europe is esti- mated at 1/1000.6 Celiac disease is rare in people of other ethnic backgrounds and is exceedingly rare in patients of pure Japanese, Chinese, or Afro- Caribbean descent.
North Americans of European descent have gen- erally been thought to have a lower prevalence than similar populations in Europe. A study of healthy blood donors in Maryland, however, screened for antigliadin and antiendomysial antibodies and the
prevalence of celiac disease at 1/2507 (level II evi- dence). It is unclear whether prevalence of the dis- ease is in fact lower in North America or whether it is simply underdiagnosed. It appears to aff ect men and women equally.
Pathophysiology
Celiac disease is an immune disorder triggered by an environmental agent (gluten) in genetically pre- disposed people. Th e exact molecular mechanism by which gluten causes damage remains unclear, but is the focus of much research.
Environmental factors. Th e environmental agent gluten is the protein fraction of wheat, rye, and barley grain giving the property of stickiness.
Wheat, rye and barley are in the same taxonomic species and thus have similar gluten structure and cross-reactivity. Grains that do not cause disease (rice, corn, sorghum, and millet) are from a diff er- ent subfamily and are, therefore, genetically further removed from wheat, rye, and barley. Oats, which at one time were thought to have intermediate cross-reactivity, have been shown to be acceptable,8 provided that the oats eaten are not contaminated with wheat (which is common in most commercial preparations of oats).
Genetic factors. Most patients who develop celiac disease have a genetic predisposition for it. It is asso- ciated with specifi c alleles at the HLA-DQ2 locus, which is found in 95% of suff erers. Concordance rates for monozygotic twins approach 100%, but despite the strong HLA association, there is only a 30% to 50% concordance in HLA-identical siblings.
Risk for fi rst-degree relatives is 10% to 20%.
Pathogenesis. Th e current model of pathogenesis focuses on the combination of ingestion of wheat gluten and patients with the susceptible HLA-DQ2 makeup. Gluten causes a T-cell–mediated infl am- matory response in the proximal small bowel that damages the mucosa and leads to malabsorption.
The inflammatory response continues as long as patients continue to ingest gluten.
Drs Devlin, Andrews,and Beck teach in the Division of Gastroenterology in the Faculty of Medicine at the University of Calgary in Alberta.
eliac disease (also known as celiac sprue or gluten-sensitive enteropathy) is a small- intestine enteropathy characterized by an infl ammatory response to gluten protein found in
C
Clinical presentation and diagnosis
Presentation. Th e classic presentation in children manifests as failure to thrive, abdominal disten- tion, and steatorrhea that occurs a few weeks to a few months after grain is introduced into the diet, usually between 4 and 24 months old.9 Th is classic presentation is rarely seen in modern times, how- ever, for reasons that are not clear.5 Nausea and vomiting are common in childhood-onset celiac disease. Some patients have more subtle symptoms and signs that can include edema, anemia, growth retardation, and recurrent dental caries related to defective dental enamel.10 In older children, recur- rent abdominal pain, fall in growth percentile, or iron deficiency should suggest the possibility of celiac disease.
Presentation of celiac disease in adults varies.
Adults sometimes present in a similar fashion to children with diarrhea and weight loss, but they rarely have nausea and vomiting. Adults are more likely to have milder symptoms or no symptoms.
Patients often have symptoms suggesting irritable bowel syndrome (IBS) and thus can be misdiag- nosed. Two recent studies evaluated the association between IBS symptoms and celiac disease (level II evidence). In one study, 20% of celiac patients ful- fi lled the Rome criteria for IBS,11 and in the other, IBS symptoms carried with them an odds ratio of 7.0 for having celiac disease on the basis of small- bowel biopsy.12 This association is controversial and needs more study, but it illustrates the impor- tance of considering celiac disease in patients with nonspecifi c gastrointestinal complaints.13
Awareness of the more atypical features of celiac disease is important, as they might be the only clues on presentation (Table 1). About half of adult celiac patients do not have diarrhea (level II evidence).10 Other clues include recurrent aphthous stomatitis, iron defi ciency without obvious cause, osteoporo- sis or osteopenia at an early age, short stature, and folate defi ciency. Th e appearance of Howell-Jolly bodies on peripheral blood smear should also raise suspicion because they are seen in splenectomized patients and patients with hyposplenism, which is seen in many untreated celiac patients (level II evidence).14 Most adult patients are diagnosed at a
younger age, but up to 20% of cases are diagnosed in patients older than 60 (level II evidence).15 Disease associations. Celiac disease is associated with several other disorders (Table 2). It is impor- tant for family physicians to be aware of the more common associations.
