Non-celiac Wheat Sensitivity: Emerging from the Shadow of Celiac Disease
When it comes to gluten-specific conditions, celiac disease is by far the most well-known. An estimated 2.5 million Americans are affected by the disease, and its main treatment, the gluten-free diet, has become part of the mainstream culture as a fad diet or near cure-all for diet-related problems. The science on celiac spans back several decades and has provided clinicians with a bevy of diagnostic tools at their disposal, though many individuals with celiac disease may still be undiagnosed.
The same cannot be said about another condition that can resemble celiac disease but for which there might be up to 10 times as many patients. Non-celiac gluten sensitivity (NCGS) has lived in celiac’s shadow for years, and despite an increase in research on the condition during the last decade, many questions remain about its cause, its prevalence and how to diagnose it.
According to Anthony J. DiMarino, MD, chief of the division of gastroenterology and hepatology at Thomas Jefferson University Hospital, treating patients with NCGS is difficult because gluten affects so many people in a variety of ways.
“The spectrum of gluten sensitivity starts with people who really have celiac, which is an autoimmune issue, and they have an adaptive immunity. ... That’s a pretty serious thing. It has widespread issues,” he told Healio Gastroenterology and Liver Disease. “On one end of the spectrum are all these people who are eating a gluten-free diet for some unknown reason. They perceive they have a sensitivity or think that it’s just a healthier diet.”
In the middle of the spectrum lies a complex group. Daniel Leffler, MD, MS, director of clinical research at the Celiac Center at Beth Israel Deaconess Medical Center, told Healio Gastroenterology and Liver Disease that it can include people with a wheat allergy or gluten sensitivity.
“A lot of people just confuse the terms. They just tell someone who might have celiac disease, ‘just go gluten-free,’ without testing, which is a mistake and misses an opportunity to understand what the patient has and what kind of follow up they need,” he said. “Anyone who’s having symptoms that are associated with either gluten sensitivity, wheat allergy or celiac disease should be tested for celiac disease first, because that testing is very straightforward. If that’s positive and you make a diagnosis of celiac disease, you really know exactly what the patient has and how they need to be treated. It gets more complicated after that.”
While wheat allergy is typically well-managed by allergists, managing and diagnosing NCGS is much less exact. Patients with NCGS experience many of the same gastrointestinal symptoms that patients experience with celiac disease, like bloating, gas and digestive pain, as well as some of the same systemic issues, like brain fog or depression.
An Elusive Culprit
For years, physicians questioned whether gluten was triggering a specific immune reaction in patients without celiac disease. While some studies, including one published in Gut in 2016, have shown that wheat or its components were triggering an immunologic response in patients, the exact culprit has been elusive. In addition to gluten, a grain of wheat also contains fermentable oligo-, di-, monosaccharides and polyols (FODMAPs), which have also been suggested as a possible cause of NCGS. Researchers have found separating these pieces difficult, making it harder to pinpoint the specific offender in individual patients. Experts say that any one, or even several, of these components could have something to do with NCGS.
“Gluten sensitivity is probably not one disorder,” Leffler said. “It’s probably a variety of different disorders which occur when you eat wheat or other related foods. Some of those are direct immune reactions to some part of the wheat, some are reactions to other non-gluten proteins in wheat. Some [are] likely the sugars, the FODMAPs and fructans in grains that some people can be sensitive to. There are ... multiple subtypes, which is why it makes it difficult to make any diagnostic criteria because it’s not one disease.”
In a systematic review of randomized controlled trials that involved double-blind placebo re-challenges, published in Frontiers in Physiology in 2017, researchers found that most patients with self-reported NCGS showed no signs of relapse after ingesting gluten or a placebo. However, despite showing that most of these patients might be triggered by different agents, Benjamin Lebwohl, MD, MS, director of clinical research at the Celiac Disease Center at Columbia University, said this indicates that for some individuals, gluten truly is the cause of their condition.
“There’s definitely a proportion of people for whom gluten is the culprit,” he said in an interview. “We need to better understand how gluten is causing symptoms in those patients, but studies suggest that this tends to be the minority of patients.”
However, that leaves another group whose gastrointestinal problems are caused by a sensitivity to a different part of wheat. Researchers have started looking at FODMAPs as a potential trigger, specifically fructans, a type of FODMAP, and studies are being designed around challenges that further separate wheat sensitivity into more specific groups. Patients can be randomly assigned placebo, a gluten bar or a fructan bar to categorize patients and define the condition.
