Gluten-related Disorders

What are Gluten-related Disorders?
Doctors and scientists agreed that celiac disease is an autoimmune condition triggered by the consumption of gluten. Breakthrough research developments in celiac disease published over the past 10 years have revealed that celiac disease is more common than once thought, affecting 1% of the worldwide population1. What’s more, the United States has observed a true increase in the prevalence of the disease by four-fold since 19502. In combination with diagnostic improvements in serological testing and general awareness, these research advancements have spurred an increase in celiac disease diagnoses. 
But despite these advancements, 95% of the 3 million Americans with celiac disease currently remain undiagnosed. Further, this autoimmune disease’s treatment, the gluten-free diet, is demonstrating to be more recognized than the condition itself. The gluten-free market has escalated in response to rising demand from gluten-free consumers, as gluten-free product sales in 2011 exceeded $6.2 billion - a 16.9% increase from 20103.
Initially designed as treatment for celiac disease, it is clear that the gluten-free diet is proving to have more applications than originally thought. In fact, researchers are finding that there is a spectrum of gluten-related disorders4, 5.
Two recent papers published by internationally renowned celiac disease experts provide guidance on classifying gluten-related disorders and outline suggestions for preferred terminology when communicating about these conditions4, 5. Because these publications are helping to shape the rapidly evolving spectrum of gluten-related disorders, it is imperative that healthcare providers stay abreast on the latest reports from this field.
What is the Quest Diagnostics Difference?
We are excited to help you incorporate this up to date knowledge into your practice. To support your practice, Quest Diagnostics provides you with the laboratory tools and educational materials to assist all physicians, especially experts on the diagnosis and management of gluten-related disorders.
New research suggests that the gluten-related disorders spectrum include three categories, based on pathogenesis5:
Autoimmune Response:
  • Perhaps the most well-known of the gluten-related disorders, the adaptive immune system diseases include celiac disease, dermatitis herpetiformis and gluten ataxia4, 5.  
Allergic Response:
  • Some research5 includes an allergic response in the reaction to one of the toxic protein fractions of gluten found in wheat, gliadin. Thus, it is prudent to incorporate wheat allergy into the gluten-related disorders spectrum.  
Innate-Immune Response:
  • A non-allergic, non-autoimmune response to gluten has also been identified. This condition is known as non-celiac gluten sensitivity, or in short NCGS4,5.
What is Gluten?
Gluten is a general term used to describe the similar proteins found in wheat, barley and rye that elicit an adverse effect in individuals with celiac disease4. More recently, research has shown that gluten is also harmful to persons without celiac disease, thus yielding to a new set of conditions called “gluten-related disorders” 4, 5, 11.
The major seed proteins in cereals are the alcohol-soluble prolamins. In wheat, gluten refers to the group of prolamins, or toxic protein fractions, known as gliadins and glutenins. Similar proteins are also found in prolamins in rye, known as secalins, and in barley, known as hordeins. Other closely related grains containing gluten include kamut, spelt and hybrids, such as triticale. Because oats were once thought to be included as a gluten-containing grain, it is important to note that pure, uncontaminated oats have not been found to elicit an immune response in most patients with celiac disease6.
The human gut has difficulty digesting gluten in persons with or without celiac disease4. The 33 residue peptide fragment 13 , rich in glutamine and proline, is particularly resistant to enzymatic degradation 14.

