International Journal of Celiac Disease
ISSN (Print): 2334-3427 ISSN (Online): 2334-3486 Website: Editor-in-chief: Samasca Gabriel
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International Journal of Celiac Disease. 2014, 2(3), 76-85
DOI: 10.12691/ijcd-2-3-8
Open AccessMeta-Analysis

Non-classical Celiac Disease: Often Missed

Prashant Singh1 and Govind K Makharia2,

1Massachusetts General Hospital, Boston, USA

2Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari nagar, New Delhi, India

Pub. Date: September 13, 2014

Cite this paper:
Prashant Singh and Govind K Makharia. Non-classical Celiac Disease: Often Missed. International Journal of Celiac Disease. 2014; 2(3):76-85. doi: 10.12691/ijcd-2-3-8


Celiac disease (CeD) is an immune-mediated enteropathy triggered by ingestion of gluten in genetically susceptible individuals. CeD is a global disease and estimated to affect approximately one percent of the global population. With advent of simple serological tests for the diagnosis, the number of individuals diagnosed with CeD is increasing exponentially. It was initially thought that gluten hypersensitivity in CeD is limited to small intestine only and all other features are secondary to malabsorption, but it is now recognized that the hypersensitivity to gluten is not limited to small intestine alone and may affect other organs such as skin, brain, and bones independent of intestinal involvement. CeD is now considered a multi-system disorder and their clinical presentation may be with gastrointestinal symptoms, called “classical CeD” or more often with non-gastrointestinal symptoms called “non-classical CeD”. These patients may present with short stature, anemia, liver dysfunction (asymptomatic increase in transaminases, chronic liver disease, autoimmune hepatitis), cutaneous manifestations (dermatitis herpetiformis, oral ulcers), reproductive diseases (infertility, recurrent abortions), neurological manifestations (ataxia, peripheral neuropathy), and metabolic disorders (osteopenia/osteoporosis). What determines these variable phenotypes remain unclear but likely is a result of genetic as well as environmental factors. Many of these patients with non-classical CeD are likely to report to specialists other than gastroenterologists such as hematologists, endocrinologists, rheumatologists or gynecologists. Unfortunately, the awareness about non-classical presentations of CeD amongst health care professionals remains low. There is an urgent need to increase awareness among health care professionals about varied manifestations of CeD in order to decrease the burden of undiagnosed CeD.

short stature anemia autoimmune hepatitis gluten ataxia dermatitis herpatiformis atypical celiac disease cirrhosis of liver

