Gluten sensitivity (GS) encompasses a collection of medical conditions in which gluten has an adverse effect. For individuals with gluten-sensitive enteropathy, removal of gluten generally results in the restoration of villus architecture[1] or lower lymphocyte densities in the intestine.[2] With some sensitivities, improvements may be seen in the neurological state, but a clinical finding may not be clear.[3][4] GS also can affect blood chemistry,[5] treatability of certain autoimmune diseases,[6] and/or an untreated improvement in autoimmune conditions.[7][8][9]
Gluten is composed of the sticky, storage proteins found in wheat. Gluten-sensitive enteropathy (GSE) can range from mild inflammation of the mucosa of the small intestine to severe coeliac disease. The term gluten-sensitive is applicable when a probable diagnosis of GSE based on conditions such as dermatitis herpetiformis. However, GS may be used in ambiguous situations when other conditions may be possible. For example, wheat allergies to gluten can result in anaphylaxis while others may be difficult to diagnose because of some of the cryptic inflammatory properties of wheat proteins. The term 'gluten sensitivity' is typically applied when diagnostic testing is not done because of prolonged gluten-free diet and/or refusal of gluten-challenge prior to biopsy. The gluten-sensitive designation may not be appropriate in all cases, as wheat allergies are often directed toward albumins or globulins of wheat, or the person may have a sensitivity to proteins commonly found with wheat products (e.g. fungal amylase or bread-yeast mannins). Therefore diagnostic criteria are preferred. The relationship between gluten and these various sensitivities is complex. For gluten enteropathy, T-cell reactivity is almost entirely restricted to prolamin-glutelin/species within the grass tribe Triticeae, and especially α-gliadins of wheat.[10][11] For a tiny minority of GSE, inflammatory responses may extend to cover oats.[12] Gluten allergies may extend over wide taxa or may be specific to certain wheat proteins and allergies may include oats.
Gluten sensitivity should have a defined cause, although not apparent always with first examination, affected individuals should eventually fall into GSE or wheat allergy. Only rarely should gluten sensitivity be idiopathic. Idiopathic gluten sensitivity (IGS) arises "spontaneously or from an obscure or unknown cause" and may involve neuropathy, myopathy, dermal, or intestinal abnormalities. Anti-gliadin antibodies are the primary link between gluten and idiopathic sensitivity in instances in which enteropathy or allergy are not clearly involved.[13] This form of gluten sensitivity is controversial at the moment.
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Symptoms
Gluten sensitivity is a collection of diseases in which wheat prolamins and glutelins are the sensitizing factor. As such the symptoms are dependent on the specific pathology. In the overwhelming majority of cases gluten sensitivity are asymptomatic or clinical presentation often occurs in followup to idiopathic instances of other diseases (e.g. peripheral neuropathy, autoimmune disease) and these other conditions can vary widely(coeliac disease has been called 'the great imitator', see Coeliac disease - signs and symptoms). In the case of allergic responses, symptoms may appear as dermatitis but could also present as difficulty breathing during exercise. In both cases gastrointestinal symptoms may occur. In the case of idiopathic gluten sensitivity all known symptoms are confined to the nervous system.
Etiology
Gluten sensitivity can develop at any point in life, and symptomatic disease may appear years after disease develop. When enteropathy develops in early childhood symptomatic disease is more rapidly evident. A survey of geriatrics in Finland revealed that the incidence of disease was much higher than the general population. Allergic disease may rise or fall with age, however certain evidence points to the increased or daily use of non-steroidal anti-inflammatory factors (aspirin, ibuprofen) as increased risk factor for urticaria or anaphylaxis, and the sensitizing dose of may include low-dose aspirin therapy used in the treatment of heart disease. Idiopathic disease appears largely late onset.
Gluten-sensitive enteropathy develops as a consequence of genetic and environmental factors. Other than the involvement of certain HLA-DQ isoforms (antigen presenting proteins in humans) and certain wheat proteins, there is no clarity in the involvement of other genes or other environmental factors (see Risk modifiers). Strong genetic factors such as seen in GSE have not been seen in gluten allergy, and with idiopathic gluten-sensitivity the HLA-DQ associations are weak.
