Non-celiac gluten sensitivity

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Non-celiac gluten sensitivity
Classification and external resources

Non-celiac gluten sensitivity (NCGS) or gluten sensitivity[1] is defined as "a clinical entity induced by the ingestion of gluten leading to intestinal and/or extraintestinal symptoms that improve once the gluten-containing foodstuff is removed from the diet, and celiac disease and wheat allergy have been excluded".[2]

NCGS is included in the spectrum of gluten-related disorders.[3][4] The definition and diagnostic criteria of non-celiac gluten sensitivity were debated and established by three consensus conferences.[1][2][4][5][6]

The pathogenesis of NCGS is not yet well understood. There is evidence that not only gliadin (main cytotoxic antigen of gluten), but also other proteins present in gluten and gluten-containing cereals (wheat, rye, barley, and their derivatives) may have a role in the development of symptoms.[3] FODMAPs are present in gluten-containing grains and have recently been identified as a possible cause of gastrointestinal symptoms in NCGS patients,[3][7][8] but do not justify extra-digestive symptoms.[3]

For these reasons, NCGS is a controversial clinical condition[9] and some authors still question it.[10][11] It has been suggested that "non-celiac wheat sensitivity" is a more appropriate term, without forgetting that other gluten-containing cereals are implicated in the development of symptoms.[10][12]

NCGS is the most common syndrome of gluten-related disorders[4][13] with prevalence rates between 0.5–13% in the general population.[14] As no biomarker for diagnosing this condition is available, its diagnosis is made by exclusion of other gluten-related disorders, namely by excluding celiac disease and wheat allergy.[9] Many people have not been diagnosed following strict criteria and there is a "fad component" to the recent rise in popularity of the gluten-free diet, which leads to debate surrounding the evidence for this condition, its relationship to celiac disease and to irritable bowel syndrome.[3][15]

Signs and symptoms[edit]

Reported symptoms of NCGS are similar to those of celiac disease,[16][17] with most patients reporting both gastrointestinal and non-gastrointestinal symptoms.[18][19] In the "classical" presentation of NCGS, gastrointestinal symptoms are similar to those of irritable bowel syndrome, and are also not distinguishable from those of wheat allergy, 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 can be anaphylaxic.[19]

Gastrointestinal symptoms[edit]

Gastrointestinal symptoms may include any of the following: abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation),[4][20] nausea, aerophagia, gastroesophageal reflux disease, and aphthous stomatitis.[3][4]

Other[edit]

A range of extra-intestinal symptoms, which can be the only manifestation of NCGS in absence of gastrointestinal symptoms,[3][4][20] have been suggested, but remain controversial.[15][21] These include any of the following: headache, migraine, "foggy mind", fatigue, fibromyalgia,[21][22] joint and muscle pain, leg or arm numbness, tingling of the extremities, dermatitis (eczema or skin rash), atopic disorders such as asthma, rhinitis, other allergies, depression, anxiety, iron-deficiency anemia, folate deficiency, or autoimmune diseases.[3][4][20][21] NCGS has also been controversially implicated in some neuropsychiatric disorders, including schizophrenia, eating disorders, autism, peripheral neuropathy, ataxia, and attention deficit hyperactivity disorder (ADHD).[3][4][15][20][21]

Above 20% of people with NCGS have IgE-mediated allergy to one or more inhalants, foods, or metals, among which most common are mites, graminaceae, parietaria, cat or dog hair, shellfish, and nickel.[20] Approximately 35% of patients suffer other food intolerances, mainly lactose intolerance.[21]

Causes[edit]

The pathogenesis of NCGS is not yet well understood. It was hypothesized that gluten, as occurs in celiac disease, is the cause of NCGS. Besides gluten, other components in wheat, rye, barley, and their derivatives, including amylasetrypsin inhibitors (ATIs) and FODMAPs, may cause symptoms.[3]

Other proteins[edit]

Some people may have a reaction to other proteins present in gluten-containing cereals that are able to inhibit amylase and trypsin (-α-amylase/trypsin inhibitors [ATIs]).[3][23] ATIs are part of the plant's natural defense against insects and may cause toll-like receptor 4 (TLR4)-mediated intestinal inflammation in humans.[24][25] These TLR4-stimulating activities of ATIs are limited to gluten-containing cereals (wheat, rye, barley, and derivatives) and may induce innate immunity in people with celiac disease or NCGS. ATIs resist proteolytic digestion.[3] ATIs are about 2–4% of the total protein in modern wheat and are present in commercial gluten.[3]

