Gluten Sensitivity

Problems of an Emerging Condition Separate From Celiac Disease

Amy C Brown


Expert Rev Gastroenterol Hepatol. 2012;6(1):43-55. 

In This Article

Lack of Diagnostic Criteria

Both celiac disease and gluten sensitivity are non-IgE-mediated immune-mediated food reactions,[6] but differ in how they are diagnosed.

Biopsy Criteria

The gold standard for celiac disease is detection of flat villi through an upper endoscopy biopsy of the small intestine. However, according to the classification proposed by Marsh in 1992, the spectrum of gluten enteropathy is wide and can range from only intraepithelial increased lymphocytes to complete villous atrophy.[6] The four Marsh stages reflect a series of mucosal changes presented as a continuous spectrum of mucosal deterioration due to gluten exposure.

According to the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) current criteria, duodenal villous atrophy (Marsh stage III and onwards) is the necessary criteria for diagnosing celiac disease and recommending a gluten-free diet. This now obsolete assumption was based on the traditional misinterpretation that Marsh I infiltrative lesions (also known as lymphocytic enteritis) were not associated with any symptom or sign of malabsorption. Multiple findings have since suggested that villous intraepithelial lymphocytosis can now serve as histological index for many untreated adult celiac disease patients.[7–11] Moreover, the majority of patients with dermatitis herpetiformis only exhibit duodenal biopsies consistent with the Marsh I stage.[12–14] Tortora and Colleagues in Italy suggested that an in vitro response of mucosal HLA-DR to gliadin is an accurate tool for the diagnosis of celiac disease and also in patients with difficult diagnosis.[15]

Despite these observations, caution is still necessary before diagnosing celiac disease in patients with Marsh I lesions. Intraepithelial lymphocytic infiltration can be a common, nonspecific inflammatory response of the epithelium to a number of noxious or inflammatory signals. A new committee of experts is currently working on new revised ESPGHAN guidelines, in which Marsh I will be considered as a part of the celiac disease diagnostic spectrum, as well as avoiding biopsies in cases of very high antitransglutaminase antibodies.[16]

Gluten Sensitivity

People with gluten sensitivity test negative for celiac disease and wheat allergy, but experience resolution of symptoms on a gluten-free diet. Confirmation is obtained by following the gluten-free diet with a monitored reintroduction of gluten. The possibility of a placebo effect exists, unless blinded capsules containing gluten or nongluten material are offered during the challenge. The American Dietetic Association has published guidelines for the dietary treatment of celiac disease. Referrals to a registered dietitian for dietary instruction would best benefit these patients.[202]

Laboratory Tests

A primary serological test is the current diagnosis of celiac disease – that is, antitransglutaminase IgA. Although controversial, others suggest that deamidated gliadin peptide IgA, IgG[17] and anti-endomysial antibodies (EMAs) can also be ordered.[18] Unlike a classic allergy, which involves an IgE response, celiac disease involves an IgA and/or IgG immune system response to dietary gluten. Sapone et al. suggested that the big difference between celiac disease and gluten sensitivity is that the latter is negative for autoantibodies against tissue transglutaminase and EMAs or autoimmune comorbidities.[19]

Table 2 shows that this leaves few, if any, laboratory tests in the detection of gluten sensitivity. The field continues to wax and wane as other experimental tests surface to aid in the detection of celiac disease (Box 1).

Testing Problems

Serological tests for celiac disease can be problematic. Transglutaminase IgA titers correlate linearly with the stage of the histological lesion, with a higher sensitivity for celiac disease diagnosis in patients with villous atrophy.[20–22] As such, transglutaminase IgA sensitivity approximates 90% in pediatric cases, but only 15–30% in adults. In addition, transglutaminase IgA is very low in children in whom only lymphocytic enteritis is observed. On the other hand, Marsh I can represent >50% of cases in adults. This well-known low sensitivity of transglutaminase IgA in diagnosing adult-onset celiac disease also limits its use in population screening.

Unfortunately, prior gluten ingestion by celiac disease patients is required to make the above biopsy or serological tests accurate. This may not be an option for some patients experiencing abdominal pain and or other symptoms following gluten ingestion. It is additionally difficult for patients who have already eliminated gluten from their diet. The duration of gluten exposure is debated because histological changes occur in some cases within as little as 1 day, while others suggest 3 or more months.[23] Catassi and Fasano suggested that 50 mg of daily gluten for at least 3 months was necessary to deteriorate intestinal villous height and crypt depth ratio.[24] One slice of bread contains approximately 4500 mg of gluten, so 50 mg is a 90th of a slice. Gluten exposure is just one of the possible factors contributing to negative or inconclusive tests.

Another problem in testing people for celiac disease or gluten sensitivity is that the biopsy procedure can be invasive and expensive. Serologically positive patients in China preferred the simpler gluten-free diet over the invasive procedure of a duodenal biopsy.[25]

Unfortunately, people seeking relief of symptoms may be subjected to advertised nonstandard and expensive 'stool, saliva or allergy' tests with limited reliability.