gluten-related disorders gluten-related disorders gluten-related disorders is the term for the diseases triggered by gluten, including celiac disease (cd), non-celiac gluten sensitivity (ncgs), gluten ataxia, dermatitis herpetiformis (dh) and wheat allergy. the umbrella category has also been referred to as gluten intolerance, though a multi-disciplinary physician-led study, based in part on the 2011 international coeliac disease symposium, concluded that the use of this term should be avoided due to a lack of specificity. this article is about disorders related to gluten, a natural ingredient in many cereals. it is not to be confused with sensitivities related to glutamate, a flavor-enhancing additive. gluten-related disorders gluten is a group of proteins, such as prolamins and glutelins, stored with starch in the endosperm of various cereal (grass) grains. as of 2017, gluten-related disorders were increasing in frequency in different geographic areas. the increase might be explained by the popularity of the western diet, the expanded reach of the mediterranean diet (which also includes grains with gluten), the growing replacement of rice by wheat in many countries, the development in recent years of new types of wheat with a higher amount of cytotoxic gluten peptides, and the higher content of gluten in bread and bakery products, due to the reduction of dough fermentation time. however, a 2020 study by the leibniz-institute for food systems biology casts doubt on the idea that modern wheat has higher gluten levels. from a seed bank, they grew and analyzed 60 wheat cultivars from between 1891 and 2010 and found no changes in albumin/globulin and gluten contents over time. "overall, the harvest year had a more significant effect on protein composition than the cultivar. at the protein level, we found no evidence to support an increased immunostimulatory potential of modern winter wheat." types the following classification of gluten-related disorders was announced in 2011 by a panel of experts in london, and published in february 2012: 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 disorders main articles: celiac disease and gluten-sensitive enteropathy-associated conditions autoimmune conditions related to gluten include celiac disease, dermatitis herpetiformis, and gluten ataxia. there is research showing that in people with gluten ataxia early diagnosis and treatment with a gluten-free diet can improve ataxia and prevent its progression. the population of people with gluten ataxia and other neurological conditions appears to have a different hla distribution, in particular more hla-dq1, compared to most persons with celiac disease, who have hla-dq2 and hla-dq8. coeliac disease main article: coeliac disease 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 oats and derivatives. 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. 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. this is where the innate and adaptive immune response systems collide. villous atrophy of the small intestine 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 serological markers (anti-tissue transglutaminase ) are not always present and many people may have minor mucosal lesions, without atrophy of the intestinal villi. diagnosis of cd should be based on a combination of person's familial history, genetics (i.e. presence of hla dq2/dq8) serology and intestinal histology. cd affects approximately 1–2% of general population all over the world, but most cases remain unrecognized, undiagnosed and untreated, and exposed to the risk of long-term complications. people may experience severe disease symptoms and be subjected to extensive investigations for many years, before a proper diagnosis is achieved. untreated cd may result in the lack of absorption of nutrients, reduced quality of life, iron deficiency, osteoporosis, an increased risk of intestinal lymphomas and greater mortality. cd is associated with some autoimmune diseases, such as diabetes mellitus type 1, thyroiditis, gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, dermatitis herpetiformis, primary sclerosing cholangitis, and more. 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. cd with "non-classic symptoms" is the most common clinical found type and occurs in older children (over two years old), adolescents and adults. 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. as previously mentioned, cd very frequently may be completely asymptomatic both in children (at least in 43% of the cases) and adults. to date, the only available medically accepted treatment for people with coeliac disease is to follow a lifelong gluten-free diet. dermatitis herpetiformis main article: dermatitis herpetiformis dermatitis herpetiformis (dh), or duhring-brocq disease, is a chronic blistering skin autoimmune condition, characterized by the presence of skin lesions that have an extensive and symmetrical distribution, predominating in areas of greater friction, and affecting mainly both elbows, knees, buttocks, ankles, and may also affect the scalp and other parts of the body, and non-symmetrical occasionally. the lesions are vesicular-crusted and when flake off, they evolve to pigmented areas or achromic an intense burning, itchy and blistering rash. despite its name, dh is neither related to nor caused by herpes virus: the name means that it is a skin inflammation having an appearance similar to herpes. 