Gluten-related disorders

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Gluten-related disorders is the umbrella term for all diseases triggered by gluten.^[1][2] Gluten-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.

Symptoms include bloating, abdominal discomfort or pain, diarrhea, constipation, muscular disturbances, headaches, migraines, severe acne, fatigue, and bone or joint pain.^[3][4]

Also other substances of wheat other than gluten have been found to contribute to symptoms, casting doubt on the role of gluten in functional bowel disorders like irritable bowel syndrome.^[5]

Gluten, named from the Latin gluten meaning glue,^[6] is a substance that gives elasticity to dough helping it to rise and to keep its shape. It is found in many staple foods in the Western diet.

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:^[7]

• 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.^[8] 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.^[9]

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)".^[10] 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.^[5] An editorial in Gastroenterology calls into question the existence of NCGS as a discrete entity.^[11] 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.^[12]

Antibodies to α-gliadin have been significantly increased in non-celiacs individuals with oral ulceration.^[13] 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.^[14] 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 GSE^{[clarification needed]}, the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive.^[15]

More than 250 symptoms of gluten sensitivity have been reported, including bloating, abdominal discomfort or pain, constipation and diarrhea. ^[16] 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;^[3][4][17] also neuropsychiatric manifestations ("gluten-sensitive idiopathic neuropathies") have been reported on.^[18]

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.^[19] 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.^[20]

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.^[21] However a more detailed follow-up trial by the same authors found no difference between gluten or placebo groups.^[5]

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.^[22] In NCGS, there is high AGA IgG in more than half of the cases.^[23] In wheat allergy, there appears to be an innate component and the response pathways are mediated through IgE against gliadin and other wheat proteins.^[24][25][26]

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".^[27]

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.^[2] Nearly all CD patients are NLA-DQ2/HLA-DQ8 positive,^[28] with 95% HLA-DQ2 and the rest usually HLA-DQ8 (which is carried by 30% of Caucasians).^[2] 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.^[2][28]

Studies using anti-gliadin antibodies (AGA) reveal that diagnosed or untreated^{[clarification needed]} individuals with AGA have an increasing risk for lymphoid cancers and decreased risk for other conditions associated with affluence.^[29]

A literature review of 2014 found that non-coeliac gluten sensitivity diagnosis can be reached only by excluding celiac disease (CD) and wheat allergy.^[27]

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.^[30]

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,^[2][31] 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).Template:Citationneeded 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.

A four-of-five rule was proposed 2010 for confirming celiac disease, with the disease confirmed if at least four of the following five criteria are satisfied:^[2][32]

• 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 patients with celiac disease, a lifelong strict gluten-free diet is the only effective treatment to date;^[33][34] 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.^[34]

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.^[35] 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.^[36] 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.^[37]

Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates.^[38] 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.^[39] 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.Template:Citationneeded Guidelines are also available for the introduction of pure, uncontaminated oats into the gluten-free diet.^[40]

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; estimates range from 0.6% to 6%.^[34]

In Europe, the average consumption of gluten is 10g to 20g per day, with parts of the population reaching 50g or more per day.^[2]

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".^[41] 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.^[42]

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.^[43][44]

• List of allergies
• Vomitoxin, a mycotoxin which currently occurs abundantly in grains in Norway due to climate change.^[45] It might give rise to somewhat comparable symptoms.

Template:Gluten sensitivity