User login
The Medical Roundtable: Celiac Disease and Gluten Free: What's Real and What's Myth?
DR. LEFFLER: My name is Dr. Daniel Leffler. I’m in the Division of Gastroenterology at Beth Israel Deaconess Medical Center, and I direct the clinical research at our Celiac Center.
MS. DENNIS: My name is Melinda Dennis and I’m the nutrition coordinator of the Celiac Center at Beth Israel Deaconess Medical Center. I work with Dr. Leffler, Dr. Kelly, and the other Celiac Center gastroenterologists.
DR. MUSHLIN: Great. So, as the moderator of this conversation, I’d like to start us off with a case. This case presented to me in my primary care practice.
I saw a Harvard Medical student who came to see me regarding a stress fracture in her right foot. She was a runner and had run in 3marathons over the last 4 years. She was quite slender and had a BMI of only 19, but she quite adamantly denied being anorectic or bulimic.
She had been treated for anemia in her senior year of college with iron. She had no idea whether her anemia had improved. She had always had irregular menses since menarche, but for the past year as her running increased, she was completely amenorrheic.
After physical examination, x-ray examination revealed that she did indeed have a fracture of a metatarsal. I then obtained a bone density examination that showed osteoporosis—not just osteopenia but osteoporosis. She also had an anemia with a hematocrit of 33%, and she had microcytic hypochromic indices. I then, because of her osteoporosis, got a vitamin D level, which was definitely low. It was under 20, and that’s the lower limit of normal in our institution. She also had slightly elevated parathyroid hormone levels.
I obtained an IgA tissue transglutaminase (tTG) antibody test, and it was highly positive. I then placed her on a gluten-free diet with calcium, vitamin D, and oral iron supplementation, and that’s the case.
Dr. Leffler, would you say that this would be a pretty typical presentation of celiac disease?
DR. LEFFLER: Yes. I think all of us working with celiac disease have seen patients just like this, but it also highlights the fact that there really is no typical patient with celiac disease. A picture of what was previously considered typical involved severe malabsorptive symptoms, but that was really just scratching the tip of the iceberg for what is out there. While iron-deficiency anemia, osteoporosis, and vitamin D deficiency are very common in celiac disease, you can have all or none of these symptoms. Like this patient, you can have no gastrointestinal symptoms. Alternatively, you can have predominantly gastrointestinal symptoms.
Certainly, this patient had a number of red flags that would make you worry about celiac disease such as the early onset fracture, the osteoporosis, and the iron-deficiency anemia. Although the latter is not an uncommon thing to see in a young woman, it’s the combination of all these factors that, in my mind, would alert a clinician to the fact that these are not normal findings for a young healthy woman.
DR. MUSHLIN: If you looked at all the patients who were ultimately diagnosed with celiac disease who presented to the family practitioner or the primary care internist, what would you say would be the most common red flags? I know this case, which is a true case, had a lot of red flags, but what would be the most common symptoms that might raise your consciousness that you might be dealing with celiac disease?
DR. LEFFLER: Approximately 40% of patients with celiac disease will have chronic gastrointestinal symptoms. These can vary and can be very similar to those of irritable bowel syndrome, but gastrointestinal symptoms in the presence of a significant nutritional deficiency like iron deficiency or vitamin D deficiency, as in this case, would be very typical of celiac disease and raise a lot of red flags. A lot of these patients will also have either a personal history or a family history of other autoimmune diseases, type 1 diabetes, thyroid disease, and other similar conditions.
So, very common presentations and red flag conditions would include a patient who says, “my mother has thyroid disease” or “I have thyroid disease and now I’m iron deficient,” or “now I’m experiencing significant fatigue.” Overall, the most common presentations of celiac disease these days are gastrointestinal symptoms, iron-deficiency anemia, vitamin D deficiency, and fatigue.
DR. MUSHLIN: Certainly, all of those things are seen in an internist’s or a family practitioner’s office. I guess the real key here is that when you start to see this constellation, you should raise your consciousness that there may be one unifying diagnosis rather than multiple diagnoses.
DR. LEFFLER: Exactly. I think that the response to therapy can also be a good hint that there might be something else going on. Most young women with iron-deficiency anemia simply due to menses will do pretty well on oral iron supplementation alone. If they have severe and significant anemia and it’s just not responding to iron supplementation for instance, or if their vitamin D level is low and it does not improve with a regular dose of vitamin D, then you really have to wonder whether there is something that’s preventing absorption of this nutrient in the intestinal tract. Once you get to that level, then celiac disease is by far the most common diagnosis in these situations.
DR. MUSHLIN: We are having this colloquium here in Boston and there are a lot of people in the greater Boston area who are of Northern European extraction. Are there certain ethnic groups that have a predominance of celiac disease, or can it be found in virtually any ethnic group?
DR. LEFFLER: Earlier, we used to say this was essentially an Irish/Italian or western European disease, but now we can more easily pick out the populations that celiac disease doesn’t occur in. Celiac disease has a strong genetic predisposition with human leukocyte antigen (HLA) types, but really the populations that are at risk for celiac disease cover most of the globe: all of North and South America, Europe, the Middle East, North Africa, India, and northern China. Southeast Asians and Sub-Saharan Africans have a very low risk, but the majority of people have a significant risk of celiac disease, and I think that like all other autoimmune and inflammatory disorders, whether it’s type 1 diabetes or asthma or inflammatory bowel disease, the prevalence of celiac disease just continues to rise over time. We’re seeing it in populations that never had this disorder before.
DR. MUSHLIN: Why do you think the prevalence is increasing? Is it that our diagnostic ability is better, or do you think it’s truly increasing?
DR. LEFFLER: Well, we’ve certainly gotten a lot better at diagnosing celiac disease. You mentioned the celiac tTG antibody test earlier, which has really revolutionized the way that we diagnose celiac disease because it’s so accurate, affordable, and widespread. That being said, even in prevalence studies,1,2 there really is a dramatic increase—something in the range of a doubling—and true prevalence every 30 years or so. This is right alongside these other autoimmune and inflammatory diseases.
Clearly, nothing in our genetic heritability is changing that quickly. It’s something in the environment that is leading to an increase in the incidence of celiac disease and autoimmune diseases in general. Lots of people have theories about what that might be, and the most common theory is that we live in such a clean environment now that our immune system doesn’t have the normal feedback it needs to develop in a healthy way, and so, our immune function may start to become abnormal.
DR. MUSHLIN: This is similar to the asthma hypothesis.
DR. LEFFLER: Exactly. All of this can in some way be explained by the hygiene hypothesis.
DR. MUSHLIN: Right. When you live in Germany and the cows are housed in the same house that you live in, there’s less asthma.
DR. LEFFLER: Exactly. The same phenomenon has been seen in celiac disease in some populations, especially in northern Europe where you cross a national border and you encounter very different socioeconomic conditions. Even though you have virtually the same genetic lineage, you can have very different rates of celiac disease. I think this is very much the case.
DR. MUSHLIN: Ms. Dennis, I have a large number of patients who come into my office and say to me, “I went on a gluten-free diet and I feel so much better.” Can you address the question of gluten sensitivity versus true celiac disease? Do you feel comfortable doing that?
MS. DENNIS: Sure. We know that celiac disease is a genetic autoimmune disease, and we know that non-celiac gluten sensitivity is not considered an autoimmune disease. Dr. Leffler would be in a better position to address the issue of whether there is an inflammatory response, but there are plenty of people who come into the office confused about the 2. In order to obtain a diagnosis of non-celiac gluten sensitivity, celiac disease and wheat allergy would both need to be ruled out.
There is no positive gene testing for non-celiac gluten sensitivity, but what makes it difficult for patients is that the symptoms can mimic one another almost exactly. All the gastrointestinal symptoms, as well as some of the other extraintestinal manifestations like headaches, poor concentration, memory loss, and other similar conditions, can occur in both conditions. It’s complicated, and there is much more research that needs to be done in this area.
DR. LEFFLER: I’ll just corroborate all of that. We’ve known about celiac disease for a long time. Gluten intolerance, or non-celiac gluten sensitivity as it’s becoming more commonly known, is a very new entity that we’ve really only starting believing in, clinically at least, over the last couple of years. We’re learning about it quickly, but we still don’t have a very good sense of its prevalence.
It does appear to be a non-inflammatory disorder, which separates it from celiac disease. It doesn’t appear to have any autoimmune component and likely does not have a lot of the long-term risks associated with celiac disease such as osteoporosis or even cancer and infection risk, but at the same time, it can be associated with significant quality of life impairment, and the symptoms can mimic celiac disease. So, it is something that everyone needs to be aware of; however, while the diet-related treatment is similar, it seems that a lot of the peripheral things that we should do for our celiac patients such as getting them vaccinated and performing a bone mineral density study are not required for patients who have non-celiac gluten intolerance or gluten sensitivity. We do recommend that people work with their physicians to make a clear distinction between these 2 disorders.
DR. MUSHLIN: Just to expand on that point, would a negative tTG antibody test basically exclude celiac disease with a high degree of certainty and leave you with a diagnosis of gluten sensitivity without celiac disease (assuming the symptoms were consistent)?
DR. LEFFLER: Yes. For a typical patient who is on a regular gluten-containing diet and doesn’t have a strong family history of celiac disease or other factors that would increase risk, a negative tTG would certainly be sufficient and would imply that the chances that the patient has true celiac disease are quite low. We can then proceed with a non-celiac gluten sensitivity diagnosis and see how the patient does clinically.
DR. MUSHLIN: It seems that everywhere I go, there are more and more gluten-free choices. In fact, the wife of my closest friend here in town just started a gluten-free bakery and she’s so busy that he’s making deliveries for her now every day instead of 3 times a week. Are there any dangers to adhering to a gluten-free diet?
MS. DENNIS: There are inherent nutritional deficiencies in a gluten-free diet. So, if the diet is not proper, yes, you can lack certain vitamins and minerals. For example, wheat is a major source of protein and B vitamins as well as iron, trace minerals, and fiber.
When you switch to the gluten-free diet, you need to be able to replace those nutrients. Many people don’t focus immediately on the alternative whole and healthier gluten-free grains like amaranth, buckwheat, millet, quinoa, sorghum, and teff. They tend to move toward rice, corn, and potatoes, which tend to be lower in fiber, nutrient poor, and can cause or exacerbate constipation and weight gain when eaten in large quantities. So, that’s one of the main issues.
Additionally, we find that many people are concurrently lactose intolerant when they’re first diagnosed with celiac disease. So, we need to consider the possibility that their calcium and vitamin D intakes may be inadequate. Then, of course, we need to consider the B vitamins, which are present throughout the food chain but are present in large quantities in grains.
DR. MUSHLIN: Ms. Dennis, a lot of my patients are curious about purchasing gluten-free materials either from stores or online. Do you feel comfortable recommending any websites that you feel are legitimate for our patients to access?
Regarding consumer access, it is important to find safe gluten-free foods that are not cross-contaminated. We now have a Food Allergen Labeling and Consumer Protection Act in place that states that if wheat protein is in an FDA-regulated food, it must be labeled as such on the package. That applies to FDA foods but not USDA foods. Dieticians know the difference between these two and can educate their patients, but it’s not obvious by just reading a label.
The most obvious sources of gluten are wheat, rye, barley, malt, oats (unless they are specifically labeled and processed such that they are gluten free), and brewer’s yeast. These are easily identifiable, but it takes a little bit of education to get familiar with hidden gluten sources. One of the primary things that a person can do is make sure that their grains and flour-based products are labeled “gluten free” to help avoid some of the risks of cross-contamination that come when gluten-free grains are contaminated with wheat, rye, or barley during the farming, processing, or milling practices that typically occur in this country.
