Absence of reliable biomarkers and the fact that some people do not have digestive symptoms make the recognition and diagnosis of<unk>  (NCGS) difficult. Diagnosis is generally performed only by exclusion criteria. NCGS diagnostic recommendations have been established by several consensus conferences. Exclusion of<unk>  disease and wheat allergy is important because these two conditions also appear in people who experience symptoms similar to those of NCGS, which improve with a<unk>  withdrawal and worsen after<unk>  consumption. The onset of NCGS symptoms may be delayed hours to a few days after<unk>  ingestion, whereas in<unk>  disease it can take days to weeks. Wheat allergy has a fast onset (from minutes to hours) after the consumption of food containing wheat and can lead to anaphylaxis. The presence of related extraintestinal manifestations has been suggested to be a feature of NCGS. When symptoms are limited to gastrointestinal effects, there may be an overlap with wheat allergy, irritable bowel syndrome (IBS), and (less likely) intolerance to FODMAPs. Proposed criteria for a diagnosis of NCGS suggest an improvement of gastrointestinal symptoms and extra-intestinal manifestations higher than 30% with a<unk> -free diet (GFD), assessed through a rating scale, is needed to make a clinical diagnosis of NCGS. To exclude a placebo effect, a double-blind placebo-controlled<unk>  challenge is a useful tool, although it is expensive and complicated for routine clinical use, and so is usually performed in research studies. These suggestions were incorporated in the Salerno expert consensus on diagnostic criteria for NCGS. These recommend assessment of the response to a 6-week trial of a<unk> -free diet using a defined rating scale (Step 1), followed by a double-blind, placebo-controlled challenge of<unk>  (or placebo) for a week of each (Step 2). A variation of greater than 30% in the main symptoms when challenged by<unk>  or placebo is needed for a positive result. Further research on possible biomarkers was also identified. Differential diagnosis Examinations evaluating<unk>  disease and wheat allergy should be performed before patients remove<unk>  from their diet. It is critical to make a clear distinction between<unk>  disease and NCGS.<unk>  disease The main goal in diagnosing NCGS is to exclude<unk>  disease. NCGS and<unk>  disease cannot be separated in diagnosis because many gastrointestinal and<unk> -gastrointestinal symptoms are similar in both diseases, and there are people with<unk>  disease having negative serology (absence of specific<unk>  disease antibodies in serum) or without villus atrophy. There is no test capable of eliminating a diagnosis of a<unk>  disease, but such a diagnosis is unlikely without confirming HLA-DQ2 and/or HLA-DQ8 haplotypes. The prevalence of undiagnosed<unk>  disease has increased fourfold during the past half-century, with most cases remaining unrecognized, undiagnosed and untreated, leaving<unk>  patients with the risk of long-term complications. Some people with NCGS may indeed have<unk>  disease. A 2015 systematic review found that 20% of people with NCGS presenting with HLA-DQ2 and/or HLA-DQ8 haplotypes, negative serology, and normal histology or duodenal lymphocytosis had<unk>  disease. The presence of autoimmune symptoms in people with NCGS suggests the possibility of undiagnosed<unk>  disease. Autoimmune diseases typically associated with<unk>  disease are diabetes mellitus type 1, thyroiditis,<unk>  ataxia, psoriasis, vitiligo, autoimmune hepatitis, dermatitis herpetiformis, primary sclerosing cholangitis, and others. To evaluate the possible presence of<unk>  disease, specific serology and duodenal biopsies are required while the person is still on a diet that includes<unk> . Serological markers Serological CD markers (IgA tissue transglutaminase , IgA endomysial EmA and IgG deamidated gliadin peptide DGP antibodies) are always negative in those with NCGS; in addition to specific IgA autoantibody levels, it is necessary to determine total IgA levels. IgG antibodies should be checked in selective IgA deficiency, which can be associated with<unk>  disease and occurs in as many as one in 40<unk>  patients. Nevertheless, the absence of serological markers does not certainly exclude<unk>  disease. In those with<unk>  disease before diagnosis (on a<unk> -containing diet),<unk>  disease serological markers are not always present. 