Questions Raised About Gluten Sensitivity

Patients who've had celiac disease ruled out may have another form of gluten sensitivity, but there's little clinical evidence to explain the latter condition, researchers said.

More patients have been reporting a resolution of symptoms with a gluten-free diet even though they have never tested positive for celiac disease, reported Antonio Di Sabatino, MD, and Gino Roberto Corazza, MD, of the University of Pavia in Italy, in the Feb. 21 issue of Annals of Internal Medicine.

But there is insufficient evidence in the literature on nonceliac gluten sensitivity or what may cause it, they wrote.

Meanwhile, they went on, patient groups, manufacturers, and the media have been touting a gluten-free diet as the answer to patients' unexplained gastrointestinal symptoms.

Indeed, some marketers have touted a figure of 17 million Americans affected by gluten sensitivity, although there are no official data on its prevalence, according to Di Sabatino and Corazza.

"'Sense' should prevail over 'sensibility' to prevent a gluten preoccupation from evolving into the conviction that gluten is toxic for most of the population," they said. "We must prevent a possible health problem from becoming a social health problem."

There have been many names for the syndrome, including gluten sensitivity, gluten hypersensitivity, nonceliac gluten intolerance and nonceliac gluten sensitivity.

Whatever the name, the syndrome is characterized by diarrhea, abdominal discomfort or pain, bloating, and flatulence.

There also can be extra-intestinal symptoms, such as headache, lethargy, attention-deficit hyperactivity disorder (ADHD), ataxia, or recurrent oral ulceration.

However, these symptoms do not necessarily correlate with positive results for celiac disease on tests such as serum anti-transglutaminase or anti-endomysial antibody testing or small-bowel villous flattening.

So far, only a few studies have sought to characterize the condition. One randomized controlled rechallenge trial found gluten worsened functional symptoms in celiac-free patients (Am J Gastroenterol 2011; 106: 508-514).

Another uncontrolled, unblinded subgroup study found a gluten-free diet brought relief to patients who had gastrointestinal symptoms but did not have confirmed celiac disease, the researchers reported (Clin Gastroenterol Hepatol 2007; 5: 844-850).

The apparent heterogeneity of the etiology of the condition, however, could make it difficult to diagnose, they said.

Some say it may be triggered by activation of the innate stress response, rather than an adaptive immune pathway as seen in celiac.

But others caution that gluten is just one component in the "complex protein mixture" in wheat flour, and may not be solely responsible for symptoms. Other proteins, such as alpha-amylase/trypsin inhibitors or yeast, could play a role. Starch malabsorption could trigger a similar reaction, the researchers wrote.

Clinicians can't rule out the nocebo effect of wheat or gluten ingestion, which has been demonstrated in double-blind studies of patients who believe themselves to be food-sensitive (N Engl J Med 1995; 333: 1-4).

"Many of these patients were formerly on highly restrictive diets, had already withdrawn gluten from their diet, and were convinced that it had helped to limit their irritable bowel syndrome-like symptoms," the authors explained.

Given that gluten-free advocates have gained considerable traction, particularly on the Internet, Di Sabatino and Corazza called for further study of nonceliac gluten sensitivity.

And until a specific biomarker of nonceliac gluten sensitivity can be identified, clinicians should perform open or single-blind gluten challenge tests to rule out celiac disease, even though more expensive double-blind, placebo-controlled challenge testing has the highest diagnostic accuracy.

"I think this may be a real entity, and it certainly is one that patients are increasingly asking about," commented Lawrence Brandt, MD, a gastroenterologist at Montefiore Medical Center in New York City, who wasn't involved in the study.

"I do not believe it is a media-made condition, but rather it probably is another 'new' disease," Brandt told MedPage Today.

Walter Coyle, MD, of the Scripps Clinic in La Jolla, Calif., agreed, adding that gastroenterologists have been struggling with gluten sensitivity for the last decade.

"There are a whole host of people who do not meet celiac criteria but have symptoms with gluten," Coyle said in an email to MedPage Today. "It may not be gluten, but other substances in those foods, like fructans. I think we need more science and less hype."

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