DR. MUSHLIN: So let’s say I’ve got a patient who says to me, “Doc, I’ve got celiac disease. Can I ever eat out again? Can I ever go to a restaurant?” How would you advise them?
MS. DENNIS: I have celiac disease myself, and yes you can absolutely eat out. I was diagnosed 22 years ago. So much has changed in these last 2 decades that makes life a lot easier for us, but you do have to pay attention when dining out, not only to the ingredients that are going into the food but also to the preparation technique used.
If a newly diagnosed person goes out to eat, they would want to first choose a celiac-friendly restaurant, meaning a restaurant that has a gluten-free menu. Even then, I would suggest asking questions related to the ingredients and the preparation methods. For example, it’s pretty common knowledge among people with celiac disease that fryers are contaminated, but what’s less commonly known is that scrambled eggs can often be mixed with pancake batter to make them fluffy and increase their volume. Roasts and beef cuts that are served in a restaurant are often held in a broth that contains wheat, prior to being served. Baked potatoes may be put into a fryer just before serving them at the table.
It’s important that in the kitchen, where the food is being prepared, different utensils and skillets are used, and that the person preparing the food is paying attention to what cutting boards he/she is using and not cross-contaminating with other gluten-containing products. All of this being said, there is much more opportunity for people to dine out these days. However, you have to be very, very careful, and there are resources that can lead you to restaurants that are more inclined to understand food allergies and make allowances and substitutions for those on the gluten-free diet.
DR. MUSHLIN: Ms. Dennis, would you elaborate on how to access those resources, and can you also discuss a few reputable websites that can be used by people with gluten sensitivity?
MS. DENNIS: There are a number of national organizations that are deeply committed to celiac disease, the gluten-free diet, and those with non-celiac gluten sensitivity. In no particular order, these include the Celiac Disease Foundation (www.celiac.org), the Gluten Intolerance Group (www.gluten.net), the Celiac Sprue Association of the United States (CSA/USA, Inc; www.csaceliacs.info), the American Celiac Disease Alliance (americanceliac.org), and the National Foundation for Celiac Awareness (www.celiaccentral.org). These can all be easily found by a Google search. Each of them contains multiple listings of resources including restaurants, information about dining out, tips on how to eat when traveling, nutrition information, hidden gluten sources, blogs, and how to budget on the gluten-free diet. Many of them list celiac centers across the United States and describe how to find specific clinicians who are experts in this field. All of these are reputable sites.
I should mention that we have also launched a multi-level website especially designed for the nutritional management of celiac disease: CeliacNow.org. It’s useful for anyone on the gluten-free diet as well as practitioners who want to gain more information.
Back to your original question about dining out in particular, there are 2 resources that I recommend to patients. One of them is TriumphDining.com. Not only do they list grocery stores and food sources across the state, they also list restaurants. CeceliasMarketplace.com is also another excellent website. Both of these sites also offer books on the topic. Finally, the forum at www.celiac.com is a place that most people find almost immediately when they’re diagnosed.
DR. MUSHLIN: Good. Is there any special designation for people who do nutritional work such as yourself who specialize in celiac counseling, or can any registered nutritionist counsel someone appropriately?
MS. DENNIS: They are actually working on a certification program for the counseling of patients with celiac disease. I joined a taskforce about 5 years ago that developed nutritional guidelines for the Academy of Nutrition and Dietetics.3 These guidelines are available if dieticians want to train themselves on how to counsel a patient on the gluten-free diet, beginning with the initial visit through the follow-up visits. The guidelines include laboratory tests, case studies, and multiple patient handouts, and they constitute the industry’s major educational piece on celiac disease. Beyond that, you can examine books, articles, etc, written by a number of experts in the field. There’s currently no certification.
DR. LEFFLER: A lot of patients will come to me saying, “I saw a dietician and I knew more about the diet than they did. They were no help at all.” That is really a terribly frustrating thing for patients. So, clinicians want to make sure that they send their patients to somebody who has a fair degree of knowledge, interest, and expertise in celiac disease. Unfortunately, this expertise is just not that common these days.
DR. MUSHLIN: Ms. Dennis, how many hours do you normally have to spend to get a newly diagnosed patient with true celiac disease, not just gluten sensitivity, up to speed assuming they have normal intelligence, at least a high school education, and some kind of familiarity with the basics of nutrition. How many hours might it take for you to meet with them? Often when physicians send a patient for a consultation, it’s helpful to tell the patient that they may need to be seen a few times to get it right because sometimes patients are surprised or dismayed that 20minutes with someone hasn’t fixed them.
MS. DENNIS: In this hospital setting, I’m not able to see patients as often or for as long of a period of time as I would like, and that’s common across many, many nutrition practices. We have an hour to educate patients initially. In an ideal world, the patients would be back within a few weeks for part 2 for at least an hour, and then they would check in periodically for the next 3months, 6months, and then yearly for a wellness check.
You can absolutely not do this in one session, and so, I’ve designed nutrition counseling sessions to give patients a tremendous amount of information that they can read. I also instruct them to explore reputable sites, read the material that we’ve created, and then come back with questions. I always link them to a local support group, which is absolutely critical for the management of this lifestyle adjustment. They can’t cope with the condition alone, and they certainly can’t do it on a few hours of nutrition consulting.
DR. MUSHLIN: Are you folks doing group counseling yet at your institution? For example, patients who’ve spent an hour or greater with you can come back in a group setting to get their questions answered, have an open discussion, and obtain support from other fellow patients or from other individuals following the same diet.
MS. DENNIS: Our clinic visits are one-on-one, but we do offer patient education nights 3 times a year where 10 to 40 people join us, and one of the doctors and I sit and answer questions for an hour and a half. That is a great experience for the patients. It’s always a very warm environment, and we again connect them to our larger support group that serves all of New England, the Healthy Villi, and they’re able to attend conferences, expos, or large meetings at least 3 times a year.
DR. MUSHLIN: I certainly think that if the paradigms of helping patients with chronic ongoing illness can be managed, their illnesses are going to gravitate more and more toward exactly those kinds of group support models.
MS. DENNIS: I agree.
DR. MUSHLIN: Dr. Leffler, you’ve mentioned briefly that in follow-up with your patients who have celiac disease, you need to be careful or be aware of the possibility of low bone density, and you also mentioned that they need vaccinations. What vaccinations do they require and why?
DR. LEFFLER: One of the things that is not widely known about celiac disease is that it’s actually associated with functional hyposplenism. So, people with celiac disease have an increased risk of infections—primarily those involving encapsulated organisms but also other infections—and these infections can be more severe. Our general recommendations are to vaccinate all celiac patients for flu and pneumococcus regardless of their age. Unfortunately, we have seen cases of very severe pneumococcal sepsis in otherwise totally healthy immunocompetent patients with celiac disease. So, it is something that we recommend routinely to all of our patients.
DR. MUSHLIN: Regarding the unusual association of celiac disease with other medical situations, one of my colleagues here saw a patient with pulmonary hemosiderosis who happened to have celiac disease. Are there other unusual conditions that are associated with celiac disease?
DR. LEFFLER: Yes. That pulmonary condition is called Lane-Hamilton syndrome. It is quite rare, but we’ve seen a few cases of it.
One of the fascinating things about celiac disease is that it can affect any organ system in the body. You can see effects in the central nervous system, skin, bones, kidneys, reproductive system, lungs, and heart, and there are a number of reasons why celiac disease can be so far-reaching.
Part of it is just that chronic nutritional deficiencies can lead to widespread problems, but more fundamentally, people with celiac disease produce antibodies to tTG. That’s the blood test that is most commonly ordered—the IgA anti-tTG blood test. The enzyme tTG is found in all parts of the body. Its main job is to crosslink collagen. It’s very active in wound repair and building connective tissue, and when antibodies attack this enzyme, inflammation can occur anywhere in the body. Presumably, depending on the exact type of antibodies produced and polymorphisms in tTGs, you can have a direct autoimmune effect that’s triggered in the intestine but attacks the brain or virtually any other organ.
Gluten ataxia is a cardinal well-known phenomenon where you have cerebellar inflammation and cerebellar atrophy due to the celiac reaction. You can have dermatitis herpetiformis, which is an inflammatory reaction of the skin that mostly affects extensor surfaces. So, you have this autoimmune reaction that can attack any part of the body but starts in the intestine. Once you get celiac disease under control, for example by going on a gluten-free diet, these antibody levels decrease and the autoimmune reactions cease just as they do in the intestine. This is really a very unique way of thinking about an autoimmune disease.
DR. MUSHLIN: Because we’re talking so much about antibodies, do you follow antibody titers in people you’ve placed on a gluten-free diet?
DR. LEFFLER: Yes, I do. I follow them not because they’re really wonderful at monitoring celiac disease, because they’re not. There is plenty of research including some that we’ve done ourselves4,5 that shows that they’re not great at telling, for instance, recent gluten exposure or the degree of intestinal healing. There are lots of people who have completely normal antibody levels, but their intestine’s ability to heal is significantly damaged and vice versa. Some people still have mild elevations in their antibody levels, but their intestine looks pretty good.
On the other hand, there’s really no other tool that we have, and if you have somebody with antibody levels that are persistently elevated and never drop, or drop slightly but are still 2 to 3 times the upper limit of normal, you can be fairly certain that gluten is sneaking in somewhere, and they may not know it. They may be doing their best to follow a gluten-free diet. It could be something as simple as a single generic medication or a supplement that has gluten in it that they’re taking on a daily basis. We’ve seen issues of that sort, but if their antibody level is still high, it’s very helpful as a red flag that something’s not going right.
The first thing I’ll do is send them back to see Ms. Dennis to review the diet and see where the problems are cropping up. That will fix many of the problems, but it can take an awful lot of detective work to sort through basically everything that they’re putting in their mouth and see where that bit of gluten might be.
DR. MUSHLIN: So let’s say the family practitioner diagnoses celiac disease based on the patient’s history and physical findings, and the tTG antibody test is highly positive. The practitioner then sends the patient to a nutritionist, and the patient goes on a gluten-free diet. How should that family practitioner then follow up with the patient? You mentioned immunizations—influenza yearly and Pneumovax. What else should be routinely done by that practitioner, for example, in a rural community where the patient might not have access to a specialist?
DR. LEFFLER: I want to just mention that even with a positive antibody level, endoscopy is still necessary at the beginning for diagnosis. The standard of care for celiac disease these days includes checking celiac serologies approximately every 3 to 6months until they normalize, which depends on how high they are at the beginning. Some people start off with a relative titer of 1000, and some start off with a relative titer of 50. Obviously, the latter will normalize much more quickly.
What you want to see is an improvement in those levels, so you follow them approximately every 6months until they normalize. Then you perform a celiac blood test approximately every year just to make sure that the levels are staying low and that something hasn’t changed such that the patient suddenly has an elevated level. At least 1 bone mineral density test should be performed approximately 1 year after diagnosis once their vitamin D and any other nutritional deficiencies have been repleted. We can mention the nutrients to check in a second, and if those are normal, then the patient can go back to the bone mineral density recommendations for the regular population.
If their bone mineral density is low, then you want to keep a closer eye on them depending on how low it is. You can see a lot of improvement in bone mineral density in the first year after diagnosis with celiac disease, which is why we don’t typically check bone density right off the bat unless the patient has had fractures or something that we’re really worried about. It’s only the residual osteopenia or osteoporosis that they have after a year that we would treat differently.
Even after the initial dietary counseling, we strongly recommend that patients check in with their dietician once a year. Again, a gluten-free diet is a really big change. It’s tough. Things change all the time, and by following up with a specialist, you can tell them about how the foods you eat have changed. New recommendations on a yearly basis are also recommended.
