Gluten-related disorders is the umbrella term for all diseases triggered by gluten. Gluten-related disorders/gliadin-related disorders include celiac disease and non-celiac gluten sensitivity (NCGS). Formerly, also gluten intolerance has been used as umbrella term, and the expression gluten sensitivity has been used either as umbrella term or for NCGS.
- 1 Types
- 2 Symptoms
- 3 Etiology
- 4 Causes of gluten sensitivity
- 5 Pathophysiology
- 6 Diagnosis
- 7 Treatment
- 8 Epidemiology
- 9 Society and culture
- 10 See also
- 11 References
The following classification of gluten-related disorders was announced 2011 by an expert's panel in London, published 2012 and further expanded on later that year:
- Autoimmune disorders: celiac disease, dermatitis herpetiformis, gluten ataxia
- Non-autoimmune, non-allergic: disorder with unknown cause, likely immune-modulated: non-celiac gluten sensitivity (NCGS)
- Allergic: food allergy (IgE-mediated and non-IgE-mediated), wheat dependent exercise induced anaphylaxis (WDEIA), baker's asthma, contact dermatitis.
Autoimmune conditions related to gluten include celiac disease, dermatitis herpetiformis, and gluten ataxia. There is research showing that in certain patients with gluten ataxia early diagnosis and treatment with a gluten-free diet can improve ataxia and prevent its progression. The population of patients with gluten ataxia and other neurological conditions appears to have a different HLA distribution, in particular more HLA-DQ1, compared to the population of typical celiac disease patients.
Non-celiac gluten sensitivity
In a 2009 paper, Verdu et al. defined gluten sensitivity as "one or more of a variety of immunological, morphological or symptomatic manifestations that may also be shared by celiac disease and irritable bowel syndrome (IBS)". In cases where there is reactivity to gluten, yet celiac disease and wheat allergy are eliminated as possibilities, NCGS may be considered. While the general clinical picture for NCGS is similar to celiac disease in particular, it is usually less severe and neither anti-tissue transglutaminase antibodies nor autoimmune comorbidities are found.
However, in 2013, Biesiekierski JR et al. concluded that NCGS, as currently defined, might not be a discrete entity (or its effects might be confounded by FODMAP restriction), and that gluten might not cause functional gut symptoms once dietary FODMAPs are reduced. An editorial in Gastroenterology calls into question the existence of NCGS as a discrete entity. The authors suggest that reduction of FODMAPs, rather than gluten or other wheat proteins, might be mechanism by which low-gluten diets improve gastrointestinal symptoms. These findings suggest that gluten sensitivity may not play a significant role in the etiology of functional gastrointestinal disorders like irritable bowel syndrome.
NCGS, which is possibly immune-mediated, now appears to be more common than celiac disease.
|This section relies too much on references to primary sources. (January 2015)|
Antibodies to α-gliadin have been significantly increased in non-celiacs individuals with oral ulceration. Anti-α-gliadin antibodies are frequently found in celiac disease (CD), to a lesser degree subclinical CD, but are also found in a subset who do not have the disease. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA. One fourth of people with Sjögren's syndrome had responses to gluten, of 5 that had positive response to gluten, only one could be confirmed as CD and another was potentially [clarification needed], the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive.
More than 250 symptoms of gluten sensitivity have been reported, including bloating, abdominal discomfort or pain, constipation and diarrhea.  Sensitivity may also present with extraintestinal symptoms, including headache, "brain fog", tingling and/or numbness in hands and feet, fatigue, as well as muscular disturbances and bone or joint pain; also neuropsychiatric manifestations ("gluten-sensitive idiopathic neuropathies") have been reported on.
When enteropathy develops in early childhood, symptomatic disease is more rapidly evident. A survey of geriatrics with celiac disease in Finland revealed that the incidence of disease was much higher than the general population. Allergic disease may rise or fall with age; certain evidence points to the increased or daily use of non-steroidal anti-inflammatory factors (aspirin, ibuprofen) as an increased risk factor for urticaria or anaphylaxis, and the sensitizing dose may include low-dose aspirin therapy used in the treatment of heart disease. NCGS may be a late-onset condition: in a prospective study performed among adults of 18 to 80 years, the median age of disease onset was found to be 55 years, with a six times higher prevalence in females than in males.
