Non-celiac gluten sensitivity (NCGS) or gluten sensitivity is "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".NCGS is included in the spectrum of gluten-related disorders. The definition and diagnostic criteria of non-celiac gluten sensitivity were debated and established by three consensus conferences. However, as of 2019, there remained much debate in the scientific community as to whether or not NCGS was a distinct clinical disorder.The pathogenesis of NCGS is not well understood, but the activation of the innate immune system, the direct cytotoxic effects of gluten and probably other wheat components, are implicated. There is evidence that not only gliadin (the main cytotoxic antigen of gluten), but also other proteins named ATIs which are present in gluten-containing cereals (wheat, rye, barley, and their derivatives) may have a role in the development of symptoms. ATIs are potent activators of the innate immune system. FODMAPs, especially fructans, are present in small amounts in gluten-containing grains and have been identified as a possible cause of some gastrointestinal symptoms in NCGS patients. As of 2019, reviews have concluded that although FODMAPs may play a role in NCGS, they explain only certain gastrointestinal symptoms, such as bloating, but not the extra-digestive symptoms that people with NCGS may develop, such as neurological disorders, fibromyalgia, psychological disturbances, and dermatitis.For these reasons, NCGS is a controversial clinical condition and some authors still question it.
IgG tTGA antibodies should be checked in selective IgA deficiency, which can be associated with celiac disease and occurs in as many as one in 40 celiac patients.Nevertheless, the absence of serological markers does not certainly exclude celiac disease. In those with celiac disease before diagnosis (on a gluten-containing diet), celiac 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 celiac disease-specific antibodies is more common in patients without villous atrophy who only have duodenal lymphocytosis (Marsh 1 lesions) and who respond to a gluten-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 celiac disease in symptomatic people with negative specific celiac disease antibodies. Because of the patchiness of the celiac 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.