Non-celiac gluten sensitivity

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Non-celiac gluten sensitivity (NCGS) or gluten sensitivity[1] is a syndrome in which patients develop a variety of intestinal and/or extraintestinal symptoms that improve when gluten is removed from the diet,[2] after celiac disease and wheat allergy are excluded.[3]

It is was originally described in the 1980s.[4] Since 2010, NCGS has been included in the spectrum of gluten-related disorders.[3][4] The definition and diagnostic criteria of non-celiac gluten sensitivity was debated and established by three consensus conferences.[5][6][7]

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 that are present in gluten-containing grains have recently been identified as a possible cause of gastrointestinal symptoms in NCGS patients.[3][8][9] (see section "Causes" and section "Research") For these reasons, NCGS is a controversial syndrome[10] and some authors still question it.[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.[11][12]

Although there is an evident "fad component" to the recent rise in popularity of the gluten-free diet, there is growing evidence to confirm non-celiac gluten sensitivity.[3]

NCGS is the most common syndrome of gluten-related disorders.[4][13] A 2015 systematic review showed that its prevalence rates are 0.5–13% of 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.[10]

Signs and symptoms[edit]

Reported symptoms of NCGS are similar to those of celiac disease,[15][16] with most patients reporting both gastrointestinal and non-gastrointestinal symptoms.[17][18] 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 could be anaphylaxis.[18]

Gastrointestinal symptoms[edit]

Gastrointestinal symptoms may include any of the following: abdominal pain, bloating, bowel habit abnormalities (either diarrhea or constipation),[4][19] nausea, aerophagia, gastroesophageal reflux disease, and aphthous stomatitis.[3][4]

Other[edit]

Extra-intestinal symptoms, which can be the only manifestation of NCGS even in absence of gastrointestinal symptoms, may be any of the following systemic manifestations: headache or migraine, "foggy mind", fatigue,[3][4][19] fibromyalgia,[19][20][21] joint and muscle pain,[3][4][19] leg or arm numbness,[3][4][19] tingling of the extremities,[3][4] dermatitis (eczema or skin rash),[3][4] allergies,[3][19] atopic disorders,[3] depression,[3][4][19] anxiety,[19] anemia,[3][4] iron-deficiency anemia, folate deficiency, asthma, rhinitis, eating disorders[19] or autoimmune diseases.[3]

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.[19]

Approximately, 35% of patients suffer some food intolerances associated to gluten sensitivity, mainly lactose intolerance.[22]

Among extra-intestinal manifestations, NCGS seems to be involved in some neuropsychiatric disorders, principally schizophrenia,[4][23] autism[4][19][23] and peripheral neuropathy,[4][23] and also ataxia[23] and attention deficit hyperactivity disorder (ADHD).[3]

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][24] ATIs are part of the plant's natural defense against insects and may cause toll-like receptor 4 (TLR4)-mediated intestinal inflammation in humans.[25][26] 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 80–90% in 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.[27] 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.[28]

Also, wheat germ agglutinin is considered to be a possible trigger of NCGS-like symptoms.[22]

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,[29] or in addition to, gluten.[9] 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,[24] and this is generally performed only by exclusion criteria.[10][30] NCGS diagnostic recommendations were established by two consensus conferences (London 2011 and Munich 2012) based on exclusion of celiac disease and wheat allergy[19] 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][19][31]

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.[18]

The presence of related extraintestinal manifestations is increasingly recognized as a hallmark of NCGS and provides high diagnostic accuracy.[12] 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 criteria to 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.[10][19]

Differential diagnosis[edit]

Examinations for evaluating celiac disease and wheat allergy must be performed, before the patients remove the gluten from the diet.[19] Among these diseases, it is critical to make a clear distinction between CD and NCGS.[30]

Celiac disease[edit]

The main difficulty for differential diagnosis of NCGS is to exclude adequately the presence of celiac disease,[22] which is difficult to accurately diagnose.[8]

NCGS and celiac disease cannot be distinguished clinically because gastrointestinal and non-gastrointestinal symptoms are similar in both diseases,[8][15][17][18] and there are celiac disease patients with negative serology (absence of specific celiac disease antibodies in serum) and/or without villus atrophy.[30] There is no test capable of discarding a celiac disease diagnosis completely.[32]

