A study of search engine queries shows people at risk for celiac are hard to identify based on symptoms. The analysis from Columbia University tried to identify what inquiries users made prior to being diagnosed with celiac but found no common set of terms.

The cost of screening everyone for celiac would be high, but so is the burden of undiagnosed disease. This study explores an alternative to screening: case finding, which identifies and screens only groups most at risk. While experts advise testing everyone with a family history of celiac, finding patients outside this group requires other information, such as symptoms. This study confirms that undiagnosed patients experience such variable symptoms that they are hard to distinguish from the general population.

The study extracted all queries submitted to Bing in the United States from January to October 2017. It identified 90,142 users who submitted a new celiac-related inquiry in October without any in the previous nine months. This narrowed to 6,528 who showed sustained interest by querying celiac more than once, likely indicating a new diagnosis. The study then analyzed all symptom inquiries prior to the supposed diagnosis.

This approach helped include symptoms patients might feel embarrassed to discuss. The data showed an increase in queries about celiac symptoms such as diarrhea, bloating and weight loss prior to the date of diagnosis. Searches about depression and anxiety also increased.

The glow has dimmed on the gluten-free halo. The diet is no panacea, no formula for peak performance.

“A gluten-free cookie or a brownie is no more nutritious than a regular brownie or cookie or cake made with gluten,” says Shelley Case, RD, of Calgary, Canada, author of Gluten Free: The Definitive Resource Guide. “There’s nothing magical about going gluten free.”

However, for people with celiac disease, it is the only treatment available. Having removed all sources of gluten from their diet, they must also achieve good nutrition. As with any diet, convenience foods may not be the healthiest choices.

“Every time you go on a restrictive diet, there is a risk for nutritional deficiency,” says Jocelyn Silvester, MD, instructor of pediatrics at Harvard Medical School in Boston. “While treating celiac disease helps you absorb nutrients better, it might also put you at risk for not absorbing the right profile of nutrients.”

Medical literature contains little data about long-term nutrition of patients on a gluten-free diet. The Manitoba celiac cohort study is following a group two years after diagnosis to see how treatment affects their nutrition. Silvester, who completed her residency training at University of Manitoba in Winnipeg, Canada, maintains ties with this research. She hopes it will show whether patients normally achieve good nutrition or need more follow-up. So what’s lacking when it comes to nutrients in the gluten-free diet? Read on for more on missing nutrients and what steps to take when going gluten free. 

Malabsorption and the Gluten-Free Diet 

The first hurdle for new patients is avoiding gluten so they can heal. Celiac flattens the villi, small, finger-like projections lining the small intestine. Damaged villi have less surface area and absorb fewer nutrients. If children do not get enough calories, they may fail to thrive or have delayed growth. Adults can suffer unwanted weight loss.

“Oftentimes, kids will adapt to this by increasing their caloric density to try to keep their weight stable. Once the gut heals, that higher caloric diet is suddenly too much for them,” says Hilary Jericho, MD, director of pediatric clinical research at University of Chicago Celiac Disease Center.

Adopting a new mindset that they do not need to consume 3,000 calories a day can be a big adjustment along with many other changes during childhood.

Malabsorption can cause specific nutrient deficiencies. Silvester says, “Nutrients that are absorbed in the first part of the duodenum—iron and calcium—are two of the main nutrients we see difficulties with.”

Iron and the Gluten-Free Diet 

Iron maintains a healthy red blood supply and stores oxygen in the muscles. Iron-deficiency anemia is common in new patients and often alerts doctors that a patient might have celiac. Fatigue, weakness and dizziness are common symptoms.

Adopting a gluten-free diet should be the first step to address iron deficiency, says Case. When the villi heal, they should absorb nutrients normally again.

Jericho says, “If you are having ongoing iron deficiency problems, then we really need to look into this and understand why. Once the gut is fully healed, you should not run into that problem.”

Case adds that iron supplements can be hard on the stomach, often problematic for people recovering from celiac.

She advises that the human body absorbs iron most readily from meat, fish and shellfish. The form of iron occurring in plants is less easily absorbed. Plant foods rich in iron include beans, peas, lentils, tofu, quinoa, seeds and eggs. The gut absorbs iron from plants better if they are eaten alongside meats or vitamin C foods like citrus fruit, strawberries, cantaloupe, peppers, tomatoes and potatoes.

Vitamin D, calcium and the Gluten-Free Diet 

Malabsorption can affect calcium and vitamin D. Both nutrients support healthy bones. Calcium in the bones alone contributes up to 2% of body weight. Children need a lot of it to grow and lay down critical bone mass.

“Adolescence and early 20s is a peak age when bone mineral density is accrued,” says Silvester. “Then, like so many other things in life, it’s a downhill slope from there. It’s really important to get kids better and make sure they’re getting adequate calcium and vitamin D so they can start with normal stores. If they start with a lower bone mass, then they are at greater risk of developing osteoporosis later in life.”

Calcium is also necessary for functions of the muscles, nerves, heart and other systems. If the body lacks enough for these vital tasks, it extracts calcium from the bones. Calcium deficiency can cause osteopenia, a thinning of the bones, or osteoporosis, making the bones more porous and fragile.

The prevalence of bone disease in celiac is unclear. However, patients face a greater risk of bone fracture. Experts consider poor bone density one of the potentially serious effects of untreated celiac.

Adding to the problem, damaged villi produce less lactase enzyme to digest lactose. Before being diagnosed with celiac, many patients compensate for lactose intolerance by restricting their milk consumption. This could potentially increase risk for bone disease, says Silvester.

Sometimes new celiac patients need a temporary lactose-free diet, says Case. Once the villi heal, they begin producing lactase enzyme normally. Then dairy products can be reintroduced to the diet. Intestinal healing also restores normal absorption of calcium and vitamin D.

Bone mass is difficult to improve in adulthood, Silvester says, “There is some interesting recent data from people diagnosed with celiac disease in adulthood that suggests that they might be able to recover their bone mass when they start a gluten-free diet.”

Exposure to sunlight provides the most important natural source of vitamin D. However, people in the northern states and Canada don’t get enough and need more from fortified food or supplements.

Milk, cheese and yogurt are the best dietary sources of calcium. Leafy green vegetables, seafood, nuts and dried beans offer smaller amounts.

Dairy products, cereals, juices and some other foods may be fortified with vitamin D depending on the producer in the United States. In Canada, vitamin D fortification is mandatory for milk and margarine. Fortified foods can also provide vital calcium.

Fiber and the Gluten-Free Diet 

Once the body heals, it needs the right profile of macronutrients: protein, carbohydrates and fat. Here convenience foods often fall short. For example, many gluten-free breads rely heavily on starch and fat to compensate for the missing textural properties of gluten.

Fiber is often overlooked. Case says it used to be assumed everyone with celiac had diarrhea, so no one considered adding fiber to the diet. However, one-third of celiac patients now present with constipation.

“If they already were constipated and then you remove your whole grains and wheat bran and all those high-fiber foods because they’re full of gluten, now we’ve got even more problems. All the more reason why we need to focus on fiber-rich foods,” says Case.

She advises checking nutritional information to compare products and see which contain more fiber. Whole fruits, vegetables, pulses (part of the legume family), nuts and seeds are naturally good sources of fiber. With oats and pulses like dried beans, peas and lentils, it is critical to look for a gluten-free label because they are subject to cross-contamination from wheat.

“I’m delighted to see a lot more pulse-based pastas coming on the market, such as lentils and chickpeas,” Case adds. “Traditional gluten-free pastas are usually made with white rice flour, corn flour and maybe quinoa. If you look at the label, again, they’re not enriched with iron and B vitamins like wheat-based pasta, and they don’t tend to have a lot of fiber. If you can switch to a pulse-based pasta, you get a lot more fiber and protein and more satiety.”

Convenience Foods and the Gluten-Free Diet 

“Convenience foods tend to be higher in sugar and fat and have less vitamins and nutrients than if you’re eating non-processed foods,” says Silvester. “Previously, going gluten free often meant cooking a lot of food for yourself. People would often substitute in more healthy foods, more whole foods, more fruits and vegetables. Now it’s easier to follow a low-quality gluten-free diet than ever before. It’s not enough to just be gluten free. You have to make sure that they’re eating a balanced, healthy gluten-free diet.”

To investigate the effect of gluten-free products, Jericho’s research team compared patient records before and after 2011, when gluten-free products became widely available. Specifically, they looked at how quickly body weight increased after diagnosis and treatment. The new study in Journal of Pediatric Gastroenterology and Nutrition found no significant change overall due to small sample size. However, adolescents showed a tendency toward higher body mass index after 2011.

In follow-up phone surveys, her team asked the teen patients now in their 20s to recall their eating habits at the time. All respondents diagnosed after 2011 said they consumed processed gluten-free foods sometimes or all of the time. One reported never eating processed foods before 2011 but admitted to always using them after they became available in stores. Besides the products being convenient and easy to prepare, patients reported it helped them fit in with their friends.

If further research shows an impact on adolescents, Jericho suggests they would benefit from a refresher nutrition course two years after diagnosis. It will affect their health down the road.

As a consulting dietitian, Case often receives products from companies. Her responsibility is to make sure they are safe, and the gluten-free claim is valid: “But then I look at the nutrition facts and have to say, ‘Is this product really all that great, or would I be better to eat something else, like some fruit, nuts and seeds or a trail mix, rather than these gluten-free cookies?’”

Case is not against eating treats: “Remember, we all like to celebrate birthday parties and special occasions. Children like to have a treat with their friends. Just be aware that some foods can be a lot more nutritious.”

See a dietitian

Case emphasizes, “It’s critical to work with a registered dietitian with expertise in celiac to individualize the treatment. Everybody has different issues going on, likes and dislikes, their lifestyle, what their cooking ability is or access to different foods. These are all things that the dietitian will go through.”

Case encourages people on the diet to watch for and consider using brands that enrich their products. Only a few do so now.

Silvester says folate deficiency in the North American diet has been addressed with fortification of grain products. Many gluten-free products don’t have folate added, so this especially can be a problem for patients with celiac.

“Patients with CD are going back to the pre-supplementation era,” says Silvester, but adds, “One of the great things about the body is it’s very good at absorbing what it needs and can scavenge minimal amounts from the diet to have adequate amounts in the body.”

Most children with potential celiac can continue to eat gluten and will never develop overt disease, according to research from Italy. Potential celiac is a condition in which patients develop typical blood antibodies but without damage to the small intestine. Patients may or may not have celiac-like symptoms. In this 10-year study, most cases spontaneously reverted to normal blood antibodies and remained healthy while consuming gluten.

The data came from a larger study attempting to understand how celiac develops. It is following from birth 553 children who are genetically at risk for the disease. Twenty-six individuals were diagnosed with potential celiac, all without symptoms. Biopsies showed a healthy intestinal lining. These diagnoses all occurred between age 15 months and 5 years. Parents of three children chose to start them on a gluten-free diet.

Twenty-three children continued a normal diet and were screened again for blood antibodies every year. If antibodies remained high or reappeared later, the patients underwent further biopsies. From this group, 19 children reverted to normal antibodies a year after their first biopsy and did not develop any autoimmune disease within 10 years. Three of this group (14 percent) developed celiac within three years of the first biopsy. One patient showed fluctuating antibodies, but their healthy gut persisted.

These findings will inform the debate about whether to start children with potential celiac on a gluten-free diet, especially if they lack symptoms. The authors suggest that in families with celiac history, children who test positive for blood antibodies should always undergo a biopsy to confirm a diagnosis before adopting a gluten-free diet for life. If the intestinal lining remains healthy, children can continue consuming gluten but should receive regular blood tests to make sure antibodies return to normal. Most young children with elevated antibodies will likely revert to normal and never develop celiac. However, the continued presence of antibodies indicates a high risk for developing celiac and calls for careful follow-up. The ongoing study will continue to monitor these patients.

The study notes that one of the three children who started a gluten-free diet later developed autoimmune thyroiditis. The authors suggest this contradicts the theory that a gluten-free diet protects children with potential celiac.

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Lionetti E, Castellaneta S, Francavilla R, Pulvirenti A, Catassi GN, Catassi C. Long-term outcome of potential celiac disease in genetically at-risk children: the prospective CELIOREV cohort study. Journal of Clinical Medicine. 2019; 8;186. doi:10.3390/jcm8020186.

Limited evidence exists for a link between celiac and autism spectrum disorder (ASD), according to a review from University of Calgary, Canada.

The analysis identified 15 studies made between 1946 and 2018 examining co-occurrence of the two conditions. Four studies screened celiac patients for ASD while 12 screened ASD patients for celiac. The three largest studies showed a significant link between celiac and ASD. The rest did not support a link, but these suffered from poor study design or small size.