As for vitamins, the most common nutrient deficiencies in people with celiac disease are currently vitamin D, iron, and zinc. Zinc is not one that’s commonly on people’s radar, but it is actually responsible for a lot of the hair and skin manifestations that people with celiac disease complain about and potentially responsible for some of the immune dysregulation as well.
DR. LEFFLER: Correct. Sometimes we will encounter people with a normal B12level and macrocytosis, and we will wonder where that’s coming from. That’s a good thing to check. B12and folate are rarely low in people with celiac disease, so we don’t always check them.
We’ll also check liver function tests at least once in the beginning because autoimmune liver disease can be associated with celiac disease. Thyroid disease is also often associated with celiac disease, so it’s important to make sure patients have had a thyroid stimulating hormone (TSH) test at least once, and you should consider repeating that every few years. Those are the routine things that we keep an eye on in celiac disease. So, there’s a little bit of a to-do list for your patients with celiac disease.
DR. MUSHLIN: Do you ever do genetic HLA testing?
DR. LEFFLER: Yes, we do. The genetic testing for celiac disease is very interesting. Most of the genes we test for, for example those involved in hemochromatosis or cystic fibrosis, are relatively diagnostic, ie, if you have the gene, you worry that you have the disease. Celiac disease is just the opposite. The celiac genes are HLA-DQ2 and DQ8. They are actually prevalent in approximately 40% of the general population. So, they’re prerequisite genes, but they are not diagnostic genes.
If you have these genes, it means nothing because obviously the vast majority of people with these genes never get celiac disease. On the other hand, if you don’t have these genes, then you virtually cannot get celiac disease. So, these genes are helpful for 2 types of people specifically.
First, genetic testing is helpful for people who are already on a gluten-free diet and aren’t willing to do a gluten challenge. Obviously, your genes don’t change with diet, so if you get a negative genetic test, you can rule out celiac disease even while the patient is on a diet, and there’s no other way you can do that. Second, genetic testing is helpful for patients with a strong family history of celiac disease. The testing is very popular now among children whose parents have celiac disease. They have a pretty high chance of having the gene—at least 50%—but if they don’t, they’re off the hook for life, which is a nice thing to be able to tell someone. So, I think this test really does have its utility.
DR. MUSHLIN: Let’s go back to the initial diagnosis and the role of endoscopy.
DR. LEFFLER: The modern celiac blood tests, which are tTG, deamidated gliadin peptide (DGP), and endomysial antibody (EMA), are all highly accurate, have >90% sensitivity, and are specific. On the other hand, the average patient you’re going to test probably has a 5% to 10% pretest probability of celiac disease. Even the best of our tests only have a positive predictive value of approximately 80%, which means that if you rely on a serology alone, 1 out of 5 patients you diagnose with celiac disease is probably going to be a false positive. So, for that reason, because it’s a life-long diagnosis, you’re going to expose people to a lot of inconvenience to say the least as well as other medical testing, bone density analysis, and immunizations they may not need. The recommendation is still that all patients with a positive serology should follow up and get an endoscopy, which continues to be the gold standard for diagnosis.
DR. MUSHLIN: Would that be an endoscopy with a small bowel biopsy?
DR. LEFFLER: Right. A duodenal biopsy.
DR. MUSHLIN: So, depending on your population, there would be a 1in 5 chance of a false positive test. What would be the chance of a false negative test?
DR. LEFFLER: That would be well under 5% depending on the population.
DR. MUSHLIN: So, it’s 95% sensitive in picking it up, correct?
DR. LEFFLER: Right. In general, the one thing that can throw off some of these blood tests is IgA deficiency, which is a common problem that is also enriched in the celiac population. Approximately 2% of people with celiac disease have IgA deficiency, and because these blood tests are typically IgA-based, if you’re really worried about the diagnosis, you can check the total IgA level at the time of tTG measurement. If both of those are normal, and your patient is on a regular gluten-containing diet, you’re really fine in the vast majority of circumstances.
DR. MUSHLIN: In antibody testing, do you assay for endomysial antibodies in addition to transglutaminase, or do you assay for only one? Do you think that your ability to trust these tests is very dependent on the laboratory you’re using? How many of these antibody tests do you get?
DR. LEFFLER: Typically just one. There’s very little data to suggest that doing multiple tests at the same time does anything but drive up the cost. They’re all similar. They’re all typically very concordant.
So, you’re going to have one positive, and you’re going to have a second one positive. The only times I’ll consider it again are with somebody who has a borderline test and I’m considering whether or not they need an endoscopy. In that case, maybe a second one to help push me one way or the other would be helpful, but really, tTG is your workhorse. Although there are multiple assays available and almost all of them are good, I think that physicians across the country really can’t go wrong just sticking with IgA-tTG as their primary test.
DR. MUSHLIN: Terrific. Ms. Dennis, do you have anything else you want to articulate?
MS. DENNIS: Standard multivitamin mineral supplementation is a general recommendation for people with celiac disease. So, when they come into the clinic, I always recommend a gluten-free multivitamin and mineral supplement with or without iron depending on their age, gender, and laboratory values.
Sometimes our patients need vitamin B complex supplements. Sometimes it’s just a simple complaint of energy and may suggest that their B12level is lower than normal. We like to see it around 400mg/mL or above.
Calcium and vitamin D supplementation is also very common. In general, it’s difficult to get about 1200mg of calcium a day through diet alone, particularly if lactose intolerance is present. So, we often prescribe calcium supplements with vitamin D to get to that total goal.
Then, of course, Dr. Leffler was mentioning vitamin D. We recommend it based on laboratory values and diet, and almost all of our patients need vitamin D supplementation. I would also suggest that omega-3 fatty acids be considered in the dietary assessment of our patients.
DR. MUSHLIN: Why is that?
MS. DENNIS: In general, Americans aren’t getting the required amounts of omega-3 fatty acids, and eating fish is not always popular. Very few of our patients can tell me that they get approximately 6 ounces of a dark deep-water fatty fish per week, which is a general recommendation. So, if it’s necessary, I’ll suggest an omega-3supplement, but that’s always individually determined.
The last thing I wanted to mention was that just recently the North American Society for the Study of Celiac Disease was formed. It’s a clinician group, and their intention and mission is to spearhead celiac awareness in the medical and nutrition communities as well as in the public sector. They aim to be a guiding force because up until now, support has generally come from volunteer nonprofit organizations all across the country. So, we’re looking for a little bit more of a structured single entity that can help us bring awareness much more quickly to all populations.
DR. MUSHLIN: In the multivitamin supplement, would you also want to make sure that they got some zinc?
MS. DENNIS: Yes. All the multivitamins contain zinc, but often, we need to recommend extra zinc. There’s typically not 100% of your daily recommended zinc in a multi. It’s present in trace amounts. So, if needed, we’ll check serum zinc and give zinc for 6 to 8 weeks before retesting.
DR. MUSHLIN: Dr. Leffler, let’s go quickly to the question of malignancy associated with long-standing celiac disease. In my own clinical practice experience, I’ve actually had 2 patients with celiac disease who developed non-Hodgkin’s lymphoma. Do you think there’s a definite association between malignancies and celiac disease?
DR. LEFFLER: Unfortunately, it seems like that association is clear. The overall risk of malignancy in people with celiac disease is about twofold higher than what we see in the general population. The majority of that, as you saw with your patient, is due to non-Hodgkin’s lymphoma.
There’s also an increased risk of small intestinal adenocarcinomas and small intestinal lymphomas. They’re also known as enteropathy-associated T-cell lymphomas. So, there is a significant risk.
However, we don’t screen for malignancies in patients with celiac disease any differently than we do in the general population. This is because, thankfully, the risk of malignancy drops after diagnosis, and at approximately 5 years after diagnosis, the risk is pretty close to that of the general population. So, the risk seems to be related to chronic immune activation, and once you get that immune activation under control, the risk drops. It’s a little bit of a reward that helps patients to actually follow the diet and control their disease.
DR. MUSHLIN: Well, this has been a wonderful conversation. I’ve learned a tremendous amount, and I’m very grateful to you both.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
DR. LEFFLER: My name is Dr. Daniel Leffler. I’m in the Division of Gastroenterology at Beth Israel Deaconess Medical Center, and I direct the clinical research at our Celiac Center.
MS. DENNIS: My name is Melinda Dennis and I’m the nutrition coordinator of the Celiac Center at Beth Israel Deaconess Medical Center. I work with Dr. Leffler, Dr. Kelly, and the other Celiac Center gastroenterologists.
DR. MUSHLIN: Great. So, as the moderator of this conversation, I’d like to start us off with a case. This case presented to me in my primary care practice.
I saw a Harvard Medical student who came to see me regarding a stress fracture in her right foot. She was a runner and had run in 3marathons over the last 4 years. She was quite slender and had a BMI of only 19, but she quite adamantly denied being anorectic or bulimic.
She had been treated for anemia in her senior year of college with iron. She had no idea whether her anemia had improved. She had always had irregular menses since menarche, but for the past year as her running increased, she was completely amenorrheic.
After physical examination, x-ray examination revealed that she did indeed have a fracture of a metatarsal. I then obtained a bone density examination that showed osteoporosis—not just osteopenia but osteoporosis. She also had an anemia with a hematocrit of 33%, and she had microcytic hypochromic indices. I then, because of her osteoporosis, got a vitamin D level, which was definitely low. It was under 20, and that’s the lower limit of normal in our institution. She also had slightly elevated parathyroid hormone levels.
I obtained an IgA tissue transglutaminase (tTG) antibody test, and it was highly positive. I then placed her on a gluten-free diet with calcium, vitamin D, and oral iron supplementation, and that’s the case.
Dr. Leffler, would you say that this would be a pretty typical presentation of celiac disease?
DR. LEFFLER: Yes. I think all of us working with celiac disease have seen patients just like this, but it also highlights the fact that there really is no typical patient with celiac disease. A picture of what was previously considered typical involved severe malabsorptive symptoms, but that was really just scratching the tip of the iceberg for what is out there. While iron-deficiency anemia, osteoporosis, and vitamin D deficiency are very common in celiac disease, you can have all or none of these symptoms. Like this patient, you can have no gastrointestinal symptoms. Alternatively, you can have predominantly gastrointestinal symptoms.
Certainly, this patient had a number of red flags that would make you worry about celiac disease such as the early onset fracture, the osteoporosis, and the iron-deficiency anemia. Although the latter is not an uncommon thing to see in a young woman, it’s the combination of all these factors that, in my mind, would alert a clinician to the fact that these are not normal findings for a young healthy woman.
DR. MUSHLIN: If you looked at all the patients who were ultimately diagnosed with celiac disease who presented to the family practitioner or the primary care internist, what would you say would be the most common red flags? I know this case, which is a true case, had a lot of red flags, but what would be the most common symptoms that might raise your consciousness that you might be dealing with celiac disease?
DR. LEFFLER: Approximately 40% of patients with celiac disease will have chronic gastrointestinal symptoms. These can vary and can be very similar to those of irritable bowel syndrome, but gastrointestinal symptoms in the presence of a significant nutritional deficiency like iron deficiency or vitamin D deficiency, as in this case, would be very typical of celiac disease and raise a lot of red flags. A lot of these patients will also have either a personal history or a family history of other autoimmune diseases, type 1 diabetes, thyroid disease, and other similar conditions.
So, very common presentations and red flag conditions would include a patient who says, “my mother has thyroid disease” or “I have thyroid disease and now I’m iron deficient,” or “now I’m experiencing significant fatigue.” Overall, the most common presentations of celiac disease these days are gastrointestinal symptoms, iron-deficiency anemia, vitamin D deficiency, and fatigue.
DR. MUSHLIN: Certainly, all of those things are seen in an internist’s or a family practitioner’s office. I guess the real key here is that when you start to see this constellation, you should raise your consciousness that there may be one unifying diagnosis rather than multiple diagnoses.