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.[24][33] In fact, some NCGS patients may indeed have celiac disease.[30] A 2015 systematic review showed that at least 20% of NCGS patients presented negative serology, HLA-DQ2 and/or HLA-DQ8 haplotypes, and Marsh grade 1 intestinal lesion, which are part of the spectrum of 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.[30] Autoimmune diseases typically associated with celiac disease are diabetes mellitus type 1, thyroiditis,[34][35] gluten ataxia, psoriasis, vitiligo, autoimmune hepatitis, dermatitis herpetiformis, primary sclerosing cholangitis, and others.[34]

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][24]

Serological markers[edit]

Serological CD markers (IgA tissue transglutaminase [tTGA], IgA endomysial [EmA][19][24] and IgG deamidated gliadin peptide [DGP][19][30] antibodies) are always negative in NCGS people;[8][19][24][31] in addition to specific IgA autoantibody levels, it is necessary to determine total IgA levels.[15][31] If deficient, it should test IgG tTGA antibodies. Furthermore, selective IgA deficiency is typically associated with celiac disease, which occurs in up to 1 in 40 celiac patients.[31]

Nevertheless, the absence of serological markers do not certainly exclude celiac disease. In celiac people before the diagnosis (in a gluten containing diet), celiac disease serological markers are not always present.[18] As the age of diagnosis increases, these antibody titers decrease, and frequently are low or even negative in older children and adults.[36] The absence of celiac disease specific antibodies is more common in celiac disease patients without villous atrophy (Marsh 1 and 2 lesions). Nevertheless, these forms of celiac disease may have similar symptoms to those with villous atrophy and improve with a gluten-free diet.[30]

Duodenal biopsies[edit]

According to diagnostic criteria established by the consensus conferences (2011 and 2013), it is necessary to perform duodenal biopsies, especially to exclude an underlying celiac disease in symptomatic patients with negative specific celiac disease antibodies.[19]

Due to 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.[8][15] Even in the same bioptic fragments, different degrees of pathology may exist.[15]

Duodenal biopsies in NCGS patients are always almost normal,[8][15][22][31] which is an essential parameter for achieve a diagnosis of NCGS,[15] although is generally accepted that a subgroup of NGCS patients may have an increased number of duodenal intraepithelial lymphocytes (IELs)[22][24][30] ( ≥25/100 enterocytes), which represent Marsh I lesions.[30] Nevertheless, Marsh I is considered compatible with celiac disease[8] and the most frequent cause of these findings, especially in patients positive for HLA DQ2 and/or DQ8 haplotypes, is celiac disease,[22][30] with a documented prevalences ranging from 16% to 43%.[30] In fact, it is common to find at diagnosis in older children and adult celiac patients showing only an inflammatory pattern in duodenal mucosa (Marsh I or II), without villous atrophy.[36][37] As occurs with celiac disease antibodies, as the age of diagnosis increases, the degree of histological lesions decreases.[36]

In these cases (patients with Marsh I), 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[22][30] and/or anti-endomysial[22] intestinal deposits, might be specific markers for celiac disease.[22][30] 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.[30]

Wheat allergy[edit]

Clinical presentation may be sufficient in most cases to distinguish a wheat allergy from other entities.[15] 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.[19] Nevertheless, these tests are not always completely reliable.[12]

If allergy reaction can not be clearly identified, diagnosis should be confirmed by food provocation tests, ideally performed in a double-blinded and placebo-controlled. 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.[8] 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.[19][22][24] (only 7% of the cases).[24] In these patients, unlike in celiac disease people, the IgG AGA became undetectable within 6 months of using a gluten-free diet.[19]

Gluten-free diet[edit]

Many people remove gluten from the diet before seeking medical attention.[19][22][24] This fact can diminish the CD serological markers titers and may attenuate the inflammatory changes found in the duodenal biopsies.[22][24] In these cases, the patients should be tested for the presence of HLA-DQ2/DQ8 genetic markers because negative HLA-DQ2 and HLA-DQ8 results have a high negative predictive value for celiac disease.[19][22][24] If they are positive for HLA-DQ2 and/or HLA-DQ8, then it is advisable a gluten challenge[19][22][24] under medical supervision, followed by serology and duodenal biopsies.[24] 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 most patients.[8][19][22][24]