A double-blind placebo-controlled trial found that gluten caused significantly worse pain, tiredness, bloating and stool consistency than a placebo diet in IBS patients. There was no difference in celiac or gliadin antibodies between the gluten and control groups. However a more detailed follow-up trial by the same authors found no difference between gluten or placebo groups.
Causes of gluten sensitivity
Immunochemistry of glutens
Triticeae glutens are important factors in several inflammatory diseases. The immunochemistry can be subdivided into innate responses (direct stimulation of immune system), class II mediated presentation (HLA-DQ), class I mediated stimulation of killer cells, and antibody recognition. The responses to gluten proteins and polypeptide regions differs according to the type of gluten sensitivity. The response is also dependent on the genetic makeup of the human leukocyte antigen genes. In enteropathy, there are at least 3 types of recognition, innate immunity (a form of cellular immunity priming), HLA-DQ and antibody recognition of gliadin and transglutaminase. In NCGS, there is high AGA IgG in more than half of the cases. In wheat allergy, there appears to be an innate component and the response pathways are mediated through IgE against gliadin and other wheat proteins.
Compared to the pathophysiology of celiac disease, the pathophysiology of NCGS is far less understood.
A literature review of 2014 found that patients suffering from NCGS "are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis and clinical history, and, probably, clinical course".
Celiac disease (CD) and NCGS are closely linked with human leukocyte antigen (HLA) class II genes, HLA-DQ2 and HLA-DQ8, located on chromosome 6p21. Nearly all CD patients are NLA-DQ2/HLA-DQ8 positive, with 95% HLA-DQ2 and the rest usually HLA-DQ8 (which is carried by 30% of Caucasians). However, the specificity of HLA-DQ2 and/or HLA-DQ8 for CD is low, with estimates ranging from 36% to 53%. In NCGS patients, the HLA-DQ2 and/or HLA-DQ8 alleles are present in only about 50%, which is still a greater proportion than in the general population.
|This section relies too much on references to primary sources. (December 2014)|
Studies using anti-gliadin antibodies (AGA) reveal that [clarification needed] individuals with AGA have an increasing risk for lymphoid cancers and decreased risk for other conditions associated with affluence.
Persons suspected of having celiac disease may undergo serological testing for IgA anti-tissue transglutaminase antibodies (abbreviated anti-tTG antibodies or anti-TG2 antibodies) and anti-endomysial antibodies (abbreviated EMA) provided the IgA-level is high, and if IgA is low, testing for certain IgG antibodies; in case of positive serological indication, a duodenal biopsy may confirm active celiac disease.
Eliminating the possibility of CD can generally also be done by adding HLA-DQ typing. The absence of HLA-DQ2 and HLA-DQ8 has a very high negative predictive value for CD, and the predictive value can be further enhanced by including HLA-DQ7.5 (HLA-DQ2 and HLA-DQ8 are found in coeliac disease 98% of the time in Caucasians, HLA-DQ7.5 present in the remaining 1.6% and only 0.4% of Caucasians are missed with the combination of these 3). Without serological or HLA-DQ2/8 positivity, celiac disease is likely not present. HLA-DQ typing has a practical advantage in that it is the only diagnostic test that allows to exclude CD when a patient is already on a gluten-free diet; however, as not only celiacs are HLA-DQ2/HLA-DQ8 positive, this method has a higher false positive rate than anti-TG2 and EMA antibody testing.
- typical symptoms of celiac disease;
- positivity of serum celiac disease immunoglobulin, A class autoantibodies at high titer;
- human leukocyte antigen (HLA)-DQ2 or DQ8 genotypes;
- celiac enteropathy at the small bowel biopsy; and
- response to the gluten-free diet.
For diagnosis of wheat allergy, allergy tests are available.