Dermatitis herpetiformis (DH) is a skin dis- ease characterized by a usually symmetric, pruritic, vesicular rash that involves the extensor surfaces.16 While only 10% of those with DH have features
of malabsorption, nearly all will have small-bowel biopsy results consistent with celiac disease if they are ingesting suffi cient gluten.16,17 Only 10% to 20%
of those with celiac disease have or have had DH.
A number of autoimmune disorders are associ- ated with celiac disease; type 1 diabetes mellitus and autoimmune thyroiditis are the most com- mon. Up to 8% of patients with type 1 diabetes have celiac disease (level II evidence).18 Celiac dis- ease should always be considered in patients with type 1 diabetes and diarrhea. An important asso- ciation for family physicians to be aware of is selec- tive immunoglobulin A (IgA) defi ciency, which has been estimated to occur in 2.6% of celiac patients
Table 1. Important clinical features of celiac disease COMMON GASTROINTESTINAL SYMPTOMS
Bloating Diarrhea Weight loss Aphthous stomatitis Abdominal pain
Steatorrhea or watery diarrhea (children) Nausea and vomiting (children) EXTRA-INTESTINAL MANIFESTATIONS
Hematologic
• Anemia (most commonly iron and folate defi ciency) Musculoskeletal
• Osteoporosis or osteopenia • Dental enamel hypoplasia Metabolic or laboratory abnormalities • Hypocalcemia
• Hypovitaminosis D • increased transaminases
(level II evidence).19 Th is is important for serologic diagnosis of celiac disease because most antibod- ies are of the IgA class and, therefore, can be falsely negative in IgA-defi cient patients.
Celiac disease can also be associated with micro- scopic colitis (both lymphocytic and collagenous) that does not generally resolve with a gluten-free diet. Celiac patients with this association can thus have continuing diarrhea despite faithfully keep- ing to their gluten-free diets.20 Colonic biopsies are required for diagnosis of microscopic colitis.
Complications. Th e main complications of celiac disease include malabsorption (including osteoporo- sis) and an association with various malignancies.
Osteoporosis (from chronic malabsorption of calcium and vitamin D by a diseased small bowel) is more common in patients with untreated celiac disease than in the general population. Although institution of a gluten-free diet leads to increased bone mineral density, density often does not return to normal in adults21 (level I evidence).
The association between celiac disease and a variety of malignancies has been extensively reported; it is the leading cause of death among these patients (Table 2).22 Evidence indicates that adherence to a gluten-free diet decreases the risk of cancer.23 The most common malignancy asso- ciated with celiac disease is non-Hodgkin’s lym- phoma (NHL), usually of T-cell origin.24 Previous studies have estimated a 30- to 70-fold increase in the risk of lymphoma in celiac patients (level II
evidence).22,23,25 A more recent study, however, ret- rospectively evaluated 11 000 hospitalized celiac patients and found only a 6-fold increase in the rate of NHL, likely a more accurate estimate (level II evidence).26 Other malignancies associated with celiac disease include squamous cell carcinoma of the oropharynx and esophagus and adenocarci- noma of the small intestine.26
Diagnosis. Most important for family physicians is knowledge of the clinical spectrum of dis- ease and use of serologic markers for celiac dis- ease. Serologic markers used in diagnosis of and screening for celiac disease are the endomysial antibody (EMA), tissue transglutaminase anti- body (tTG), and antigliadin antibodies (AGA).