Gluten challenge is discouraged before the age of 5 years and during pubertal growth.[8]

It remains unclear what daily intake of gluten is adequate and how long the gluten challenge should last.[24] Some protocols recommend eating a maximum of 10 g of gluten per day during 6 weeks. Nevertheless, recent studies have showed that 2 week challenge of 3 g of gluten per day may induces histological and serological abnormalities in most adults with proven coeliac disease.[22][24] This new proposed protocol has shown higher tolerability and compliance, and it has been calculated that its application in secondary-care gastrointestinal practice would identify celiac disease in 7% patients referred for suspected NCGS, while in the remaining 93% would confirmate NCGS,[24] but is not yet universally adopted.[22]

For people in gluten-free diet that are unable performing an oral gluten challenge, an alternative to identify a possible celiac disease is an in vitro gliadin challenge of small bowel biopsies, but this test is only available at selected specialized tertiary-care centers.[22]

Treatment[edit]

Main article: Gluten-free diet

After a reasonable exclusion of celiac disease and wheat allergy,[17] the subsequent step for diagnosis and treatment of NCGS is to start a strict gluten-free diet (GFD) and to confirm if symptoms improve or resolve completely. Normally, this occurs within days to weeks of starting a GFD.[38] As occurs in patients with celiac disease, the diet must be strict and maintained, without making any dietary transgression.[19]

The degree of tolerance of gluten cross contamination in people with NCGS is not defined.[19] In patients with celiac disease, the safe level of gluten intake is often referred to as "less than 50 mg/day" (50 ppm/day)[19] and a 2008 systematic review tentatively concluded that consumption of less than 10 mg/day (10 ppm/day) is unlikely to cause histological abnormalities,[39] but a safe level limit for gluten cross contamination in NCGS is not yet defined.[19] There is evidence that NCGS patients can present symptoms even after consumption of small amounts of gluten.[19]

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.[10][19] Theoretically, a trial of gluten reintroduction to observe reaction after 1–2 years of strict gluten-free diet might be performed.[19]

Persistent symptoms[edit]

Approximately, one third of NGCS patients, continue having symptoms, despite gluten withdrawal. Apart from a possible diagnostic error, there are multiple possible explanations.[19]

The main reason is a poor dietary compliance, whether voluntary and/or involuntary. Because these patients do not suffer celiac disease, they may be unaware of following a strict gluten-free diet, although the ingestion of even small amounts of gluten can cause more immediate and obvious symptoms in people with NGCS than those with celiac disease.[19]

Patients may be inadvertently ingesting gluten, in the form of cross contamination or food containing it, among their ingredients.[9]

In some cases, the amelioration of gastrointestinal symptoms with a gluten-free diet is only partial, in which case patients could significantly improve with a low-FODMAPs diet in addition to gluten withdrawal.[9]

Also, a subgroup of NCGS patients may not improve by eating commercially available gluten-free products, which are usually rich of preservatives and additives because chemical additives (such as sulfites, glutamates, nitrates and benzoates) might have a role in triggering functional gastrointestinal symptoms of NCGS.[9]

Furthermore, associated to gluten sensitivity, NCGS people may often present IgE-mediated allergies to one or more foods[19] and it is estimated that around 35% of patients suffer some food intolerances, mainly lactose intolerance.[22]

Research[edit]

NCGS patients may develop anti-gliadin antibodies and never have anti-tTG antibodies.[40] Recent studies indicate that AGA IgG is high in slightly more than half of NCGS patients[4] and that for these patients, 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][41]

There are many open questions on gluten sensitivity,[9] 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".[42] 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.[16][43]

The need for developing biomarkers for NCGS is frequently emphasized;[4][17][44] 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."[16]

A 2014 preliminary study found "that short-term exposure to gluten can induce depressive symptoms in people with non-celiac gluten sensitivity".[45]

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][46]

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.[22]

One study showed that although there is an evident "fad component" to the recent rise in popularity of the gluten-free diet, there is evidence for the existence of non-celiac gluten sensitivity.[3]

See also[edit]

References[edit]

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