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<unk>  disease-specific antibodies is more common in patients without villous atrophy who only have duodenal lymphocytosis (Marsh 1 lesions) and who respond to a<unk> -free diet with histological and symptomatic improvement. Duodenal biopsies According to the diagnostic criteria established by the consensus conferences (2011 and 2013), it is necessary to perform duodenal biopsies to exclude<unk>  disease in symptomatic people with negative specific<unk>  disease antibodies. Because of the patchiness of the<unk>  disease lesions, four or more biopsies are taken from the second and third parts of the duodenum, and at least one from the duodenal bulb. Even in the same biopsy fragments, different degrees of pathology may exist. Duodenal biopsies in people with NCGS are always almost normal – an essential parameter for diagnosis of NCGS, although is generally accepted that a subgroup of people with NGCS may have an increased number of duodenal intraepithelial lymphocytes (IELs) ( ≥25/100 enterocytes), which represent Marsh I lesions. Nevertheless, Marsh I is considered compatible with<unk>  disease and the most frequent cause of these findings, especially in people positive for HLA DQ2 and/or DQ8 haplotypes, is<unk>  disease, with a prevalence of 16-43%. In people with duodenal lymphocytosis – following guidelines from the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) – a high count of<unk>  disease cells (or CD/CD3 ratio) in immunohistochemical assessment of biopsies, or the presence of IgA anti-TG2 and/or anti-endomysial intestinal deposits, might be specific markers for<unk>  disease. Catassi and Fasano proposed in 2010 that in patients without<unk>  disease antibodies, either lymphocytic infiltration associated with IgA subepithelial deposits or a histological response to a<unk> -free diet, could support a diagnosis of<unk>  disease. Wheat allergy The clinical presentation may be sufficient in most cases to distinguish a wheat allergy from other entities. It is excluded when there are normal levels of serum IgE antibodies to<unk>  proteins and wheat fractions, and no skin reaction to prick tests for wheat allergy. Nevertheless, these tests are not always completely reliable. 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 two hours and five days after the oral challenge are considered delayed. Mucosal challenge followed by confocal endomicroscopy is a complementary diagnostic technique, but this technology is not yet generally available and remains experimental. Other tests 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). In these patients, unlike in those with<unk>  disease, the IgG AGA became undetectable within six months of following a<unk> -free diet. People already on a<unk> -free diet Many people remove<unk>  from their diet after a long history of health complaints and unsuccessful consultations with numerous physicians, who simply consider them to be suffering from irritable bowel syndrome, and some may eliminate<unk>  before seeking medical attention. This fact can diminish the CD serological markers titers and may attenuate the inflammatory changes found in the duodenal biopsies. 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<unk>  disease. If these markers are positive, it is advisable to undertake a<unk>  challenge under medical supervision, followed by serology and duodenal biopsies. However,<unk>  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.<unk>  challenge is also discouraged before the age of five and during pubertal growth. It remains unclear what daily intake of<unk>  is adequate and how long the<unk>  challenge should last. Some protocols recommend eating a maximum of 10 g of<unk>  per day for six weeks. Nevertheless, recent studies have shown that a two-week challenge of 3 g of<unk>  per day may induce histological and serological abnormalities in most adults with proven<unk>  disease. This new proposed protocol has shown higher tolerability and compliance. It has been calculated that its application in secondary-care gastrointestinal practice would identify<unk>  disease in 7% of patients referred for suspected NCGS, while the remaining 93% would be confirmed as NCGS; this is not yet universally adopted. For people on a<unk> -free diet who are unable to perform an oral<unk>  challenge, an alternative to identify possible<unk>  disease is an in vitro gliadin challenge of small bowel biopsies, but this test is only available at selected specialized tertiary-care centers.
Non-celiac gluten sensitivity
Hereditary diffuse gastric cancer
Intestinal neuronal dysplasia
Autoimmune gastrointestinal dysmotility
Tropical sprue
Lysinuric protein intolerance
Exocrine pancreatic insufficiency
Foreign body in alimentary tract