Due to the substantial false-positive rate, AGA tests have been supplanted by EMA and tTG tests and should no longer be used. Sensitivity and specificity of these antibodies are summa- rized in Table 3.2,27-30 Currently, small-intestine biopsy demonstrating characteristic histology is the criterion standard for diagnosis of celiac dis- ease (level III evidence).10
Th e EMA is an IgA antibody against the endo- mysium, an area of connective tissue surrounding smooth muscle cells.27 Results can be falsely neg- ative in patients with mild disease and IgA defi- ciency (2.6% of patients).19 Th e antigen for EMA is tTG; there are now both IgA- and immunoglobulin G (IgG)-based tests to detect tTG.10,28 Quantitative IgA levels should be ordered with celiac serology to rule out false-negative results from IgA defi ciency.
Patients with IgA defi ciency should have IgG-based tests (ie, IgG-based tTG).
Table 2. Diseases associated with celiac disease Dermatitis herpetiformis
Type 1 diabetes Autoimmune thyroiditis Microscopic colitis
Immunoglobulin A defi ciency Immunoglobulin A nephropathy Rheumatoid arthritis MALIGNANT NEOPLASMS
• Enteropathy-associated T-cell lymphoma
• Squamous cell carcinoma of the oropharynx and esophagus
• Adenocarcinoma of the small intestine
Th e EMA is an IgA antibody against the endo- Table 3. Sensitivity and specifi city of serologic markers for celiac disease: IgG tTG also appears to have good sensitivity and specifi city but is currently not widely available.
ASSAY SENSITIVITY (%) SPECIFICITY (%)
Endomysial antibody (IgA EMA) 85-98 97-100
Tissue transglutamase antibody (IgA tTG) 90-98 94-97
Antigliadin antibody (IgA AGA) 75-90 82-95
Antigliadin antibody (IgG AGA) 69-85 73-90
AGA—antigliadin antibody, EMA—endomysial antibody, IgA—immunoglobin A, IgG—immunoglobin G, tTG—tissue transglutamase antibody.
Data from Farrell and Kelly,2 Maki,27 Dieterich et al,28 Pink and Creamer,29 and Sulkanen et al.30
How family physicians use and interpret sero- logic markers depends on the pretest probability of celiac disease. Patients likely to have the disor- der have findings such as steatorrhea, iron defi- ciency, folate defi ciency, or premature osteoporosis.
Patients who complain of nonspecifi c symptoms, but have none of these fi ndings, can be classifi ed as having a low pretest probability. Screening is widely accepted for patients with diseases associ- ated with celiac disease (eg, type 1 diabetes, Down syndrome) and for fi rst-degree relatives of celiac patients. A diagnostic approach based on pretest probability is outlined in Figure 1.
Treatment
Conventional treatment of celiac disease is com- plete, lifelong removal of gluten from the diet. All foods containing wheat, rye, or barley products
must be avoided. Th is can be diffi cult for patients to achieve and maintain, especially since numer- ous commercially prepared foods contain trace amounts of gluten.
Ingestion of oats was once controversial. A well conducted randomized controlled trial found that adults with celiac disease who consumed 50 to 70 g of oats a day for 6 to 12 months had similar symptoms, nutritional status, and small-intestine mucosal histology to celiac patients maintained on oat-restricted gluten-free diets8; the eff ect held true for 5 years of observation31 (level I evidence).
Involving a dietitian experienced with celiac disease is recommended. Celiac support groups can also be very helpful, as they publish lists of gluten-free products and recipes (Canadian Celiac Association: http://www.celiac.ca). Most patients improve clinically after a few weeks on a gluten- free diet. Literature in the 1960s suggested that
EMA—endomysial antibody, IgA—immunoglobin A, tTG—tissue transglutamase antibody.
*Celiac disease cannot be diagnosed defi nitively without a small-bowel biopsy
Figure 1. Diagnostic approach to celiac disease
Decide on pretest probability of the diagnosis
High pretest probability based on suggestive history or abnormal
laboratory results
Low pretest probability based on nonspecifi c symptoms and absence
of suggestive history or laboratory abnormalities
Refer to gastroenterologist
for small-bowel biopsy Order IgA level and either
IgA EMA or IgA TTG test
Serology negative;
diagnosis is adequately excluded
Serology positive.
Refer to gastroenterologist for small-bowel biopsy*
70% of patients improve within 2 weeks29 (level II evidence). Failure to improve on a gluten-free diet is most often due to dietary lapses, either deliber- ate or accidental.