DR. LEFFLER: Exactly. I think that the response to therapy can also be a good hint that there might be something else going on. Most young women with iron-deficiency anemia simply due to menses will do pretty well on oral iron supplementation alone. If they have severe and significant anemia and it’s just not responding to iron supplementation for instance, or if their vitamin D level is low and it does not improve with a regular dose of vitamin D, then you really have to wonder whether there is something that’s preventing absorption of this nutrient in the intestinal tract. Once you get to that level, then celiac disease is by far the most common diagnosis in these situations.
DR. MUSHLIN: We are having this colloquium here in Boston and there are a lot of people in the greater Boston area who are of Northern European extraction. Are there certain ethnic groups that have a predominance of celiac disease, or can it be found in virtually any ethnic group?
DR. LEFFLER: Earlier, we used to say this was essentially an Irish/Italian or western European disease, but now we can more easily pick out the populations that celiac disease doesn’t occur in. Celiac disease has a strong genetic predisposition with human leukocyte antigen (HLA) types, but really the populations that are at risk for celiac disease cover most of the globe: all of North and South America, Europe, the Middle East, North Africa, India, and northern China. Southeast Asians and Sub-Saharan Africans have a very low risk, but the majority of people have a significant risk of celiac disease, and I think that like all other autoimmune and inflammatory disorders, whether it’s type 1 diabetes or asthma or inflammatory bowel disease, the prevalence of celiac disease just continues to rise over time. We’re seeing it in populations that never had this disorder before.
DR. MUSHLIN: Why do you think the prevalence is increasing? Is it that our diagnostic ability is better, or do you think it’s truly increasing?
DR. LEFFLER: Well, we’ve certainly gotten a lot better at diagnosing celiac disease. You mentioned the celiac tTG antibody test earlier, which has really revolutionized the way that we diagnose celiac disease because it’s so accurate, affordable, and widespread. That being said, even in prevalence studies,1,2 there really is a dramatic increase—something in the range of a doubling—and true prevalence every 30 years or so. This is right alongside these other autoimmune and inflammatory diseases.
Clearly, nothing in our genetic heritability is changing that quickly. It’s something in the environment that is leading to an increase in the incidence of celiac disease and autoimmune diseases in general. Lots of people have theories about what that might be, and the most common theory is that we live in such a clean environment now that our immune system doesn’t have the normal feedback it needs to develop in a healthy way, and so, our immune function may start to become abnormal.
DR. MUSHLIN: This is similar to the asthma hypothesis.
DR. LEFFLER: Exactly. All of this can in some way be explained by the hygiene hypothesis.
DR. MUSHLIN: Right. When you live in Germany and the cows are housed in the same house that you live in, there’s less asthma.
DR. LEFFLER: Exactly. The same phenomenon has been seen in celiac disease in some populations, especially in northern Europe where you cross a national border and you encounter very different socioeconomic conditions. Even though you have virtually the same genetic lineage, you can have very different rates of celiac disease. I think this is very much the case.
DR. MUSHLIN: Ms. Dennis, I have a large number of patients who come into my office and say to me, “I went on a gluten-free diet and I feel so much better.” Can you address the question of gluten sensitivity versus true celiac disease? Do you feel comfortable doing that?
MS. DENNIS: Sure. We know that celiac disease is a genetic autoimmune disease, and we know that non-celiac gluten sensitivity is not considered an autoimmune disease. Dr. Leffler would be in a better position to address the issue of whether there is an inflammatory response, but there are plenty of people who come into the office confused about the 2. In order to obtain a diagnosis of non-celiac gluten sensitivity, celiac disease and wheat allergy would both need to be ruled out.
There is no positive gene testing for non-celiac gluten sensitivity, but what makes it difficult for patients is that the symptoms can mimic one another almost exactly. All the gastrointestinal symptoms, as well as some of the other extraintestinal manifestations like headaches, poor concentration, memory loss, and other similar conditions, can occur in both conditions. It’s complicated, and there is much more research that needs to be done in this area.
DR. LEFFLER: I’ll just corroborate all of that. We’ve known about celiac disease for a long time. Gluten intolerance, or non-celiac gluten sensitivity as it’s becoming more commonly known, is a very new entity that we’ve really only starting believing in, clinically at least, over the last couple of years. We’re learning about it quickly, but we still don’t have a very good sense of its prevalence.
It does appear to be a non-inflammatory disorder, which separates it from celiac disease. It doesn’t appear to have any autoimmune component and likely does not have a lot of the long-term risks associated with celiac disease such as osteoporosis or even cancer and infection risk, but at the same time, it can be associated with significant quality of life impairment, and the symptoms can mimic celiac disease. So, it is something that everyone needs to be aware of; however, while the diet-related treatment is similar, it seems that a lot of the peripheral things that we should do for our celiac patients such as getting them vaccinated and performing a bone mineral density study are not required for patients who have non-celiac gluten intolerance or gluten sensitivity. We do recommend that people work with their physicians to make a clear distinction between these 2 disorders.
DR. MUSHLIN: Just to expand on that point, would a negative tTG antibody test basically exclude celiac disease with a high degree of certainty and leave you with a diagnosis of gluten sensitivity without celiac disease (assuming the symptoms were consistent)?
DR. LEFFLER: Yes. For a typical patient who is on a regular gluten-containing diet and doesn’t have a strong family history of celiac disease or other factors that would increase risk, a negative tTG would certainly be sufficient and would imply that the chances that the patient has true celiac disease are quite low. We can then proceed with a non-celiac gluten sensitivity diagnosis and see how the patient does clinically.
DR. MUSHLIN: It seems that everywhere I go, there are more and more gluten-free choices. In fact, the wife of my closest friend here in town just started a gluten-free bakery and she’s so busy that he’s making deliveries for her now every day instead of 3 times a week. Are there any dangers to adhering to a gluten-free diet?
MS. DENNIS: There are inherent nutritional deficiencies in a gluten-free diet. So, if the diet is not proper, yes, you can lack certain vitamins and minerals. For example, wheat is a major source of protein and B vitamins as well as iron, trace minerals, and fiber.
When you switch to the gluten-free diet, you need to be able to replace those nutrients. Many people don’t focus immediately on the alternative whole and healthier gluten-free grains like amaranth, buckwheat, millet, quinoa, sorghum, and teff. They tend to move toward rice, corn, and potatoes, which tend to be lower in fiber, nutrient poor, and can cause or exacerbate constipation and weight gain when eaten in large quantities. So, that’s one of the main issues.
Additionally, we find that many people are concurrently lactose intolerant when they’re first diagnosed with celiac disease. So, we need to consider the possibility that their calcium and vitamin D intakes may be inadequate. Then, of course, we need to consider the B vitamins, which are present throughout the food chain but are present in large quantities in grains.
DR. MUSHLIN: Ms. Dennis, a lot of my patients are curious about purchasing gluten-free materials either from stores or online. Do you feel comfortable recommending any websites that you feel are legitimate for our patients to access?
Regarding consumer access, it is important to find safe gluten-free foods that are not cross-contaminated. We now have a Food Allergen Labeling and Consumer Protection Act in place that states that if wheat protein is in an FDA-regulated food, it must be labeled as such on the package. That applies to FDA foods but not USDA foods. Dieticians know the difference between these two and can educate their patients, but it’s not obvious by just reading a label.
The most obvious sources of gluten are wheat, rye, barley, malt, oats (unless they are specifically labeled and processed such that they are gluten free), and brewer’s yeast. These are easily identifiable, but it takes a little bit of education to get familiar with hidden gluten sources. One of the primary things that a person can do is make sure that their grains and flour-based products are labeled “gluten free” to help avoid some of the risks of cross-contamination that come when gluten-free grains are contaminated with wheat, rye, or barley during the farming, processing, or milling practices that typically occur in this country.
DR. MUSHLIN: So let’s say I’ve got a patient who says to me, “Doc, I’ve got celiac disease. Can I ever eat out again? Can I ever go to a restaurant?” How would you advise them?
MS. DENNIS: I have celiac disease myself, and yes you can absolutely eat out. I was diagnosed 22 years ago. So much has changed in these last 2 decades that makes life a lot easier for us, but you do have to pay attention when dining out, not only to the ingredients that are going into the food but also to the preparation technique used.
If a newly diagnosed person goes out to eat, they would want to first choose a celiac-friendly restaurant, meaning a restaurant that has a gluten-free menu. Even then, I would suggest asking questions related to the ingredients and the preparation methods. For example, it’s pretty common knowledge among people with celiac disease that fryers are contaminated, but what’s less commonly known is that scrambled eggs can often be mixed with pancake batter to make them fluffy and increase their volume. Roasts and beef cuts that are served in a restaurant are often held in a broth that contains wheat, prior to being served. Baked potatoes may be put into a fryer just before serving them at the table.
It’s important that in the kitchen, where the food is being prepared, different utensils and skillets are used, and that the person preparing the food is paying attention to what cutting boards he/she is using and not cross-contaminating with other gluten-containing products. All of this being said, there is much more opportunity for people to dine out these days. However, you have to be very, very careful, and there are resources that can lead you to restaurants that are more inclined to understand food allergies and make allowances and substitutions for those on the gluten-free diet.
DR. MUSHLIN: Ms. Dennis, would you elaborate on how to access those resources, and can you also discuss a few reputable websites that can be used by people with gluten sensitivity?
MS. DENNIS: There are a number of national organizations that are deeply committed to celiac disease, the gluten-free diet, and those with non-celiac gluten sensitivity. In no particular order, these include the Celiac Disease Foundation (www.celiac.org), the Gluten Intolerance Group (www.gluten.net), the Celiac Sprue Association of the United States (CSA/USA, Inc; www.csaceliacs.info), the American Celiac Disease Alliance (americanceliac.org), and the National Foundation for Celiac Awareness (www.celiaccentral.org). These can all be easily found by a Google search. Each of them contains multiple listings of resources including restaurants, information about dining out, tips on how to eat when traveling, nutrition information, hidden gluten sources, blogs, and how to budget on the gluten-free diet. Many of them list celiac centers across the United States and describe how to find specific clinicians who are experts in this field. All of these are reputable sites.
I should mention that we have also launched a multi-level website especially designed for the nutritional management of celiac disease: CeliacNow.org. It’s useful for anyone on the gluten-free diet as well as practitioners who want to gain more information.
Back to your original question about dining out in particular, there are 2 resources that I recommend to patients. One of them is TriumphDining.com. Not only do they list grocery stores and food sources across the state, they also list restaurants. CeceliasMarketplace.com is also another excellent website. Both of these sites also offer books on the topic. Finally, the forum at www.celiac.com is a place that most people find almost immediately when they’re diagnosed.
DR. MUSHLIN: Good. Is there any special designation for people who do nutritional work such as yourself who specialize in celiac counseling, or can any registered nutritionist counsel someone appropriately?
MS. DENNIS: They are actually working on a certification program for the counseling of patients with celiac disease. I joined a taskforce about 5 years ago that developed nutritional guidelines for the Academy of Nutrition and Dietetics.3 These guidelines are available if dieticians want to train themselves on how to counsel a patient on the gluten-free diet, beginning with the initial visit through the follow-up visits. The guidelines include laboratory tests, case studies, and multiple patient handouts, and they constitute the industry’s major educational piece on celiac disease. Beyond that, you can examine books, articles, etc, written by a number of experts in the field. There’s currently no certification.
DR. LEFFLER: A lot of patients will come to me saying, “I saw a dietician and I knew more about the diet than they did. They were no help at all.” That is really a terribly frustrating thing for patients. So, clinicians want to make sure that they send their patients to somebody who has a fair degree of knowledge, interest, and expertise in celiac disease. Unfortunately, this expertise is just not that common these days.
