Non-celiac gluten sensitivity: the path towards diagnosis

  1. Non-celiac gluten sensitivity: the path towards diagnosis

Diagnosis of non-celiac gluten sensitivity (NCGS) requires clinical improvement of symptoms while on a gluten free diet, after celiac disease and wheat allergy have been excluded.

If a patient reports non-specific symptoms, such as abdominal pain, bloating, diarrhea, headaches, or fatigue after consuming foods containing gluten, it is important first to exclude celiac disease and wheat allergy. The diagnosis is confirmed by an improvement or disappearance of symptoms with a gluten-free diet and a return of symptoms and  deterioration once gluten is reintroduced. The symptoms usually improve within a few days to two weeks. It is important that the patient follows a diet that contains gluten before the diagnostic process begins.

Medical history

Identifying symptoms and signs
First, it is important to determine if the symptoms described by the patient are typical of NCGS and whether they could be related to the consumption of foods containing gluten. Before starting the diagnosis, the patient should follow a normal diet, i.e. one containing gluten, for at least six weeks.

Excluding celiac disease

Celiac disease antibody test and biopsy
Since the symptoms of NCGS may resemble those of celiac disease, it is important to first exclude celiac disease. It is crucial to ensure that patients are on a gluten containing diet before and during the diagnostic process. The first step in excluding celiac disease is celiac serology (endomysial antibody or tissue transglutaminase antibody). A negative serological test has an excellent negative predictive value in excluding celiac disease, provided the patient has been consuming a gluten containing diet for 6 weeks prior to the test. In cases with positive serology, a small intestine biopsy is required to confirm a diagnosis of celiac disease [1]. Patients with NCGS will not have evidence of villous atrophy on duodenal biopsy, although the levels of intra-epithelial lymphocytes (IELs) may be slightly elevated (equating to Marsh scale 1) [2].
 

Gluten challenge to exclude celiac disease
If patients are on a gluten free diet at the time of investigation consideration having the patient undergo a gluten challenge must be considered. Current guidelines recommend a 6 week challenge of 10 grams of gluten per day. However many patients with NCGS may not be able to tolerate this amount of gluten and recent evidence suggests that shorter challenges of 2 weeks with 3 grams of gluten are able to confirm coeliac disease in 75% of cases [3]. However duodenal biopsy is required in these cases.

Excluding wheat allergy

IgE-antibody test and skin prick test
The clinical picture of wheat allergy may also be similar to that of NCGS. An IgE antibody test and skin prick test may be used to determine whether a patient is allergic to wheat.

Other evidence of NCGS

IgG anti-gliadin antibody test
IgG anti-gliadin antibodies (AGAs) may be seen more frequently in NCGS [4]. However, AGAs may also be present in people with celiac disease and in a small proportion of the healthy population. Research is ongoing to clarify the diagnostic procedure for NCGS in the future. At the present time IgG AGA cannot be used for diagnosis.

Gluten-free diet

Confirming the diagnosis
As with food allergies, a gluten challenge may be necessary for a definitive diagnosis of NCGS. Following a period of at least 4 weeks on strict gluten free diet, patients should re-introduce gluten. If the symptoms recur within two days patients should restart a gluten free diet followed by a double-blind (for studies) or single-blind (in practice), placebo-controlled oral provocation. The most suitable foods for this purpose are gluten-free bars (as a placebo) and bars containing gluten that do not differ in appearance, texture or flavor. The first one-week trial period is followed by a one-week strict gluten-free diet and a second one-week trial period. The standardized diagnostic protocol should be used for the weekly assessment of symptoms. If a 30% reduction in 1 of the 3 symptom domains is demonstrated in the gluten free period compared to gluten containing period, gluten sensitivity is present.

Re-exposure to gluten

Confirming the diagnosis
As with food allergies, a gluten challenge may be necessary for a definitive diagnosis of NCGS. Following a period of at least 4 weeks on strict gluten free diet, patients should re-introduce gluten. If the symptoms recur within two days patients should restart a gluten free diet followed by a double-blind (for studies) or single-blind (in practice), placebo-controlled oral provocation. The most suitable foods for this purpose are gluten-free bars (as a placebo) and bars containing gluten that do not differ in appearance, texture or flavor. The first one-week trial period is followed by a one-week strict gluten-free diet and a second one-week trial period. The standardized diagnostic protocol should be used for the weekly assessment of symptoms. If a 30% reduction in 1 of the 3 symptom domains is demonstrated in the gluten free period compared to gluten containing period, gluten sensitivity is present.

Diagnostic protocol for gluten/wheat sensitivity

This  standardized diagnostic protocol was developed by leading researchers in the field of gluten-related disorders at the 3rd International Expert Meeting on Non-Celiac Gluten Sensitivity in October 2014 [5]. This stipulates a uniform two-stage dietary process for which a modified version of the gastrointestinal symptom rating scale is used. Patients use this scale to assess the effects the introduction of a gluten-free diet and the reintroduction of gluten on their symptoms. Both gastrointestinal and extraintestinal symptoms are rated on a scale of 1 to 10. This questionnaire is designed to standardize diagnosis.

Non-celiac gluten sensitivity: the path towards diagnosis

References

  1. Mooney, P. D., Hadjivassiliou, M. & Sanders, D. S. Coeliac disease. BMJ 348, g1561 (2014).
  2. Sapone, A. et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Med. 9, 23 (2011).
  3. Leffler DA, Schuppan D, Pallav K et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut. 2013 Jul;62(7):996-1004.
  4. Caio, G., Volta, U., Tovoli, F. & De Giorgio, R. Effect of gluten free diet on immune response to gliadin in patients with non-celiac gluten sensitivity. BMC Gastroenterol. 14, 26 (2014).
  5. Catassi C, Elli L et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. Nutrients. 2015 Jun 18;7(6):4966-77.