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. dh can relatively commonly present with atypical manifestations, which makes its diagnosis more difficult. some people may show erythema or severe pruritus alone, wheals of chronic urticaria, purpuric lesions resembling petechiae on hands and feet, palmo-plantar keratosis, leukocytoclastic vasculitis-like appearance, and/or lesions mimicking prurigo pigmentosa. dh may be confused with many different cutaneous lesions, such as atopic dermatitis, eczema, urticaria, scabies, impetigo, polymorphic erythema and other autoimmune blistering diseases. 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. people with dh have different degrees of intestinal involvement, ranging from milder mucosal lesions to the presence of villous atrophy. 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. gluten ataxia gluten ataxia is an autoimmune disease triggered by the ingestion of gluten. 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. early diagnosis and treatment with a gluten-free diet can improve ataxia and prevent its progression. the effectiveness of the treatment depends on the elapsed time from the onset of the ataxia until diagnosis, because the death of neurons in the cerebellum as a result of gluten exposure is irreversible. gluten ataxia accounts for 40% of ataxias of unknown origin and 15% of all ataxias. less than 10% of people with gluten ataxia present any gastrointestinal symptom, yet about 40% have intestinal damage. non-celiac gluten sensitivity (ncgs) main article: non-celiac gluten sensitivity non-celiac gluten sensitivity (ncgs), or gluten sensitivity (gs), is a possible syndrome in which people develop a variety of intestinal and/or extraintestinal symptoms that improve when gluten is removed from the diet, after coeliac disease and wheat allergy are excluded. ncgs, which is possibly immune-mediated, now appears to be more common than coeliac disease, with a prevalence estimated to be 6–10 times higher. gastrointestinal symptoms, which resemble those of irritable bowel syndrome (ibs), may include any of the following: abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation), nausea, aerophagia, gastroesophageal reflux disease, and aphthous stomatitis. extra-intestinal symptoms, which can be the only manifestation of ncgs even in absence of gastrointestinal symptoms, may be any of the following: headache or migraine, "foggy mind", fatigue, fibromyalgia, joint and muscle pain, leg or arm numbness, tingling of the extremities, dermatitis (eczema or skin rash), atopic disorders, allergy to one or more inhalants, foods or metals (such as mites, graminaceae, parietaria, cat or dog hair, shellfish, or nickel), depression, anxiety, anemia, iron-deficiency anemia, folate deficiency, asthma, rhinitis, eating disorders, or autoimmune diseases. among extra-intestinal manifestations, ncgs seems to be involved in some neuropsychiatric disorders, principally schizophrenia, autism and peripheral neuropathy, and also ataxia and attention deficit hyperactivity disorder (adhd). 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. atis are about 2–4% of the total protein in modern wheat and 80–90% in gluten. 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. 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. as occurs in people with coeliac disease, the treatment is a gluten-free diet (gfd) strict and maintained, without making any dietary transgression. 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. the results of a 2017 study suggest that ncgs may be a chronic disorder, as is the case with celiac disease. theoretically, a trial of gluten reintroduction to observe reaction after 1–2 years of strict gluten-free diet might be advisable. 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 gluten free diet. however, the ingestion of even a small amount of gluten may cause more immediate symptoms in people with ncgs as compared with those with coeliac disease. people with ncgs should carefully read ingredient labels on food and be aware of potential cross contamination as a source of gluten in otherwise gluten-free foods. to find out if there are unintended ingestions of gluten, an exhaustive evaluation with the advice of a coeliac disease specialized dietitian could be necessary. in some cases, people can significantly improve with a low fodmaps diet in addition to gluten withdrawal and/or a gfd with a low content of preservatives and additives. furthermore, associated to gluten sensitivity, ncgs people may often present ige-mediated allergies