Causes of gluten sensitivity
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Triticeae and the potential role of selective evolution in gluten sensitivities. The fruiting bodies of plants contain genes as well as reserves of nutrients that allow seedlings to grow. The enrichment of nutrients is an attractant to herbivores and omnivores. For annual grasses that release seeds during a brief period each year there is a need to protect seeds during maturation from insects or animals, which might stock seeds for year round usage. For wheat, alpha-gliadins are seed-storage proteins, but also an inhibitor the alpha-amylase activities of other animals, particularly insects.[14] It is also known that wheat gliadins creates intestinal disease when fed to very young rodents.[15] One recent publication even raises the question 'is wheat safe for anyone to eat?'.[16] Critically, pathology in insects or artificially fed rodents does not reflect what causes disease in humans, but it is interesting that toxicological effects of wheat are being uncovered that do have the potential to cause pathology in humans. One interesting consequence of these studies is that there may be a general gluten sensitivity that underlies various pathological manifestations, such as coeliac disease, urticaria and idiopathic sensitivity.
The rise of gluten sensitivity (particularly in adults) may reflect the convergence of many phenomena. An aging population, genetic risks associated with westernization, excesses in the diet, sensitizing chemicals (e.g.MSG, aspirin, NSAIDs), and allergy-enhancing chemical treatment of foods (e.g. enzymatic deamidation of gluten) may act together with natural defensive agents in foods to cross the threshold between normality and pathology.
Gluten toxicity
An increasing number of studies on gliadin indicate gluten has a direct and modifying effect on the cells of the small intestine. Two different lines of research show that different gliadins can increase permeability of the epithelial cells (outermost cells of the villus) allowing food proteins to enter. One study examined the effect of ω-5 gliadin, the primary cause of exercise/aspirin induced anaphylaxis, and found increased permeability of intestinal cells caused by this gliadin and another wheat albumin.[17] Another line of research shows gliadin binds a chemoattractant receptor and causes increases of a factor that destroys tight junctions.[18] These junctions prevent leakage around the cells that line the small intestine, resulting in the leaking of food proteins into the body.[19] These toxicities of gluten that are not part of the adaptive immune response may be the link between wheat and gluten sensitivity, and possibly type 1 diabetes.
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.[20] With idiopathic disease only antibody recognition to gliadin has been resolved. In wheat allergy, there appears to be an innate components and the response pathways are mediated through IgE against gliadin and other wheat proteins.[21][22][23]
Separating forms of gluten sensitivity
Only rarely should gluten sensitivity be without cause. Generally the sensitivity can be split between gluten-sensitive enteropathy and wheat allergy. Since individuals with GSE can also have wheat allergy, a finding of wheat allergy does not eliminate the possibility of enteropathy. Individuals highly suspect of gluten-sensitive enteropathy may be tested for anti-transglutaminase antibodies followed by duodenal biopsy, this will confirm or refute active coeliac disease.[24] The study that recommends this, however, has a number of ATA positive/biopsy-negative individuals, this could result from patchy villous atrophy or subclinical pathology.[25][26] One current study recommended at biopsy samples running distally from the duodenum to avoid the risk of false negatives. Eliminating the possibility of GSE can generally be done by adding HLA-DQ typing, in which DQ2 and DQ8 are found in enteropathy 98% of the time in caucasians, DQ7.5 the remaining 1.6% and 0.4% not found with either of these 3. Without ATA or HLA-DQ2/8 positivity, GSE is not likely the cause of the sensitivity. In either case, other avenues of diagnostics, such as allergy testing are available.[27] Rarely gluten sensitivity maybe idiopathic, a potential that wheat proteins play a role in other disease, in these instances DQ1 may be associated with sensitivity, but for neurological issues, a gluten-free diet has not been shown to positively effect the outcome of patients as in enteropathy or allergy.