DR. MUSHLIN: Ms. Dennis, how many hours do you normally have to spend to get a newly diagnosed patient with true celiac disease, not just gluten sensitivity, up to speed assuming they have normal intelligence, at least a high school education, and some kind of familiarity with the basics of nutrition. How many hours might it take for you to meet with them? Often when physicians send a patient for a consultation, it’s helpful to tell the patient that they may need to be seen a few times to get it right because sometimes patients are surprised or dismayed that 20minutes with someone hasn’t fixed them.
MS. DENNIS: In this hospital setting, I’m not able to see patients as often or for as long of a period of time as I would like, and that’s common across many, many nutrition practices. We have an hour to educate patients initially. In an ideal world, the patients would be back within a few weeks for part 2 for at least an hour, and then they would check in periodically for the next 3months, 6months, and then yearly for a wellness check.
You can absolutely not do this in one session, and so, I’ve designed nutrition counseling sessions to give patients a tremendous amount of information that they can read. I also instruct them to explore reputable sites, read the material that we’ve created, and then come back with questions. I always link them to a local support group, which is absolutely critical for the management of this lifestyle adjustment. They can’t cope with the condition alone, and they certainly can’t do it on a few hours of nutrition consulting.
DR. MUSHLIN: Are you folks doing group counseling yet at your institution? For example, patients who’ve spent an hour or greater with you can come back in a group setting to get their questions answered, have an open discussion, and obtain support from other fellow patients or from other individuals following the same diet.
MS. DENNIS: Our clinic visits are one-on-one, but we do offer patient education nights 3 times a year where 10 to 40 people join us, and one of the doctors and I sit and answer questions for an hour and a half. That is a great experience for the patients. It’s always a very warm environment, and we again connect them to our larger support group that serves all of New England, the Healthy Villi, and they’re able to attend conferences, expos, or large meetings at least 3 times a year.
DR. MUSHLIN: I certainly think that if the paradigms of helping patients with chronic ongoing illness can be managed, their illnesses are going to gravitate more and more toward exactly those kinds of group support models.
MS. DENNIS: I agree.
DR. MUSHLIN: Dr. Leffler, you’ve mentioned briefly that in follow-up with your patients who have celiac disease, you need to be careful or be aware of the possibility of low bone density, and you also mentioned that they need vaccinations. What vaccinations do they require and why?
DR. LEFFLER: One of the things that is not widely known about celiac disease is that it’s actually associated with functional hyposplenism. So, people with celiac disease have an increased risk of infections—primarily those involving encapsulated organisms but also other infections—and these infections can be more severe. Our general recommendations are to vaccinate all celiac patients for flu and pneumococcus regardless of their age. Unfortunately, we have seen cases of very severe pneumococcal sepsis in otherwise totally healthy immunocompetent patients with celiac disease. So, it is something that we recommend routinely to all of our patients.
DR. MUSHLIN: Regarding the unusual association of celiac disease with other medical situations, one of my colleagues here saw a patient with pulmonary hemosiderosis who happened to have celiac disease. Are there other unusual conditions that are associated with celiac disease?
DR. LEFFLER: Yes. That pulmonary condition is called Lane-Hamilton syndrome. It is quite rare, but we’ve seen a few cases of it.
One of the fascinating things about celiac disease is that it can affect any organ system in the body. You can see effects in the central nervous system, skin, bones, kidneys, reproductive system, lungs, and heart, and there are a number of reasons why celiac disease can be so far-reaching.
Part of it is just that chronic nutritional deficiencies can lead to widespread problems, but more fundamentally, people with celiac disease produce antibodies to tTG. That’s the blood test that is most commonly ordered—the IgA anti-tTG blood test. The enzyme tTG is found in all parts of the body. Its main job is to crosslink collagen. It’s very active in wound repair and building connective tissue, and when antibodies attack this enzyme, inflammation can occur anywhere in the body. Presumably, depending on the exact type of antibodies produced and polymorphisms in tTGs, you can have a direct autoimmune effect that’s triggered in the intestine but attacks the brain or virtually any other organ.
Gluten ataxia is a cardinal well-known phenomenon where you have cerebellar inflammation and cerebellar atrophy due to the celiac reaction. You can have dermatitis herpetiformis, which is an inflammatory reaction of the skin that mostly affects extensor surfaces. So, you have this autoimmune reaction that can attack any part of the body but starts in the intestine. Once you get celiac disease under control, for example by going on a gluten-free diet, these antibody levels decrease and the autoimmune reactions cease just as they do in the intestine. This is really a very unique way of thinking about an autoimmune disease.
DR. MUSHLIN: Because we’re talking so much about antibodies, do you follow antibody titers in people you’ve placed on a gluten-free diet?
DR. LEFFLER: Yes, I do. I follow them not because they’re really wonderful at monitoring celiac disease, because they’re not. There is plenty of research including some that we’ve done ourselves4,5 that shows that they’re not great at telling, for instance, recent gluten exposure or the degree of intestinal healing. There are lots of people who have completely normal antibody levels, but their intestine’s ability to heal is significantly damaged and vice versa. Some people still have mild elevations in their antibody levels, but their intestine looks pretty good.
On the other hand, there’s really no other tool that we have, and if you have somebody with antibody levels that are persistently elevated and never drop, or drop slightly but are still 2 to 3 times the upper limit of normal, you can be fairly certain that gluten is sneaking in somewhere, and they may not know it. They may be doing their best to follow a gluten-free diet. It could be something as simple as a single generic medication or a supplement that has gluten in it that they’re taking on a daily basis. We’ve seen issues of that sort, but if their antibody level is still high, it’s very helpful as a red flag that something’s not going right.
The first thing I’ll do is send them back to see Ms. Dennis to review the diet and see where the problems are cropping up. That will fix many of the problems, but it can take an awful lot of detective work to sort through basically everything that they’re putting in their mouth and see where that bit of gluten might be.
DR. MUSHLIN: So let’s say the family practitioner diagnoses celiac disease based on the patient’s history and physical findings, and the tTG antibody test is highly positive. The practitioner then sends the patient to a nutritionist, and the patient goes on a gluten-free diet. How should that family practitioner then follow up with the patient? You mentioned immunizations—influenza yearly and Pneumovax. What else should be routinely done by that practitioner, for example, in a rural community where the patient might not have access to a specialist?
DR. LEFFLER: I want to just mention that even with a positive antibody level, endoscopy is still necessary at the beginning for diagnosis. The standard of care for celiac disease these days includes checking celiac serologies approximately every 3 to 6months until they normalize, which depends on how high they are at the beginning. Some people start off with a relative titer of 1000, and some start off with a relative titer of 50. Obviously, the latter will normalize much more quickly.
What you want to see is an improvement in those levels, so you follow them approximately every 6months until they normalize. Then you perform a celiac blood test approximately every year just to make sure that the levels are staying low and that something hasn’t changed such that the patient suddenly has an elevated level. At least 1 bone mineral density test should be performed approximately 1 year after diagnosis once their vitamin D and any other nutritional deficiencies have been repleted. We can mention the nutrients to check in a second, and if those are normal, then the patient can go back to the bone mineral density recommendations for the regular population.
If their bone mineral density is low, then you want to keep a closer eye on them depending on how low it is. You can see a lot of improvement in bone mineral density in the first year after diagnosis with celiac disease, which is why we don’t typically check bone density right off the bat unless the patient has had fractures or something that we’re really worried about. It’s only the residual osteopenia or osteoporosis that they have after a year that we would treat differently.
Even after the initial dietary counseling, we strongly recommend that patients check in with their dietician once a year. Again, a gluten-free diet is a really big change. It’s tough. Things change all the time, and by following up with a specialist, you can tell them about how the foods you eat have changed. New recommendations on a yearly basis are also recommended.
As for vitamins, the most common nutrient deficiencies in people with celiac disease are currently vitamin D, iron, and zinc. Zinc is not one that’s commonly on people’s radar, but it is actually responsible for a lot of the hair and skin manifestations that people with celiac disease complain about and potentially responsible for some of the immune dysregulation as well.
DR. LEFFLER: Correct. Sometimes we will encounter people with a normal B12level and macrocytosis, and we will wonder where that’s coming from. That’s a good thing to check. B12and folate are rarely low in people with celiac disease, so we don’t always check them.
We’ll also check liver function tests at least once in the beginning because autoimmune liver disease can be associated with celiac disease. Thyroid disease is also often associated with celiac disease, so it’s important to make sure patients have had a thyroid stimulating hormone (TSH) test at least once, and you should consider repeating that every few years. Those are the routine things that we keep an eye on in celiac disease. So, there’s a little bit of a to-do list for your patients with celiac disease.
DR. MUSHLIN: Do you ever do genetic HLA testing?
DR. LEFFLER: Yes, we do. The genetic testing for celiac disease is very interesting. Most of the genes we test for, for example those involved in hemochromatosis or cystic fibrosis, are relatively diagnostic, ie, if you have the gene, you worry that you have the disease. Celiac disease is just the opposite. The celiac genes are HLA-DQ2 and DQ8. They are actually prevalent in approximately 40% of the general population. So, they’re prerequisite genes, but they are not diagnostic genes.
If you have these genes, it means nothing because obviously the vast majority of people with these genes never get celiac disease. On the other hand, if you don’t have these genes, then you virtually cannot get celiac disease. So, these genes are helpful for 2 types of people specifically.
First, genetic testing is helpful for people who are already on a gluten-free diet and aren’t willing to do a gluten challenge. Obviously, your genes don’t change with diet, so if you get a negative genetic test, you can rule out celiac disease even while the patient is on a diet, and there’s no other way you can do that. Second, genetic testing is helpful for patients with a strong family history of celiac disease. The testing is very popular now among children whose parents have celiac disease. They have a pretty high chance of having the gene—at least 50%—but if they don’t, they’re off the hook for life, which is a nice thing to be able to tell someone. So, I think this test really does have its utility.
DR. MUSHLIN: Let’s go back to the initial diagnosis and the role of endoscopy.
DR. LEFFLER: The modern celiac blood tests, which are tTG, deamidated gliadin peptide (DGP), and endomysial antibody (EMA), are all highly accurate, have >90% sensitivity, and are specific. On the other hand, the average patient you’re going to test probably has a 5% to 10% pretest probability of celiac disease. Even the best of our tests only have a positive predictive value of approximately 80%, which means that if you rely on a serology alone, 1 out of 5 patients you diagnose with celiac disease is probably going to be a false positive. So, for that reason, because it’s a life-long diagnosis, you’re going to expose people to a lot of inconvenience to say the least as well as other medical testing, bone density analysis, and immunizations they may not need. The recommendation is still that all patients with a positive serology should follow up and get an endoscopy, which continues to be the gold standard for diagnosis.
DR. MUSHLIN: Would that be an endoscopy with a small bowel biopsy?
DR. LEFFLER: Right. A duodenal biopsy.
DR. MUSHLIN: So, depending on your population, there would be a 1in 5 chance of a false positive test. What would be the chance of a false negative test?
DR. LEFFLER: That would be well under 5% depending on the population.
DR. MUSHLIN: So, it’s 95% sensitive in picking it up, correct?
DR. LEFFLER: Right. In general, the one thing that can throw off some of these blood tests is IgA deficiency, which is a common problem that is also enriched in the celiac population. Approximately 2% of people with celiac disease have IgA deficiency, and because these blood tests are typically IgA-based, if you’re really worried about the diagnosis, you can check the total IgA level at the time of tTG measurement. If both of those are normal, and your patient is on a regular gluten-containing diet, you’re really fine in the vast majority of circumstances.
DR. MUSHLIN: In antibody testing, do you assay for endomysial antibodies in addition to transglutaminase, or do you assay for only one? Do you think that your ability to trust these tests is very dependent on the laboratory you’re using? How many of these antibody tests do you get?
