Gluten-related disorders

Gluten-related disorders is the term for the diseases triggered by

Gluten is a group of proteins, such as prolamins and glutelins,^[3] stored with starch in the endosperm of various cereal (grass) grains.

As of 2017^[update], gluten-related disorders were increasing in frequency in different geographic areas. The increase might be explained by the popularity of the

The following classification of gluten-related disorders was announced in 2011 by a panel of experts in London, and published in February 2012:[7]^[8]

• gluten ataxia
• Non-autoimmune, non-allergic: disorder with unknown cause, likely immune-modulated: non-celiac gluten sensitivity (NCGS)
• baker's asthma, contact dermatitis
  .

Coeliac disease (American English: celiac) (CD) is one of the most common chronic, immune-mediated disorders, triggered by the eating of gluten, a mixture of proteins found in wheat, barley, rye, and derivatives.^[11][12] Evidence has shown that this condition not only has an environmental component but a genetic one as well, due to strong associations of CD with the presence of HLA (Human leukocyte antigen) type II, specifically DQ2 and DQ8 alleles.^[13] These alleles can stimulate a T cell, mediated immune response against tissue transglutaminase (TTG), an enzyme in the extracellular matrix, leading to inflammation of the intestinal mucosa and eventually villous atrophy of the small intestine.^[14] This is where the innate and adaptive immune response systems collide.

CD is not only a gastrointestinal disease. It may involve several organs and cause an extensive variety of non-gastrointestinal symptoms. Most importantly, it may often be completely asymptomatic. Added difficulties for diagnosis are the fact that

CD with "classic symptoms", which include gastrointestinal manifestations such as chronic diarrhea and bloating, malabsorption of certain vitamins and minerals, loss of appetite, impaired growth and even bone pain, is currently the least common presentation form of the disease and affects predominantly to small children generally younger than two years of age.[14]^[19][20]

CD with "non-classic symptoms" is the most common clinical found type^[20] and occurs in older children (over two years old),^[20] adolescents and adults.^[20] It is characterized by milder or even absent gastrointestinal symptoms and a wide spectrum of non-intestinal manifestations that can involve any organ of the body such as, cerebellar ataxia, hypertransaminasemia and peripheral neuropathy.^[17] As previously mentioned, CD very frequently may be completely asymptomatic^[19] both in children (at least in 43% of the cases^[22]) and adults.^[19]

To date, the only available medically accepted treatment for people with coeliac disease is to follow a lifelong gluten-free diet.^[17][23][24]

With continuous mass genetic modification of grain crops, for instance for drought resistance and pest repellence, the occurrence of diagnosed CD had increased by 400% in the past 50 years alone.^[19]

Dermatitis herpetiformis

The age of onset is variable starting in children and adolescence but can also affect individuals of both sexes indistinctly at any age of their lives.[26]^[27]

DH can relatively commonly present with atypical manifestations, which makes its diagnosis more difficult. Some people may show

DH is considered to be the "coeliac disease of the skin". For this reason, the new guidelines of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition for the diagnosis of coeliac disease conclude that a proven diagnosis of DH, by itself, confirms the diagnosis of coeliac disease. Nevertheless, duodenal biopsy is recommended in doubtful cases, or if there are suspected gastrointestinal complications, including lymphoma.^[27] People with DH have different degrees of intestinal involvement, ranging from milder mucosal lesions to the presence of villous atrophy.^[25]

The main and more efficacious treatment for DH is following a lifelong gluten-free diet, which produces the improvement of skin and gut lesions. Nevertheless, the skin lesions may take several months or even years to disappear. To calm itching, dapsone is often recommended as a temporary treatment, during the time it takes for the diet to work, but it has no effect on the gastrointestinal changes and may have important side effects.^[25][28]