What is Celiac Disease?
Celiac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed people4. The genes involved in celiac disease include the HLA class II: HLA-DQ2 and/or HLA-DQ8.
Additionally, increased gut permeability has been associated with pathogenesis7. Zonulin, a hormone in the presence of gluten, is secreted by the enterocytes in elevated concentrations. Zonulin facilitates increased gut permeability by loosening tight junctions 7. This process facilitates an influx of gluten absorption through the epithelium and into the lamina propria where the HLA and gliadin deamidated by transglutaminase form a complex 15. This complex is presented to T cells that become sensitized to gluten, triggering an autoimmune milieu where cytokines are released and an adaptive immune response ensues, resulting in auto-antibodies and antigliadin antibodies. 11, 15, 25
This gluten exposure results in some degree of intestinal damage and leads to nutritional deficiencies and their associated conditions and symptoms. The autoimmune process can affect multiple organs and bodily systems. While it is clear that some autoimmune diseases such as thyroid disease and Type 1 diabetes are more common in the celiac disease population, the research is conflicting with regard to undiagnosed celiac disease initiating the development of other autoimmune diseases16-18. Nonetheless, left untreated, people with celiac disease have an increased risk of mortality2, a diminished quality of life and a greater risk for some malignancies 8. The degree of intestinal damage varies from person to person 9, 10.
For a detailed description of the symptoms of celiac disease, click here.  
What is non-responsive celiac disease?
Non-responsive celiac disease affects 10% to 19% of those diagnosed with celiac25. It can be defined as primary or secondary. Primary non-responsive celiac disease consists of those individuals who initially did not demonstrate a positive response to the gluten-free diet within six months of diagnosis. Secondary non-responsive celiac disease defines those who initially did respond to the gluten-free diet as indicated by symptoms and/or biochemical indices, but that have relapsed after normalization.25
A multitude of causes must be considered and can include the following:
  • (inadvertent) Gluten exposure
  • Pancreatic insufficiency
  • Irritable bowel syndrome (IBS)
  • Small intestinal bacterial overgrowth (SIBO)
  • Disaccharidase deficiency
  • Refractory celiac disease
  • Microscopic colitis
  • Food allergies and intolerances
  • Eating disorder
Approximately 35% to 50% of cases occur in response to inadvertent gluten ingestion, making it the most common cause of non-responsive celiac disease25. Aside from oral gluten, inhaled gluten has reportedly provoked non-responsive celiac disease as well26.

How does Wheat Allergy Apply Here?
Some research suggests that wheat allergy is included in the gluten-related disorders spectrum, and that in order for non-celiac gluten sensitivity to be diagnosed, wheat allergy must be excluded along with celiac disease5. As such, it can be recommended that healthcare providers be prudent when suspicious of the gluten-related disorder non-celiac gluten sensitivity and consider wheat allergy as a possibility.
Wheat allergy includes a spectrum of IgE mediated immune responses involving histamine that occurs within minutes to hours after wheat exposure. Along the spectrum, classic food allergy, wheat-dependent exercise-induced anaphylaxis (WDEIA) and wheat dependent aspirin-induced anaphylaxis (WDAIA) are included. It has become evident that in some individuals, particularly with WDEIA, protein components in rye and barley can cross-react with gluten, thereby indicating the need to avoid gluten and not just wheat 5, 12.
For further information on allergy, including wheat allergy, visit ImmunoCAP Specific IgE Blood Test.

What is Non-Celiac Gluten Sensitivity?
Non-celiac gluten sensitivity is a condition that is different from celiac disease, despite the significant overlap in clinical presentations 4, 5, 11. Within hours to days after gluten ingestion, patients develop symptoms, which can be can be both intestinal, such as diarrhea and abdominal pain, and extra-intestinal, such as fatigue, “foggy brain” and peripheral numbness.  (For a further description of the symptoms of non-celiac gluten sensitivity, click here).
Despite the overlapping symptoms with celiac disease, it is important to note that non-celiac gluten sensitivity is not accompanied by “the enteropathy, elevations in tissue-transglutaminase, endomysium or deamidated gliadin antibodies, and increased mucosal permeability that are characteristic of celiac disease” 4, 5, 11. Thus, patients with non-celiac gluten sensitivity would not test positive for celiac disease based on blood testing, nor do they have the same type of intestinal histology found in individuals with celiac disease. They can experience an increase in lymphocytic infiltration. If minimal intestinal damage is present, this will recede with a gluten-free diet 11. Early research suggests that non-celiac gluten sensitivity is the result of an activated innate immune response 11.
In order to diagnose non-celiac gluten sensitivity, celiac disease must first be ruled out4, 5. In addition, other recent research suggests that wheat allergy must be excluded along with celiac disease before non-celiac gluten sensitivity can be diagnosed due to further overlapping symptoms5.