DR. LEFFLER: Typically just one. There’s very little data to suggest that doing multiple tests at the same time does anything but drive up the cost. They’re all similar. They’re all typically very concordant.
So, you’re going to have one positive, and you’re going to have a second one positive. The only times I’ll consider it again are with somebody who has a borderline test and I’m considering whether or not they need an endoscopy. In that case, maybe a second one to help push me one way or the other would be helpful, but really, tTG is your workhorse. Although there are multiple assays available and almost all of them are good, I think that physicians across the country really can’t go wrong just sticking with IgA-tTG as their primary test.
DR. MUSHLIN: Terrific. Ms. Dennis, do you have anything else you want to articulate?
MS. DENNIS: Standard multivitamin mineral supplementation is a general recommendation for people with celiac disease. So, when they come into the clinic, I always recommend a gluten-free multivitamin and mineral supplement with or without iron depending on their age, gender, and laboratory values.
Sometimes our patients need vitamin B complex supplements. Sometimes it’s just a simple complaint of energy and may suggest that their B12level is lower than normal. We like to see it around 400mg/mL or above.
Calcium and vitamin D supplementation is also very common. In general, it’s difficult to get about 1200mg of calcium a day through diet alone, particularly if lactose intolerance is present. So, we often prescribe calcium supplements with vitamin D to get to that total goal.
Then, of course, Dr. Leffler was mentioning vitamin D. We recommend it based on laboratory values and diet, and almost all of our patients need vitamin D supplementation. I would also suggest that omega-3 fatty acids be considered in the dietary assessment of our patients.
DR. MUSHLIN: Why is that?
MS. DENNIS: In general, Americans aren’t getting the required amounts of omega-3 fatty acids, and eating fish is not always popular. Very few of our patients can tell me that they get approximately 6 ounces of a dark deep-water fatty fish per week, which is a general recommendation. So, if it’s necessary, I’ll suggest an omega-3supplement, but that’s always individually determined.
The last thing I wanted to mention was that just recently the North American Society for the Study of Celiac Disease was formed. It’s a clinician group, and their intention and mission is to spearhead celiac awareness in the medical and nutrition communities as well as in the public sector. They aim to be a guiding force because up until now, support has generally come from volunteer nonprofit organizations all across the country. So, we’re looking for a little bit more of a structured single entity that can help us bring awareness much more quickly to all populations.
DR. MUSHLIN: In the multivitamin supplement, would you also want to make sure that they got some zinc?
MS. DENNIS: Yes. All the multivitamins contain zinc, but often, we need to recommend extra zinc. There’s typically not 100% of your daily recommended zinc in a multi. It’s present in trace amounts. So, if needed, we’ll check serum zinc and give zinc for 6 to 8 weeks before retesting.
DR. MUSHLIN: Dr. Leffler, let’s go quickly to the question of malignancy associated with long-standing celiac disease. In my own clinical practice experience, I’ve actually had 2 patients with celiac disease who developed non-Hodgkin’s lymphoma. Do you think there’s a definite association between malignancies and celiac disease?
DR. LEFFLER: Unfortunately, it seems like that association is clear. The overall risk of malignancy in people with celiac disease is about twofold higher than what we see in the general population. The majority of that, as you saw with your patient, is due to non-Hodgkin’s lymphoma.
There’s also an increased risk of small intestinal adenocarcinomas and small intestinal lymphomas. They’re also known as enteropathy-associated T-cell lymphomas. So, there is a significant risk.
However, we don’t screen for malignancies in patients with celiac disease any differently than we do in the general population. This is because, thankfully, the risk of malignancy drops after diagnosis, and at approximately 5 years after diagnosis, the risk is pretty close to that of the general population. So, the risk seems to be related to chronic immune activation, and once you get that immune activation under control, the risk drops. It’s a little bit of a reward that helps patients to actually follow the diet and control their disease.
DR. MUSHLIN: Well, this has been a wonderful conversation. I’ve learned a tremendous amount, and I’m very grateful to you both.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
DR. LEFFLER: My name is Dr. Daniel Leffler. I’m in the Division of Gastroenterology at Beth Israel Deaconess Medical Center, and I direct the clinical research at our Celiac Center.
MS. DENNIS: My name is Melinda Dennis and I’m the nutrition coordinator of the Celiac Center at Beth Israel Deaconess Medical Center. I work with Dr. Leffler, Dr. Kelly, and the other Celiac Center gastroenterologists.
DR. MUSHLIN: Great. So, as the moderator of this conversation, I’d like to start us off with a case. This case presented to me in my primary care practice.
I saw a Harvard Medical student who came to see me regarding a stress fracture in her right foot. She was a runner and had run in 3marathons over the last 4 years. She was quite slender and had a BMI of only 19, but she quite adamantly denied being anorectic or bulimic.
She had been treated for anemia in her senior year of college with iron. She had no idea whether her anemia had improved. She had always had irregular menses since menarche, but for the past year as her running increased, she was completely amenorrheic.
After physical examination, x-ray examination revealed that she did indeed have a fracture of a metatarsal. I then obtained a bone density examination that showed osteoporosis—not just osteopenia but osteoporosis. She also had an anemia with a hematocrit of 33%, and she had microcytic hypochromic indices. I then, because of her osteoporosis, got a vitamin D level, which was definitely low. It was under 20, and that’s the lower limit of normal in our institution. She also had slightly elevated parathyroid hormone levels.
I obtained an IgA tissue transglutaminase (tTG) antibody test, and it was highly positive. I then placed her on a gluten-free diet with calcium, vitamin D, and oral iron supplementation, and that’s the case.
Dr. Leffler, would you say that this would be a pretty typical presentation of celiac disease?
DR. LEFFLER: Yes. I think all of us working with celiac disease have seen patients just like this, but it also highlights the fact that there really is no typical patient with celiac disease. A picture of what was previously considered typical involved severe malabsorptive symptoms, but that was really just scratching the tip of the iceberg for what is out there. While iron-deficiency anemia, osteoporosis, and vitamin D deficiency are very common in celiac disease, you can have all or none of these symptoms. Like this patient, you can have no gastrointestinal symptoms. Alternatively, you can have predominantly gastrointestinal symptoms.
Certainly, this patient had a number of red flags that would make you worry about celiac disease such as the early onset fracture, the osteoporosis, and the iron-deficiency anemia. Although the latter is not an uncommon thing to see in a young woman, it’s the combination of all these factors that, in my mind, would alert a clinician to the fact that these are not normal findings for a young healthy woman.
DR. MUSHLIN: If you looked at all the patients who were ultimately diagnosed with celiac disease who presented to the family practitioner or the primary care internist, what would you say would be the most common red flags? I know this case, which is a true case, had a lot of red flags, but what would be the most common symptoms that might raise your consciousness that you might be dealing with celiac disease?
DR. LEFFLER: Approximately 40% of patients with celiac disease will have chronic gastrointestinal symptoms. These can vary and can be very similar to those of irritable bowel syndrome, but gastrointestinal symptoms in the presence of a significant nutritional deficiency like iron deficiency or vitamin D deficiency, as in this case, would be very typical of celiac disease and raise a lot of red flags. A lot of these patients will also have either a personal history or a family history of other autoimmune diseases, type 1 diabetes, thyroid disease, and other similar conditions.
So, very common presentations and red flag conditions would include a patient who says, “my mother has thyroid disease” or “I have thyroid disease and now I’m iron deficient,” or “now I’m experiencing significant fatigue.” Overall, the most common presentations of celiac disease these days are gastrointestinal symptoms, iron-deficiency anemia, vitamin D deficiency, and fatigue.
DR. MUSHLIN: Certainly, all of those things are seen in an internist’s or a family practitioner’s office. I guess the real key here is that when you start to see this constellation, you should raise your consciousness that there may be one unifying diagnosis rather than multiple diagnoses.
DR. LEFFLER: Exactly. I think that the response to therapy can also be a good hint that there might be something else going on. Most young women with iron-deficiency anemia simply due to menses will do pretty well on oral iron supplementation alone. If they have severe and significant anemia and it’s just not responding to iron supplementation for instance, or if their vitamin D level is low and it does not improve with a regular dose of vitamin D, then you really have to wonder whether there is something that’s preventing absorption of this nutrient in the intestinal tract. Once you get to that level, then celiac disease is by far the most common diagnosis in these situations.
DR. MUSHLIN: We are having this colloquium here in Boston and there are a lot of people in the greater Boston area who are of Northern European extraction. Are there certain ethnic groups that have a predominance of celiac disease, or can it be found in virtually any ethnic group?
DR. LEFFLER: Earlier, we used to say this was essentially an Irish/Italian or western European disease, but now we can more easily pick out the populations that celiac disease doesn’t occur in. Celiac disease has a strong genetic predisposition with human leukocyte antigen (HLA) types, but really the populations that are at risk for celiac disease cover most of the globe: all of North and South America, Europe, the Middle East, North Africa, India, and northern China. Southeast Asians and Sub-Saharan Africans have a very low risk, but the majority of people have a significant risk of celiac disease, and I think that like all other autoimmune and inflammatory disorders, whether it’s type 1 diabetes or asthma or inflammatory bowel disease, the prevalence of celiac disease just continues to rise over time. We’re seeing it in populations that never had this disorder before.
DR. MUSHLIN: Why do you think the prevalence is increasing? Is it that our diagnostic ability is better, or do you think it’s truly increasing?
DR. LEFFLER: Well, we’ve certainly gotten a lot better at diagnosing celiac disease. You mentioned the celiac tTG antibody test earlier, which has really revolutionized the way that we diagnose celiac disease because it’s so accurate, affordable, and widespread. That being said, even in prevalence studies,1,2 there really is a dramatic increase—something in the range of a doubling—and true prevalence every 30 years or so. This is right alongside these other autoimmune and inflammatory diseases.
Clearly, nothing in our genetic heritability is changing that quickly. It’s something in the environment that is leading to an increase in the incidence of celiac disease and autoimmune diseases in general. Lots of people have theories about what that might be, and the most common theory is that we live in such a clean environment now that our immune system doesn’t have the normal feedback it needs to develop in a healthy way, and so, our immune function may start to become abnormal.
DR. MUSHLIN: This is similar to the asthma hypothesis.
DR. LEFFLER: Exactly. All of this can in some way be explained by the hygiene hypothesis.
DR. MUSHLIN: Right. When you live in Germany and the cows are housed in the same house that you live in, there’s less asthma.
DR. LEFFLER: Exactly. The same phenomenon has been seen in celiac disease in some populations, especially in northern Europe where you cross a national border and you encounter very different socioeconomic conditions. Even though you have virtually the same genetic lineage, you can have very different rates of celiac disease. I think this is very much the case.
DR. MUSHLIN: Ms. Dennis, I have a large number of patients who come into my office and say to me, “I went on a gluten-free diet and I feel so much better.” Can you address the question of gluten sensitivity versus true celiac disease? Do you feel comfortable doing that?
MS. DENNIS: Sure. We know that celiac disease is a genetic autoimmune disease, and we know that non-celiac gluten sensitivity is not considered an autoimmune disease. Dr. Leffler would be in a better position to address the issue of whether there is an inflammatory response, but there are plenty of people who come into the office confused about the 2. In order to obtain a diagnosis of non-celiac gluten sensitivity, celiac disease and wheat allergy would both need to be ruled out.
There is no positive gene testing for non-celiac gluten sensitivity, but what makes it difficult for patients is that the symptoms can mimic one another almost exactly. All the gastrointestinal symptoms, as well as some of the other extraintestinal manifestations like headaches, poor concentration, memory loss, and other similar conditions, can occur in both conditions. It’s complicated, and there is much more research that needs to be done in this area.