Gluten-sensitive enteropathy
Coeliac disease is the classically defined gluten-sensitivity and dermatitis herpetiformis was appended to a broadening definition of gluten sensitivity. The diagnostic "gold standard" of coeliac disease as the villus atrophy detected in duodenal biopsies. However, it is now recognized that inflammation of the epithelial tissue of the small intestine precedes atrophy. Early in the disease, gluten elicits T-lymphocyte recognition of gluten hydrolysates (polypeptides of gluten) and gluten peptides bind to mammalian tissue transglutaminase (tTG). This second interaction results in the production of "self" antibodies to tTG. This increases lymphocytes within the epithelia of the small intestine (Marsh grade 1 and 2) and antibody-tTG complexes seen as deposits. This usually progresses to coeliac disease (Marsh grade 3 and 4). The dietary cause of GSE is not limited to wheat gluten, 'glutens' from all known edible cultivars of Triticeae can induce GSE in susceptible individuals (see: Gluten immunochemistry).
| DQ haplotypes -Celiac Disease | |||||
|---|---|---|---|---|---|
| DQ hap | 2.5 | 2.2 | 7.5 | 8.0 | Other |
| 2.5 | 34 | 22 | 4.0 | 2.0 | 22 |
| 2.2 | 1.1 | 4.0 | 1.1 | 2.9 | |
| 7.5 | 0.3 | 0.0 | 1.3 | ||
| 8.1 | 2.9 | 2.0 | |||
| other | 0.4 | ||||
| DQ haplotypes -Normal Population | |||||
| DQ hap | 2.5 | 2.2 | 7.5 | 8.1 | Other |
| 2.5 | 1.7 | 2.9 | 2.9 | 1.8 | 15.1 |
| 2.2 | 1.2 | 2.4 | 1.6 | 12.8 | |
| 7.5 | 1.2 | 1.5 | 1.3 | ||
| 8.1 | 0.5 | 8.0 | |||
| other | 33.4 | ||||
| Odds ratios | |||||
| DQ hap | 2.5 | 2.2 | 7.5 | 8.1 | Other |
| 2.5 | 20:11 | 8:12 | 1.4:16 | 1.1:1 | 1.5:15 |
| 2.2 | 1:1.1 | 1.6:14 | 1:1.3 | 1:5 | |
| 7.5 | 1:4 | 0 | 1:10 | ||
| 8.1 | 6:13 | 1:4 | |||
| other | 1:100 | ||||
There are a large number of medical conditions that result from GSE that can occur prior to the development of coeliac disease and might be gluten responsive. While the level of villus atropy in some cases of GSE may not reach clinical coeliac disease recognition, the elevation of cellular immunity is capable of producing disorders more frequently found in coeliac disease. Conditions secondary to GSE are important diagnostic criteria for gluten sensitivity when there may be no obvious intestinal abnormality. Presentation of GSE is often the result of initial recognition of the secondary condition which in followup testing (ATA test, AGA test, HLA-DQ typing, and/or biopsy) recognizes the primary condition. The secondary conditions associated with GSE tend to make late onset coeliac disease a systemic phenomena.
Idiopathic gluten sensitivity
Idiopathic diseases are proposed as an expansion of the gluten-sensitivity. By the definition of idiopathic disease the cause is not well defined. One hundred years ago, before gluten was discovered as the cause of coeliac disease, coeliac disease in adults was called adult idiopathic steatorrhoea, non-tropical sprue, and many other names. The debate over this subset stems from the fact that identification of all grades of GSE and allergies is not uniformly approached. Most cases of early GSE go undetected, particularly before 2005. There appears to be a small fraction of non-GSE gluten-sensitive individuals that show neither gluten-allergies but do have elevated anti-gliadin IgA or IgG. Common symptoms are peripheral neuropathies and cerebral ataxia. Within the GSE set these may be explained by calcification of brain channels and avitaminosis. Within the remaining 'DQ2 and DQ8'less cohort. Given that this cohort of GS is idiopathic, the role of allergies, other sensitivies (e.g. aspirin), or other factors in IGS is also unresolved.
Silent Disease. Depending on testing somewhere between 3 and 15% of the normal population have anti-gliadin antibodies (AGA). Studies using anti-gliadin antibodies (AGA) reveal that in undiagnosed or untreated individuals with AGA, with increasing risk for lymphoid cancers and decreased risk for other associated with affluence.[28] Though it is unknown in these studies the percentage that are early stage GSE.