Modern wheat cultivation, by breeding for high ATI content, may play a role in the onset and course of disorders such as celiac disease and gluten sensitivity.[26] However, it has been questioned whether there is sufficient empirical evidence to support this claim, as there are no known studies that directly compare heritage and modern wheat genotypes for ATI activity.[27]

Also, wheat germ agglutinin is considered to be a possible trigger of NCGS-like symptoms.[21]

FODMAPs[edit]

FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) that are present in gluten-containing grains have recently been identified as a possible cause of gastrointestinal symptoms in people with NCGS, in place of,[28] or in addition to, gluten.[8] FODMAPs cause mild wheat intolerance mainly limited to gastrointestinal symptoms.[3]

Diagnosis[edit]

Absence of reliable biomarkers makes a clear diagnosis of non-celiac gluten sensitivity (NCGS) difficult,[23] and this is generally performed only by exclusion criteria.[9][14] NCGS diagnostic recommendations were established by two consensus conferences (London 2011 and Munich 2012) based on exclusion of celiac disease and wheat allergy[20] because these two conditions also appear in people who experience symptoms similar to those of NCGS, which improve with a gluten withdrawal and worsen after gluten consumption.[12][20][29]

The onset of NCGS symptoms may be delayed hours to a few days after gluten ingestion, but in celiac disease, can take days to weeks.[12] Wheat allergy has a fast onset (from minutes to hours) after the consumption of food containing wheat and could lead to anaphylaxis.[19]

The presence of related extraintestinal manifestations has been suggested to be a feature of NCGS[12] but is a source of controversy. When symptoms are limited to gastrointestinal alterations, there may be an overlap with wheat allergy, irritable bowel syndrome (IBS), and (less likely) intolerance to FODMAPs.[12]

A recently proposed criterion for NCGS diagnosis concludes that an improvement of gastrointestinal symptoms and extra-intestinal manifestations higher than 50% with a gluten-free diet (GFD), assessed through a rating scale, may confirm the clinical diagnosis of NCGS. Nevertheless, this rating scale, is not yet applied worldwide. To exclude a placebo effect, a double-blind placebo-controlled gluten challenge is a useful tool, although it is expensive and complicated in routine clinical ground, and therefore, is only performed in research studies.[9][20]

Differential diagnosis[edit]

Examinations evaluating celiac disease and wheat allergy must be performed before patients remove gluten from their diet.[20] It is critical to make a clear distinction between celiac disease and NCGS.[14]

Celiac disease[edit]

The main differential diagnosis of NCGS is the exclusion of celiac disease,[21] which can be difficult.[7] NCGS and celiac disease cannot be distinguished clinically because many gastrointestinal and non-gastrointestinal symptoms are similar in both diseases,[7][16][18][19] and there are celiac disease patients with negative serology (absence of specific celiac disease antibodies in serum) and/or without villus atrophy.[14] It has been stated there is no test capable of discarding a celiac disease diagnosis completely[30] but it is highly unlikely in the absence of HLA-DQ2 or DQ8.[19]

The prevalence of undiagnosed celiac disease increased 4-fold during the past half century[3] with most cases remaining unrecognized, undiagnosed and untreated, leaving patients with risk of long-term complications.[23][31] Some NCGS patients may indeed have celiac disease.[14] A 2015 systematic review showed that 20% of NCGS patients who presented with negative serology, HLA-DQ2 and/or HLA-DQ8 haplotypes, and normal histology or duodenal lymphocytosis, could be shown with advanced diagnostic techniques to have celiac disease.[14]

Some authors conclude that the presence of autoimmune conditions in NCGS patients suggests the presence of an unrecognized and undiagnosed celiac disease.[14] Autoimmune diseases typically associated with celiac disease are diabetes mellitus type 1, thyroiditis,[32] gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, dermatitis herpetiformis, primary sclerosing cholangitis, and others.[32]

To evaluate the possible presence of celiac disease, it is necessary to perform specific serology and duodenal biopsies while the patient is still on a gluten-containing diet.[3][23]

Serological markers[edit]

Serological CD markers (IgA tissue transglutaminase [tTGA], IgA endomysial [EmA][20][23] and IgG deamidated gliadin peptide [DGP][14][20] antibodies) are always negative in NCGS people;[7][20][23][29] in addition to specific IgA autoantibody levels, it is necessary to determine total IgA levels.[16][29] IgG tTGA antibodies should be checked in selective IgA deficiency which can be associated with celiac disease and occurs in up to 1 in 40 celiac patients.[29]