Experts continue to debate the importance of screening people with ASD for celiac. Any patient should be tested for celiac before launching a gluten-free diet in the hope of treating ASD symptoms. This review suggests there may be a link but emphasizes a need for further research.

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Quan J, Panaccione N, King JA, et al. Association between celiac disease and autism spectrum disorder: a systematic review. Journal of the Canadian Association of Gastroenterology. 2019 March. doi:10.1093/jcag/gwz006.256. 

Claire Jansson-Knodell, MD, entered gastroenterology partly because it was a male-dominated profession. She wanted to change that. Then, during her medical residency, she researched another kind of gender discrimination—by a disease.

Celiac, like other autoimmune diseases, affects women more than men. As high as 70 percent of American patients are female. The rate of undiagnosed celiac is also higher among women.

Jansson-Knodell was the lead author of several studies from Mayo Clinic in Rochester, Minnesota, investigating how celiac affects the sexes. Using medical records and patient blood samples, she studied the gender gap in both undiagnosed and diagnosed celiac in Olmstead County, Minnesota. Local findings prompted a systematic review and meta-analysis of all medical research that detected rates of celiac in undiagnosed populations.

Among the patients referred to the celiac center, 71 percent of cases were women. In the studies of diagnosed and undiagnosed celiac in Olmstead County, the figures were 65 and 62 percent female, respectively.

“What struck me doing these research studies is that the trend persists across the different populations,” said Jansson-Knodell of the high rate of cases in women.

In the meta-analysis, 59 percent of people with undiagnosed celiac were women. The disparity appeared in data from every continent and consistently between individual studies. The overall risk for undiagnosed celiac is small: slightly under half a percent for men and slightly over half a percent for women. In comparison, however, a woman is 42 percent more likely to have undetected celiac disease.

“Overall, I think this is an important study which shows the incredibly high rate of undiagnosed celiac disease. The numbers the authors suggest is astonishing,” said Maureen Leonard, MD, clinical director of the Center for Celiac Research and Treatment, Massachusetts General Hospital for Children in Boston.

The study estimates there are 965,960 American women with undiagnosed and untreated celiac. Worldwide, the number is approximately 21.7 million. For men, the figures are 659,850 in the United States and 15.5 million worldwide.

Medical research often draws data from university hospitals. The patients who attend these centers are relatively self-motivated and can afford specialist care, possibly skewing the data. Experts call this referral bias. The Olmstead County studies took another perspective by drawing data from the community around Rochester. It found the rate of undiagnosed celiac in waste or extra blood from routine lab samples patients consented to provide for study.

Still, the findings reflect a particular community. One noted weakness is that nearly all participants were non-Hispanic whites. Other studies have consistently found the highest prevalence of celiac among white Americans.

Meta-analysis is another way to compensate for weak data such as small study size by pooling results. In the systematic review, Jansson-Knodell and colleagues narrowed 4,070 articles down to 87 that met their criteria for relevance and accuracy.

The findings have important implications for public health. The county studies found significantly higher rates of related health problems that affect women disproportionately. Among adult women with undiagnosed celiac, the prevalence of depression was 29 percent compared to a national rate of 6.7 percent. Among women over 50 with diagnosed celiac, the prevalence of osteoporosis was 35 percent compared to 16 percent nationally.

Notably, celiac also increased the rates of depression and osteoporosis among men. Most surprisingly, women and men with undiagnosed celiac had the same risk for other autoimmune diseases, 31.6 percent, though these are normally more common in women.

The reason why celiac affects more women remains unknown. A 2018 study from another team at Mayo Clinic identified differences in intestinal permeability and microbial diversity between healthy men and women. However, no research yet has connected these factors to the gender imbalance in celiac.

Potential explanations might involve environmental factors, hormones and genetics, said Jansson-Knodell: “When we wrote our first version of the systematic review and meta-analysis, we had a long discussion section about all these potential explanations for why is there this gender difference. At the end of the day, we cut out a lot of that because we simply don’t know. It was all theories. The research isn’t there yet to back up why we might see these differences.”

Leonard said, “I agree with the authors that more research into gender differences is appropriate, especially given the possibility that alternative therapies for patients with celiac disease are in the pipeline. When these therapies are successfully developed, it will be extremely important to understand these differences.”

With undiagnosed celiac so common, it is incumbent upon patients and doctors to look out for it.

Jansson-Knodell said, “I think the bottom line is to get tested, to seek medical care. If you’re having symptoms, if you’re iron deficient, if you have a family member with celiac disease, are a Type 1 diabetic or have some other risk factor, it’s important to seek medical care and to look into having your primary care doctor or your gastroenterologist consider doing some serology testing and then possibly a biopsy to confirm diagnosis.”

To emphasize the importance of pursuing a diagnosis while on a normal, gluten-containing diet, she tells of a good friend from medical school whose mother has celiac.

“My friend sees her primary care doctor once a year. Before going in for that visit, she makes sure she’s getting adequate gluten in her diet so that her testing will be accurate. She’s eating a piece of bread a day at least for the month prior to her visit. When she told me this, I was like, ‘Good for you! Staying on top of things and giving it a good shot for accurate testing.’”

After diagnosis with celiac, women should look after the key areas of bone health and mental health, said Jansson-Knodell.

Leonard said, “While more research is needed, the presentation for men and women with celiac disease and the treatment is exactly the same: a strict gluten-free diet. Women with celiac who are of child-bearing age should ensure that they are obtaining enough folic acid from their diet or a supplement to prevent neural tube defects in pregnancy. Gluten-free grains are not fortified with folic acid like their gluten-containing counterparts, so this is very important. Along the same lines, patients with unexplained infertility should talk with their doctor about getting tested for celiac disease.”

The gender divide in gastroenterology

We asked Claire Jansson-Knodell, MD, about her career goal to improve patient care for women in gastroenterology.

GFL: When and why did you decide to pursue a career in medicine?

CJK: In high school. I had a wonderful pediatrician growing up. I idolized him, and he provided excellent care for my sister, my brother and me.

I had rotavirus when I was a toddler before there was a vaccine. My pediatrician asked his nurse to drive my mom along with me to children’s hospital so I could be given IV fluids and supportive care right away.

Children in the developing world still have a high mortality rate related to rotavirus because the diarrhea can be so dehydrating. [My pediatrician] once told me that his gift in medicine as a pediatrician was to tell the difference between a sick kid and a not-sick kid. Because he knew I was a sick kid in his office, I was able to recover and have a healthy childhood. That practically made him a part of the family.

He helped me celebrate my high school graduation and my medical school graduation, where he joked that perhaps we could have a role reversal; I would love nothing more than to be able to care for him someday.

GFL: What drew you to study gender-based differences in celiac disease?

CJK: The interest in gender-based differences comes from a couple different angles. One is that I joined a male-dominated profession: 16.4 percent of practicing gastroenterologists in the United States are women. I was drawn to GI for that reason.

Within celiac disease, there’s this gender discrepancy within a population of people that we’re caring for. One of my goals was to provide excellent care for patients in general and in particular women with digestive issues.

Theoretically, half of the population is women. Many women prefer a female doctor. Given the male-to-female ratio of gastroenterologists right now, this isn’t always possible for our patients.

Sometimes in GI, we talk about sensitive issues such as bowel movements, patterns and habits. I want patients to feel as comfortable as possible because for most people this is not a typical topic of conversation. I can understand why some patients may prefer a doctor of the same sex, and one of many reasons why I chose GI was to help fill that gap in patient needs.

On a personal level, I would like to drive forward research in women’s health. Much of [the] research in the past, including in animal models, was done on males. This over-reliance on male cells and animals does not give us a clear understanding of sex differences in health and outcomes. Women used to be excluded from clinical trials, but the National Institutes of Health has changed that.

We need more female researchers, scientists and physicians to continue to make important contributions to their fields.

GFL: In writing for Gluten-Free Living, it seems women are equally represented among the top experts on celiac I’ve interviewed. Do you think celiac research attracts women because the disease seems biased toward them?

CJK: I am not sure. I am glad there are wonderful top experts in celiac disease who are women.  Personally, I had two male mentors in the field of celiac disease: Alberto Rubio-Tapia, MD, and Joseph Murray, MD.

You will also note that for the American College of Gastroenterology guidelines on the diagnosis and management of celiac disease, four of the five authors are men. This is one of the key references gastroenterologists use when diagnosing and caring for individuals with celiac disease.  

There are a growing number of female gastroenterologists. What is exciting right now is that all four major GI societies in the United States have female presidents.

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Van Waffle is a freelance journalist based in Waterloo, Canada, and research editor for Gluten-Free Living. He blogs at vanwaffle.com.

The largest population study to date has found a lower prevalence of diagnosed celiac disease in the United States than was estimated by previous screening studies. This adds strong evidence that the vast majority of people with celiac remain undiagnosed.

Researchers at University Hospitals Cleveland Medical Center in Ohio identified 83,090 celiac cases in a commercial database of 35.9 million patients. This indicates about 0.23 percent, or 1 in 435 Americans, have been diagnosed with celiac.

Previous screening studies found celiac (both diagnosed and undiagnosed) affects up to 0.95 percent, or 1 in 105, Americans. The prevalence in some European countries is even higher. These new figures support estimates that more than three-quarters of American patients remain undiagnosed.

The data come from over 300 health centers across the country. It was aggregated to remove personal information so regional variations could not be determined. However, women, whites and adults were more than twice as likely to be diagnosed with celiac as men, non-whites and children, respectively. Age data suggests diagnoses peak during early childhood and again in women during their 30s and men during their 40s.

Celiac often occurred alongside other health complaints, especially autoimmune disorders such as lupus, inflammatory bowel diseases and Type 1 diabetes. The authors call for liberal use of celiac testing whenever unexplained symptoms could be related to celiac.

A new study in Finland concluded celiac disease can be diagnosed accurately without a biopsy in some adults. These patients must score a triple positive on blood tests: 10 times the normal upper limit of tissue transglutaminase antibodies, positive for endomysial antibodies and a positive genetic test. In the study from University of Tampere, one-third of new celiac patients could have been diagnosed conclusively without a biopsy.

The group included 421 high-risk adults suspected of having celiac, 2,357 at moderate risk who were tested due to a family member having celiac and 2,722 low-risk individuals identified in a general population study. All participants underwent the three blood tests and a biopsy.

The tests diagnosed celiac in 274 people, with 90 meeting the triple positive criteria. In this latter group, biopsies proved blood tests diagnosis alone would have been 100 percent accurate. Triple positive diagnosis was possible in 37 percent of the high-risk, 20 percent of medium-risk and 48 percent of low-risk patients.

This large study of Finnish adults provides strong evidence for accurate diagnosis without biopsy. The authors advocate using non-invasive tests when appropriate in adults to save medical costs without sacrificing accuracy.

European gastroenterologists previously recommended the triple positive standard but only for children suspected of having celiac due to symptoms such as diarrhea. North American experts still disagree on its reliability, with some still holding biopsy as the gold standard. The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has not yet endorsed celiac diagnosis without biopsy.

A study from University of Bologna, Italy, supports screening for celiac disease even among adults. Earlier detection could prevent complications of the disease.

Despite high prevalence of undiagnosed celiac in Western countries, the value of screening programs remains controversial. Benefits of early diagnosis must outweigh the cost and risk of widespread testing. Critics argue patients diagnosed before they are aware of symptoms may be less motivated to stick with the gluten-free diet. This could in turn cause medical complications later on.

This study found 90 percent of patients detected through screening stuck with the diet, the same percentage found in patients diagnosed after they were suspected of having celiac. Data came from health records of 750 adult patients diagnosed from 2004 to 2013.

Researchers found an important long-term health benefit. Screened patients had a significantly lower rate of bone disease: 31.3 percent compared to 46 percent in other patients. They were also less affected by anemia.

The authors advocate screening adults to help diagnose the large hidden population of celiac patients. Improved health and reduced medical costs later on would balance costs of testing.

Celiac disease can impact bone development at a crucial stage in childhood. Compliance with a gluten-free diet is the prime contributor to bone recovery, according to a study from Virgen del Rocío University Hospital, Seville, Spain.

Intestinal damage from celiac prevents proper absorption of vitamin D and calcium for good bone health. Patients face an increased risk for osteoporosis and are twice as likely to break a bone. The gluten-free diet heals the gut lining and allows nutrients to reach the bones.

This study looked at 43 children ages 1 to 13 newly diagnosed with celiac between 2012 and 2016. A food questionnaire tracked dietary nutrition from before diagnosis to one year later. Both gluten-containing and gluten-free diets contained most of the necessary nutrients. Contrary to concerns that a gluten-free diet may be high in fat, researchers noted an improvement in the type of fat consumed. The patients consumed less saturated fats and more polyunsaturated fats.

Poor bone mineral density was found in 35.5 percent of patients at diagnosis. This improved significantly to 18.2 percent after one year on a gluten-free diet. The length of time required for full bone recovery remains unknown.