One such study — published in Gastroenterology earlier this year — found that patients who took the fructan bar experienced worse gastrointestinal symptoms than patients who took either the gluten or placebo bars. Leffler said it is important to find these different kinds of patients, because the gluten-free diet, which is generally adhered to by most of the NCGS population, might be too restrictive for patients who are only sensitive to fructans or other FODMAPs.
The lack of a defined cause has put limitations on methods clinicians can use to diagnose patients.
“[Celiac disease] testing is very straightforward,” Leffler said. “There’s blood testing. If that’s positive and you make a diagnosis of celiac with intestinal biopsy, you really know exactly what the patient has and how they need to be treated. ... The diagnosis of [NCGS] is really one of exclusion. The patient comes in, celiac is excluded, they confirm they feel better on a gluten-free diet, and by default you have gluten sensitivity.”
Currently, the gold standard for NCGS research is the double-blind gluten challenge. Patients are randomly assigned to receive food that either has gluten or is gluten-free, and investigators record their response. However, Lebwohl said implementing such a test in clinical practice is difficult.
“Patients might not be eager to basically be part of an experiment that involves taking a placebo for any period of time,” he said. “They might not also be keen to agree to take gluten even for a short period of time if they think there’s a chance that it will make them very ill. The third reason is, from a practical perspective, most institutions don’t have a readily available source of placebo and the blinding mechanism to set this up.”
While a gluten challenge kit is being developed for commercial use, Lebwohl believes that many patients would be hesitant to use it if they thought it would cause their symptoms to flare severely and make them very sick.
Considering the multiple potential causes of NCGS, one test for gluten sensitivity might not be enough. Joseph Murray, MD, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., said for any test to be effective, patients need to be more carefully defined in terms of their symptoms.
“The real challenge is coming up with a clinical design where you can separate out the gluten effect, from the fructan effect, from the other protein effects in wheat,” he told Healio Gastroenterology and Liver Disease. “There are people trying very hard; doesn’t mean it’s easy.”
One biotech company, ImmunsanT, announced plans to develop a test that it said could differentiate between celiac and NCGS by measuring cytokine activity following a one-off oral gluten challenge. The test is based on research presented at UEG Week 2017 that found an increase in IL-8, IL-10 and IL-12 in patients with celiac following the challenge. However, patients with NCGS had almost no measured immune response, but did show a symptom response to FODMAPs and fructans. Experts believe, however, that such a test, specifically one that can be used to diagnose NCGS, isn’t likely to be available for some time.
“It’s still pretty early days for any gluten sensitivity test. People are making a lot of progress in that area, and it’s a huge unmet need,” Leffler said. “But it’s not something that I expect to have in the clinic in the next few years.”
Treating the Self-diagnosed
According to the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, roughly 30% of people in the United States limit their gluten intake. However, people who actually have a gluten-related disorder only account for a small part of that population. Lebwohl said patients often notice a link between their gastrointestinal issues and their diet, and the absence of validated clinical tests that identify the cause of a specific sensitivity leaves the door open for self-diagnosis. This can ultimately lead to missing the much more serious diagnosis of celiac disease, he said.
“One of the biggest challenges is separating out [NCGS] from celiac disease,” he said. “Often the diagnosis of [NCGS] is made by the patient before coming to a health care provider. When that’s the case, the patient is already on a self-prescribed gluten-free diet. Once that diet has begun, it becomes more difficult to determine if that person has celiac disease or not.”
Patients on a gluten-free diet without a medical diagnosis of a specific gluten-related disorder — sometimes known as “PWAGs” (people who avoid gluten) — have a risk for celiac disease, but their adherence to the gluten-free diet can make it much more difficult to diagnose.
“For people who have already gone on a gluten-free diet and feel better, some actually have celiac disease, but they don’t know because they never got tested,” Murray said. “When a patient with celiac goes gluten-free, their antibody blood test goes negative. Those antibodies are reacting to the eating of gluten. It’s like the fuel for the fire has gone away. The second thing is the biopsy can also heal.”
Murray said traditional diagnostic tests for celiac can be difficult for patients who have been on a gluten free-diet, particularly ones who have stuck with it for an extended time. The probability of making a diagnosis without putting the patient on a gluten challenge is “pretty low,” he said. If a patient on a gluten-free diet refuses to do a gluten challenge, Murray instead will take a full history of their symptoms before starting the diet, then conduct genetic testing to see if the patient has the markers that show susceptibility for celiac disease.