What is dermatitis herpetiformis?
Known as the cutaneous form of celiac disease, it presents initially as erythematous macule, ultimately developing into an urticarial papule. Granular deposition of IgA autoantibodies to transglutaminase and frequently to epidermal transglutaminase5, 19. appear in the tips of the dermal papillae and the basement membranes19. Scratching the vesicles may cause excoriations, making it visually difficult to distinguish between another similar appearing rash19. In males it appears more frequently5, while most children are spared with the exception of those in the Mediterranean (3). The mean age of onset is 40 years. Those of Northern European descent are most afflicted. In the United States the prevalence is an estimated 1 in 10,00022, and 15% - 25% of patients with celiac disease will develop dermatitis herpetiformis at some point in their life23.
The pathology is gluten dependent and involves oral gluten exposure. Ninety-five percent with multiple samples taken on biopsy reveal varying degrees of enteropathy4. Incidentally, many patients do not present with classical symptoms (signs of malabsorption) of celiac disease. Dermatitis herpetiformis does respond rapidly to gluten intake. Upon gluten withdrawal, months to several years may lapse before the rash completely clears20. Sulfones, such as Dapsone, are often indicated to better control pruritus. Dietery iodine such as shellfish can exacerbate dermatitis herpetiformis19. There are reports that iodine-containing substances used for therapeutic reasons, such as Triiodomethane-containing material for dental procedures, have also exacerbated dermatitis herpetiformis21.  
For a detailed description of the symptoms of dermatitis herpetiformis, click here.
What is gluten ataxia?
Gluten ataxia is also known as idiopathic sporadic ataxia and positive antigliadin (AGA) - IgA or IgG antibodies in the presence or absence of enteropathy4. Research indicates that cross reactivity between gluten and Purkinje cells exists resulting in transglutaminase antibody deposition, particularly found frequently in the cerebellum, medulla and pons5.

For a detailed description of the symptoms of gluten ataxia, click here.