Nutrient intake was normal except for vitamin D, found to be deficient in both gluten-containing and gluten-free diets. The authors recommend supplements for children newly diagnosed with celiac but only if they have low vitamin D.

This is a common prescription for celiac disease: anxiety. Worry about every meal, every bite you take. If you happen to eat some gluten either accidentally or deliberately, it causes intestinal damage, increasing the risk for certain kinds of cancer, bone fractures and other complications.

While a gluten-free diet is the only treatment for celiac, hypervigilance can lead to mental illness.

A study from Harvard University and Columbia University recently reported people with celiac are more likely to recover from intestinal damage if they have a mood disorder. The scientific paper states prosaically, “Prior psychiatric disease was associated with mucosal healing.”

The pattern was especially strong for people who developed anxiety after being diagnosed with celiac. However, people with a prior mood disorder were also more likely to score a passing grade on their follow-up biopsy. Patients who let troubles roll off them were less likely to achieve intestinal healing. The findings came from health records of 7,648 Swedish patients collected over 40 years.

The Unseen Toll

“We see healing as a good thing. Healing is a reflection of strict adherence to the gluten-free diet,” says Benjamin Lebwohl, MD, assistant professor of medicine at Columbia University Medical Center in New York, who worked on the study. “It does appear that the treatment of celiac disease, the gluten-free diet, can exact a toll on the patients. Even if the patients are physically better off, some patients may suffer with regard to depression and anxiety.”

The impact on long-term mental health is also sobering. The study reports celiac patients who achieve complete healing of the small intestine face an almost 50 percent greater risk for future anxiety disorder and a 25 percent greater risk for depression.

“Patients who have celiac disease but have untreated depression are still patients who are suffering,” Lebwohl says. “Sometimes the presence of untreated depression can prevent a patient’s intestinal-related symptoms from improving. It comes up clinically even if a patient is strictly avoiding gluten. If they have an untreated mental illness, they will not feel better physically.”

Researchers hesitate when asked whether mood disorders are more prevalent in celiac patients than the general population.

A 2017 study of 22,000 people in the National Health and Nutrition Examination Survey found celiac patients had no increased odds for depression or sleep disorders.

Marilyn Geller, chief executive officer for the Celiac Disease Foundation (CDF) in Woodland Hills, California, points to gluten exposure itself as a frequent cause of distress: “There is a significant percentage of people with celiac disease or non-celiac gluten sensitivity (NCGS) who report anxiety, depression and brain fog from consuming gluten.”

It is often reported by patients in CDF’s online registry of 5,000, but the voluntary nature of the database prevents statistical interpretation. Geller says the percentage is significant enough that the patient advocacy group partnered with Children’s National Health System (CNHS), a children’s hospital in Washington, D.C., to develop continuing education in mental health support for celiac care providers.

Celiac and Child Psychology

In 2017, CNHS created a full-time psychologist position in its celiac program. Shayna Coburn, PhD, works directly with patients while developing a psychosocial health program to incorporate research and community outreach.

Coburn says she learned the challenges firsthand after being diagnosed with celiac while a graduate student in psychology in 2010.

“I was already interested in health psychology in children and suddenly had to face it myself,” says Coburn. “I started to notice there’s a lot of stress associated with coping with any chronic illness, especially with the challenges of the gluten-free diet. I didn’t find any resources out there. I had a lot of trouble even finding people who felt comfortable talking about the mental health struggles that come up.”

With the CNHS database in its first year, it cannot yet provide figures on how mood changes in patients over time. However, the initial baseline tells us something: “Thirty-four percent of families who come in report an existing mental health diagnosis in their child before they even walk through the doors,” says Coburn.

Anxiety disorders appear in 16 percent and attention deficit hyperactivity disorder (ADHD) also appears in 16 percent of children up to age 12 in the CNHS celiac program.

“We see large proportions of families reporting anger and overall distress in their children on an ongoing basis. That could be indicative of depression, but it is harder to diagnose that in kids. Irritability is a hallmark of depression in kids,” says Coburn.

In addition to those with a previously diagnosed psychological disorder, Coburn says she sees unrecognized cases of children who meet criteria for mental health problems. She believes 34 percent is a conservative estimate of their prevalence in children with celiac.

Parents sometimes ask if a diagnosis of anxiety disorder or ADHD could be caused by celiac itself: “We don’t fully know the answer. I usually tell them that we know there’s a link, but we don’t know if it’s going to get better. For some people it does, for some people it doesn’t, for some people it gets worse,” says Coburn, adding that CNHS’s research aims to understand the risk factors better.

Clues From Quality of Life

While not specifically a measure of mental health, quality of life has often been studied to assess the burden of chronic diseases. The questionnaire specific for celiac patients addresses problems such as social and travel barriers. In particular, patients are asked whether they feel depressed, frightened or overwhelmed by celiac.

A separate study by Columbia University in 2017 found celiac patients who were hypervigilant about their diet scored lower on quality of life. The hypervigilant group knew how to read food labels better. They cooked at home and used internet apps and sites to help stay gluten free. They chose celiac-friendly restaurants and asked questions of their servers—all things they are supposed to do.

“Eating out was particularly problematic,” the study reports.

Scoring lower on quality of life pushed hypervigilant patients into a worse category of self-rated health, stress, pain and ability to cope. The study included 50 adults and 30 teenagers enrolled at the Celiac Disease Center of Columbia University, New York. Psychological patterns were similar for both age groups.

The study notes a contrast with earlier research on quality of life in European celiac patients. However, in Europe, the gluten-free diet is more widely understood as a medical necessity for people with celiac. In North America, the gluten-free trend can lead to trivialization by food services. Some restaurants that brand themselves gluten free may not take adequate precautions. This makes celiac patients work harder to ensure their food is safe.

Both studies of hypervigilance suggest a gluten-free diet is achievable and promotes complete healing of celiac damage in the gut. However, it can restrict lifestyle and impose significant distress on many patients.

Beating Social Isolation

“It’s common that people feel socially isolated because of the combination of factors that go into trying to keep a strict gluten-free diet,” says Coburn. “In addition, when somebody experiences anxiety about potential exposure or about embarrassing or uncomfortable physical symptoms, they will cope by withdrawing from the feared situation. Social situations are scary at first. They’re overwhelming. People can accidentally reinforce avoidance and strengthen their anxiety by doing what they think keeps them safe and healthy. It’s a tough balancing act because they need to be vigilant, but it might become hypervigilant.”

For example, when attending an event where the food might not be safe, a patient can choose not to eat it. That is a reasonable coping strategy.

However, avoiding contact with friends or family out of fear of being pressured to eat something causes unreasonable social isolation.

“Shrinking into your world and only doing what you know to be safe can become a terrible feedback loop of feeling low, unmotivated and losing enjoyment in things. That makes it even harder to advocate for yourself and change the situation,” says Coburn.

A Holistic View

Lebwohl puts responsibility on doctors to become more aware of the interplay between physical and mental health, especially in celiac.

“In today’s climate, often we focus on the diagnosis at hand. We tend not to take a holistic view of the patient. If a gastroenterologist is taking care of the patient, he or she may be more likely to focus on intestinal symptoms, not impact on quality of life and mood. Because the treatment of celiac disease is a diet, too often patients report they were told by a practitioner to, ‘Google the diet, and you’ll be fine.’ This is really not enough,” says Lebwohl.

“Some patients will be very forward with regard to their psychic state and their physical state, whereas other patients may be less likely to see a connection or to raise it,” he adds. “For some, it’s not much of an issue. For others, it can really impact quality of life. For still others, there may be undiagnosed or untreated mental illness that impacts their ability to thrive.”

A holistic approach takes into account not only intricacies of the diet but also emotional challenges likely to come up, he says.

These include social challenges, impact on family life, the burden on a patient’s partner and how the diet affects work and travel. For new patients, Lebwohl says, “There’s no substitute for a session with an expert dietitian competent in the intricacies of a gluten-free diet. That competence speaks not only to what foods must be avoided but also knowing what measures might not be necessary and how to navigate a successful gluten-free diet that does not require social isolation and over-restriction.”

Van Waffle is a freelance journalist based in Waterloo, Canada, and research editor for Gluten-Free Living. He blogs at vanwaffle.com.

 

 7 HEALTHY WAYS TO COPE

Shayna Coburn, MD, offers coping strategies for living with celiac disease and a gluten-free diet.

1. Know what you want your life to look like. Identify your goals and move toward them gradually. Take your time. If you feel anxious about something you want to do, try not to do it all at once but break it down into baby steps. Keep your priorities in mind to balance being vigilant with having good quality of life.
2. Think about how to advocate for yourself. Decide how you want to communicate with other people. How much information do you want to disclose? Create a script to explain your needs. Practice it.
3. You do not have to tell everybody. Usually people will not even notice you avoid gluten. You can find out what you need to know from party hosts and restaurant managers without drawing attention to yourself.
4. Parents are sometimes not careful about what they share because they are trying to advocate for their child. Some kids will not mind, but others just want to fit in and do not want people knowing all the details. Coburn encourages families to discuss what needs to be said for safety and what is optional.
5. Reach out to people in the celiac community. Connect with people who reassure you that you are not alone.
6. Fact check everything you hear about gluten safety, especially from online support groups, because misinformation can cause unnecessary anxiety. The best source is a dietitian knowledgeable about celiac.
7. Parents of children with celiac are prone to feeling stressed and overwhelmed, too. They need to reach out for their own support.

A drug has been found that can relieve the most rare and serious form of celiac disease. While approval for treatment will still take several years, experts hope it could also treat milder cases of the disease.

The drug AMG 714 is a form of a human antibody, anti-interleukin 15. It prevents inflammation and damage to the lining of the small intestine on exposure to small amounts of gluten.

California-based pharmaceutical company Amgen previously licensed AMG 714 to Celimmune, a smaller company focused exclusively on celiac research, to conduct early trials in people with celiac. In 2018, Celimmune reported AMG 714 relieved symptoms and stopped progress of the disease in patients with refractory celiac type II (RCDII). This is a severe, often fatal condition in which inflammation evolves into a type of cancer (see sidebar).

“While I’ve seen a reasonable number of RCDII patients in the past, they’ve all done very poorly and died,” says Peter Green, MD, director of the celiac disease center at Columbia University in New York, who worked on the study. “It is uncommon, but when one sees them, they sometimes don’t survive all that long. It is a disease that is in need of a therapy.”

The yet-unpublished study highlights how rare the condition is. Within the United States, Green says he found only two patients to enroll, one in the east and one in the west.

“I called most of the university gastrointestinal divisions in the eastern side of the country to see if they had patients,” he explains. “Either the patients are not there, or they’re not being recognized, or they’re not being looked after in university medical centers.”

However, results of the study were hopeful, says Fernando Leon, PhD, a cofounder of Celimmune.

“We showed that anti-IL 15 was able to ameliorate or reduce the effects of gluten consumption in celiac patients,” says Leon. It reduced gut inflammation and improved symptoms while being well tolerated by the patients.

Evidence in celiac monkeys

Support for the drug has come from treatment of rhesus macaque monkeys with celiac-like disease. In a recent study, six gluten-sensitive monkeys showed improvement when treated with the drug while on a normal, gluten-containing diet.

Karol Sestak, PhD, core scientist at Tulane National Primate Research Center in Covington, Louisiana, has spent 12 years describing and comparing celiac in monkeys with that in humans. Medical research has more often used mice genetically engineered to be gluten-sensitive. However, macaques are more similar to humans both genetically and physiologically, offering advantages when studying therapy for humans.

Besides, they do not need to be genetically altered. The disease naturally occurs in a small percentage of macaques as it does in people. Sestak says his team discovered this while studying digestive problems in the primate colony in 2006. Various viral infections in the monkeys had already been isolated.

“Occasionally, there would also be some disease in these nonhuman primates where you cannot trace any kind of infectious agent when they have chronic diarrhea. Back then, we were wondering what that could be,” says Sestak. “We reformulated their diet. We removed all the gluten sources from the monkey chow. It was our first gluten-free diet. Their conditions dramatically improved.”

The researchers then found the celiac monkeys had the same disease antibodies detected in humans. Those antibodies decreased when the animals were treated with a gluten-free diet. Another similarity with human patients is that gluten-sensitive macaques display a wide spectrum of disease. Some are seriously affected, some moderately and some mildly. When identified in their routine check-ups, these individuals are placed on a gluten-free diet or can be assigned to try out another promising therapy.

In AMG 714 trials, it reversed inflammation and damage in all six animals regardless of the seriousness of their disease. Their recovery was checked using biopsy for a close look at the gut lining. The treatment also improved some but not all markers for immune disease outside the intestine, such as antibodies detected by blood tests.