Gluten ataxia

Gluten ataxia is an autoimmune disease triggered by the ingestion of gluten.^[2] With gluten ataxia, damage takes place in the cerebellum, the balance center of the brain that controls coordination and complex movements like walking, speaking and swallowing, with loss of Purkinje cells. People with gluten ataxia usually present gait abnormality or incoordination and tremor of the upper limbs. Gaze-evoked nystagmus and other ocular signs of cerebellar dysfunction are common. Myoclonus, palatal tremor, and opsoclonus-myoclonus may also appear.^[29]

Early diagnosis and treatment with a

Gluten ataxia accounts for 40% of ataxias of unknown origin and 15% of all ataxias.[29]^[31] Less than 10% of people with gluten ataxia present any gastrointestinal symptom, yet about 40% have intestinal damage.^[29]

Non-celiac gluten sensitivity (NCGS)

Non-celiac gluten sensitivity (NCGS), or gluten intolerance,^[1] is a syndrome in which people develop a variety of intestinal and/or extraintestinal symptoms that improve when gluten is removed from the diet,^[32] after coeliac disease and wheat allergy are excluded.^[33] NCGS, which is possibly immune-mediated, now appears to be more common than coeliac disease,^[34] with a prevalence estimated to be 6–10 times higher.^[35]

Gastrointestinal symptoms, which resemble those of irritable bowel syndrome (IBS),^[32][36] may include any of the following: abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation),^[36][37] nausea, aerophagia, gastroesophageal reflux disease, and aphthous stomatitis.^[33][36]

Extra-intestinal symptoms, which can be the only manifestation of NCGS even in absence of gastrointestinal symptoms, may be any of the following:

Gluten is likely responsible for the appearance of symptoms, but it has been suggested than in a subgroup of people with NCGS and symptoms like IBS, other components of wheat and related grains (oligosaccharides like fructans), or other plant proteins contained in gluten-containing cereals (agglutinins, lectins, and amylase trypsin inhibitors (ATIs)) may play a role in the development of gastrointestinal symptoms.^[17] ATIs are about 2–4% of the total protein in modern wheat and 80–90% in gluten.^[33] In a review of May 2015 published in Gastroenterology, Fasano et al. conclude that ATIs may be the inducers of innate immunity in people with coeliac disease or NCGS.^[33] As of 2019, reviews conclude that although FODMAPs present in wheat and related grains may play a role in non-celiac gluten sensitivity, they only explain certain gastrointestinal symptoms, such as bloating, but not the extra-digestive symptoms that people with non-celiac gluten sensitivity may develop, such as neurological disorders, fibromyalgia, psychological disturbances, and dermatitis.^[41][42][33] As occurs in people with coeliac disease, the treatment is a gluten-free diet (GFD) strict and maintained, without making any dietary transgression.^[37] Whereas coeliac disease requires adherence to a strict lifelong gluten-free diet, it is not yet known whether NCGS is a permanent, or a transient condition.^[22][37] The results of a 2017 study suggest that NCGS may be a chronic disorder, as is the case with celiac disease.^[42] Theoretically, a trial of gluten reintroduction to observe reaction after 1–2 years of strict gluten-free diet might be advisable.^[37]

Approximately one-third of persons with NCGS continue having symptoms despite gluten withdrawal. This may be due to diagnostic error, poor dietary compliance, or other reasons. Those with NCGS may be under the impression that they do not need to follow a strictly

In some cases, people can significantly improve with a low FODMAPs diet in addition to gluten withdrawal[5] and/or a GFD with a low content of preservatives and additives.^[43] Furthermore, associated to gluten sensitivity, NCGS people may often present IgE-mediated allergies to one or more foods^[37] and it is estimated that around 35% of people with some food intolerances, mainly lactose intolerance.^[44]

Wheat allergy

People can also experience adverse effects of wheat as result of a wheat allergy.^[17] Gastrointestinal symptoms of wheat allergy are similar to those of coeliac disease and non-celiac gluten sensitivity, but there is a different interval between exposure to wheat and onset of symptoms. Wheat allergy has a fast onset (from minutes to hours) after the consumption of food containing wheat and could be anaphylaxis.^[15][45]

The treatment of wheat allergy consists of complete withdrawal of any food containing wheat and other gluten-containing cereals.^[45][46] Nevertheless, some people can tolerate barley, rye or oats.^[47]

Other conditions or risk factors

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Complications

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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.^[57]

Causes

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.

