Thursday, September 13, 2012

Celiac Disease and Gluten Sensitivity: An Interview With Medical Experts



by S. Z. Berg

In honor of National Celiac Disease Awareness Day and to kick off my William Edwards book series, a new series of novels for kids ages 8-12 years in which the main character, William Edwards, has celiac and a food allergy, I'm writing a series of posts about celiac, gluten sensitivity and food allergies, including interviews with actress Jennifer Esposito (Crash) , musician Allie Moss (Corner), and Disney's Kenton Duty.



What follows are email interviews with both Alessio Fasano, M.D., medical director of the University of Maryland Center for Celiac Research, and Daniel Leffler, M. D., director of clinical research, The Celiac Center at BIDMC. Both are NFCA scientific/medical advisory board members.

S.Z. Berg: What is the difference between gluten sensitivity and celiac disease? Is it a spectrum? Can you have gluten sensitivity and not have the gene for celiac?

Dr. Alessio Fasano: Think of gluten ingestion on a spectrum. At one end, you have people with celiac disease. This autoimmune disorder triggered by gluten causes intestinal damage leading to malabsorption of nutrients, which results in a wide variety of symptoms and potential complications. It can affect the gastrointestinal system, the central nervous system, and other areas of the body. It can affect anyone at any age and is treatable through the implementation of a strict gluten-free diet for life. People with celiac disease can't tolerate one "crumb" of gluten in their diet.

At the other end are the lucky folks who can consume all the pasta, bread and beer they want with no ill effects whatsoever. In the middle, we have this murky area of gluten reactions, including gluten sensitivity. This is where we are looking for answers about how to best diagnose and treat this recently-identified group of gluten-sensitive individuals.

Although symptoms of gluten sensitivity (particularly gastrointestinal) are often similar to those of celiac disease, the overall clinical picture is less severe. Recent research at the University of Maryland Center for Celiac Research shows that gluten sensitivity is a different clinical entity. It doesn't seem to result in the intestinal inflammation that leads to a flattening of the villi of the small intestine that characterizes celiac disease.

The development of tissue transglutaminase (tTG) autoantibodies, used to diagnose celiac disease, is not present in gluten sensitivity. A different immune mechanism, the innate immune response, comes into play in reactions of gluten sensitivity, as opposed to the long-term adaptive immune response that arises in celiac disease.

We use the term gluten sensitivity when celiac disease, wheat allergy, and other clinically-overlapping diseases (Type 1 diabetes, inflammatory bowel diseases and Helicobacter pylori infection) have been ruled out. Symptoms in gluten sensitivity are triggered by gluten exposure and alleviated by gluten withdrawal.

In gluten sensitivity, there is often a prevalence of extraintestinal instead of gastrointestinal symptoms, including behavioral changes, skin rash, bone or joint pain, muscle cramps, leg numbness, weight loss, "foggy mind," and fatigue. Typical gastrointestinal symptoms include abdominal bloating and gas.

Typically, the diagnosis is made by exclusion, and an elimination diet and "open challenge" -- we carefully reintroduce foods with gluten -- are most often used to evaluate whether the patient's health improves with the elimination or reduction of gluten from the diet.

Through clinical data from the Center for Celiac Research, we estimate that approximately six percent of the U.S. population, or 18 million people, suffers from gluten sensitivity. This group reacts with some of the same symptoms as people with celiac disease, but gluten-sensitive individuals typically test negative for celiac disease in diagnostic blood tests and show no signs of the damage to the small intestine that defines celiac disease.

Contrary to celiac patients who almost invariably (the percentage is close to 100 percent) express the HLA DQ2 and/or DQ8 genes, only 50 percent of subjects with gluten sensitivity are positive for these genes (compared to approximately 35-40 percent of the general population).

Dr. Daniel Leffler: Celiac disease is an immune-mediated disease triggered by gluten, which results in significant inflammation and damage to the small intestine as well as formation of antibodies, which can attack tissues in your body. Gluten sensitivity is a disorder where people have symptoms related to gluten exposure that may be indistinguishable from celiac disease but does not damage the intestine or result in abnormal antibody production. Whether gluten sensitivity is more related to celiac disease or irritable bowel syndrome is unclear, though most investigators currently favor the latter. One reason for this is that it is clear that you can have gluten sensitivity without the gene for celiac disease, while it is very rare for people with celiac disease not to carry these genes.

S.Z. Berg: What are the tests for diagnosing both of these conditions? What tests are available for people who are already gluten-free? How accurate are the tests? What's the gold standard?

Dr. Alessio Fasano: Blood tests are used for the initial screening of celiac disease to measure specific autoantibodies that develop in the blood in reaction to gluten. If these tests are positive, an endoscopy is conducted to confirm the diagnosis by showing the intestinal damage typical of celiac disease (blunted villi).

The endoscopy has long been considered the "gold standard" for the diagnosis of celiac disease. But if the other diagnostic indicators are all strongly present (typical symptoms of celiac disease, positive blood tests, positive genetic markers, and symptom alleviation on gluten-free diet) sometimes the endoscopy can be avoided, particularly in the pediatric population.

There are currently no evidence-based tests to measure biomarkers for gluten sensitivity. The Center for Celiac Research is currently conducting very promising research to develop a reliable evidence-based test.