AMG 714 works by suppressing IL 15, which appears to be a major immune agent but not the only one active in celiac. Since the drug healed intestinal tissue but did not reduce all disease markers, this suggests it might work best alongside a gluten-free diet or other therapy.

Next step for AMG 714

After the trial in humans, Amgen acquired Celimmune. Then, later last year, Amgen offered AMG 714 for further study to Provention Bio, which focuses on autoimmune diseases. Leon is once again a cofounder and chief scientific officer of this smaller company, based in Washington, D.C.

Provention Bio will conduct the next stage of research in non-responsive celiac. This condition includes patients who have persistent disease despite a gluten-free diet, but it is not as severe as RCDII. Toxicology tests must first be performed.

“With any molecule that you block in the immune system, you’re always blocking physiological function. Then the question is, what is essential for our survival and what is not essential?” says Leon. “The goal of drug development is to identify a target which is more important in disease than it is in healthy life. That’s when you get a good benefit-risk profile.”

Amgen initially developed AMG 714 to treat rheumatoid arthritis. These large human trials already showed the drug is well tolerated by patients, says Leon. For the next round, however, more evidence is needed to support using it over a longer period of six months. This will delay starting a study in non-responsive celiac patients until 2020, Leon says. If warranted, studies of safety and effectiveness in progressively larger groups will take several more years.

“I think we’re going to see the first drugs in celiac in the next four to six years,” says Leon.

Neither AMG 714 nor any other therapy currently under study is designed to replace the gluten-free diet, says Green. Medical research prioritizes therapy for people who remain sick despite a gluten-free diet. Once such drugs are approved, further efforts could investigate a drug’s ability to restore gluten tolerance.

Leon says, “We shouldn’t leave patients on their own like we’ve been doing for decades: ‘Just avoid gluten, goodbye.’ Celiac patients need to be provided tools corresponding to the severity of this disease. They need to be provided first and foremost with a nutritional tool: How to avoid gluten. They need to be provided with diagnostics to confirm the gluten-free diet. Finally, for patients who despite best efforts do not manage to avoid gluten, they need to be provided with medicine.”

Compassionate grounds

Meanwhile, drug companies can make treatments like AMG 714 available on compassionate grounds for people with life-threatening illness like RCDII, says Green, “but I’m not sure. I don’t have any patient currently on the drug. It’s not clear how many patients with RCDII are out there, as they aren’t being seen at the few celiac centers where people are equipped to look after them.”

Patients with severe forms of celiac could play an important role in medical research, Green adds. However, they must go to university celiac centers where therapies are being developed.

Degrees of celiac disease

Are you following a gluten-free diet but still experiencing symptoms? First, give it time. Even in the absence of gluten, the gut lining can take a while to heal. If symptoms continue more than a few months, they should be investigated by a doctor. Here is what can happen with poorly controlled celiac.

Non-responsive celiac disease

Symptoms continue and the small intestine fails to heal despite adherence to a gluten-free diet. This can occur for various reasons that need thorough investigation with a doctor. The most likely cause is unknown sources of gluten. A dietitian knowledgeable about the gluten-free diet can help sort it out.

RCDI might occur if gluten exposure continues to damage the small intestine. In rare cases, the immune system produces abnormal attack cells in its ongoing defense against gluten.

This is different from non-responsive celiac. RCDI is rare even among celiac patients who continue to experience symptoms. However, people with non-responsive celiac have an increased risk of developing refractory celiac disease. Likewise, patients with RCDI have a 50 percent risk of developing the next, most serious condition.

Refractory celiac type II

RCDII occurs when one abnormal attack cell starts reproducing itself uncontrollably. This is a type of blood cancer, specifically non-Hodgkin lymphoma localized in the intestinal lining. RCDII is rare, affecting an unknown minority of adult celiac patients, probably 2 percent or less. Unfortunately, the prognosis is poor.

How AMG 714 works

Interleukin 15 (IL 15) is a small protein the immune system uses to send signals between cells. Normally it helps defend the body against viral infections. When a virus is detected, immune cells release IL 15 to stimulate production of natural killer (NK) cells and killer T-cells. They in turn destroy virus-infected cells.

However, NK cells and killer T-cells act indiscriminately. In celiac, they attack cells in the gut lining when gluten is present.

AMG 714 is a human antibody that neutralizes IL 15, breaking the signal to attack. It stops killer cells from reproducing themselves and halts damage to the small intestine.

Many people at risk for celiac are not being tested according to medical guidelines. Columbia University found 30 percent of people with relevant symptoms, who had a first-degree relative with celiac disease, were not screened.

Current national guidelines do not recommend screening people without symptoms. However, experts call for a more aggressive approach to diagnose patients early and improve their outcomes. Even patients without symptoms benefit from going gluten free because they have fewer digestive problems, less intestinal damage and less anxiety about the illness.

Studies estimate the disease affects 10 percent of people who have a first-degree relative with celiac. To achieve earlier diagnosis, guidelines recommend screening parents, siblings and children of those with celiac.

Columbia University Irving Medical Center and New York-Presbyterian Hospital compiled medical data from relatives of 2,081 patients with celiac, identifying 539 relatives who later attended the center. In this group, 39.3 percent were tested for celiac. Among 165 first-degree relatives with celiac symptoms, only 71.5 percent were screened. Screening was much more likely for patients seen by a gastroenterologist (rather than another type of doctor) and those who had a family history of celiac clearly documented in their health records.

The authors speculate screening may be even less common in institutions that, unlike Columbia, do not specialize in celiac. This study calls for including family history in electronic health records and wider screening of first-degree relatives.

Faye AS, Polubriaginof F, Green PHR, Vawdrey DK, Tatonetti N and Lebwohl B, “Low rates of screening for celiac disease among family members,” Clinical Gastroenterology and Hepatology, 15 June 2018, doi:10.1016/j.cgh.2018.06.016.

People with celiac experience the rising gluten-free industry as a double-edged sword with benefits and challenges. Subjective experience is hard to quantify, but a new study utilized a novel technique.

The study at University of Calgary, Canada, relied on a psychological approach called interpretive phenomenology. Instead of testing a hypothesis using numerical statistics, it analyzes unstructured interviews with a small number of volunteers to reveal recurring themes. Researchers must continually evaluate their own previous biases.

The study recruited 17 adults with celiac who followed a strict gluten-free diet. Three had been diagnosed as children and two as adolescents, the rest as adults. Time since diagnosis ranged from less than a year for four volunteers to more than 10 years for six individuals. Interviews lasted 45 to 60 minutes and addressed a proliferation of gluten-free foods. After transcribing the conversations, researchers then used phenomenology to categorize excerpts and identify connections. The process concentrated on ideas shared by many participants, while discarding those less common.

The results highlight three consequences for people with celiac: changing social climates one participant described as a “double-edged sword,” altered self-image and psychosocial perseverance. Gluten-free options allow patients to eat out but increase their risk of getting glutened, for example. This affects self-image because other people may perceive patients as rude or high maintenance. Patients may even see themselves this way. Psychosocial perseverance means they must accept the diagnosis and its consequences, developing strategies to avoid gluten while trying not to let it consume their lives.

The study provides objective insight on the complexity of living with celiac. The authors call for non-dietary therapies, allowing patients a more fulfilled social life.

On diagnosis, children with celiac had three times the normal risk for low bone mineral density in a study at The Children’s Hospital of Philadelphia, Pennsylvania. The risk mainly concerns children with low body mass index. Patients who received a repeat X-ray showed a significant improvement, probably due to following a gluten-free diet. The study did not find any benefit to rescreening those with good bone density on the first test.

Untreated celiac can cause poor absorption of calcium, hindering bone development. However, most gastroenterologists do not screen children with celiac for low bone mineral density because there has been a lack of supportive research. Previous studies were small and did not highlight additional risk factors to help doctors know which patients were at risk.

This study considered previous medical records from 673 children with celiac who underwent X-rays between 2009 and 2016 at the hospital. Seven percent had low bone mineral density. Among children with low body mass index, the prevalence was 10 percent, almost three times higher than for those with normal body weight. This suggests body mass index could be used to indicate a need for X-rays. Further study will be necessary to clarify the prevalence of bone problems by following new patients from diagnosis through treatment and follow-up.

Webster J, Vajravelu ME, Choi C, Zemel B and Verma R, “Prevalence of and risk factors for low bone mineral density in children with celiac disease,” Clinical Gastroenterology and Hepatology, 30 Nov 2018, doi:10.1016/j.cgh.2018.10.035.

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Van Waffle is a freelance journalist in Waterloo, Canada, and research editor for Gluten-Free Living. He blogs at vanwaffle.com.

New research has identified permanent “immune scarring” in celiac disease which persists despite recovery on a gluten-free diet. It helps explain why patients never recover tolerance for gluten. The evidence encourages early diagnosis of celiac and has implications in the search for a cure.

The study showed, “that subsets of long-lived immune cells that reside in tissues such as the intestine and function to protect us under normal conditions can be permanently lost as a consequence of chronic inflammation,” says Toufic Mayassi, graduate student in the committee on immunology at University of Chicago, who was the primary researcher and author.

In early inflammation the healthy immune arsenal continues to operate but eventually reaches a tipping point. Then pro-inflammatory cells overtake the niche previously occupied by the protective cells. In celiac these new cells are activated by gluten.

“We were able to identify a subset of pre-celiac patients where the immune compartment was not yet fully altered suggesting interventions in these individuals may allow for the preservation of their healthy immune makeup. With the current treatment strategies this would only be accomplished by placing these individuals on a gluten-free diet prior to the full development of the disease,” says Mayassi.

“In the same vein, we observe in a subset of young children where the diagnosis was made early that they preserve various features of the healthy immune compartment suggesting again if treated early the impact of disease manifestation may be blunted. We will be able to determine whether or not these children maintain the healthy subset as we study them over time,” he adds.

Once they are supplanted, the gut does not recover the population of cells normally involved in preventing infections and tumors.

“That celiac patients permanently lose these cells leaves a functional vacancy that may predispose these patients to future infections and development of intestinal tumors,” says Mayassi. “Work towards a cure for celiac disease will need to consider that complete effectiveness of a treatment may depend on fully restoring the immune composition found in the gut in a manner that fully recapitulates the healthy gut.”

Celiac provides a good model for inflammatory disease because it can be controlled by removing gluten. Mayassi says the findings may help understand other conditions where tissue-resident immunity is profoundly altered, such as inflammatory bowel disease.

Children with celiac receive inadequate medical follow-up, according to a study at Boston Children’s Hospital. Within three years, half of patients were lost to follow-up, despite national guidelines that all celiac patients need routine assessment. Children diagnosed at a younger age and those with private health coverage were found to continue seeing their gut specialist longer.

The data were collected and analyzed by Boston University student Bradley Blansky for a master’s thesis. He drew records of 250 randomly selected children diagnosed with celiac at the hospital between 2010 and 2014. After diagnosis, 9 percent did not attend any follow-up visits, 14 percent stopped attending within the first year and 17 percent failed to receive counseling from a dietitian. One quarter of patients gave abnormal blood tests on their last visit, indicating poor dietary adherence.

Experts advocate follow-up because children with celiac have a better quality of life when they receive medical support to change their diet and lifestyle. Adolescents need help with knowledge and skills adjusting to peer pressure and new situations. Follow-up can also prevent eating disorders, anxiety and depression, increased risks for children on restrictive diets.

Health providers may need to take more proactive measures to ensure children with celiac receive continued care.

For more information for gluten-free kids, click here.

Italian research shows a temporary diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can help those with persistent celiac symptoms despite adherence to a gluten-free diet. Study participants showed improvements in both digestive complaints and mental health after only three weeks.

Read Getting a Grip on Gluten Sensitivity: Do FODMAPs Play a Role?

The study at a teaching hospital at University of Milan recruited 50 volunteers with celiac. Those selected still had irritable bowel syndrome or other intestinal problems after eating gluten free for at least one year.

Half the group was randomly assigned to follow a regular gluten-free diet while the other half also went on a low-FODMAP diet for 21 days. Overall symptoms improved only for the low-FODMAP group. They reported much lower abdominal pain and better fecal consistency. Both groups showed an improvement in psychological wellbeing, but it was much higher on a low-FODMAP diet. The improvement for those eating only gluten free probably resulted from increased support for dietary adherence during the study.

Click here for a list of foods with high and low FODMAPs.

This is the first study of its kind researching a low-FODMAP diet in celiac patients. In some cases, temporary elimination of FODMAPs can restore a disturbed gut to a healthier state able to tolerate most foods.

This study did not follow up to determine whether benefits impacted long-term health. More study will be needed to prove any sustained effect on celiac patients’ quality of life.

Roncoroni L, Bascuñán KA, Doneda L, et al. “A low FODMAP gluten-free diet improves functional gastrointestinal disorders and overall mental health of celiac disease patients: a randomized controlled trial.” Nutrients. 2018;10;1023. doi:10.3390/nu10081023.