Neuropathies
Other conditions
Antibodies to α-gliadin have been significantly increased non-coeliacs individuals with oral ulceration.[29] Anti-α-gliadin antibodies are frequently found in coeliac disease(CD), to a lesser degree subclinical CD, but are also found in a subset who do not have the disease. The 1991 reference comes from a period when testing for subclinical CD was undeveloped. Of people with pseudo-exfoliation syndrome, 25% showed increased levels of anti-gliadin IgA.[30] One forth 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, the remaining 3 appear to be gluten-sensitive. All were HLA-DQ2 and/or DQ8-positive.[31] Treatment to produce remission of Crohns disease(CrD) symptoms on elimination diet indicated the most important foods provoking symptoms were wheat and dairy.[32]. A later paper showed little IgE mediated response to the except to dairy,[33] while another paper showed no significant anti-food IgE association.[34] Crohn's disease (CrD) may have a link to wheat that is independent of gluten. CrD appears to be associated with high anti-yeast antibodies (ASCA - yeast antigens that are found in bread and other cereal derived products) and affected individuals lack lectin binding proteins such that the mannins in yeast, the antibodies that bind them and aggravate inflammatory colitis. One concern of the above studies is the high prevalence of markers for gluten-sensitive enteropathy, one has to question how idiopathic these conditions are if close examination for GSE has not been undertaken.
Why treat gluten allergies as sensitivities? Over the last 10 years it has become apparent that allergies to certain substances do not behave in predictable ways. One clear example of this is exercise induced anaphylaxis and asthma, WDEIA (Wheat Dependent Exercise Induced Anaphylaxis) is now believed to be induced by ingested gluten that finds a way into the blood stream. This pathway is now believed responsible for some forms of eczema. Recent studies on two wheat allergens show that they possess the capability of bypassing the gut/blood barrier. The most active of these is ω-5 gliadin, a gluten component that is a strong allergen and causes WD_EIA. Allergy tests may not reveal allergies to gluten because the unfractionated allergens are 'hidden' from these tests, and most currently available tests cannot detect these new allergens. Finally, allergies typically involve IgE, but some studies indicate there are several classes of responses, for example IgG1,IgG2, IgG4 that are associated with IgE.[35] Gluten allergy may be a cause of some idiopathic gluten sensitivity and gluten allergy can be a secondary consequence of gluten-sensitive enteropathy.
Comparative pathophysiology
| Gluten-sensitive enteropathy | Wheat allergy | Gluten-sensitive idiopathic neuropathy | |
|---|---|---|---|
| Typical symptoms | steatorrhoea, malnutrition, diarrhea, lactose intolerance, food allergies | eczema, asthma | ataxia, peripheral neuropathies |
| Primary tissue targets | epithelia of small intestine | (epi) dermis, bronchi, intestines | CNS, Peripheral nerves |
| Atypical pathologies | other autoimmune diseases, chronic constipation, neuropathies, cancer (lymphoid) | arthritis, migraines, anaphylaxis (exercise or aspirin induced) | unknown |
| Secondary targets (common) | blood (chemistry), bowel, nervous system, autoantigens | connective tissue, CNS, vascular | |
| Immunoglobin isotype | IgA, IgG | IgE, IgG, IgA | IgG, IgA |
| Antibody recognition | α/β,γ-gliadin (AGA), transglutaminase (ATA) | albumins, globulins, prolamins (ω-gliadin)(AGA), glutelins (LMW)(AGA) | α/β-gliadin |
| HLA associations | DQ2.5, DQ8, DQ2.2/DQ7.5 | unknown | DQ2, DQ8?, DQ1? |
| Cellular immunity | T-cells, Eosinophils, Monocytes | Mast cells, Eosinophils | unknown |
| Innate responses | (α-gliadin) immune, increased permeability | (ω-5 gliadin)- increased permeability | unknown |
| Background & references | Coeliac disease, GSEA conditions | Wheat allergy | IGS Neuropathies |
Notes on table. Features of idiopathic neuropathy assume that all GSE cohort has been removed, assuming there is a gluten-sensitive, but not GSE contingent. Anti-gliadin antibodies covers all immunoglobulin isotypes and all gliadin isoforms. T-cell, Killer cell, and other gluten recognitions are covered in Gluten immunochemistry.