DR. LEFFLER: I’ll just corroborate all of that. We’ve known about celiac disease for a long time. Gluten intolerance, or non-celiac gluten sensitivity as it’s becoming more commonly known, is a very new entity that we’ve really only starting believing in, clinically at least, over the last couple of years. We’re learning about it quickly, but we still don’t have a very good sense of its prevalence.
It does appear to be a non-inflammatory disorder, which separates it from celiac disease. It doesn’t appear to have any autoimmune component and likely does not have a lot of the long-term risks associated with celiac disease such as osteoporosis or even cancer and infection risk, but at the same time, it can be associated with significant quality of life impairment, and the symptoms can mimic celiac disease. So, it is something that everyone needs to be aware of; however, while the diet-related treatment is similar, it seems that a lot of the peripheral things that we should do for our celiac patients such as getting them vaccinated and performing a bone mineral density study are not required for patients who have non-celiac gluten intolerance or gluten sensitivity. We do recommend that people work with their physicians to make a clear distinction between these 2 disorders.
DR. MUSHLIN: Just to expand on that point, would a negative tTG antibody test basically exclude celiac disease with a high degree of certainty and leave you with a diagnosis of gluten sensitivity without celiac disease (assuming the symptoms were consistent)?
DR. LEFFLER: Yes. For a typical patient who is on a regular gluten-containing diet and doesn’t have a strong family history of celiac disease or other factors that would increase risk, a negative tTG would certainly be sufficient and would imply that the chances that the patient has true celiac disease are quite low. We can then proceed with a non-celiac gluten sensitivity diagnosis and see how the patient does clinically.
DR. MUSHLIN: It seems that everywhere I go, there are more and more gluten-free choices. In fact, the wife of my closest friend here in town just started a gluten-free bakery and she’s so busy that he’s making deliveries for her now every day instead of 3 times a week. Are there any dangers to adhering to a gluten-free diet?
MS. DENNIS: There are inherent nutritional deficiencies in a gluten-free diet. So, if the diet is not proper, yes, you can lack certain vitamins and minerals. For example, wheat is a major source of protein and B vitamins as well as iron, trace minerals, and fiber.
When you switch to the gluten-free diet, you need to be able to replace those nutrients. Many people don’t focus immediately on the alternative whole and healthier gluten-free grains like amaranth, buckwheat, millet, quinoa, sorghum, and teff. They tend to move toward rice, corn, and potatoes, which tend to be lower in fiber, nutrient poor, and can cause or exacerbate constipation and weight gain when eaten in large quantities. So, that’s one of the main issues.
Additionally, we find that many people are concurrently lactose intolerant when they’re first diagnosed with celiac disease. So, we need to consider the possibility that their calcium and vitamin D intakes may be inadequate. Then, of course, we need to consider the B vitamins, which are present throughout the food chain but are present in large quantities in grains.
DR. MUSHLIN: Ms. Dennis, a lot of my patients are curious about purchasing gluten-free materials either from stores or online. Do you feel comfortable recommending any websites that you feel are legitimate for our patients to access?
Regarding consumer access, it is important to find safe gluten-free foods that are not cross-contaminated. We now have a Food Allergen Labeling and Consumer Protection Act in place that states that if wheat protein is in an FDA-regulated food, it must be labeled as such on the package. That applies to FDA foods but not USDA foods. Dieticians know the difference between these two and can educate their patients, but it’s not obvious by just reading a label.
The most obvious sources of gluten are wheat, rye, barley, malt, oats (unless they are specifically labeled and processed such that they are gluten free), and brewer’s yeast. These are easily identifiable, but it takes a little bit of education to get familiar with hidden gluten sources. One of the primary things that a person can do is make sure that their grains and flour-based products are labeled “gluten free” to help avoid some of the risks of cross-contamination that come when gluten-free grains are contaminated with wheat, rye, or barley during the farming, processing, or milling practices that typically occur in this country.
DR. MUSHLIN: So let’s say I’ve got a patient who says to me, “Doc, I’ve got celiac disease. Can I ever eat out again? Can I ever go to a restaurant?” How would you advise them?
MS. DENNIS: I have celiac disease myself, and yes you can absolutely eat out. I was diagnosed 22 years ago. So much has changed in these last 2 decades that makes life a lot easier for us, but you do have to pay attention when dining out, not only to the ingredients that are going into the food but also to the preparation technique used.
If a newly diagnosed person goes out to eat, they would want to first choose a celiac-friendly restaurant, meaning a restaurant that has a gluten-free menu. Even then, I would suggest asking questions related to the ingredients and the preparation methods. For example, it’s pretty common knowledge among people with celiac disease that fryers are contaminated, but what’s less commonly known is that scrambled eggs can often be mixed with pancake batter to make them fluffy and increase their volume. Roasts and beef cuts that are served in a restaurant are often held in a broth that contains wheat, prior to being served. Baked potatoes may be put into a fryer just before serving them at the table.
It’s important that in the kitchen, where the food is being prepared, different utensils and skillets are used, and that the person preparing the food is paying attention to what cutting boards he/she is using and not cross-contaminating with other gluten-containing products. All of this being said, there is much more opportunity for people to dine out these days. However, you have to be very, very careful, and there are resources that can lead you to restaurants that are more inclined to understand food allergies and make allowances and substitutions for those on the gluten-free diet.
DR. MUSHLIN: Ms. Dennis, would you elaborate on how to access those resources, and can you also discuss a few reputable websites that can be used by people with gluten sensitivity?
MS. DENNIS: There are a number of national organizations that are deeply committed to celiac disease, the gluten-free diet, and those with non-celiac gluten sensitivity. In no particular order, these include the Celiac Disease Foundation (www.celiac.org), the Gluten Intolerance Group (www.gluten.net), the Celiac Sprue Association of the United States (CSA/USA, Inc; www.csaceliacs.info), the American Celiac Disease Alliance (americanceliac.org), and the National Foundation for Celiac Awareness (www.celiaccentral.org). These can all be easily found by a Google search. Each of them contains multiple listings of resources including restaurants, information about dining out, tips on how to eat when traveling, nutrition information, hidden gluten sources, blogs, and how to budget on the gluten-free diet. Many of them list celiac centers across the United States and describe how to find specific clinicians who are experts in this field. All of these are reputable sites.
I should mention that we have also launched a multi-level website especially designed for the nutritional management of celiac disease: CeliacNow.org. It’s useful for anyone on the gluten-free diet as well as practitioners who want to gain more information.
Back to your original question about dining out in particular, there are 2 resources that I recommend to patients. One of them is TriumphDining.com. Not only do they list grocery stores and food sources across the state, they also list restaurants. CeceliasMarketplace.com is also another excellent website. Both of these sites also offer books on the topic. Finally, the forum at www.celiac.com is a place that most people find almost immediately when they’re diagnosed.
DR. MUSHLIN: Good. Is there any special designation for people who do nutritional work such as yourself who specialize in celiac counseling, or can any registered nutritionist counsel someone appropriately?
MS. DENNIS: They are actually working on a certification program for the counseling of patients with celiac disease. I joined a taskforce about 5 years ago that developed nutritional guidelines for the Academy of Nutrition and Dietetics.3 These guidelines are available if dieticians want to train themselves on how to counsel a patient on the gluten-free diet, beginning with the initial visit through the follow-up visits. The guidelines include laboratory tests, case studies, and multiple patient handouts, and they constitute the industry’s major educational piece on celiac disease. Beyond that, you can examine books, articles, etc, written by a number of experts in the field. There’s currently no certification.
DR. LEFFLER: A lot of patients will come to me saying, “I saw a dietician and I knew more about the diet than they did. They were no help at all.” That is really a terribly frustrating thing for patients. So, clinicians want to make sure that they send their patients to somebody who has a fair degree of knowledge, interest, and expertise in celiac disease. Unfortunately, this expertise is just not that common these days.
DR. MUSHLIN: Ms. Dennis, how many hours do you normally have to spend to get a newly diagnosed patient with true celiac disease, not just gluten sensitivity, up to speed assuming they have normal intelligence, at least a high school education, and some kind of familiarity with the basics of nutrition. How many hours might it take for you to meet with them? Often when physicians send a patient for a consultation, it’s helpful to tell the patient that they may need to be seen a few times to get it right because sometimes patients are surprised or dismayed that 20minutes with someone hasn’t fixed them.
MS. DENNIS: In this hospital setting, I’m not able to see patients as often or for as long of a period of time as I would like, and that’s common across many, many nutrition practices. We have an hour to educate patients initially. In an ideal world, the patients would be back within a few weeks for part 2 for at least an hour, and then they would check in periodically for the next 3months, 6months, and then yearly for a wellness check.
You can absolutely not do this in one session, and so, I’ve designed nutrition counseling sessions to give patients a tremendous amount of information that they can read. I also instruct them to explore reputable sites, read the material that we’ve created, and then come back with questions. I always link them to a local support group, which is absolutely critical for the management of this lifestyle adjustment. They can’t cope with the condition alone, and they certainly can’t do it on a few hours of nutrition consulting.
DR. MUSHLIN: Are you folks doing group counseling yet at your institution? For example, patients who’ve spent an hour or greater with you can come back in a group setting to get their questions answered, have an open discussion, and obtain support from other fellow patients or from other individuals following the same diet.
MS. DENNIS: Our clinic visits are one-on-one, but we do offer patient education nights 3 times a year where 10 to 40 people join us, and one of the doctors and I sit and answer questions for an hour and a half. That is a great experience for the patients. It’s always a very warm environment, and we again connect them to our larger support group that serves all of New England, the Healthy Villi, and they’re able to attend conferences, expos, or large meetings at least 3 times a year.
DR. MUSHLIN: I certainly think that if the paradigms of helping patients with chronic ongoing illness can be managed, their illnesses are going to gravitate more and more toward exactly those kinds of group support models.
MS. DENNIS: I agree.
DR. MUSHLIN: Dr. Leffler, you’ve mentioned briefly that in follow-up with your patients who have celiac disease, you need to be careful or be aware of the possibility of low bone density, and you also mentioned that they need vaccinations. What vaccinations do they require and why?
DR. LEFFLER: One of the things that is not widely known about celiac disease is that it’s actually associated with functional hyposplenism. So, people with celiac disease have an increased risk of infections—primarily those involving encapsulated organisms but also other infections—and these infections can be more severe. Our general recommendations are to vaccinate all celiac patients for flu and pneumococcus regardless of their age. Unfortunately, we have seen cases of very severe pneumococcal sepsis in otherwise totally healthy immunocompetent patients with celiac disease. So, it is something that we recommend routinely to all of our patients.
DR. MUSHLIN: Regarding the unusual association of celiac disease with other medical situations, one of my colleagues here saw a patient with pulmonary hemosiderosis who happened to have celiac disease. Are there other unusual conditions that are associated with celiac disease?
DR. LEFFLER: Yes. That pulmonary condition is called Lane-Hamilton syndrome. It is quite rare, but we’ve seen a few cases of it.
One of the fascinating things about celiac disease is that it can affect any organ system in the body. You can see effects in the central nervous system, skin, bones, kidneys, reproductive system, lungs, and heart, and there are a number of reasons why celiac disease can be so far-reaching.
Part of it is just that chronic nutritional deficiencies can lead to widespread problems, but more fundamentally, people with celiac disease produce antibodies to tTG. That’s the blood test that is most commonly ordered—the IgA anti-tTG blood test. The enzyme tTG is found in all parts of the body. Its main job is to crosslink collagen. It’s very active in wound repair and building connective tissue, and when antibodies attack this enzyme, inflammation can occur anywhere in the body. Presumably, depending on the exact type of antibodies produced and polymorphisms in tTGs, you can have a direct autoimmune effect that’s triggered in the intestine but attacks the brain or virtually any other organ.