For patients with celiac disease, a lifelong strict gluten-free diet is the only effective treatment to date; for patients diagnosed with NCGS, there are still open questions concerning for example the duration of such a diet; for patients with wheat allergy, the individual average is 6 years of gluten-free diet with exception for persons with anaphylaxis for whom the diet is to be wheat-free for life.
A gluten-free diet should not be started before the tests for excluding celiac disease have been performed, for the reason that the serological and biopsy tests for celiac disease are reliable only if the patient is consuming gluten.
Preferably, newly diagnosed celiacs seek the help of a dietician to receive support for identifying hidden sources of gluten, planning balanced meals, reading labels, food shopping, dining out, and dining during travel. Knowledge of hidden sources of gluten is important for celiac disease patients as they need to be very strict on eating only gluten-free food; for NCGS patients, it is not certain how strict the diet needs to be. Balanced eating is important because, unless particular care is taken, a gluten-free diet can be lacking in vitamins, minerals and fiber and too high in fat and calories.
Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates. Recent studies show that gluten-sensitive individuals on a gluten-free diet often get too much simple carbohydrate, too little fiber and vitamin B. Currently most guidelines do not include oats in a gluten-free diet. While this is likely to change, oats are not recommended within a year of diagnosis because of the risk of avenin-sensitive enteropathy (ASE), the desire to establish a clinical baseline and complexity of the contamination issue. Consuming oats when anti-gliadin antibodies or gliadin are present increases anti-avenin antibodies and may promote ASE, therefore duodenal biopsy may be recommended after oat consumption is initiated; the DQ phenotype of all 3 ASE individuals studied so far indicated DQ2 homozygotes are at risk for ASE. Guidelines are also available for the introduction of pure, uncontaminated oats into the gluten-free diet.
The incidence of celiac disease and of wheat allergy is estimated each to lie at around 1% of the population. The incidence of NCGS is unknown; some estimates range from 0.6% to 6%, and a systematic review of 2015 reported on studies with NCGS prevalence rates between 0.5% and 13%.
In Europe, the average consumption of gluten is 10g to 20g per day, with parts of the population reaching 50g or more per day.
Society and culture
In various countries, regulations and labelling requirements for gluten-free food products have been implemented.
For Europe, the Commission Regulation (EC) No. 41/2009 of 20 January 2009 concerning the composition and labelling of foodstuffs suitable for people intolerant to gluten has laid down harmonised rules on the content and labelling of these foodstuffs, setting out the conditions under which foods may be labelled as "gluten-free" or "very low gluten". Having entered into force on 10 February 2009 and taken effect on 1 January 2012, these rules have been repealed with effect as of 20 July 2016. The background is that, in line with the Regulation (EU) No 609/2013 on food for specific groups, gluten-free foods shall, in future, be legislated for under the EU Food Information for Consumers Regulation (Regulation (EU) No. 1169/2011). Furthermore, the Commission Implementing Regulation (EU) No 828/2014 of 30 July 2014 on the requirements for the provision of information to consumers on the absence or reduced presence of gluten in food extends the rules of Regulation (EC) 41/2009 on "gluten-free" and "very low gluten" statements also to non pre-packed foods such as those served in restaurants. The implementing regulation also clarifies how consumers are to be informed of the difference between foods that are naturally free of gluten and products that are specially formulated for gluten-intolerant persons.
Recognition of gluten-free packaged foods is facilitated by the crossed-grain symbol, representing a crossed ear of wheat. The symbol is used as a logo that facilitates food shopping for patients with CD and other gluten-related disorders. The symbol, which is protected as a trademark in Europe and the United States and is covered by worldwide copyright, can be represented in any colour.
- 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 (January 2013). "The Oslo definitions for coeliac disease and related terms". Gut 62 (1): 43–52. doi:10.1136/gutjnl-2011-301346. PMC 3440559. PMID 22345659.