A small capsule containing a camera can, when ingested by a patient, explore the small intestine for a celiac diagnosis. Combined with computer technology, it can diagnose the disease without an invasive procedure and with greater accuracy.

Gut experts normally use endoscopy to look for telltale damage from celiac. Human analysts sometimes misinterpret images and tissue samples from the gut lining. Some doctors and patients skip the endoscopy altogether, relying on even less accurate blood tests. Misdiagnosis is common in celiac patients.

Research from Singapore and Columbia University has developed an approach that could reduce the fuss and uncertainty. The patient would ingest a small capsule called a PillCam to capture images of the gut in its travels. The person would carry a data recorder for eight hours. The pill would pass out of the body after a day or two.

Video clips would be sent to a computer deep-learning system trained to detect celiac. It can distinguish diseased from healthy gut lining with 100 percent accuracy.

The technology still has some kinks. It needs a large volume of images and cannot make a diagnosis in real time. The researchers developing the system plan to fine tune it for efficiency to help doctors cut the rate of misdiagnosis.

Van Waffle is a freelance journalist in Waterloo, Canada, and research editor for Gluten-Free Living. He blogs at vanwaffle.com. 

Children treated for celiac heal faster than adults. In a study at the University of Chicago, most patients reported improved symptoms after two years on a gluten-free diet. However, gastrointestinal complaints like bloating and diarrhea resolved better than non-digestive problems like fatigue.

The study tracked 554 celiac patients—227 children and 227 adults. When first diagnosed, 78 percent of children and 91 percent of adults had at least one classic digestive complaint: abdominal pain, diarrhea, bloating, failure to thrive in children, weight loss in adults or constipation. Extra-intestinal symptoms appeared alongside or sometimes on their own: headache, fatigue, iron deficiency anemia and psychiatric disorders. Three percent of adults and 10 percent of children diagnosed through screening had no symptoms.

After two years of treatment, both groups showed high rates of gastrointestinal improvement. Bloating, diarrhea, weight loss and abdominal pain had each resolved by at least 81 percent in children and 71 percent in adults. Extra-intestinally, children recovered well from poor mood and anemia, less so from short stature and psychiatric disorders. Adult anemia resolved well, but poor mood and muscle pain improved by only 50 percent.

Hilary Jericho, MD, says a key message is patients need an appropriate expectation for the speed of recovery. She is director of pediatric clinical research at University of Chicago Celiac Disease Center, where she and colleagues collected data from patients treated between 2002 and 2015.

“Patients come to me for a second opinion because they were diagnosed with celiac disease three months ago. They went on the gluten-free diet and their symptoms have not fully resolved,” says Jericho. “Maybe the wrong expectation was set here. If you are a child, you have a very good chance of complete resolution. Sometimes it is going to take 12 to 24 months.”

Joseph Murray, MD, who runs the celiac disease research and clinical program at Mayo Clinic in Rochester, Minnesota, says this offers new insight about symptoms and recovery. Gastroenterologists know more about digestive problems but less about how manifestations like fatigue respond to a gluten-free diet. The study distinguishes how they progress and compares the response between children and adults.

Going gluten free is not easy for anyone, but newly diagnosed adults face particular challenges, Murray says. Old eating habits are hard to change. The diet presents social, psychological and practical difficulties. Adults have already been exposed to gluten for decades. Chronic inflammation may take longer to heal. These factors affect dietary adherence and recovery.

“Kids are very resilient,” says Jericho.

Maureen Leonard, MD, clinical director of the Center for Celiac Research and Treatment at Massachusetts General Hospital for Children, Boston, also welcomes the findings: “It is really helpful to tell children we see in our clinic that most kids feel better once they start a gluten-free diet.”

However, a few patients recovered poorly. Eight percent of children and 12 percent of adults did not follow a gluten-free diet. Most of these patients had ongoing symptoms.

Even among those who went gluten free, one-third of children and half of adults reported at least one persistent symptom, but that does not mean a lack of improvement, according to Murray.

“Persistence doesn’t necessarily take account of severity,” he says. “If I have headaches every single day because of celiac disease and after a year or two on a gluten-free diet I still have headaches but only once every two weeks, that is persistent but not anywhere near as bad.”

If symptoms do not improve, the patient should return to the doctor and make sure the diet is truly gluten free, says Jericho. Restaurants and processed foods can contain unrecognized contamination.

However, poor recovery often reveals different illnesses occurring alongside celiac. Doctors call these comorbidities.

A previous study of the same patient records found 28 percent of children who responded poorly to the diet had comorbidities. Genetic disorders like Turner syndrome are common in the celiac population. So are other autoimmune conditions, like thyroid disease. Jericho recommends close follow-up with a doctor to detect these in children.

Leonard agrees: “Patients need dietary reinforcement, so they should see a dietitian once a year. They should see a gastroenterologist to look for signs of ongoing celiac disease or comorbidities.”

Jericho says with patients recovering poorly, she uses follow-up blood tests to ensure celiac antibodies return to normal. She might also conduct endoscopies to inspect the gut lining. These tests normally reveal a healed gut, she says, prompting her to look for comorbidities.

The study only measured symptom recovery, not intestinal healing directly. Use of blood tests to track recovery is gaining popularity, but many experts express skepticism. Follow-up biopsies remain common practice at some referral centers. A 2016 study at Massachusetts General Hospital found blood tests poorly predicted gut healing as revealed by biopsy.

Leonard, who participated in that research, says relying on whether a patient feels better highlights a major issue in celiac research.

“What is our treatment endpoint for patients with celiac disease?” she asks, arguing the research community needs more data to answer the question. “Should we focus on symptoms, on what the serology tests show, on mucosal healing or a mixture of all three?”

“While the antibodies are very robust for diagnosis, they are not as good for monitoring [recovery] as we believed before,” says Alessio Fasano, MD, a co-author with Leonard of the 2016 study and director of the Center for Celiac Research and Treatment at Massachusetts General Hospital. “We need to see that the symptoms are gone and the intestine is healed. That gives a great level of confidence that the autoimmune process is completely under control.”

Jericho has a different view: “It would be over-reactive to re-biopsy all these patients and expose children to the risks of anesthesia and of having a second procedure, when, at the end of the day, most kids respond very well to the gluten-free diet and have good gut healing.”

What can a gluten-free diet treat?

A gluten-free diet is the only treatment for:

• celiac disease
• non-celiac gluten sensitivity
• wheat allergy

Some studies support screening patients with certain genetic and autoimmune disorders for celiac. These include:

• type 1 diabetes
• Crohn’s disease
• thyroid disease
• autoimmune liver disease
• Down syndrome
• Turner syndrome

Some doctors might recommend a gluten-free diet to treat other conditions, but the science remains inconclusive for:

• irritable bowel syndrome (IBS)
• rheumatoid arthritis
• fibromyalgia
• autism

Patients should consult a gastroenterologist to diagnose celiac or rule it out before adopting a gluten-free diet to treat other illnesses.

Van Waffle is a freelance journalist based in Waterloo, Canada, and research editor for Gluten-Free Living.

Complementing this study on non-classic celiac symptoms delaying diagnosis, research from Finland shows most celiac children have non-intestinal symptoms upon diagnosis. Those diagnosed because of non-intestinal problems show more severe symptoms and damage to the small intestine than children presenting mainly classic symptoms (see Extraintestinal Celiac Symptoms in Kids).

The study included 511 children with biopsy-proven celiac. The main reasons for suspected celiac were classic symptoms like diarrhea and abdominal pain in 49 percent and non-intestinal conditions in 23 percent, while 29 percent were diagnosed after screening because of risk factors like family history. Researchers compared children with celiac to 180 children diagnosed with functional gastrointestinal disorders like irritable bowel syndrome without evidence of tissue damage.

The symptoms

Non-gastrointestinal complaints included skin rashes, anemia, poor growth, enamel defects, nerve problems, headaches, joint pain, mouth sores, elevated liver enzymes, eye problems and other conditions. Poor growth and anemia were most common, affecting 27 and 18 percent of children with celiac, respectively. Patients with celiac were almost twice as likely to have non-intestinal conditions as children with functional disorders: 62 compared to 33 percent.

Disease severity

On endoscopy and biopsy, children who had non-intestinal complaints showed the most severe damage to the small intestine. Symptoms were more severe in 78 percent diagnosed because of non-intestinal conditions compared to 45 percent presenting primarily classic symptoms.

These two studies highlight a need for further research to understand the prevalence of various non-classic symptoms associated with celiac. Meanwhile, doctors should consider celiac as an underlying cause.

Nurminen S, Kivela L, Huhtala H, Kaukinen K and Kurppa K, “Extraintestinal manifestations were common in children with coeliac disease and were more prevalent in patients with more severe clinical and histological presentation,” Acta Paediatrica, March 2018, doi.org/10.1111/apa.14324.

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Research from three U.S. hospitals reveals patients with non-classic celiac symptoms face a much longer delay in diagnosis. In a cohort of 101 adult patients, 52 who initially saw a doctor with gastrointestinal complaints were typically diagnosed in 2.3 months. The median diagnosis time for people with non-gastrointestinal symptoms was 3.5 years. These patients showed signs including fatigue, anemia, thyroid, liver or bone density abnormalities, or dermatitis herpetiformis, a form of celiac causing skin blisters.

The study included only patients with biopsy-proven celiac. The authors say their findings show doctors should evaluate patients for celiac if they have unexplained anemia, thyroid disease or abnormal bone density.

Thyroid disease

Autoimmune thyroid disease commonly occurs alongside celiac. In this group of patients, a remarkable 43.2 percent of those lacking gastrointestinal symptoms had thyroid abnormalities compared to 15.5 percent of those with gastrointestinal symptoms. Overall one-third of patients had abnormal thyroid hormone levels, much higher than reported in any other study.

Anemia and bone density

A majority of the non-gastrointestinal group had anemia and abnormal bone scans: 69.4 percent and 68 percent, respectively. These problems were less prevalent among those with gastrointestinal symptoms: 11.5 percent and 41 percent, respectively. Few patients had dermatitis herpetiformis or liver abnormalities.

The authors note 11 percent of this study group were Hispanic and 3 percent were African American. This appears higher than expected as celiac is considered rare among U.S. ethnic minorities.

The authors say they are unaware of any previous study to compare gastrointestinal and other symptoms in biopsy-proven celiac. This fresh perspective comes from Howard College of Medicine in Washington D.C., Loyola Medical Center in Maywood, Illinois, and Medical University of South Carolina, Charleston. These are outside the group of several celiac clinics that conduct the most U.S. research. The study did not account for various other non-gastrointestinal conditions. These include peripheral neuropathy and mouth ulcers that may be associated with celiac.

Paez MA, Gramelspacher AM, Sinacore J, Winterfield L and Venu M, “Delay in diagnosis of celiac disease in patients without gastrointestinal complaints,” The American Journal of Medicine, November 2017, 130;11:1318-1323, doi.org/10.1016/j.amjmed.2017.05.027.

Learn more about recent headlines and research in This Week in Gluten-Free News!

Experts believe healthy gut microbes might protect children at risk for celiac. The microbiome undergoes complex changes during infancy as bacteria colonize the gut. This is an important time for the child’s immune system because it responds to both beneficial and virulent strains. A Spanish study of infants is among the first to record how the microbiome develops differently before the onset of celiac.

Previous studies noticed abnormal bacteria in celiac patients after diagnosis, but the disease itself could have caused this condition. Researchers needed to study the microbiome in healthy individuals to see how it behaved in those who remained healthy compared with those who developed the disease. The Celiac Disease Genomic Environmental Microbiome and Metabolomic (CDGEMM) study is currently recruiting participants in the U.S. to study newborns at risk.

The Spanish group identified more than 200 infants with a family history of celiac and tracked their history. They compared 10 who eventually developed celiac with 10 similar children who did not. They collected fecal samples at 4 and 6 months of age, analyzing what kinds of bacteria appeared and what antibodies the infants produced in response.

The findings

In healthy children, microbial diversity increased significantly between 4 and 6 months. In contrast, those later diagnosed with celiac showed a prematurely high microbial diversity that did not increase during that period. Bifidobacterium longum was relatively abundant in normal development, while other bacteria were associated with celiac. The two groups showed a distinct difference in immune response, suggesting microbial differences influenced how their immune systems developed.

The test matched each celiac patient with healthy children who had similar birth delivery (vaginal versus caesarean section), breastfeeding and early feeding practices. All the children were genetically susceptible to celiac. The comparison showed none of these factors caused an unhealthy microbiome.

The study was small and lacked enough data to explain what disturbed normal microbial colonization. However, these early findings encourage larger studies of the infant microbiome.