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[1]  Lerner A,Blank M, Shoenfeld Y. Celiac disease and autoimmunity. Isr J Med Sci1996; 32: 33-36.
[2]  Reif S, Lerner A. Celiac disease and infection. In: Shoenfeld, Y, Rose, N: Infections and Autoimmunity. Amsterdam: Elsevier B.V. 2004:689-692.
[3]  Reif S, Lerner A. Tissue transglutaminase – the key player in celiac disease: a review. Autoimm Rev2004; 3: 40-45.
[4]  Shamir R, Eliakim R, Lahat N, Sobel E, Lerner A. ELISA assay of anti-endomysial antibodies in the diagnosis of celiac disease: comparison with immunofluorescence assay of anti-endomysial antibodies and tissue transglutaminase antibodies. Isr Med Assoc J 2002; 4: 594-596.
[5]  Rozenberg O, Lerner A, Pacht A, Grinberg M, Reginashvili D, Henig C, Barak M. A novel algorithm for childhood celiac disease serological diagnosis based upon intestinal biopsies. Crit Rev Allerg Immunol2012; 42: 331-341.
[6]  Zarkadas M, Cranney A, case S, Molloy M, Switzer C, Graham ID, Butzner JD, Rashid M, Warren RE, Burrows V. The impact of gluten-free diet on adults with celiac disease: results of a national survey. J Hum Nutr Diet 2006; 19: 41-9.
[7]  Rashid M, Cranney A, Zarkadas M, Graham ID, Switzer C, Case S, Molloy M, Warren RE, Burrows V, Butzner JD. Celiac disease: Evaluation of the diagnosis and dietary compliance in Canadian children. Pediatrics 2005; 116: e754-9.
[8]  Hall NJ, Rubin G, Charnock A. Systematic review: adherence to a gluten free diet in adults with celiac disease. Aliment Pharmacol Ther 2009; 30: 315-30.
[9]  Fric P, Gabrovska D, Nevoral J. Celiac disease, gluten-free diet, and oats. Nutr Rev 2011; 69: 107-15.
[10]  Lerner A. New therapeutic strategies for celiac disease. Autoimmun Rev 2010; 9: 144-147.
[11]  Butt MS, Tahir-Nadeem M, Kashif Iqbal Khan M, Shabir R, Butt MS. Oat: unique among the cereals. Eur J Nutr 2008; 47: 68-79.
[12]  Pulido OM, Gillespie Z, Zarkadas M, Dubois S, Vavasour E, Rashid M, Switzer C, Godefroy SB. Introduction of oats in the diet of individuals with celiac disease: a systematic review. Adv Food Nutr Res 2009; 57: 235-85.
[13]  Comino I, Moreno MdM, Real A, Rodreguez-Herrera A, Barro F, Sousa C. The gluten-free diet: testing alternative cereals tolerated by celiac patients. Nutrients 2013; 5: 4250-4268.
[14]  Tang Y, Forsyth CB, Banan A, Fields JZ, Keshavarzian A. Oats supplementation prevents alcohol-induced gut leakiness in rats by preventing alcohol-induced oxidative tissue damage. JPET 2009; 329: 952-958.
[15]  Hoffenberg EJ, Hass J, Drescher A, Barnhurst R, Osberg I, Bao F, Eisenbarth G. A trial of oats in children with newly diagnosed celiac disease. J Pediatr 2000; 137: 361-366.
[16]  Hogberg L, Laurin P, Falth-Magnusson K, Grant C, Grodzinsky E, Jansson G, Ascher H, Browaldh L, Hammersjö JA, Lindberg E, Myrdal U, Stenhammar L. Oats to children with newly diagnosed celiac disease: a randomized double-blind study. Gut 2004; 53: 649-654.
[17]  Hollen E, Holmgren Peterson K, Sundqvist T, Grodzinsky E, Högberg L, Laurin P, Stenhammar L, Fälth-Magnusson K, Magnusson KE. Celiac children on a gluten-free diet with and without oats display equal anti-avenin antibody titres. Scand J Gastroenterol 2006; 41: 42-47.
[18]  Hollen E, Forslund T, Hogberg L, Laurin P, Stenhammar L, Fälth-Magnusson K, Magnusson KE, Sundqvist T. Urinary nitric oxide during one year of gluten-free diet with or without oats in children with celiac disease.Scand J Gastroenterol 2006; 41: 1272-1278.
[19]  Holm K, Maki M, Vuolteenaho N, Mustalahti K, Ashorn M, Ruuska T, Kaukinen K. Oats in the treatment of childhood celiac disease: a 2-year controlled trial and a long-term clinical follow-up study. Aliment PharmacolTher2006; 23: 1463-1472.
[20]  Koskinen O, Villanen M, Korponay-Szabo I, Lindfors k, Maki M, Kaukinen K. Oats do not induce systemic or mucosal autoantibody response in children with celiac disease. J Pediatr Gastroenterol Nutr 2009; 48: 559-565.
[21]  GattiS, Caporelli N, Galeazzi T, Francavilla R, Barbato M, Roggero P, Malamisura B, Iacono G, Budelli A, Gesuita R, Catassi C, Lionetti E. Oats in the diet of children with celiac disease: preliminary results of a double-blind, randomized, placebo-controlled multicenter Italianstudy. Nutrients 2013; 5: 4653-4664.
[22]  Storsrud S, Olsson M, Arvidsson Lenner R, Nilsson LA, Nilsson O, Kilander A. Adult celiac patients do tolerate large amount of oats. Eur J Clin Nutr2003; 57: 163-9.
[23]  Storsrud S, Hulthen LR, Lenner RA. Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences. Br J Nutr 2003; 90: 101-7.
[24]  Lundin KEA, Nilsen EM, Scott HG, Loberg EM,Gjøen A, Bratlie J, Skar V, Mendez E, Løvik A, Kett K. Oats induced villous atrophy in celiac disease. Gut 2003; 52: 1649-52.
[25]  Arentz-Hansen H, Fleckenstein B, Molberg O, Scott H, Koning F, Jung G, Roepstorff P, Lundin KE, Sollid LM. The molecular basis for oat intolerance in patients with celiac disease. Plos Med 2004; 1: 84-92.
[26]  Guttormsen V, Lovik A, Bye A, Bratlie J, Mørkrid L, Lundin KE. No induction of anti-avenin by oats in adults, diet-treated celiac disease. Scan J Gastroenterol2008;43:161-5.