Detailed information on how laboratory tests can be used to initiate diagnosis in all of the gluten-related disorders discussed above can be found here.
It is important to note that the conditions as listed above reflect the recommended terminology for the gluten-related disorders spectrum. Likewise, the following is a list of terminology related to celiac disease and other gluten-related disorders that are discouraged in order to improve communication among physician and patient groups. For a full outline of preferred and discouraged terminology please read The Oslo definitions for coeliac disease and related terms.
· Sprue
· Coeliac sprue
· Gluten-sensitive enteropathy
· Gluten intolerance
· Gluten sensitivity
· Non-tropical sprue
· Idiopathic steatorrhoea
To access the two recent publications on nomenclature and disease classification, and other important papers, visit the PubMed site to read the following abstracts and access some full-text articles:
Research in the gluten-related disorders spectrum is expanding daily. To learn more about breakthrough research, follow the National Foundation for Celiac Awareness’ Research Feed, proudly sponsored by, but developed independently of ,Quest Diagnostics. To leave this site and access this Research Feed click here.
1. Fasano, A., Berti, I., Gerarduzzi, T., Not, T., Colletti, R.B., Drago, S., et al. (2003). Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large multicenter study. Archives of Internal Medicine, 163, 286-292. 
2. Rubio-Tapia, A., Kyle, R.A., Kaplan, E.L., Johnson, D.R., Page, W., Erdtmann, F., et al. (1999). Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology, 137(1), 88-93.
3. SPINscan Natural, 52 weeks ending Sept. 3, 2011.
4. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C. (2012). The Oslo definitions for coeliac disease and related terms. Gut, Feb 16. [Epub ahead of print]
5. Sapone, A., Bai, J.C., Ciacci, C., Dolinsek, J., Green, P.H.R., Hadjivassiliou, M., Kaukinen, K., Rostami, K., Sanders, D., Schumann, M., Ullrich, R., Villalta, D., Volta, U., Catassi, C. and Fasano, A. (2012). Spectrum of gluten-related disorders: consensus on new nomenclature and classification BMC Medicine, 10:13
6. Koskinen, O., Villanen, M. Korponay-Szabo, I, Lindfors, K., Maki, M., & Kaukinen, KK. (2009). Oats do not induce systemic or mucosal autoantibody response in children with coeliac disease. J Pediatr Gastroenterol Nutr, 48(5), 559-565. 
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8. Elfstrom, P., Granath, F., Ye, W., & Ludvigsson, J.F. (2012). Low risk of gastrointestinal cancer among patients with celiac disease, inflammation, or latent celiac disease. Clinical Gastroenterology and Hepatology, 10(1), 30-36.
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10. Marsh, M.N. (1992). Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology, 102(1), 330-354.
11. Sapone, A., Lammers, K.M., Casolaro, V., Cammarota, M., Giuliano, M.T., De Rosa, M., et al. (2011). Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Medicine, 9(23).
12. Palosuo, K., Alenius, H., Varjonen, E., Kalkinnen, N. & Reunala, T. (2001). Rye y-70 and y-35 secalins and barley y-3 hordein cross-react with w-5 gliadin, a major allergen in wheat –dependent, exercise-induced anaphylaxis. Clin Exp Allergy, 31(3):466-473.
13. Qiao, S., Bergseng, E., Molberg, O, et al. Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion. The J. of Immunology. 2004;173:1757-1762.
14. Cabrera-Chavez, F., Amati, S., Miriani, M. et al. Maize prolamins resistant to peptic-tryptic digestion maintain immune-recognition by IgA from some celiac disease patients. 2012; 67:24-30.
15. Fasano, A. Surprises from celiac disease. Scientific American. 2009; 32-39.
16. Garud, S., Leffler, D., Dennis, M., Edwards-George, J., Saryan, D., Sheth, S., et al. (2009). Interaction between psychiatric and autoimmune disorders in coeliac disease patients in the Northeastern United States. Aliment Pharmacol Ther, 29:898-905.
17. Ventura, A., Magazzu, G., Greco, L., & SIGEP Study Group for Autoimmune Disorders in Celiac Disease. (1999). Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. Gastroenterology, 117, 297-303.
18. Sategna, Guidetti, C., Solerio, E., Scaglione, N., Aimo, G., & Mengozzi, G. (2001). Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut, 49: 502-505.
19.Bolotin, D, Petronic-Rosic. Dermatitis herpetiformis. J Am Acad   Dermatol. 2011; 64: 1017-1024.
20. Rosic, V. Dermatitis herpetiformis and celiac disease. Impact: A publication of the University of Chicago Celiac Disease Center. 2011.
21. Katz, K., Roseman, J., Roseman, R. et al. Dermatitis herpetiformis flare associated with use of triidomethane lodoform) packing strips for alveolar osteitis. J. Am Acad Dermatol. 2009; 60:352-353.
22. Smith, J.B., Tulloch, J.E., Meyer, L.J., & Zone, J.J. (1992). The incidence and prevalence of dermatitis herpetiformis in Utah. Arch Dermatol.128(12):1608-1610.
23. Zone, J.J. (2005). Skin manifestations of celiac disease. Gastroenterology, 128:S87-91.
24.Hadjivassiliou, M., Davies-Jones, G., Sanders, D, Grunewald, R. Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry. 2003; 74: 1221-1224.
25.Leffler, D, Dennis, M, Hyett, B, et al. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clinical Gastroenterol and Hepatology . 2007;5:445-450.
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