Compared to the pathophysiology of celiac disease, the pathophysiology of NCGS is far less understood.

A literature review of 2014 found that people with NCGS "are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis and clinical history, and, probably, clinical course".^[65]

Genetics

Celiac disease (CD) and NCGS are closely linked with

A literature review of 2014 found that non-coeliac gluten sensitivity diagnosis can be reached only by excluding celiac disease (CD) and wheat allergy.^[65]

Persons suspected of having celiac disease may undergo

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][67] 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 three).^{[citation needed]} 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 person 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][68]

• 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.

Treatment

For people with celiac disease, a lifelong strict gluten-free diet is the only effective treatment to date;^[23][69]

For people diagnosed with non-celiac gluten sensitivity, there are still open questions concerning for example the duration of such a diet. The results of a 2017 study suggest that non-celiac gluten sensitivity may be a chronic disorder, as is the case with celiac disease.^[42]

For people with wheat allergy, the individual average is six years of gluten-free diet, excepting persons with anaphylaxis, for whom the diet is to be wheat-free for life.^[69]

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.

Gluten proteins have low nutritional value and replacing grains that contain gluten is easy from the nutritional point of view.^[23] However, an unbalanced selection of food and an incorrect choice of gluten-free replacement products may lead to nutritional deficiencies. Replacing flour from wheat or other gluten-containing cereals with gluten-free flours in commercial products may lead to a lower intake of important nutrients, such as iron and B vitamins. Some gluten-free commercial replacement products are not enriched or fortified as their gluten-containing counterparts, and often have greater lipid/carbohydrate content. Children especially often over-consume these products, such as snacks and biscuits.^[74]

Pseudocereals (quinoa, amaranth, and buckwheat) and some minor cereals are healthier alternatives to these prepared products and have higher nutritional value.^[74][23] Furthermore, they contain protein of higher nutritional quality than those of wheat, and in greater quantities.^[74]

Nutritional complications can be prevented by a correct dietary education.^[74]

Epidemiology

In the United States, fewer cases of CD have been found compared to other countries.^[77] The incidence of celiac disease and of wheat allergy is estimated each to lie at around 1% of the population. There has been a 6.4 increase in the case reports of celiac disease between 1990 and 2009.^[50] The incidence of NCGS is unknown; some estimates range from 0.6% to 6%,^[69] and a systematic review of 2015 reported on studies with NCGS prevalence rates between 0.5% and 13%.^[78]

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]

Histology

Changes in inflammatory cells affect the body, which reduces the intake of "nutrients, fat-soluble vitamins and minerals" in the body.^[50]

Regulations

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".^[79] 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.^[80]

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 people 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.^[81][82]

Research

Research has attempted to discern, by

In a 2015 double-blind placebo cross-over trial, small amounts of purified wheat gluten triggered gastrointestinal symptoms (such as abdominal bloating and pain) and extra-intestinal manifestations (such as foggy mind, depression and aphthous stomatitis) in self-reported NCGS. Nevertheless, it remains elusive whether these findings specifically implicate gluten or proteins present in gluten-containing cereals.[44]

A 2016 review of the recent research advancements in understanding diet's role in attenuating IBS patient's symptoms concluded that gluten was a common trigger. However, because on the different compounds responsible for symptoms, many patients that could be inaccurately labelled non-coeliac gluten sensitive; and it may be more appropriate to use nomenclature such as "non-coeliac wheat sensitive" (NCWS), "non-coeliac wheat protein sensitive" (NCWPS), or even FODMAP sensitive when referring to these patients.^[84]

In a 2018 double-blind, crossover research study on 59 persons on a gluten-free diet with challenges of

• List of allergies
• Vomitoxin, a mycotoxin which can give rise to somewhat comparable symptoms.

References