[27]  Sey MS, Parfitt J, Gregor J. Prospective study of clinical and histological safety of pure and uncontaminatedCanadian oats in the management of celiac disease.JParenter Enteral Nutr2001; 35: 459-64.
[28]  Kaukinen K, Collin P, Huhtala H, Maki M.Long-term consumption of oats in adult celiac disease patients.Nutrients 2013; 5: 4380-89.
[29]  Janatuinen EK, Pikkarainen PH, KemppainenTA,Kosma VM, Järvinen RM, Uusitupa MI, Julkunen RJ. A comparison of diets with and without oats in adults with celiac disease.N Engl J Med 1995; 333: 1033-37.
[30]  Janatuinen EK, Kemppainen TA, Julkunen RJK, Kosma VM, Mäki M, Heikkinen M, Uusitupa MI. No harm from five years ingestion of oats in celiac disease. Gut 2002; 50: 332-35.
[31]  Kemppainen TA, Janatuinen R, Holm K, Kosma VM, Heikkinen M, Mäki M, Laurila K, Uusitupa M, Julkunen R. No observed local immunological response at cell level after five years of oats in adult celiac disease. Scand J Gastroenterol 2007; 42: 54-9.
[32]  Srinivasan U, Jones E, Carolan J, Feighery C. Immunohistochemical analysis of celiac mucosa following ingestion of oats. Clin Exp Immunol 2006; 144: 197-203.
[33]  Kemppainen TA, Heikkinen MT, Ristinkankare MK, Kosma VM, Sontag-Strohm TS, Brinck O, Salovaara HO, Julkunen RJ. Unkilned and large amounts of oats in the celiac disease: arandomized, controlled study. Scand J Gastroenterol 2008; 43: 1094-101.
[34]  Peraaho M, Kaukinen K, Musalahti k, Vuolteenaho N, Mäki M, Laippala P, Collin P. Effects of an oats-containing gluten-free diet on symptoms and quality of life in celiac disease, a randomized study. Scand J Gastroenterol2004; 39: 27-31.
[35]  Peraaho M, Collin P, Kaukinen L, Kekkonen L, Miettinen S, Maki M. Oats can diversify gluten-free diet in celiac disease and dermatitis herpetiformis. J Amer Diet Assoc2004; 104: 1148-150.
[36]  Picarelli A, Di Tola M, Sabatella L, Gabrielli F, Di Cello T, Anania MC, Mastracchio A, Silano M, De Vincenzi M. Immunologic evidence of no harmful effect of oats in celiac disease. Am J Clin Nutr2001; 74: 137-140.
[37]  Silano M, Dessi M, De Vincenzi M, Cornell H. In vitro tests indicate that certain varieties of oats may be harmful to patients with celiac disease. J GastroenterolHepatol 2007; 22; 528-531.
[38]  Kilmartin C, Lynch S, Abuzakouk M, Wieser H, Feighery C. Avenin fails to induce a Th1 response in celiac tissue following in vitro culture.Gut2003; 52: 47-52.
[39]  Kilmartin C, Wieser H, Abuzakouk M, Kelly J, Jacson J, Feighery C. Intestinal T cell responses to cereal proteins in celiac disease. Dig Dis Sci 2006; 51: 202-209.
[40]  Vader LW, Stepniak DT, Bunnik EM, Kooy YM, de Haan W, Drijfhout JW, Van Veelen PA, KoningF.Characterization of cereal toxicity for celiac disease patients based on protein homology in grains. Gastroenterol2003; 125: 1105-1113.
[41]  Maglio M, Mozzarella G, Barone MV, Gianfrani C, Pogna N, Gazza L, Stefanile R, Camarca A, Colicchio B, Nanayakkara M, Miele E, Iaquinto G, Giardullo N, Maurano F, Santoro P, Troncone R, Auricchio S. Immunogenicity of two oat varieties, in relation to their safety for celiac patients. Scand J Gastroenterol 2011; 46: 1194-205.
[42]  Real A, Comino I, Laura de Lorenzo, Merchan F, Gil-Humanes J, Giménez MJ, López-Casado MÁ, Torres MI, Cebolla Á, Sousa C, Barro F, Pistón F. Molecular and immunological characterization of gluten proteins isolated from oat cultivars that differ in toxicity for celiac disease. PLoS one2012; 7: e48365.
[43]  Comino I, Real A, Laura de Lorenzo, Cornell H, López-Casado MÁ, Barro F, Lorite P, Torres MI, Cebolla A, Sousa C. Diversity in oat potential immunogenicity: basis for the selection of oat varieties with no toxicity in coeliac disease. Gut 2011; 60: 915-922.
[44]  Silano M, PenasPozo E, Uberti F, ManferdelliS,Del Pinto T, Felli C, Budelli A, Vincentini O, Restani P. Diversity of oat varieties in eliciting the early inflammatory events in celiac disease.Eur J Nutr 2013; Epub head of print.PMID:24240659.
[45]  45. Thompson T. Gluten contamination of commercial oat products in the United States. NEnglJMed 2004; 351: 2021-2.
[46]  Rashid M. Butzner D, Burrows V, Zarkadas M, Case S, Molloy M, Warren R, Pulido O, Switzer C. Consumption of pure oats by individuals with celiac disease: A position statement by the Canadian celiac association. Can J Gastroenterol 2007; 21: 649-51.
[47]  Garsed K, Scott BB. Can oats be taken in gluten free diets? A systematic review.Scand J Gastroenterol 2007; 42: 171-8.
[48]  Koerner TB, Cleroux C, Poirier C, Cantin I, Alimkulov A, Elamparo H. Gluten contamination in the Canadian commercial oat supply. Food additives and contaminantsPart A. Chem Anal Control Expo Risk Assess 2011; 28: 705-10.
[49]  Koerner TB, Cleroux C, Poirier C, Cantin I, La Vieille S, Hayward S, Dubois S. Gluten contamination of naturally gluten-free flours and starches used by Canadian with celiac disease. Food Additives & contaminations: Part A.Chem Anal Control Expo Risk Assess 2013; 30: 2017-21.
[50]  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 R5 ELIZA. Eur J Gastroenterol Hepatol 2008; 20: 545-54.