Abstract and Introduction
Objectives: Non-coeliac gluten sensitivity (NCGS) refers to patients with primarily gastrointestinal symptoms without enteropathy that symptomatically benefit from gluten-free diet (GFD). Little is known about its pathophysiology, propensity to neurological manifestations, and if these differ from patients with coeliac disease (CD). We investigated the clinical and immunological characteristics of patients presenting with neurological manifestations with CD and those with NCGS.
Methods: We compared clinical, neurophysiological, and imaging data of patients with CD and NCGS presenting with neurological dysfunction assessed and followed up regularly over a period of 20 years.
Results: Out of 700 patients, 562 were included. Exclusion criteria included no bowel biopsy to confirm CD, no HLA type available, and failure to adhere to GFD. All patients presented with neurological dysfunction and had circulating anti-gliadin antibodies. Out of 562 patients, 228 (41%) had evidence of enteropathy (Group 1, CD) and 334 (59%) did not (Group 2, NCGS). The most common neurological manifestations were cerebellar ataxia, peripheral neuropathy, and encephalopathy. There was a greater proportion of patients with encephalopathy in Group 1 and with a greater proportion of neuropathy in Group 2. The severity of ataxia did not differ between the two groups. Patients in Group 1 had more severe neuropathy. All patients from both groups responded to gluten-free diet. Anti-tissue transglutaminase (TG2) antibodies were found in 91% of patients in Group 1 and in 29% of patients in Group 2. Comparison between those patients in Group 2 with HLA-DQ2/DQ8 and those without as well as those with positive TG2 compared with those with negative TG2 antibodies identified no differences within these subgroups. Serological positivity for TG6 antibodies was similar in the two groups (67 and 60%).
Conclusions: The neurological manifestations of CD and NCGS are similar and equally responsive to a GFD suggestive of common pathophysiological mechanisms.
Gluten-related disorders (GRDs) represent a spectrum of diverse clinical manifestations sharing a common trigger, the ingestion of gluten. The most widely recognized and best-characterized disease within this spectrum is coeliac disease (CD), also known as gluten-sensitive enteropathy.
Classic presentations of CD such as abdominal bloating, weight loss, diarrhea, anemia, and malabsorption are no longer the norm and patients can present with minimal or no gastrointestinal symptoms and diverse extraintestinal manifestations affecting other organs such as the skin and the nervous system.[2,3] Although the presence of enteropathy, defined by the triad of villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes, remains the cornerstone of the diagnosis of CD, the diagnosis of the whole spectrum of GRDs is problematic. This is particularly the case for the relatively new entity belonging to the spectrum of GRDs, non-coeliac gluten sensitivity (NCGS). NCGS is currently defined by clinical evidence of improvement of symptoms following the introduction of gluten-free diet (GFD) in the absence of enteropathy.[4,5] Both innate and adaptive immune responses to wheat proteins have been demonstrated in the gut of such patients. The concept of sensitivity to gluten in the absence of enteropathy is not new. Patients with extraintestinal manifestations because of sensitivity to gluten (e.g., gluten ataxia and dermatitis herpetiformis (DH) may not have enteropathy, but yet respond to a GFD. The reasons behind such differences in the gut response remain unknown. Currently, it also remains unclear which serological markers alone or in combination should be used in diagnosing the whole spectrum of GRDs, and in particular NCGS. Although some markers such as anti-tissue transglutaminase (TG2) autoantibodies detected as anti-endomysium antibodies or by ELISA (anti-TG2 antibodies) are sensitive and specific in diagnosing CD, such antibodies will usually be absent in patients with NCGS. This may reflect the absence of detectable levels of circulating antibodies in some cases where the immune response is distant from the gut (e.g., cerebellum in gluten ataxia). Anti-gliadin antibodies (AGA) may be an indicator of NCGS as up to 50% of such patients presenting to gastroenterologists have detectable circulating levels, primarily of IgG AGA. More specific markers, i.e., antibodies directed at autoantigens likely to be responsible for extraintestinal manifestations, have been identified but are not yet in general use. Antibodies against TG3, an epidermal TG, have been found in patients with DH, whereas antibodies against TG6, a brain expressed TG, have been found in patients with gluten ataxia.[9,10] However, the extent of overlap between NCGS, DH, and gluten ataxia is unclear at present and awaits the development of validated diagnostic approaches.
The use of the HLA type as an aid in the diagnosis has also been advocated given that over 95% of patients with CD have the HLA-DQ2, and the remainder having HLA-DQ8. HLA type, however, cannot be interpreted in isolation as DQ2 is found in up to 25% of the healthy population, of which only a fraction will ever develop GRDs. Furthermore, while there is over-representation of DQ2 in patients with NCGS, a significant minority do not have the HLA-DQ2 or -DQ8 and yet appear to respond to a GFD. It is plausible that patients who have serological evidence of sensitivity to gluten without enteropathy, who also have the HLA-DQ2 or -DQ8, and appear to respond to GFD may be susceptible to develop enteropathy with ongoing exposure to gluten.
Our research into the neurological manifestations of GRD started 20 years ago. The presence or absence of enteropathy did not influence our diagnosis as these patients had no clinical features, either gastrointestinal or neurological, to distinguish between those with and those without enteropathy and had no explanation other than gluten sensitivity for their neurological problem.
Here we present the spectrum of neurological manifestations seen in the context of NCGS and we compare this with neurological manifestations seen in the context of CD (with neurological presentation). Th e aim was to tease out any potential diff erences between these two groups that may imply diff erent pathophysiological mechanisms being responsible depending on the presence or not of enteropathy.
Am J Gastroenterol. 2016;111(4):561-567. © 2016 Nature Publishing Group