- Sapone A, Bai JC, Ciacci C, Dolinsek J, Green PH, Hadjivassiliou M, Kaukinen K, Rostami K, Sanders DS, Schumann M, Ullrich R, Villalta D, Volta U, Catassi C, Fasano A (2012). "Spectrum of gluten-related disorders: consensus on new nomenclature and classification". BMC Medicine (Review) 10: 13. doi:10.1186/1741-7015-10-13. PMC 3292448. PMID 22313950.
- Sapone A, Lammers KM, Mazzarella G, et al. (2010). "Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease". Int. Arch. Allergy Immunol. (Research Support, N.I.H., Extramural) 152 (1): 75–80. doi:10.1159/000260087. PMC 2956008. PMID 19940509.
- Hadjivassiliou M, Chattopadhyay AK, Grünewald RA, et al. (April 2007). "Myopathy associated with gluten sensitivity". Muscle Nerve (Research Support, Non-U.S. Gov't) 35 (4): 443–50. doi:10.1002/mus.20709. PMID 17143894.
- Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR (August 2013). "No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates". Gastroenterology (Randomized Controlled Trial) 145 (2): 320–8.e1–3. doi:10.1053/j.gastro.2013.04.051. PMID 23648697.
- "Gluten" def. 3. Oxford English Dictionary Second Edition on CD-ROM (v. 4.0) © Oxford University Press 2009
- Czaja-Bulsa G (August 2014). "Non coeliac gluten sensitivity - A new disease with gluten intolerance". Clinical Nutrition (Edinburgh, Scotland) (Review) 34: 189–194. doi:10.1016/j.clnu.2014.08.012. PMID 25245857. See section 9 and Figure 2: Classification of gluten-dependent disorders.
- Hadjivassiliou M, Sanders DS, Woodroofe N, Williamson C, Grünewald RA (2008). "Gluten ataxia". Cerebellum (Review) 7 (3): 494–8. doi:10.1007/s12311-008-0052-x. PMID 18787912.
- Troncone R, Jabri B (June 2011). "Coeliac disease and gluten sensitivity". Journal of Internal Medicine (Review) 269 (6): 582–90. doi:10.1111/j.1365-2796.2011.02385.x. PMID 21481018.
- Verdu EF, Armstrong D, Murray JA (June 2009). "Between celiac disease and irritable bowel syndrome: the "no man's land" of gluten sensitivity". Am. J. Gastroenterol. (Review) 104 (6): 1587–94. doi:10.1038/ajg.2009.188. PMC 3480312. PMID 19455131.
- Vanga R, Leffler DA (August 2013). "Gluten sensitivity: not celiac and not certain". Gastroenterology (Comment) 145 (2): 276–9. doi:10.1053/j.gastro.2013.06.027. PMID 23806541.
- Hogg-Kollars S, Al Dulaimi D, Tait K, Rostami K (2014). "Type 1 diabetes mellitus and gluten induced disorders". Gastroenterology and Hepatology from Bed to Bench (Review) 7 (4): 189–97. PMC 4185872. PMID 25289132.
- O'Farrelly C, O'Mahony C, Graeme-Cook F, Feighery C, McCartan BE, Weir DG (1991). "Gliadin antibodies identify gluten-sensitive oral ulceration in the absence of villous atrophy". J. Oral Pathol. Med. 20 (10): 476–8. doi:10.1111/j.1600-0714.1991.tb00407.x. PMID 1753350.
- Ringvold A, Overgaard RG (1995). "Increased IgA antibodies to gluten and gliadin in serum of persons with ocular pseudo-exfoliation". Acta ophthalmologica Scandinavica (Comparative Study) 73 (2): 171–2. doi:10.1111/j.1600-0420.1995.tb00662.x. PMID 7656149.
- Lidén M, Kristjánsson G, Valtýsdóttir S, Hällgren R (2007). "Gluten sensitivity in patients with primary Sjögren's syndrome". Scand. J. Gastroenterol. (Research Support, Non-U.S. Gov't) 42 (8): 962–7. doi:10.1080/00365520701195345. PMID 17613926.
- Korn, Danna. Living gluten-free for dummies. Hoboken, NJ: Wiley Pub., 2006. 14, 27-31. Print.