Olivares M, Walker AW, Capilla A, Benítez-Páez A, Palau F, Parkhill J, Castillejo G and Sanz Y, “Gut microbiota trajectory in early life may predict development of celiac disease,” Microbiome, 2018;6:36, doi:10.1186/s40168-018-0415-6.

Parents who are interested in enrolling their infant can visit the study’s website at www.cdgemm.org to see how their little ‘GEMM’ can help make celiac history. To enroll or inquire about enrollment, contact a participating center nearest you.

Want more information on celiac and kids? Check out our Kids section.

Maybe not—but it can’t hurt

Ritu Verma is a pediatrician and mother of three. Two of her children have celiac and one does not. She was unable to breastfeed one of the three.

“There were a lot of people making me feel very guilty that I could not nurse,” says Verma, MBChB, director of the Center for Celiac Disease at Children’s Hospital of Philadelphia. “Being a pediatrician, I know how important it is to breastfeed, but if you are not able to do it and you have given your all, it is not fair to the mom to make her feel guilty.”

Fortunately the child she had trouble breastfeeding is the one who does not have celiac, otherwise she says she would probably feel guilty anyway. For years experts theorized that breastfeeding and timely introduction of gluten could protect children from celiac. Early research hinted that introducing gluten while still breastfeeding between 4 and 6 months of age might prime a baby’s immune system to tolerate gluten. However, the evidence was weak, often relying on past data that did not study effects of breastfeeding directly.

More recent research

Two studies published in The New England Journal of Medicine in 2014 compared different approaches to early nutrition in children at risk for celiac. They recruited infants who had a parent or sibling diagnosed with the disease. One study randomly assigned 832 newborns to be introduced to gluten at 6 months of age, the normal age for solid foods, or at 12 months. Fewer of the late group had been diagnosed with celiac by age 2 but they caught up by age 5. At age 10, one-quarter of the study group had been diagnosed with celiac. Delaying gluten introduction delayed celiac but did not reduce long-term risk.

The other study involved 944 at-risk infants randomly assigned to receive either a small dose of gluten or a placebo daily from age 4 to 6 months. Then they were introduced normally to solid foods. Introducing gluten during the 4- to 6-month window, when most children get their first taste of gluten, made no difference. This study recorded breastfeeding in more detail, comparing whether children were breastfed, whether it was exclusive and for how long. No approach to breastfeeding gave children an advantage against celiac.

This disappointed researchers trying to understand why some children genetically predisposed for celiac remain healthy while others become sick. Commenting in The American Journal of Gastroenterology in 2016, Joseph Murray, MD, of Mayo Clinic, and Benjamin Lebwohl, MD, of Columbia University Medical Center, called this a “back to the drawing board moment” for the celiac community. They wrote that these “unequivocal and disappointing” findings force researchers to refocus the search for what causes celiac.

Experts admit this leaves parents wondering how they can prevent celiac in their children at risk, but the simple answer is: nothing unusual. The American Academy of Pediatrics adopted the standpoint that a healthy child with a family history of celiac should be treated like any other healthy child.

Breastfeeding basics

Maureen Leonard, MD, clinical director of the Center for Celiac Research and Treatment at Massachusetts General Hospital for Children in Boston, says, “If breastfeeding is available, we recommend it until 4 to 6 months of age. We always recommend that an infant be exposed to as many foods as possible, again starting between 4 and 6 months of age.”

Verma says, “Breast milk has the right balance of fat and nutrition. It is the most easily digestible for the immature gut when the baby is born. Secondly, the factors in breast milk help fight infection, building immunity. Finally, bonding happens between the child and the mother with breastfeeding. Those are the three main reasons why breastfeeding is a good thing.”

As for breastfeeding preventing celiac, Verma says, “I don’t think anyone would say it is not helpful.”

Experts expect new insight from studying the microbiome, the community of bacteria that colonize the gut and interact with the infant’s immune system as it develops.

“There are many factors that will change the microbiome. Those are the factors we need to know,” says Verma. “In celiac disease, the discussion has been about breastfeeding, the timing of gluten introduction, the amount of gluten introduced, and if there is a [viral] infection.”

She adds, “Breastfeeding does make a difference. The question is two-fold. Does the microbiome change based on breastfeeding? I will say yes. Does that have an effect on at-risk patients? I think time will tell. I personally think it will be beneficial.”

Verma stresses that if a mother has difficulty nursing for any reason, there are alternatives. A mother should never feel guilty for not breastfeeding if medical or psychological factors prevent it.

Viral infections

For children at risk, she does recommend a special precaution in the case of viral gastroenteritis, which causes symptoms such as diarrhea, fever and vomiting.

In 2017, an international team of scientists reported on an innocuous reovirus that provokes immune response in people while hardly making them sick. Celiac is more common in people who have antibodies for this reovirus, proving they have been infected by it sometime in life. The study demonstrated in theory how the bug could disrupt tolerance to gluten and cause celiac. This possible cause remains unproven, but several other investigations have pointed fingers at viral infections.

Verma advises parents of children at risk: “If at 5 months you are going to introduce gluten and your baby has viral gastroenteritis, maybe hold off a little. That infection makes the gut more permeable. Time will tell, but I think it could potentially be a trigger [for celiac].”

Wait a week or two until the child has recovered, and introduce gluten when digestion is stable, she suggests. All healthy children should be introduced to gluten in time.

Celiac stress

For parents worried about avoiding celiac, Leonard says, “While children with a family history have a higher chance of developing celiac disease compared to the general public, it is still more than three times more likely that they will not develop celiac disease. If the family decision is to keep a gluten-free household, I would encourage them to allow the child [who does not have celiac] to eat gluten outside of the home so that they can participate in the many social activities that revolve around food. At this time we have no evidence to suggest that the child should refrain from eating gluten.”

Verma agrees: “I do not recommend that parents keep their children gluten free if they don’t have celiac disease. They should treat the child like any other child.”

She points out that a normal diet including whole grains can be more nutritious and less expensive than a gluten-free diet. She also warns against the psychological burden of forcing a healthy child to follow a gluten-free diet because another family member has celiac. This can lead to resentment between siblings, for example.

Genetic testing

Leonard suggests concerned parents can have their child tested for celiac genetics. Verma does not recommend doing this at birth because the child should not be treated differently regardless of risk.

She insists on having this conversation with parents who want genetic testing: “If you know that your child has the gene, is that going to make you not want to feed them gluten? As they get a little older and complain of a bellyache or a headache, are you going to be doing a celiac [test] every week? Are you going to be in constant fear the rest of the child’s life that he or she is going to end up with celiac?”

If the parent agrees not to change anything but still wants to know, Verma says, “I will give in.”

Verma and Leonard both send children for a first panel of blood tests by age 3. They then re-screen for celiac every three to five years thereafter. However, Verma points out that blood tests for celiac are invalid in children who consume lower than normal levels of gluten. This may occur, for example, in a home where others follow a gluten-free diet. She would delay screening until the child is consuming a significant amount of gluten every day.

Current study

Infants at risk can help unravel the mystery of what role the microbiome plays. The Celiac Disease Genomic Enviromental Microbiome and Metabolomic (CDGEMM) Study is enrolling children who have a first-degree relative with celiac. Leonard is one of the researchers in this study. She says it includes a questionnaire about life history, stool collection every three months and blood every six months. Infants from across the county may participate by mail free of charge. To learn more, visit https://bit.ly/2GgpFgX.

According to legend, celiac research originated with Dr. Willem Dicke. He discovered the cause of celiac during the 1944-’45 Dutch famine under German occupation. He noticed children recovering on a starvation diet, then falling sick after bread was airdropped into Holland. Dicke conducted clinical trials for years, asking parents to remove one food or another from their children’s diets. The famine confirmed what he already knew: something in wheat, barley and rye was the culprit.

“That was one of the huge breakthroughs in celiac disease: identifying an environmental factor that drives the immune disease,” says Ciarán Kelly, MD, medical director of the celiac center at Beth Israel Deaconess Medical Center in Boston. “With most autoimmune diseases, we do not know what the environmental factor is.”

Celiac offers a unique tool to study autoimmunity, explains Daniel Leffler, MD, director of clinical research at the celiac center: “We can control celiac disease by adding and removing gluten in a so-called gluten challenge study, a degree of control we have in very few other diseases.”

Celiac often killed children before Dicke solved the puzzle. Now most patients live full, healthy lives on a gluten-free diet.

However, not everyone recovers well. Strict gluten avoidance affects quality of life. Inability to follow the diet or accidental gluten exposure—getting “glutened”—can cause ongoing symptoms. In refractory celiac disease, intestinal damage persists despite strict adherence.

Unraveling autoimmunity and developing alternative therapies hinge on patients willing to participate in studies. Medical experts say research could move faster if people living with celiac took a more active role. Apparently they tend to suffer in silence even more than people with other diseases. The reason may be that they have frequently been misunderstood in the past.

Silent problem

“The diagnosis of celiac disease is not taken adequately seriously by the medical community,” says Kelly. “There is a false impression that once a patient is diagnosed and told to follow a gluten-free diet, it is a straightforward treatment that almost always works.”

Recent studies uncover a different story. Patients rate their overall health better than people with other chronic diseases but consider their burden of treatment higher. Many fear getting glutened, worry about food costs, avoid eating out and become socially isolated.

In 2014, patient advocacy group Beyond Celiac met leading researchers and asked what they needed to investigate a cure. Experts concluded that the No. 1 gap was a lack of data about people living with celiac.

“We don’t have a good understanding of the burden of the disease,” says Alice Bast, chief executive officer of Beyond Celiac. “We don’t understand the long-term health consequences. At this meeting, we determined that the most important contribution Beyond Celiac could make to accelerate research was to get patients’ participation.”

Leffler says, “Something about the disease, about the treatment thus far, has made people need to be understated, to not complain, to minimize or hide the disorder and not talk about how it affects their lives. I wish I knew the roots of this in celiac disease.”

Marilyn Geller, chief executive officer of Celiac Disease Foundation, explains, “Our community has been told that this is a disease not worth investing in. Congressionally funded medical dollars go to other diseases…. We have to convince policy experts and the biopharmaceutical industry we need treatment alternatives to the gluten-free diet.”

Referral bias

Much research about celiac in North America comes from a handful of major referral centers. Peter Green, MD, director of the Celiac Disease Center at Columbia University Medical Center, New York, says eight doctors there receive 10,000 visits per year, mainly celiac patients.

“This is a very self-empowered patient population seeking specialty expertise,” says Benjamin Lebwohl, MD, a clinician and researcher at Columbia. “A referral center also attracts patients having more difficulty, whether due to recurrent symptoms or a borderline diagnosis.”

Studies of these groups provide skewed data, a problem known as referral bias. Experts know little about the lives of many patients without access to a celiac center. They might rarely even see a doctor regardless of whether they flourish on a gluten-free diet or not.

Lebwohl says, “While we are proud of our research, we are unable to answer seemingly simple questions, such as what proportion of patients with celiac disease still have symptoms despite attempting to adhere to a gluten-free diet.”

Extending the community

To go deeper, celiac advocacy groups have launched patient registries. The Celiac Disease Foundation’s iCureCeliac and Beyond Celiac’s program Go Beyond Celiac have enrolled thousands.

Geller explains, “You go online and create an account. There are a number of questions that you complete regarding your health, from diagnosis to current experiences, not just the medical data points but also your opinion on how difficult it is to exist in this world with celiac disease.”

Participants provide data anonymously. Researchers can peruse the data for clues and patterns. Columbia University used iCureCeliac to investigate whether patients with depression are more likely to have trouble staying gluten free.

Investigators testing a new drug provide a profile of patients who meet criteria such as age or location. The Celiac Disease Foundation does not release contact information but informs everyone in the registry who is eligible to participate, Geller says. Each patient may then choose whether to contact the researcher.

The case for drugs

Registry data may convince larger drug companies to help look for a cure.

Linda Deal, head of patient-centered outcomes for Pfizer, Inc., and a member of Beyond Celiac’s board of directors, says, “Folks in my discipline are interested in understanding insights from the patient’s perspective, what is their journey with their disease.”

Stating she does not speak for Pfizer or Beyond Celiac, Deal says drug companies and the FDA must balance treatment benefits against risks. They must also ensure treatment could be made affordable and available.

“The sooner patients get listed in registries and have their consequences tracked, the sooner we will understand the cost of this disease to society,” Deal says.

No trivial undertaking

“The real bottleneck is patient involvement. If I have patients willing to work with me, I can find funding or ways to partner with industry,” Leffler says. “Participating in a clinical trial, while a rigorous process, gives patients a tremendous amount of information about themselves. Often trial participation involves undergoing measurements of symptom activity and [dietary] adherence, checking in with investigators.”

Kelly says, “While an individual may have a general openness toward participating, to actually take the time and effort may not be a trivial undertaking.”

Filling out a 20-minute survey is far less demanding than a 15-week trial. Patients have an opportunity to ask any and all questions before a trial and can opt out at any time.