There are no screening tests available for people who already are on a gluten-free diet, since the biomarkers used to diagnose celiac disease (anti-TTG antibodies, anti-deamidatedgliadin antibodies) disappear once the gluten-free diet is implemented.

Dr. Daniel Leffler: For celiac disease, modern blood tests including tissue transglutaminase (tTG), anti-endomysial antibody (EMA), and deamidatedgliadin peptide (DGP) are all quite good, with accuracy about 90 percent. However, it is both possible to have positive results to these blood tests and to not have celiac disease and conversely have celiac disease but not have positive blood tests. For these reasons, small intestinal biopsy is still the gold standard for celiac diagnosis. Currently, there are no tests for gluten sensitivity; however, if someone tests negative for celiac disease but has clear symptomatic improvement on a gluten-free diet, gluten sensitivity is quite likely.

For people already on a gluten-free diet, options are somewhat limited at this time. Our typical recommendation would be to have tTG and genetic testing done first. If the genetic testing is negative, you can be confident that this is not celiac disease. If genetic testing is positive and tTG is positive, this is likely active celiac disease and you can proceed to endoscopy with small intestinal biopsy. However, if genetic testing is positive and tTG is negative, the only way to sort out if someone has celiac disease is through a gluten challenge, which should be conducted under the guidance of a physician experienced in celiac disease.

S.Z. Berg: Why are the symptoms so varied? What are the cascade of events that lead to symptoms?

Dr. Alessio Fasano: That's a very good question. Although we have a fairly good understanding of celiac disease and the mechanisms, we're just learning about gluten sensitivity.

One of the interesting -- and surprising things -- about gluten sensitivity is that it seems to be less related to the intestinal permeability -- leaky gut -- that characterizes celiac disease.

We're still trying to figure out precisely what triggers the onset of celiac disease, gluten sensitivity, or wheat allergy in genetically-susceptible individuals. The immune system, along with possible environmental triggers, including the microbial makeup in the gut, presents a complicated puzzle in that regard that we're trying to unravel. By studying the timing of introducing gluten to infants, we're shedding some light on this area, as well.

Taking into consideration all the current knowledge in the field, we can hypothesize that exposure to gluten fragments can activate immune cells that, once activated, can stay in the intestine, causing local inflammation and, therefore, gastrointestinal symptoms. They can also migrate to other districts where they can cause local inflammation leading to skin rashes, joint pain, foggy mind, etc.

If the inflammatory response is exclusively driven by cells of the innate immune system, then we will have the clinical outcome typical of gluten sensitivity. If the adaptive immune system, including immune cells expressing HLA DQ2 and/or DQ8, also is involved, then the inflammatory process progresses to autoimmune damages typical of celiac disease.

Dr. Daniel Leffler: Symptoms are so varied, because celiac disease is a complex disorder, and the small intestine is a complex organ, and the intersection of these two can be quite unpredictable. For instance, the intestine has an advanced nervous system that controls sensation, motility and is highly connected to the brain so that anything that affects the intestine can cause changes in motility (diarrhea, constipation, vomiting, etc.), changes in sensation (abdominal pain, cramping, etc.) and also affect the brain, causing fatigue, difficulty concentrating and raising the risk of mood disorders, including anxiety and depression. Then, add to this the fact that in celiac disease the immune system is activated and chronic inflammation can affect bones and joints as well as predispose to infections and cancer. Also, as noted above, the antibodies to tTG, which are produced by people with active celiac disease, can attack other parts of the body, causing rashes and possibly also contributing to neurologic dysfunction, thyroid disease, and adverse pregnancy outcomes. Finally, when the intestine is damaged, nutrients are not properly absorbed and various vitamin deficiencies can have different manifestations. Each person with celiac disease has a different combination of these effects and thus will have a different clinical presentation.

S.Z. Berg: What is the link to these conditions and neurological symptoms?

Dr. Alessio Fasano: As I said above, celiac disease can affect any organ or system in the body. So that gluten can cause neurological symptoms is not surprising to us at all.

In our clinic, it's very rare to see a patient who doesn't have symptoms involving the brain or nervous system. The most frequent symptoms include headaches, migraines, anxiety, depression, tingling of the fingertips, and "foggy mind." Loss of coordination or "gluten ataxia" is a less-common manifestation of the effect of gluten on the brain.

At the Center for Celiac Research, we are currently conducting some very promising research into the efficacy of the gluten-free diet in a subset of patients with schizophrenia and autism-spectrum disorders.

S.Z. Berg: What are the symptoms people should be aware of?

Dr. Alessio Fasano: Certainly the classic gastrointestinal symptoms of diarrhea, constipation, bloating, nausea, and discomfort should be evaluated in terms of gluten-related disorders. But it's even more important to evaluate the extraintestinal symptoms discussed above, such as headaches, fatigue, anxiety, depression, and other neurological manifestations.

Of course, many of these symptoms can be related to other conditions. This is what makes diagnosis so tricky, especially with gluten sensitivity.

Dr. Daniel Leffler: Beyond the classic symptoms of diarrhea, weight loss, anemia, and abdominal discomfort, I believe that whenever someone has a chronic medical problem that is not readily explained by another condition, celiac disease testing should be considered.

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