Gluten ataxia is a cardinal well-known phenomenon where you have cerebellar inflammation and cerebellar atrophy due to the celiac reaction. You can have dermatitis herpetiformis, which is an inflammatory reaction of the skin that mostly affects extensor surfaces. So, you have this autoimmune reaction that can attack any part of the body but starts in the intestine. Once you get celiac disease under control, for example by going on a gluten-free diet, these antibody levels decrease and the autoimmune reactions cease just as they do in the intestine. This is really a very unique way of thinking about an autoimmune disease.
DR. MUSHLIN: Because we’re talking so much about antibodies, do you follow antibody titers in people you’ve placed on a gluten-free diet?
DR. LEFFLER: Yes, I do. I follow them not because they’re really wonderful at monitoring celiac disease, because they’re not. There is plenty of research including some that we’ve done ourselves4,5 that shows that they’re not great at telling, for instance, recent gluten exposure or the degree of intestinal healing. There are lots of people who have completely normal antibody levels, but their intestine’s ability to heal is significantly damaged and vice versa. Some people still have mild elevations in their antibody levels, but their intestine looks pretty good.
On the other hand, there’s really no other tool that we have, and if you have somebody with antibody levels that are persistently elevated and never drop, or drop slightly but are still 2 to 3 times the upper limit of normal, you can be fairly certain that gluten is sneaking in somewhere, and they may not know it. They may be doing their best to follow a gluten-free diet. It could be something as simple as a single generic medication or a supplement that has gluten in it that they’re taking on a daily basis. We’ve seen issues of that sort, but if their antibody level is still high, it’s very helpful as a red flag that something’s not going right.
The first thing I’ll do is send them back to see Ms. Dennis to review the diet and see where the problems are cropping up. That will fix many of the problems, but it can take an awful lot of detective work to sort through basically everything that they’re putting in their mouth and see where that bit of gluten might be.
DR. MUSHLIN: So let’s say the family practitioner diagnoses celiac disease based on the patient’s history and physical findings, and the tTG antibody test is highly positive. The practitioner then sends the patient to a nutritionist, and the patient goes on a gluten-free diet. How should that family practitioner then follow up with the patient? You mentioned immunizations—influenza yearly and Pneumovax. What else should be routinely done by that practitioner, for example, in a rural community where the patient might not have access to a specialist?
DR. LEFFLER: I want to just mention that even with a positive antibody level, endoscopy is still necessary at the beginning for diagnosis. The standard of care for celiac disease these days includes checking celiac serologies approximately every 3 to 6months until they normalize, which depends on how high they are at the beginning. Some people start off with a relative titer of 1000, and some start off with a relative titer of 50. Obviously, the latter will normalize much more quickly.
What you want to see is an improvement in those levels, so you follow them approximately every 6months until they normalize. Then you perform a celiac blood test approximately every year just to make sure that the levels are staying low and that something hasn’t changed such that the patient suddenly has an elevated level. At least 1 bone mineral density test should be performed approximately 1 year after diagnosis once their vitamin D and any other nutritional deficiencies have been repleted. We can mention the nutrients to check in a second, and if those are normal, then the patient can go back to the bone mineral density recommendations for the regular population.
If their bone mineral density is low, then you want to keep a closer eye on them depending on how low it is. You can see a lot of improvement in bone mineral density in the first year after diagnosis with celiac disease, which is why we don’t typically check bone density right off the bat unless the patient has had fractures or something that we’re really worried about. It’s only the residual osteopenia or osteoporosis that they have after a year that we would treat differently.
Even after the initial dietary counseling, we strongly recommend that patients check in with their dietician once a year. Again, a gluten-free diet is a really big change. It’s tough. Things change all the time, and by following up with a specialist, you can tell them about how the foods you eat have changed. New recommendations on a yearly basis are also recommended.
As for vitamins, the most common nutrient deficiencies in people with celiac disease are currently vitamin D, iron, and zinc. Zinc is not one that’s commonly on people’s radar, but it is actually responsible for a lot of the hair and skin manifestations that people with celiac disease complain about and potentially responsible for some of the immune dysregulation as well.
DR. LEFFLER: Correct. Sometimes we will encounter people with a normal B12level and macrocytosis, and we will wonder where that’s coming from. That’s a good thing to check. B12and folate are rarely low in people with celiac disease, so we don’t always check them.
We’ll also check liver function tests at least once in the beginning because autoimmune liver disease can be associated with celiac disease. Thyroid disease is also often associated with celiac disease, so it’s important to make sure patients have had a thyroid stimulating hormone (TSH) test at least once, and you should consider repeating that every few years. Those are the routine things that we keep an eye on in celiac disease. So, there’s a little bit of a to-do list for your patients with celiac disease.
DR. MUSHLIN: Do you ever do genetic HLA testing?
DR. LEFFLER: Yes, we do. The genetic testing for celiac disease is very interesting. Most of the genes we test for, for example those involved in hemochromatosis or cystic fibrosis, are relatively diagnostic, ie, if you have the gene, you worry that you have the disease. Celiac disease is just the opposite. The celiac genes are HLA-DQ2 and DQ8. They are actually prevalent in approximately 40% of the general population. So, they’re prerequisite genes, but they are not diagnostic genes.
If you have these genes, it means nothing because obviously the vast majority of people with these genes never get celiac disease. On the other hand, if you don’t have these genes, then you virtually cannot get celiac disease. So, these genes are helpful for 2 types of people specifically.
First, genetic testing is helpful for people who are already on a gluten-free diet and aren’t willing to do a gluten challenge. Obviously, your genes don’t change with diet, so if you get a negative genetic test, you can rule out celiac disease even while the patient is on a diet, and there’s no other way you can do that. Second, genetic testing is helpful for patients with a strong family history of celiac disease. The testing is very popular now among children whose parents have celiac disease. They have a pretty high chance of having the gene—at least 50%—but if they don’t, they’re off the hook for life, which is a nice thing to be able to tell someone. So, I think this test really does have its utility.
DR. MUSHLIN: Let’s go back to the initial diagnosis and the role of endoscopy.
DR. LEFFLER: The modern celiac blood tests, which are tTG, deamidated gliadin peptide (DGP), and endomysial antibody (EMA), are all highly accurate, have >90% sensitivity, and are specific. On the other hand, the average patient you’re going to test probably has a 5% to 10% pretest probability of celiac disease. Even the best of our tests only have a positive predictive value of approximately 80%, which means that if you rely on a serology alone, 1 out of 5 patients you diagnose with celiac disease is probably going to be a false positive. So, for that reason, because it’s a life-long diagnosis, you’re going to expose people to a lot of inconvenience to say the least as well as other medical testing, bone density analysis, and immunizations they may not need. The recommendation is still that all patients with a positive serology should follow up and get an endoscopy, which continues to be the gold standard for diagnosis.
DR. MUSHLIN: Would that be an endoscopy with a small bowel biopsy?
DR. LEFFLER: Right. A duodenal biopsy.
DR. MUSHLIN: So, depending on your population, there would be a 1in 5 chance of a false positive test. What would be the chance of a false negative test?
DR. LEFFLER: That would be well under 5% depending on the population.
DR. MUSHLIN: So, it’s 95% sensitive in picking it up, correct?
DR. LEFFLER: Right. In general, the one thing that can throw off some of these blood tests is IgA deficiency, which is a common problem that is also enriched in the celiac population. Approximately 2% of people with celiac disease have IgA deficiency, and because these blood tests are typically IgA-based, if you’re really worried about the diagnosis, you can check the total IgA level at the time of tTG measurement. If both of those are normal, and your patient is on a regular gluten-containing diet, you’re really fine in the vast majority of circumstances.
DR. MUSHLIN: In antibody testing, do you assay for endomysial antibodies in addition to transglutaminase, or do you assay for only one? Do you think that your ability to trust these tests is very dependent on the laboratory you’re using? How many of these antibody tests do you get?
DR. LEFFLER: Typically just one. There’s very little data to suggest that doing multiple tests at the same time does anything but drive up the cost. They’re all similar. They’re all typically very concordant.
So, you’re going to have one positive, and you’re going to have a second one positive. The only times I’ll consider it again are with somebody who has a borderline test and I’m considering whether or not they need an endoscopy. In that case, maybe a second one to help push me one way or the other would be helpful, but really, tTG is your workhorse. Although there are multiple assays available and almost all of them are good, I think that physicians across the country really can’t go wrong just sticking with IgA-tTG as their primary test.
DR. MUSHLIN: Terrific. Ms. Dennis, do you have anything else you want to articulate?
MS. DENNIS: Standard multivitamin mineral supplementation is a general recommendation for people with celiac disease. So, when they come into the clinic, I always recommend a gluten-free multivitamin and mineral supplement with or without iron depending on their age, gender, and laboratory values.
Sometimes our patients need vitamin B complex supplements. Sometimes it’s just a simple complaint of energy and may suggest that their B12level is lower than normal. We like to see it around 400mg/mL or above.
Calcium and vitamin D supplementation is also very common. In general, it’s difficult to get about 1200mg of calcium a day through diet alone, particularly if lactose intolerance is present. So, we often prescribe calcium supplements with vitamin D to get to that total goal.
Then, of course, Dr. Leffler was mentioning vitamin D. We recommend it based on laboratory values and diet, and almost all of our patients need vitamin D supplementation. I would also suggest that omega-3 fatty acids be considered in the dietary assessment of our patients.
DR. MUSHLIN: Why is that?
MS. DENNIS: In general, Americans aren’t getting the required amounts of omega-3 fatty acids, and eating fish is not always popular. Very few of our patients can tell me that they get approximately 6 ounces of a dark deep-water fatty fish per week, which is a general recommendation. So, if it’s necessary, I’ll suggest an omega-3supplement, but that’s always individually determined.
The last thing I wanted to mention was that just recently the North American Society for the Study of Celiac Disease was formed. It’s a clinician group, and their intention and mission is to spearhead celiac awareness in the medical and nutrition communities as well as in the public sector. They aim to be a guiding force because up until now, support has generally come from volunteer nonprofit organizations all across the country. So, we’re looking for a little bit more of a structured single entity that can help us bring awareness much more quickly to all populations.
DR. MUSHLIN: In the multivitamin supplement, would you also want to make sure that they got some zinc?
MS. DENNIS: Yes. All the multivitamins contain zinc, but often, we need to recommend extra zinc. There’s typically not 100% of your daily recommended zinc in a multi. It’s present in trace amounts. So, if needed, we’ll check serum zinc and give zinc for 6 to 8 weeks before retesting.
DR. MUSHLIN: Dr. Leffler, let’s go quickly to the question of malignancy associated with long-standing celiac disease. In my own clinical practice experience, I’ve actually had 2 patients with celiac disease who developed non-Hodgkin’s lymphoma. Do you think there’s a definite association between malignancies and celiac disease?
DR. LEFFLER: Unfortunately, it seems like that association is clear. The overall risk of malignancy in people with celiac disease is about twofold higher than what we see in the general population. The majority of that, as you saw with your patient, is due to non-Hodgkin’s lymphoma.
There’s also an increased risk of small intestinal adenocarcinomas and small intestinal lymphomas. They’re also known as enteropathy-associated T-cell lymphomas. So, there is a significant risk.
However, we don’t screen for malignancies in patients with celiac disease any differently than we do in the general population. This is because, thankfully, the risk of malignancy drops after diagnosis, and at approximately 5 years after diagnosis, the risk is pretty close to that of the general population. So, the risk seems to be related to chronic immune activation, and once you get that immune activation under control, the risk drops. It’s a little bit of a reward that helps patients to actually follow the diet and control their disease.
DR. MUSHLIN: Well, this has been a wonderful conversation. I’ve learned a tremendous amount, and I’m very grateful to you both.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
FoxP2 Media LLC