- Nijeboer P, Bontkes HJ, Mulder CJ, Bouma G (December 2013). "Non-celiac gluten sensitivity. Is it in the gluten or the grain?". Journal of Gastrointestinal and Liver Diseases : JGLD (Review) 22 (4): 435–40. PMID 24369326.
- Genuis S, Lobo RA (2014). "Gluten Sensitivity Presenting as a Neuropsychiatric Disorder". Gastroenterology Research and Practice (Review) 2014: 1–6. doi:10.1155/2014/293206. ISSN 1687-6121. PMID 24693281.
- Vilppula A, Collin P, Mäki M, et al. (October 2008). "Undetected coeliac disease in the elderly: a biopsy-proven population-based study". Dig Liver Dis (Research Support, Non-U.S. Gov't) 40 (10): 809–13. doi:10.1016/j.dld.2008.03.013. PMID 18467196.
- Volta U, Caio G, Tovoli F, De Giorgio R (September 2013). "Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness". Cellular & Molecular Immunology (Review) 10 (5): 383–92. doi:10.1038/cmi.2013.28. PMC 4003198. PMID 23934026.
- Biesiekierski, Jessica R; et al. (March 2011). "Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial". Am J Gastroenterol (Controlled Clinical Trial) 106 (3): 508–514. doi:10.1038/ajg.2010.487. PMID 21224837.
- van Heel DA, West J (July 2006). "Recent advances in coeliac disease". Gut (Review) 55 (7): 1037–46. doi:10.1136/gut.2005.075119. PMC 1856316. PMID 16766754.
- Catassi C, Bai J, Bonaz B, Bouma G, Calabrò A, Carroccio A, Castillejo G, Ciacci C, Cristofori F, Dolinsek J, Francavilla R, Elli L, Green P, Holtmeier W, Koehler P, Koletzko S, Meinhold C, Sanders D, Schumann M, Schuppan D, Ullrich R, Vécsei A, Volta U, Zevallos V, Sapone A, Fasano A (2013). "Non-celiac gluten sensitivity: the new frontier of gluten related disorders". Nutrients (Review) 5 (10): 3839–3853. doi:10.3390/nu5103839. ISSN 2072-6643. PMID 24077239.
- Bittner C, Grassau B, Frenzel K, Baur X (March 2008). "Identification of wheat gliadins as an allergen family related to baker's asthma". Journal of Allergy and Clinical Immunology (Research Support, Non-U.S. Gov't) 121 (3): 744–9. doi:10.1016/j.jaci.2007.09.051. PMID 18036646.
- Matsuo H, Dahlström J, Tanaka A, et al. (February 2008). "Sensitivity and specificity of recombinant omega-5 gliadin-specific IgE measurement for the diagnosis of wheat-dependent exercise-induced anaphylaxis". Allergy (Evaluation Studies) 63 (2): 233–6. doi:10.1111/j.1398-9995.2007.01504.x. PMID 18186814.
- Akagawa M, Handoyo T, Ishii T, Kumazawa S, Morita N, Suyama K (August 2007). "Proteomic analysis of wheat flour allergens". Journal of Agricultural and Food Chemistry (Research Support, Non-U.S. Gov't) 55 (17): 6863–70. doi:10.1021/jf070843a. PMID 17655322.
- Mansueto P, Seidita A, D’Alcamo A, Carroccio A (2014). "Non-Celiac Gluten Sensitivity: Literature Review". Journal of the American College of Nutrition (Review) 33 (1): 39–54. doi:10.1080/07315724.2014.869996. ISSN 0731-5724. PMID 24533607.
- Sestak K, Fortgang I (October 2013). "Celiac and Non-Celiac Forms of Gluten Sensitivity: Shifting Paradigms of an Old Disease". British Microbiology Research Journal (Review) 3 (4): 585–589. doi:10.9734/BMRJ/2013/6083. PMC 4224078. PMID 25383340.
- Anderson LA, McMillan SA, Watson RG, et al. (2007). "Malignancy and mortality in a population-based cohort of patients with coeliac disease or "gluten sensitivity"". World J. Gastroenterol. (Retrospective Studies) 13 (1): 146–51. doi:10.3748/wjg.v13.i1.146. PMID 17206762.
- Tonutti E, Bizzaro N (2014). "Diagnosis and classification of celiac disease and gluten sensitivity". Autoimmunity Reviews (Review) 13 (4-5): 472–6. doi:10.1016/j.autrev.2014.01.043. PMID 24440147.
- Lundin KEA, Alaedini A, Non-celiac Gluten Sensitivity. In: Lebwohl B, Green PHR (1 November 2012). Celiac Disease, An Issue of Gastrointestinal Endoscopy Clinics. Elsevier Health Sciences. ISBN 1-4557-4735-1.
- Catassi C, Fasano A (August 2010). "Celiac disease diagnosis: simple rules are better than complicated algorithms". The American Journal of Medicine (Research Support, Non-U.S. Gov't) 123 (8): 691–3. doi:10.1016/j.amjmed.2010.02.019. PMID 20670718.
- Lamacchia C, Camarca A, Picascia S, Di Luccia A, Gianfrani C (2014). "Cereal-based gluten-free food: how to reconcile nutritional and technological properties of wheat proteins with safety for celiac disease patients". Nutrients (Review) 6 (2): 575–90. doi:10.3390/nu6020575. PMC 3942718. PMID 24481131.
- Czaja-Bulsa G (August 2014). "Non coeliac gluten sensitivity - A new disease with gluten intolerance". Clinical Nutrition (Edinburgh, Scotland) (Review) 34: 189–194. doi:10.1016/j.clnu.2014.08.012. PMID 25245857. See Table 2: Characteristics of gluten-dependent disorders.
- Pelkowski TD, Viera AJ (January 2014). "Celiac disease: diagnosis and management". American Family Physician 89 (2): 99–105. PMID 24444577.
- Cristofori F, Arezzo F, Gentile A, Francavilla R (September 2014). "Gluten Sensitivity in Pediatrics: A Clinical Conundrum". Current Pediatrics Reports 2 (3): 204–210. doi:10.1007/s40124-014-0053-9.
- Capili B, Chang M, Anastasi JK (October 2014). "A Clinical Update: Nonceliac Gluten Sensitivity—Is It Really the Gluten?". The Journal for Nurse Practitioners. Special Focus: Legal Matters 10 (9). pp. 666–673.
- Størsrud S, Hulthén LR, Lenner RA (July 2003). "Beneficial effects of oats in the gluten-free diet of adults with special reference to nutrient status, symptoms and subjective experiences". Br. J. Nutr. (Research Support, Non-U.S. Gov't) 90 (1): 101–7. doi:10.1079/BJN2003872. PMID 12844381.
- Rashid, Mohsin (2007-06-08). "Guidelines for Consumption of Pure and Uncontaminated Oats by Individuals with Celiac Disease". Professional Advisory Board of Canadian Celiac Association. Retrieved 2008-08-14.
- Rashid M, Butzner D, Burrows V, et al. (October 2007). "Consumption of pure oats by individuals with celiac disease: a position statement by the Canadian Celiac Association". Can. J. Gastroenterol. (Guideline) 21 (10): 649–51. PMC 2658132. PMID 17948135.
- Molina-Infante J, Santolaria S, Sanders DS, Fernández-Bañares F (2015). "Systematic review: noncoeliac gluten sensitivity". Alimentary Pharmacology & Therapeutics (Review) 41 (9): 807–20. doi:10.1111/apt.13155. PMID 25753138.
- "Gluten-free foodstuffs". EUR-Lex. 22 February 2011. Retrieved 4 January 2015.
- "Foods for people intolerant to gluten (gluten-free foods)". European Commission. Retrieved 4 January 2015.
- "The Crossed Grain Symbol". Coeliac UK. Retrieved 12 January 2015.
- "Licensing the Crossed Grain symbol". Association of European Coeliac Societies (AOECS). Retrieved 12 January 2015.