Nevertheless, the absence of serological markers do not certainly exclude celiac disease. In celiac people before the diagnosis (on a gluten containing diet), celiac disease serological markers are not always present.[19] As the age of diagnosis increases, these antibody titers decrease, and may be low or even negative in older children and adults. The absence of celiac disease specific antibodies is more common in patients without villous atrophy who only have duodenal lymphocytosis (Marsh 1 lesions) and which responds to a gluten-free diet with histological and symptomatic improvement.[14]

Duodenal biopsies[edit]

According to the diagnostic criteria established by the consensus conferences (2011 and 2013), it is necessary to perform duodenal biopsies to exclude celiac disease in symptomatic patients with negative specific celiac disease antibodies.[20] Due to the patchiness of the celiac disease lesions, four or more biopsies should be taken from the second and third parts of the duodenum, and at least one from the duodenal bulb.[7][16] Even in the same biopsy fragments, different degrees of pathology may exist.[16]

Duodenal biopsies in NCGS patients are always almost normal,[7][16][21][29] which is an essential parameter for achieve a diagnosis of NCGS,[16] although is generally accepted that a subgroup of NGCS patients may have an increased number of duodenal intraepithelial lymphocytes (IELs)[14][21][23] ( ≥25/100 enterocytes), which represent Marsh I lesions.[14] Nevertheless, Marsh I is considered compatible with celiac disease[7] and the most frequent cause of these findings, especially in patients positive for HLA DQ2 and/or DQ8 haplotypes, is celiac disease,[14][21] with a documented prevalences ranging from 16% to 43%.[14]

In these patients with duodenal lymphocytosis, and following the consensus guidelines from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), a high count of celiac disease cells (or CD/CD3 ratio) in immunohistochemical assessment of biopsies, or the presence of IgA anti-TG2[14][21] and/or anti-endomysial[21] intestinal deposits, might be specific markers for celiac disease.[14][21] Catassi and Fasano proposed in 2010 that in patients without celiac disease antibodies, either lymphocytic infiltration associated with IgA subepithelial deposits or a histological response to a gluten-free diet, could support a diagnosis of celiac disease.[14]

Wheat allergy[edit]

The clinical presentation may be sufficient in most cases to distinguish a wheat allergy from other entities.[16] It is excluded when there are normal levels of serum IgE antibodies to gluten proteins and wheat fractions, and no skin reaction to Prick tests for wheat allergy.[20] Nevertheless, these tests are not always completely reliable.[12]

If an allergic reaction can not be clearly identified, the diagnosis should be confirmed by food provocation tests, ideally performed in a double-blinded and placebo-controlled manner. Delayed allergic reactions may occur with these type of tests, which have to be negative over time, but there are no international consensus statements on diagnosing delayed wheat/food-related symptoms. Usually, reactions that appear between 2 hours and up to five days after the oral challenge, are considered as delayed.[7] Mucosal challenge followed by confocal endomicroscopy is a complementary diagnostic technique, but this technology is not yet generally available and remains as an experimental procedure.[12]

Other tests[edit]

Evaluating the presence of antigliadin antibodies (AGA) can be a useful complementary diagnostic test. Up to 50% NCGS patients may have elevated AGA IgG antibodies, but rarely AGA IgA antibodies (only 7% of the cases).[20][21][23] In these patients, unlike in celiac disease people, the IgG AGA became undetectable within 6 months of using a gluten-free diet.[20]

Already on a gluten-free diet[edit]

Many people remove gluten from the diet before seeking medical attention.[20][21][23] This fact can diminish the CD serological markers titers and may attenuate the inflammatory changes found in the duodenal biopsies.[21][23] In these cases, patients should be tested for the presence of HLA-DQ2/DQ8 genetic markers because a negative HLA-DQ2 and HLA-DQ8 result has a high negative predictive value for celiac disease.[20][21][23] If these markers are positive, it is advisable to undertake a gluten challenge under medical supervision, followed by serology and duodenal biopsies.[20][21][23] However, gluten challenge protocols have significant limitations, because a symptomatic relapse generally precedes the onset of a serological and histological relapse, and therefore becomes unacceptable for many patients.[7][20][21][23] Gluten challenge is also discouraged before the age of 5 years and during pubertal growth.[7]

It remains unclear what daily intake of gluten is adequate and how long the gluten challenge should last.[23] Some protocols recommend eating a maximum of 10 g of gluten per day for 6 weeks. Nevertheless, recent studies have shown that a 2-week challenge of 3 g of gluten per day may induces histological and serological abnormalities in most adults with proven celiac disease.[21][23] This new proposed protocol has shown higher tolerability and compliance. It has been calculated that its application in secondary-care gastrointestinal practice would identify celiac disease in 7% patients referred for suspected NCGS, while the remaining 93% would be confirmed as NCGS;[23] this is not yet universally adopted.[21]

For people on a gluten-free diet who are unable to perform an oral gluten challenge, an alternative to identify possible celiac disease is an in vitro gliadin challenge of small bowel biopsies; this test is only available at selected specialized tertiary-care centers.[21]

Treatment[edit]

Main article: Gluten-free diet

After exclusion of celiac disease and wheat allergy,[18] the subsequent step for diagnosis and treatment of NCGS is to start a strict gluten-free diet (GFD) to assess if symptoms improve or resolve completely. This may occur within days to weeks of starting a GFD, but improvement may also be due to a non-specific, placebo response.[33]

Recommendations may resemble those for celiac disease, for the diet to be strict and maintained, with no transgression.[20] The degree of gluten cross contamination tolerated by people with NCGS is not clear but there is some evidence that they can present with symptoms even after consumption of small amounts.[20]

Whereas celiac disease requires adherence to a strict lifelong gluten-free diet, it is not yet known whether NCGS is a permanent or a transient condition.[9][20] A trial of gluten reintroduction to observe any reaction after 1–2 years of strict gluten-free diet might be performed.[20]

Persistent symptoms[edit]

Approximately one third of presumed NGCS patients continue to have symptoms, despite gluten withdrawal. Apart from a possible diagnostic error, there are multiple possible explanations.[20]

One reason is a poor compliance with gluten withdrawal, whether voluntary and/or involuntary.[20] There may be ingestion of gluten, in the form of cross contamination or food containing hidden sources.[8] In some cases, the amelioration of gastrointestinal symptoms with a gluten-free diet is only partial, and these patients could significantly improve with the addition of a low-FODMAPs diet.[8]

A subgroup may not improve when eating commercially available gluten-free products, as these can be rich in preservatives and additives such as sulfites, glutamates, nitrates and benzoates, which can also have a role in triggering functional gastrointestinal symptoms.[8] Furthermore, people with NCGS may often present with IgE-mediated allergies to one or more foods.[20] It has been estimated that around 35% suffer other food intolerances, mainly lactose intolerance.[21]

History[edit]

The subject of "food intolerance", including gluten sensitivity and elimination diets, was discussed in 1976.[34]

Patients with symptoms including abdominal pain and diarrhea, which improved on gluten withdrawal, and who did not have celiac disease were initially described in 1976 and 1978 with the first series in 1980.[35][36][37] Debate regarding the existence of a specific condition has continued since then, but the three consensus conferences held since 2010 produced consistent definitions of NCGS and its diagnostic criteria.[1][4][5]

Society and culture[edit]

NCGS has been a topic of popular interest.[38][39][40] Gluten has been named "the new diet villain".[41] Gluten-free diets have become the latest diet craze and have been advocated and followed by many celebrities. Estimates suggest that 10%–20% of people in USA and Australia are consuming gluten-free foods. On the other hand, there is another school of thought that suggests that NCGS is largely imaginary and has been overestimated by patients and gluten-free food industry.[11][42][43]

Debate around NCGS as a genuine clinical condition can be heightened because often patients are self diagnosed, or a diagnosis is made by alternative health practitioners.[15] People who avoid gluten rarely have celiac disease excluded before adopting a gluten-free diet, and when fully evaluated, alternative diagnoses may be identified such as fructose intolerance or small intestinal bacterial overgrowth, or a better response to a low FODMAP diet obtained.[44]

Research[edit]

There are many open questions on gluten sensitivity,[8] emphasized in one review that "it is still to be clarified whether this disorder is permanent or transient and whether it is linked to autoimmunity".[45] It has not yet been established whether innate or adaptive immune responses are involved in NCGS, nor whether the condition relates specifically to gluten or rather relates to other components of grains.[17][46]

NCGS patients may develop anti-gliadin antibodies and never have anti-tTG antibodies.[47] Studies indicate that AGA IgG is high in slightly more than half of NCGS patients[4] and that, unlike for celiac disease patients, the IgG AGA decreases strongly over 6 months of gluten-free diet; AGA IgA is usually low or absent in NGCS patients.[4][48]

The need for developing biomarkers for NCGS is frequently emphasized;[4][18][49] for example, one review indicated: "There is a desperate need for reliable biomarkers ... that include clinical, biochemical and histopathological findings which support the diagnosis of NCGS."[17]

A 2014 preliminary study found "that short-term exposure to gluten can induce depressive symptoms in people with non-celiac gluten sensitivity".[50]

Research has also attempted to discern, by double-blind placebo-controlled trials, between a "fad component" to the recent popularity of the gluten-free diet and an actual sensitivity to gluten or other components of wheat.[3][4][51]

In a 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.[21]

See also[edit]

References[edit]

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