Other disorders, such as IBS, lactose intolerance, pancreatic insufficiency, or microscopic colitis, sometimes coexist with celiac disease. Disease that does not respond to therapy once these conditions have been ruled out is termed refractory sprue. A gastroenterologist should do further workup and management.
Follow up
Once a gluten-free diet has been started and improvement noted, at least yearly follow up has been suggested1 (level III evidence). Weight;
complete blood count; and folate, alkaline phos- phatase, and calcium levels should be measured.
Awareness of possible complications is important.
Osteodensitometry should be considered for adults at least 1 year after starting a gluten-free diet to monitor stabilization of bone density21 (level III evidence). Patients with celiac disease should be assessed yearly not only by a family physician but also by a gastroenterologist.
Conclusion
Celiac disease is more common than previously thought and can lead to serious complications over time. Since many patients have few signs or symp- toms, the diagnosis can be missed if primary care physicians do not maintain a high index of sus- picion. Fortunately, diagnostic testing and man- agement are straightforward, and most patients improve substantially on a gluten-free diet.
Competing interests None declared
Correspondence to: Dr Paul L. Beck, Division of Gastroenterology, Faculty of Medicine, University of Calgary Health Sciences Centre, 3330 Hospital Dr NW, Calgary, AB T2N 4N1; telephone (403)-220-4500; fax (403)-270-0995; e-mail [email protected]
References
1. Ciclitira PJ, King AL, Fraser JS. AGA technical review on celiac sprue. American Gastroenterological Association. Gastroenterology 2001;120:1526-40.
2. Farrell RJ, Kelly CP. Diagnosis of celiac sprue. Am J Gastroenterol 2001;96:3237-46.
3. Bontems P, Deprettere A, Cadranel S, Vandenplas Y. Th e coeliac iceberg: a consensus in paediatrics. Acta Gastroenterol Belg 2000;63:157-62.
4. Freeman HJ. Survey of gastroenterologists on the diagnosis and treatment of adult patients with celiac disease in British Columbia. Can J Gastroenterol 1998;12:149-52.
5. Farrell RJ, Kelly CP. Celiac sprue and refractory sprue. In: Feldman M, Friedman LS, Sleisinger MH, editors. Sleisinger and Fordtran’s gastrointestinal and liver disease. 7th ed.
Vol 2. Philadephia, Pa: Saunders; 2002. p. 1817-41.
6. Logan RF. Descriptive epidemiology of celiac disease. In: Branski D, Rozen P, Kagnoff MF, editors. Gluten-sensitive enteropathy. Basel, Ger: Karger; 1992. p. 1-14.
7. Not T, Horvath K, Hill ID, Partanen J, Hammed A, Magazzu G, et al. Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors. Scand J Gastroenterol 1998;33:494-8.
8. Janatuinen EK, Pikkarainen PH, Kemppainen TA, Kosma VM, Jarvinen RM, Uusitupa MI, et al. A comparison of diets with and without oats in adults with celiac disease. N Engl J Med 1995;333:1033-7.
9. Catassi C, Fabiani E. Th e spectrum of coeliac disease in children. Baillieres Clin Gastroenterol 1997;11:485-507.
10. Kumar V, Jarzabek-Chorzelska M, Sulej J, Karnewska K, Farrell T, Jablonska S. Celiac dis- ease and immunoglobulin A defi ciency: how eff ective are the serological methods of diag- nosis? Clin Diagn Lab Immunol 2002;9:1295-300.
EDITOR’S KEY POINTS
• In young children, celiac disease often presents with nausea and vomiting. In older children, recurring abdominal troubles, slowed growth, or sideropenia should raise suspicion.
• Adults often have less specifi c symptoms, and celiac disease can be confused with irritable bowel syndrome.
• Patients in whom clinical suspicion is low should have a serum immunoglobulin A assessment combined with either endomysial antibody or tissue transglutaminase antibody as a screening test.
Antigliadin antibodies are no longer used because of high false- positive rates.
• Patients in whom clinical suspicion is high should be referred to a gastroenterologist for a biopsy of the small intestine.
• Treatment of celiac disease consists of complete elimination of gluten from the diet.