“Trials of medications for celiac disease require that patients be exposed to gluten,” Lebwohl warns. “These gluten challenge studies, while critical, are not for everyone. Some people get very ill when exposed even to small amounts of gluten. Those studies can be difficult to recruit for.”

Such trials rely on a small number of volunteers to minimize harm. However, a larger group provides better statistical proof of the findings.

Leffler explains, “We typically err on the side of being a little large, but overpowering a study is not the right thing to do.”

“This is a transformational time for celiac disease,” says Leffler. “Finally, after a period of being stalled, we are getting a critical mass of scientific knowledge, numbers of diagnosed patients and effective advocacy to move celiac disease to a next level where the burden is lower and treatment outcomes are better. If you are in the celiac community and want to be engaged, I see these next five years as critical.”

Van Waffle has a Bachelor of Science in biology and is research editor of Gluten-Free Living. A freelance writer based in Waterloo, Ontario, Canada, he blogs at vanwaffle.com.

Celiac affects an estimated 3 percent of children in the Denver area, according to University of Colorado researchers. They uncovered this startlingly high figure while evaluating screening children for celiac and type 1 diabetes. This is the highest prevalence detected anywhere. Previous data have suggested that 1 in 100 North Americans has celiac, and its prevalence is increasing. However, most people affected do not know they have it. To find the hidden patients, some experts advocate celiac screening for all people with risk factors or even the general population.

Standard heath care responds to patients who present complaints. Screening takes a more active approach, looking for signs of disease in patients who lack symptoms. This might help doctors detect celiac in people before they report painful problems such as indigestion, diarrhea and bloating. Early diagnosis could prevent long-term health problems and occasionally fatal complications.

However, these benefits remain theoretical. Medical research has yet to prove general screening programs would benefit patients in the long term. That does not even begin to address the potential public health cost of widespread screening.

Controversial recommendation

In 2017, the U.S. Preventive Services Task Force (USPSTF) issued a recommendation that research has not given enough evidence to support screening patients who lack celiac symptoms. General screening in the United States is not out of the question, but the key questions still need answers.

Still, the task force’s conclusion surprised some patients and experts.

“I agree with the overall conclusion that more evidence needs to be collected for [screening] the general population,” says Marian Rewers, Ph.D., executive director of the Barbara Davis Center for Diabetes in Aurora, Colorado. He is a principal investigator in the Denver studies. “However, the USPSTF missed a lot of published information from high-risk groups.”

Joseph Murray, MD, professor of medicine in charge of the celiac program at Mayo Clinic in Rochester, Minnesota agrees: “The task force took their charge very seriously but also took it quite narrowly.”

The USPSTF specifically asked, “What is the role for testing in patients who are asymptomatic?” Murray explains. In combing through medical research, the panel carefully excluded studies screening the general population because they might include people with symptoms who had not yet complained about them. Few studies have focused explicitly on people who lack symptoms.

Murray proposes trying to convince the USPSTF to ask a different question: “Is there evidence to support screening people who are at risk for celiac disease who may or may not have symptoms?”

Edwin Liu, MD, director of the Colorado Center for Celiac Disease and a colleague of Rewers’ at the University of Colorado, is concerned that the recommendation sends an incorrect message about the importance of celiac symptoms.

“Does it mean that if I’ve got celiac disease and I have symptoms, I only need to treat myself enough to control my symptoms? I don’t think that’s what they mean, but it might lead someone to start thinking this way,” Liu argues.

In some gastrointestinal diseases, the treatment focuses only on reducing symptoms, Liu explains.

However, that is not the case with celiac. Patients must maintain a gluten-free diet for life even after the condition is effectively controlled.

Research challenges

Public disappointment about the task force’s recommendation prompted the Celiac Disease Foundation (CDF) based in Woodland Hills, California, to post its position earlier this year on its website. The patient advocacy group supports the call for more research, but chief executive officer Marilyn Geller understands the community’s concern.

“A tremendous amount of unnecessary patient suffering occurs with undiagnosed celiac disease,” explains Geller. The average patient suffers painful symptoms for six to 10 years prior to a correct diagnosis. They may view this recommendation from the government as a step away from recognizing serious impacts of celiac.

It is a difficult but important challenge to design research to investigate screening people who have no symptoms, says Murray. Rigorous studies would be fraught with problems.

For example, he describes a theoretical study in which researchers would recruit volunteers without symptoms who agree to be tested for celiac but go untreated and not be informed of the results for five years. This would demonstrate the long-term health outcome in people who have celiac without knowing it. Not only would this be expensive, but it presents ethical problems for doctors who pledge to prevent harm.

The diabetes link

However, the ongoing Denver research that found a high celiac prevalence in children is providing an opportunity. The charitable organization JDRF, which funds research to prevent type 1 diabetes, has supported the program through the University of Colorado and Barbara Davis Center for Diabetes. The Autoimmunity Screening for Kids (ASK) study is recruiting 55,000 children ages 2 to 17 from Denver over three years to find out what happens when they are screened for type 1 diabetes and celiac.

Diabetes receives greater public awareness and funding. The two conditions share genetics and other risk factors, and patients with one appear to be predisposed for the other, so it is useful to study them together.

ASK was set up primarily to screen for type 1 diabetes, explains Rewers: “Celiac disease screening was added as a relatively easy and important secondary goal.”

Celiac disease autoimmunity

Asymptomatic children will undergo testing for what researchers call celiac disease autoimmunity (CDA). It means their immune systems have begun making antibodies against gluten but without causing any obvious symptoms. At this stage, some patients still might not show damage to the intestinal lining, the essential test for celiac.

The Denver celiac prevalence study identified 1,339 children with celiac risk factors born at St. Joseph’s Hospital between 1993 and 2004 and followed them for up to 20 years. Eventually, 66 developed CDA and also celiac, while 46 met criteria for CDA only.

The health-care community considers CDA a precursor to celiac. It remains unclear what triggers the onset of disease damage to the intestine, how long this takes and why a significant proportion of cases never appear to progress beyond producing antibodies. Some people only test positive for antibodies temporarily.

A blood test to screen newborn children for celiac might seem simple and inexpensive, but it is not enough to settle the question. People with a genetic predisposition require continual follow-up to watch for the onset of CDA or celiac at any age. Often it does not appear until adulthood.

Geller points out that infant screening would fail to detect most cases.

Some gastroenterologists recommend people with CDA adopt a gluten-free diet to prevent potential complications once the disease gets going.

Here Liu puts a positive spin on the USPSTF recommendation. In the recent past many pediatricians like himself tended to screen children at risk and treat them for CDA even if they did not have symptoms. However, it was difficult for families of children who felt fine at the outset to have their doctors impose a gluten-free diet.

Liu adds, “These official recommendations say exactly what we already know: that there’s not enough data to support this. It allows us to step back and be more thoughtful about how we approach each patient.”

This shift can also help research.

“Several years ago, I thought that we had lost our window of opportunity to study kids who are asymptomatic without treatment, because everyone was leaning toward screening them and treating them,” says Liu. “Now, with the conclusions by the USPSTF, this gives us more permission to not treat these kids but monitor them. We will be able to get some studies of the natural history of untreated, asymptomatic celiac disease.”

The ASK study should shed some light on what happens from early childhood through adolescence.

“We’re going to look at the acceptability of large-scale screening,” says Liu. “We’ll look at the potential harms that we can cause by screening, like are we going to cause kids to get a lot of unnecessary endoscopies? Are we causing a lot more anxiety and depression in families? And we are also looking at the benefits.”

He expects the study to identify about 1,000 children with celiac. An estimated one-half of them will have no symptoms.

Rather than concealing their CDA status, as in the study design Murray described, it will rely on patients’ autonomy and right to choose. Everyone is different. Some patients have more risk tolerance than others.

Liu says, “We find somebody who’s antibody-positive, and we don’t treat them, but we monitor them carefully to make sure they don’t get themselves into trouble. They come in every six months. They find out they’re still antibody-positive.

“At some point, a lot of these individuals may say, ‘You know what? These antibodies aren’t going away. Let’s just chase this and take care of it, OK?’ Or they may eventually recognize they have symptoms. I anticipate that the majority of people who continue to follow up and monitor, knowing that they’re still antibody-positive, may end up choosing to be on a gluten-free diet. There’s just no rush if you’re asymptomatic.”

Regardless of their decision, the study will continue to follow their progress. The data will allow researchers to compare people who choose early treatment with those who do not. It will indicate how earlier diagnosis and treatment through a screening program might improve long-term health outcomes.

Rewers says he believes adequate evidence will eventually prove the value of screening.

Murray says, “A lot of people who have celiac disease have no symptoms now but will get symptoms in the future. They might even get serious or fatal complications of celiac disease before they are ever diagnosed. We could prevent those if we found them and treated them early.” But, he adds, “How do we predict who is going to go on to complications and who’s not? That’s something
that’s really not understood.”

In patients with risk factors such as a first-degree family member with celiac, research has proven the benefit of screening. Murray says he tells his newly diagnosed patients their family members should undergo testing because they have a substantial risk for celiac.

In other cases, experts simply feel strongly about recommending it, for example, in children with type 1 diabetes. According to Diabetes Canada, they have a 4 to 9 percent risk of having celiac but up to 70 percent show no symptoms of it.

Murray says, “There isn’t yet enough evidence to say people with type 1 diabetes benefit from being tested, but a lot of us actively support testing in that context because we know people with atypical symptoms are often hidden from view.”

CDF works to raise awareness among doctors about who should receive testing for celiac, based on good evidence. Based on CDF’s advice, Anthem Health Insurance recently adopted guidelines to encourage testing symptomatic patients and screening their first-degree relatives.

“The real key is simply educating physicians on what to look for,” says Geller. “My son wasn’t diagnosed until he was 15. He had clear symptoms from when he was very little, but they weren’t classic symptoms. I think we’ve come a long way now in terms of realizing this broad array of symptoms.”

In the absence of screening, the broader public must rely on their doctors’ awareness of celiac risk and willingness to test for it.

Van Waffle has a Bachelor of Science degree in biology. He is research editor for Gluten-Free Living. He blogs about nature, gardening and local food at vanwaffle.com.

The body depends on a balanced community of gut bacteria to support health and nutrition. Imbalance can cause illness. Some medical researchers are investigating whether such a disturbance could trigger celiac disease. Even though the human intestine on its own does not have the ability to digest gluten, gut bacteria normally help. This community, known as the microbiome, might also prevent the body from launching a needless war on gluten.

A new long-term study through Massachusetts General Hospital for Children in Boston will investigate these effects in infants at risk for celiac disease. The findings might explain why some people with the same genetic predisposition get sick while others do not. Future therapies to cure or prevent celiac disease might target the microbiome.

a sum of its parts

In 2008, the National Institutes of Health (NIH) launched the human microbiome project to describe some 100 trillion microbes that live on and in the human body. Medical science has viewed these microbes as a community for only about 10 years, according to Robert Karp, Ph.D., program director for genomic and microbiome studies at the National Institute of Diabetes and Digestive and Kidney Diseases based in Bethesda, Maryland. He specializes in genetics, the study of how all life—whether humans or microbes—inherits traits from one generation to the next.

More than 10 years ago, “Scientists tended to think in terms of what individual strains or species were doing, that they were acting on their own,” Karp explains. “People distinguished [disease-causing] pathogens from commensal bacteria that live in us but cause no harm and possibly cause benefit, but were not thinking in terms of how the whole community acts in a way that’s more than a sum of its parts.”

Dental microbiologists were first to note cooperation between bacteria, he says. Meanwhile, for decades ecologists had been studying microbial communities in nature. After these concepts spread to general medical research, the NIH’s human microbiome project began.

About 1,000 species have been associated with the human microbiome, but the average person has only about 500 or so, Karp says. Some are obscure and poorly understood even by scientists, such as archaea, which have a completely different metabolism than bacteria and are also found in deep ocean hydrothermal vents.

a revolution in research

According to Karp, “In classical microbiology, the only way to study a particular strain of microbe is to culture it in pure form in a test tube. Since we do not know how to culture the vast majority of members of the human microbiome, it is impossible to study them in this way.”

Innovative technology is providing new clues by decoding deoxyribonucleic acid (DNA), which stores the functional instructions in all life forms.

Karp says, “Fast, cheap DNA sequencing and advanced computational methods” allow scientists to sample the microbiome and disentangle the individual DNA sequences of all the microbes contained. “It is possible to deduce a great deal of information about the metabolism, physiology and general lifestyle of a previously unknown microbe from its genome sequence. Even if we can’t culture this microbe, we can clone its unfamiliar genes into a well-studied lab microbe in order to learn something about their function,” he says.