“If that comes back positive, and they gave a fairly good history, I would scope them,” he said. “What I’m looking for is if they have healed their intestine. If their intestine is normal, I’ll tell them ‘if you have celiac disease, you’ve healed it. If you really want to know if you have celiac, they only way to know is to challenge you.’”
If they agree to the challenge and complete it, then they can be tested for relevant biomarkers and, if applicable, biopsied, Murray said.
Beyond eliminating the risk for celiac disease, treatment of NCGS is limited by the lack of any validated diagnostic test. The gluten-free diet may lead to decreased symptoms for patients, but relying on it to treat a condition that could have several different causes might not be right for individuals who are not sensitive to gluten.
Lebwohl said it is common for some patients who previously experienced improvement on the gluten-free diet to see some of their symptoms return after a few weeks or months. Knowing the actual cause of their problems could help clinicians direct the patient’s diet going forward following this kind of relapse.
“Two possibilities are that the patient is being exposed to trace amounts of gluten, and the solution is to become more strict and vigilant,” he said. “Or, gluten was never the culprit, and the solution is to liberalize the diet.”
This kind of nutritional fine tuning can play a critical role in the health of patients with NCGS, but Leffler said it’s something that shouldn’t be taken up without expert direction.
“Diet modification can be very effective for GI symptoms,” he said. “But restriction can be problematic. There’s certainly a danger to over-restricting. Anyone who’s going to make long-term, significant changes in their diet really should do that in consultation with a dietitian. I’ve seen just as many problems from over-restriction and unhealthy modification as people that benefit.”
While identifying a more specific cause or diagnosis would be beneficial, DiMarino said if a gluten-free diet is working, that might be enough for some patients. Being able to rule out celiac disease gives patients a chance to work with their doctors to modify their diet in a way that makes meal planning and dining out a little easier.
“We tell them if they go out to dinner and they’re not sure of exactly what they’re getting, and they happen to get cross contaminated and get sick, just be reassured that you don’t have celiac,” he said. “You’re just paying the price for going out to dinner. You don’t want that to happen, but you’re not getting the lasting effect that you get with celiac disease.”
The trick, he said, is to sit down with the patient and find out exactly what they are looking for.
“Are they trying to find out if they have celiac disease? Well that’s easy enough to do,” he said. “Are they saying they’d like to eat more than just a strict gluten-free diet? We’ll help them find that. The way we find it is on the FODMAP diet, and we gradually reintroduce — working with a dietician — foods back one at a time. We see what it is that might be your trouble. Even if we don’t have a test to tell us exactly what it is, we can narrow it down.”
With all the different people that experience NCGS in different ways, many questions remain about its cause, the best way to identify it and how to treat it. Some question if it’s one disease, or many. Some question whether gluten or another agent is the root cause or if these components of wheat are just causing flare-ups in an existing condition. Murray believes that patients in this group have underlying irritable bowel syndrome causing the symptoms rather than their diet.
“People will look at their diet and ask, ‘is there something in my diet I can avoid to make me feel better,’ but it’s not that it’s the cause of the symptoms so much as it is that the disease is the cause of their symptoms,” he said. “I liken it to if I’ve got a bad leg, the more walking I do the more it hurts me. I might say, ‘it must be walking that’s the cause of my problem.’ No, it’s the bad hip that’s the cause of the problem.”
No matter what the answers might be to all the remaining questions in the realm of NCGS, Lebwohl urged clinicians to find an individualized approach to help each patient.
“Despite the uncertainty about [NCGS], we need to recognize that many patients are coming to celiac centers and to GIs looking for answers,” he said. “It’s our obligation to take their symptoms seriously and to study this condition and work to advance the science so we can take better care of these patients.” – by Alex Young
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- For more information:
- Anthony J. DiMarino, MD, can be reached at Anthony.DiMarino@jefferson.edu.
- Benjamin Lebwohl, MD, MS, can be reached at firstname.lastname@example.org.
- Daniel Leffler, MD, can be reached at email@example.com.
- Joseph Murray, MD, can be reached at Murray.Joseph@mayo.edu.
Disclosures: DiMarino and Lebwohl reports no relevant financial disclosures. Leffler serves as a medical director of Takeda Pharmaceuticals. Murray reports financial ties to ImmunogenX – Crohn’s and Colitis Foundation of America funded to Mayo Clinic, ImmunogenX – National Institute of Health funded to Mayo Clinic, DBV Technologies, Evelo, Vibrant Technologies, Alvine Pharmaceuticals and ActoGeniX.