POINTS DE REPÈRE DU RÉDACTEUR
• Chez les jeunes enfants, la maladie cœliaque se présente souvent par des nausées et des vomissements. Chez les enfants plus âgés, les douleurs abdominales récidivantes, le ralentissement de la crois- sance ou l’anémie ferriprive devraient alerter le médecin.
• Les adultes ont souvent des symptômes peu spécifiques et la maladie cœliaque peut être confondue avec le syndrome du colon irritable.
• Chez les individus dont la probabilité clinique de souffrir de la maladie cœliaque est faible, le dépistage inclut une évaluation des immunoglobines A avec des anticorps endomysiaux ou anticorps transglutamases tissulaires. Les anticorps antigliadines ne sont plus utilisés en raison du nombre élevé de faux-positifs.
• Les individus ayant une probabilité clinique élevée de souff rir de la maladie cœliaque doivent être dirigés en gastro-entérologie pour une biopsie du grêle.
• Le traitement de la maladie cœliaque repose sur l’élimination com- plète du gluten de la diète.
11. Sanders DS, Carter MJ, Hurlstone DP, Pearce A, Ward AM, McAlindon ME, et al.
Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001;358:1504-8.
12. O’Leary C, Wieneke P, Buckley S, O’Regan P, Cronin CC, Quigley EM, et al. Celiac disease and irritable bowel-type symptoms. Am J Gastroenterol 2002;97:1463-7.
13. Hasler WL. Celiac sprue as a possible cause of symptoms in presumed irritable bowel syn- drome. Gastroenterology 2002;122:2086-7.
14. O’Grady JG, Stevens FM, Harding B, O’Gorman TA, McNicholl B, McCarthy CF.
Hyposplenism and gluten-sensitive enteropathy. Natural history, incidence, and relation- ship to diet and small bowel morphology. Gastroenterology 1984;87:1326-31.
15. Hankey GL, Holmes GK. Coeliac disease in the elderly. Gut 1994;35:65-7.
16. Otley C, Hall RP III. Dermatitis herpetiformis. Dermatol Clin 1990;8:759-69.
17. Brow JR, Parker F, Weinstein WM, Rubin CE. The small intestinal mucosa in dermatitis herpetiformis. I. Severity and distribution of the small intestinal lesion and associated mal- absorption. Gastroenterology 1971;60:355-61.
18. Cronin CC, Feighery A, Ferriss JB, Liddy C, Shanahan F, Feighery C. High prevalence of celiac disease among patients with insulin-dependent (type I) diabetes mellitus. Am J Gastroenterol 1997;92:2210-2.
19. Cataldo F, Marino V, Ventura A, Bottaro G, Corazza G. Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study.
Italian Society of Paediatric Gastroenterology and Hepatology (SIGEP) and “Club del Tenue” Working Groups on Coeliac Disease. Gut 1998;42:362-5.
20. Gillett HR, Freeman HJ. Prevalence of celiac disease in collagenous and lymphocytic coli- tis. Can J Gastroenterol 2000;14:919-21.
21. Bernstein CN, Leslie WD, Leboff MS. AGA technical review on osteoporosis in gastroin- testinal diseases. Gastroenterology 2003;124:795-841.
22. Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358:356-61.
23. Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease.
Gastroenterology 1989;97:265-71.
24. Isaacson PG, O’Connor NT, Spencer J, Bevan DH, Connolly CE, Kirkham N, et al.
Malignant histiocytosis of the intestine: a T-cell lymphoma. Lancet 1985;2:688-91.
25. Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten-free diet. Gut 1989;30:333-8.
26. Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis her- petiformis. Gastroenterology 2002;123:1428-35.
27. Maki M. The humoral immune system in coeliac disease. Baillieres Clin Gastroenterol 1995;9:231-49.
28. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tis- sue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3:797-801.
29. Pink IJ, Creamer B. Response to a gluten-free diet of patients with the coeliac syndrome.
Lancet 1967;1:300-4.
30. Sulkanen S, Halttunen T, Laurila K, Kolho KL, Korponay-Szabo IR, Sarnesto A, et al.
Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology 1998;115:1322-8.
31. Janatuinen EK, Kemppainen TA, Julkunen RJ, Kosma VM, Maki M, Heikkinen M, et al.
No harm from five-year ingestion of oats in coeliac disease. Gut 2002;50:332-5.
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