The human genome contains a mere 20,000 protein-coding genes, on par with the fruit fly. However, a 2005 review in the journal Science estimated the human microbiome collectively has at least 100 times as many genes. Its diversity empowers the human gut to extract more essential nutrients than we could manage on our own.

symbiosis

Karp says what fascinates him most about the microbiome is “how its members are adapted to life with us, how we have adapted to life with them. We survive better as a species than we would without them. [There are] hundreds of different ways in which they influence most aspects of our physiology. We don’t even know what most of those ways are.”

Alessio Fasano, M.D., director of the Center for Celiac Research and Treatment at Massachusetts General Hospital in Boston, leads research on the role of the microbiome in celiac disease. He says, “It’s a true symbiotic relationship. We give them hospitality, and in exchange they give us stuff that’s useful for us. For example, we can’t digest fiber, but when fiber reaches the colon, microorganisms can make products that are very good for us.”

For example, bacterial fermentation produces butyrate, which is essential for colon health.

“There’s a great deal of variability in the microbiome between different individuals,” says Karp. “Identical twins have a more similar microbiome than fraternal twins or other pairs of first-degree relatives. People who are cohabiting also tend to have microbiomes that are more similar to each other than people who are living someplace else.”

Lifestyle also affects the composition, he adds, “so someone living as a hunter-gatherer in Africa has a rather different microbiome from a Western European.”

focus on function

This variability makes it hard to draw conclusions about how the microbiome operates. Studies of individual bacterial species associated with disease often make contradictory observations. To sort them out, Karp points to the importance of meta-analysis.

This technique scans the scientific literature for all titles on a particular topic, weighs their research according to size and statistical integrity, and then combines them to see whether any significant effect can be measured overall. This combats the common error of cherry picking studies to make broad statements on health.

Research is also shifting focus from individual species to their functions. Early studies often conducted censuses of microbes, which “mask a greater functional uniformity,” according to Karp. A species that serves an important role in one person may be absent from someone else, in whom a different group serves the same purpose.

To study function, researchers can grow a microbe to identify the products of its metabolism or measure these metabolites in human blood or urine. Functional analysis is still in its infancy but may reveal more robust patterns, Karp says.

the infant microbiome

A key question is how an infant’s microbiome develops from birth. Although the fetus is exposed to a few microbes prenatally, many experts believe that passage through the birth canal provides an essential transplant of microbes. A child’s early microbiome resembles the mother’s vaginal microbiome.

“Over the first two to three years of life, the microbiome matures, so that by the time you’re 3 years old [it] looks like an adult microbiome,” says Karp. “We know something about when different strains appear. But we know very little about the mechanisms of how those changes happen.”

Fasano says, “One of the key functions for the microbiome, particularly early in life, is to teach the immune system to mature and make the right decision if and when to unleash inflammation.”

Beneficial microbes help the immune system recognize and defend itself against microbes that cause infection. A well-balanced microbiome will set the bar high for inflammation, Fasano explains. Otherwise the immune system becomes hypersensitive, reacting too easily and leading to continued injuries.

association with celiac

A nationwide Swedish study published in Gastroenterology in 2012 found children born by elective caesarean section were more likely to develop celiac disease. The authors say these findings support “the hypothesis that the bacterial flora of the newborn plays a role in the development of celiac disease.”

How this might occur remains unclear and yet to be investigated in detail, according to Yolanda Sanz, M.Sc., professor of research at the Spanish National Research Council based in Madrid, who studies the microbiome in children with celiac disease.

Sanz coauthored a 2009 paper in the Journal of Clinical Pathology that found an unbalanced microbiome in children with celiac disease. The sick microbiome included greater or lesser prevalance of certain bacterial species and, perhaps more importantly, a general reduction in species diversity. The microbiome only partially recovered after long-term treatment on a gluten-free diet.

More recently, Sanz and colleagues studied healthy infants who were genetically predisposed to celiac disease but had not developed it. Again, they found a distinctly atypical microbiome. The study, published in 2014 in Gut, suggests host genetics influence which specific microbes colonize the gut, which could in turn influence the onset of disease risk.

Further research published in 2015 in The American Journal of Pathology found certain bacteria trigger celiac disease in mice by promoting an inflammatory response to gluten in the diet. A microbiome free of disease-causing bacteria appeared to protect mice against inflammation. Notably they lost their protection after receiving a bacterium from a human celiac disease patient.

While these studies indicate bacterial associations, research has yet to prove that an altered microbiome causes celiac disease in humans.

Sanz says, “We know that exposure to microbes makes the immune system maturate, but we don’t know the type of interactions between the microbiome and gluten in the diet” and how they together might lead to celiac disease.

beyond simple genetics

The microbiome can also profoundly influence how the host interprets its own genetic code. While human DNA contains the entire library of functional tools that pass from parents to their children, many genes remain silent. Environmental factors can switch them off or on, and these switch positions may also pass from one generation to the next. Fasano says this field of study, called epigenetics, may explain why a previously rare inheritable disorder like celiac disease has become an epidemic.

“We thought that we had everything straight with celiac disease,” explains Fasano. “We knew a lot of the genetics. We know that the environmental trigger is gluten. For many years, we’ve been under the impression that there were two necessary sufficient conditions to develop celiac disease. Then, over the years, we learned that that’s not true, that there are people who eat gluten for 50 years and they stay healthy, and then at a certain point they lose the [ability] to tolerate it and develop celiac disease.”

The rapid increase in cases pointed to some environmental factor at play. Doctors speculated that changes in breastfeeding behavior and infant nutrition might be to blame, but extensive research has ruled these out.

Now Fasano is turning attention to what he calls “cross-talk between us and this parallel world [of gut microbes].” Changes in the microbiome likely alter gene expression, causing the immune system to behave differently, he says. Instead of defending the body, it begins attacking the lining of the gut, marking the onset of celiac disease.

Fasano is one of the principal investigators in the Celiac Disease Genomic, Environmental, Microbiome and Metabolomics (CDGEMM) Study through Massachusetts General Hospital for Children. It aims to follow 500 children at risk for celiac disease from birth until age 5. Participants will provide stool samples, allowing investigation of the bacteria and metabolites produced in the gut. Further, the study will explore interactions between genetics and environmental factors such as diet, infections and antibiotic use.

Fasano says a study such as CDGEMM is necessary because it follows a group of people over time, ideally from birth. It will compare the microbiome before and after onset of celiac disease, shedding light on changes when they occur. This data will help predict why an individual took the wrong turn rather than stay the course and maintain tolerance to gluten.

Eventually doctors may be able to prevent celiac disease by manipulating the microbiome to “bring it back to the right course,” Fasano says.

supporting microbiome health

While experts are still looking for evidence, they can offer advice on how to support a healthy microbiome. One of the most important practices is to avoid overuse of antibiotics.

Karp says, “There are times when antibiotics are absolutely essential, and they’ll save you from a life-threatening disease. You have to use them then.” However, in the United States, the average person receives antibiotics many times during the course of childhood. Antibiotics “totally upset the composition of your microbiome,” he says.

Research suggests that dietary fiber also supports a healthy microbiome, he adds. “Probably the best way to maintain a healthy microbiome is [through] a healthy diet, also good exercise, a good amount of sleep and try to decrease the level of stress. Laugh a lot, because that helps to boost the immune system and therefore helps the microbiota to keep us healthy.”

Van Waffle has a Bachelor of Science degree in biology and lives in Waterloo, Ontario, Canada. He is research editor for Gluten-Free Living. He blogs about nature, gardening and local food at vanwaffle.com.

 

Once thought to afflict mostly Caucasians, celiac disease is becoming cosmopolitan. It appears with higher-than-expected frequency in parts of North Africa, the Middle East and Asia. In India, it poses a growing public health concern. Meanwhile, in North America, evidence suggests patients and doctors need to stop assuming it affects primarily white people from Western Europe.

A new study of celiac disease and ethnicity in the United States emphasizes its diversity. Researchers found that people from the Punjab region of northern India were more likely than other Americans to have celiac disease, while the prevalence is also high among people of Jewish and Middle Eastern background.

One thing is clear: Celiac disease is becoming more common almost everywhere. A 2015 review of research by German and Israeli scientists found that the worldwide incidence has increased by 9.8 percent per year over the past 60 years. Many factors may have contributed, such as increased wheat consumption, changes in microbiology of the human gut, increasing awareness by doctors and patients, and improved means of diagnosis. However, environment seems to play a bigger role than genetics in the rising problem of celiac disease, because people from diverse genetic backgrounds are getting sick.

“Celiac disease is present in nearly 1 percent of the U.S. population,” says Benjamin Lebwohl, M.D., gastroenterologist and researcher at the Celiac Disease Center at Columbia University, New York. “Though the ‘nearly 1 percent’ figure has been cited for more than a decade in the U.S., we live in a multi-ethnic society, and to date there has been very little known about how rates of celiac disease vary between ethnic groups.”

The study, published in Clinical Gastroenterology and Hepatology, looked at 454,885 people who had biopsies of the small intestine submitted to a national laboratory between 2008 and 2015. A biopsy detects characteristic damage to the gut lining and is considered the gold standard method for diagnosing celiac disease. Researchers compared the prevalence of such damage among patients from various ethnic groups.

Lebwohl, one of the study’s authors, explains, “we used a previously developed method that categorized patients’ ethnicities based on first and last names.”

Self-identified individuals within each ethnic group checked the name classifications. Then the lists were checked with physicians in sample practices containing members of ethnic groups. “The method was found to classify ethnicity with a high degree of accuracy, well over 90 percent,” says Lebwohl.

Among all U.S. patients who had biopsies submitted, the study found a celiac disease prevalence of 1.74 percent. Celiac disease was more common in patients originating in Punjab (3.08 percent) while other North Indian (1.51 percent), Jewish (1.80 percent) and Middle Eastern (1.52 percent) ethnicities had a prevalence similar to that of other Americans. Celiac disease was rarer among Americans of South Indian (0 percent), East Asian (0.15 percent) and Hispanic (1.06 percent) origin.

“I was struck by the results regarding patients from India,” says Lebwohl. “The rate of celiac disease varies tremendously depending on the region of that country that we’re considering.”

He adds, “As we were doing this analysis, and came upon this result, we discovered that a screening study conducted in India had just come to a similar conclusion: wide variability in the rate of celiac disease depending on the region, with a northern dominance.”

The Indian study, published this year in the American Journal of Gastroenterology, screened 23,331 people across India using blood tests. Researchers found a prevalence of celiac disease antibodies of 1.23 percent in northern regions, 0.87 percent in the northeast, and 0.10 percent in the south.

Alessio Fasano, M.D., director of the Center for Celiac Research and Treatment at Massachusetts General Hospital in Boston, says the variation among ethnic groups in the United States comes as no surprise.

“I would say that this study confirms what was known already,” says Fasano. “If you have a genetic predisposition and you are exposed to gluten in the environment to trigger it—and the United States is definitely a perfect terrain in terms of exposure to gluten—the recipe [to develop celiac disease] is there.” Cultural habits also have an effect, he adds.

Different regions, different diet

Disparities of prevalence have been recognized for decades in India, where genetic variability is much more limited than the range of cultural practices. Diets are particularly variable. Southern India relies much more heavily on rice, which is gluten free, whereas wheat is more popular in the north, particularly Punjab.

Celiac disease was first described in Punjab as summer diarrhea, says Fasano. The same patients experienced this condition every year. With no apparent intestinal parasite to blame, the patients’ diet was determined to be the culprit—specifically chapatis, flatbreads eaten as a staple food.

“The bread they ate during the summer is made with wheat and during the winter it is made with maize, which is gluten-free,” says Fasano. This observation led to screening, which indicated a high prevalence of celiac disease in Punjab.

The problem followed ethnic Punjabis wherever they went. A 1993 study in Leicestershire, England, found that residents with a Punjabi background were three times more likely than Europeans and eight times more likely than East Indians to have celiac disease.

Highlighting the point that celiac disease arises from cultural practices, it has recently been documented in China. It had never been described there before, but as the Western diet becomes more popular, it opens the borders to celiac disease.

The genetics of celiac disease

In North America, few studies concerning ethnicity have been undertaken. Most concentrated on the difference between non-Hispanic whites and Hispanic people or non-Hispanic blacks. Both these minority groups appear to be less susceptible to celiac disease. However, some experts argue that celiac disease may be underdiagnosed in their communities.

A 2015 study by the Mayo Clinic in Rochester, Minnesota, drew conclusions based on the annual National Health and Nutrition Examination Survey (NHANES), which included blood tests for antibodies associated with celiac disease from 2009 to 2012. Of 14,701 participants who underwent tests, 39 percent were non-Hispanic white, 22 percent were non-Hispanic black, 28 percent were Hispanic and 11 percent belonged to other races. The study found celiac disease affecting 1 percent of non-Hispanic whites, 0.2 percent of non-Hispanic blacks and 0.3 percent of Hispanics. