Celiac Disease and Non-Celiac Gluten Sensitivity: The Evolving Spectrum

In the last 3 years, the acceptance of Non-Celiac Gluten Sensitivity (NCGS) in the medical community as a distinct clinical entity has gone from that of being an orphaned child crying in the world for recognition, to an accepted, unique component of the triad of gluten-related disorders.i Differentiating among gluten-related disorders guides clinicians in making an accurate diagnosis and recommending specific dietary, nutritional and other medical advice; however, clinical and laboratory diagnosis is complex and evolving.ii For example, Irritable Bowel Syndrome (IBS) is the most common abdominal complaint patients suffer from. Although the frequency of IBS with accompanying Celiac Disease (CD) is about 1%, the frequency of IBS with accompanying NCGS is over 30%. Resolution of IBS symptoms occurs in these individuals with a GFD.iii

Gluten Sensitivity (GS) is a state of heightened immunological responsiveness to ingested gluten in genetically susceptible people. It represents a spectrum of diverse manifestations, of which, the gluten sensitive enteropathy known as CD is one of many. Adverse reactions to the toxic family of gluten proteins found in wheat, barley, rye, and their derivatives may trigger a heterogeneous set of conditions, including wheat allergy (IgE), NCGS, and CD, that, combined, affect between 10–35% of the population.iv,v,vi,vii Once believed to fall exclusively into the domain of allergic conditions (e.g., wheat allergy), it is now clear that the intestinal and extra-intestinal manifestations of CD are entities that may differ from allergy, and are mediated by innate and adaptive immune pathways.viii

True or False
1) Even in the presence of negative small bowel biopsy, positive Endomysial antibody (EMA) IgA
predicts development of CD.
2) The prevalence of CD varies by race/ethnicity, with a marked predominance among non-
Hispanic whites.
3) With more sophisticated diagnostic markers now available, the majority of CD cases are
being recognized.
4) Complete histological normalization of the small-intestinal mucosa occurs in the
majority of adult patients after commencing a gluten-free diet (GFD).
5) An American College of Gastroenterology Task force recommends that patients presenting
with diarrhea-predominant IBS type symptoms should be serologically tested for CD.
6) What percent of individuals with NCGS suspect they may have a problem with wheat?
A. 32%
B. 76%
C. 50%
D. 12%
7) Of the following three scenarios, which is the most dangerous for increased mortality in CD?
a) Total villous atrophy
b) Positive celiac serology with negative villous atrophy
c) Increased intraepithelial lymphocytes (IEL) with negative serology and negative villous
8) In differentiating wheat sensitivity from IBS, which one of the following features is
significantly more frequent in wheat sensitive (WS) patients compared to IBS patients?
A. Anemia
B. Self-reported fructose intolerance
C. Weight gain
D. Self-reported lactose intolerance
9) Compared to patients with CD, what are the characteristic features, other than
self-reported wheat intolerance, of patients with wheat sensitivity?
A. Anemia and family history of CD
B. Weight loss and increased IEL count
C. Coexistent atopy and food allergy in infancy
D. Increased serum C reactive protein and erythrocyte sedimentation rate

Current therapeutic protocols for CD, NCGS and wheat allergy include dietary counseling from a trained professional, nutritional therapy addressing biomarkers of malabsorption and creating a more balanced intestinal environment.ix Currently, there are no approved pharmaceutical treatments for this silent epidemic, however a number of Phase 3 trials are underway. Promising gluten-based research is currently being done including wheat alternatives and wheat selection, enzymatic alteration of wheat, oral enzyme supplements and polymeric binders as exciting new therapies for treatment of CD.x

There appears to be at least two distinct groups of NCGS individuals. There are those who are sensitive to wheat and those who have multiple food sensitivities. In a recent study 75% of NCGS patients with IBS had multiple food sensitivities including cow’s milk protein, eggs and tomato. This may explain the frustration of Clinicians when a GFD is less-than-optimally-effective in suspected and/or identified NCGS.

Those NCGS patients with IBS and wheat sensitivity had more features in keeping with CD (higher frequency of anemia, weight loss, and HLA DQ2 or DQ8) than those with multiple food sensitivities. Furthermore, the multiple food sensitivity group had a higher prevalence of coexisting atopy or food allergy in infancy. xi It is critically important to identify whether a NCGS
individual has multiple food sensitivities or exclusively has NCGS.xii This suggests the world of NCGS is greater than just one mechanism and invites the Clinician to explore its pathophysiology.

1) True. The presence of IgA EMA antibodies predicted deterioration of the microvilli with
subsequent development of CD.xiii, xiv
2) True. “Our results confirm prior data showing that a substantial burden of CD in the United
States predominantly affects the non-Hispanic white population”. ibid
3) False. Current estimates from Mayo Clinic are that 1.8 million Americans have celiac disease
and a whopping 78 percent of sufferers don’t realize they have the condition. Study co-
author, gastroenterologist Joseph Murray, in a clinic news release summarizes, “If you
detect one person for every five or six [who have it], we aren’t doing a very good job
detecting CD.” xv, xvi
4) False. In CD, complete histological normalization of the small-intestinal mucosa
occurs in only 8 – 20 % of adult patients after commencing a GFD.xvii If you
let that sink in, you MUST ask the question, “Why is that?”
5) True. Patients with undetected CD may present with IBS type symptoms. This has led to the
recommendation by the American College of Gastroenterology Task Force that
patients presenting with diarrhea predominant IBS type symptoms should be
serologically tested for CD.xviii
6) C. “It is interesting to note that 50% of the 276 patients self-reported wheat
7) C. The incidence of increased mortality in CD with total villous atrophy is 39%.
The incidence of increased mortality with just positive serology is 35%.
The incidence of increased mortality with just increased IEL’s is 72%.xix
8) A. “As regards the clinical characteristics of WS patients and the identification
of possible diagnostic markers, our data indicated that the presence of anemia and
weight loss and a history of food allergy in infancy and of coexistent atopic diseases are
more frequent in WS patients than in IBS controls. Other studies have not shown
changes in intestinal permeability and absorption.” xx
9) C. ibid

 i Ludvigsson JF, Leffler DA, Bai JC, Biagi F, et.al., The Oslo definitions for coeliac disease and
 related terms, Gut. 2013 Jan;62(1):43-52
 ii O’Bryan T, Ford R, Kupper C, Celiac Disease and Non-Celiac Gluten Sensitivity-An Evolving
 Spectrum, in Advancing Medicine with Diet and Nutrients, Johns Hopkins, CRC Press,
 December 2012
 iii Carroccio A, Mansueto P, Iacono G, Soresi M, et.al., Non-celiac wheat sensitivity diagnosed by
 double-blind placebo-controlled challenge: exploring a new clinical entity, Am J Gastroenterol.
 2012 Dec;107(12):1898-1906
 iv Catassi, C. and Fasano, A. 2008. Celiac disease. Curr Opin Gastroenterol 24: 687-91.
 v Anderson, L.A., McMillan, S.A., Watson, R.G., et al. 2007. Malignancy and mortality in a
 population based cohort of patients with coeliac disease or ‘gluten sensitivity’. World J
 Gastroenterol 13: 146-51.
 vi Ferguson, A., Gillett, H., Humphreys, K., and Kingstone, K. 1998. Heterogeneity of celiac
 disease: clinical, pathological, immunological, and genetic. Intestinal Plasticity in Health and
 Disease. 859: 112-20.
 vii Constantin, C., Huber, W.D., Granditsch, G., Weghofer, M. and Valenta, R. 2005. Different
 profiles of wheat antigens are recognised by patients suffering from coeliac disease and IgE-
 mediated food allergy. Int Arch Allergy Immunol 138: 257-66.
 viii Vermeersch P, Geboes K, Mariën G, Hoffman I, Hiele M, Bossuyt X. Diagnostic performance of
 IgG anti-deamidated gliadin peptide antibody assays is comparable to IgA anti-tTG in celiac
 disease. Clin Chim Acta. 2010 Jul 4;411(13-14):931-935.
 ix Ibid, reference #2
 x Stoven S, Murray JA, Marietta E., Celiac disease: advances in treatment via gluten
 modification, Clin Gastroenterol Hepatol. 2012 Aug;10(8):859-62
 xi ibid reference 3
 xii Bondsa, R., Midoro-Horiutib, T. and Goldblum, R. 2008. A structural basis for food allergy: the
 role of cross-reactivity. Current Opinion in Allergy and Clinical Immunology 8: 82-86.
 xiii Kurppa K, Ashorn M, Iltanen S et al. Celiac disease without villous atrophy in children: a
 prospective study. J Pediatr 2010;157:373–380
 xiv Kurppa K, Collin P, Viljamaa M et al. Diagnosing mild enteropathy celiac disease: a
 randomized, controlled clinical study. Gastroenterology 2009;136:816–823
 xv Mayo Clinic, news release, July 31, 2012
 xvi Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE., The prevalence of celiac
 disease in the United States. Am J Gastroenterol. 2012 Oct;107(10):1538-44
 xvii Tuire I, Marja-Leena L, Teea S, Katri H, et.al. Persistent duodenal intraepithelial
 lymphocytosis despite a long-term strict gluten-free diet in celiac disease, Am J
 Gastroenterol. 2012 Oct;107(10):1563-9
 xviii Sanders DS, Aziz I. Editorial: non-celiac wheat sensitivity: separating the wheat from the
 chat! Am J Gastroenterol. 2012 Dec;107(12):1908-12
 xix Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F., Small-intestinal
 histopathology and mortality risk in celiac disease, JAMA. 2009 Sep 16;302(11):1171-8
 xx Carroccio A, Mansueto P, Iacono G, Soresi M, et.al., Non-celiac wheat sensitivity diagnosed
 by double-blind placebo-controlled challenge: exploring a new clinical entity, Am J
 Gastroenterol. 2012 Dec;107(12):1898-906

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