Gluten sources
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From the perspective of gluten sensitivity there is no single definition of gluten that concisely defines all potentially pathogenic glutens. With wheat allergies, there can be a wide spectrum of species that may trigger allergies with similar proteins, the omega-gliadin proteins have similar proteins found in oats at high frequency, but omega-gliadin allergy is not a predictor of oat allergy or intolerance.[42] A person can have an allergy to wheat, but not rye.[43]
Glutelins have not been characterized over broad taxa. With idiopathic gluten sensitivity, the antibodies that correlate with disease are anti-gliadin antibodies. Whether these antibodies are pathogenic or are simply indicators of circulating gliadin is unknown. For gluten-sensitive enteropathy, gliadin and homologous proteins from rye and barley cause disease. T-cell epitopes implicated in disease have been found in glutinous protein genes in all species sequenced within the tribe Triticeae.[44] Also, since barley is distantly related to wheat, but carries pathogenic epitopes it can be assumed that all members of Triticeae should carry T-cell sites capable of sustaining disease (see also Genetics of Triticeae). While often not explicitly stated in some standards, pathogenic glutens found in wheat are also found in Spelt and Kamut(both types of wheat), Triticale (a trans-species Triticeae hybrid).
The oat controversy
Oats are a species within the grass tribe Aveneae, which is in the Pooideae subfamily along with Triticeae (contains wheat, rye, barley and many other genera). Oats are the most closely related cereal species to Triticeae cereals. Oats may contain pathogenic proteins that sustain gluten-sensitive disease. Alternatively, oat seeds appear similar to seeds of wheat, barley and rye and cross-contamination between these grains is difficult to resolve.
Origin of controversy
After World War II, wheat was suspected as the cause of coeliac disease, and the gluten from wheat was identified as a cause soon after. At the time, duodenal biopsy—the current "gold standard" of diagnosis—had not yet been developed[45]; indirect measures of disease were used. In two studies, three children were fed 75 to 150 grams of oats per day and developed symptoms. In three concurrent studies, 10 children and two adults were allowed to eat 28 to 60 grams of oats and developed no symptoms.[46] Since wheat, barley and sometimes rye are common contaminants in oats,[38][47] until this was investigated, oats were considered to be toxic to coeliacs.
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Further information: History of coeliac disease
Current findings
While the problem of contamination has been known for several years, a study published in June 2008 found that of 109 sources of oats screened, 85 had unacceptable levels of gluten from wheat, barley or rye.[48] Triticeae contaminated oats in the study came from many countries indicating that most sources of oats are unacceptable for GS based on contamination.
Tolerable levels of gluten
In summary of recent developments, oats can be tolerated in a gluten-free diet, but oat products should be limited in contamination from Triticeae derived gluten to 20 PPM (20 mg per kg). US states are free to deny the GF-label standard for oat products, if warranted (see Politics of Gluten-Free and oats).
Gluten-free testing
A new barley-sensitive ELISA called the R5 sandwich assay does not detect gluten in any of 25 pure oat varieties, but it does detect barley, wheat and rye.[48] Disease-sensitive farming practices, antibody testing and species specific genetic testing are capable of producing pure oats.[48] In the United States, 3 domestic GF-brands are available and one brand imported from Ireland 'reckons' to be 99.95% pure oats.[49][50] Two brands in the United States use the R5 antibody test and claim to be below 20 PPM in defined gluten. [49][51]
Diets
Gluten-free oats in a gluten-free diet. Gluten-free oats can provide a valuable source of fiber, vitamin B, iron, zinc and complex carbohydrates.[52] Recent studies show that gluten-sensitive individuals on a gluten-free diet often get too much simple starch, too little fibre 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 oat-sensitive enteropathy (ASE) risk, 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. 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. Preferably, newly diagnosed celiacs seek the help of a dietician. However, guidelines are also available for the introduction of pure, uncontaminated oats into the gluten-free diet.[53]
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Further information: Oat sensitivity
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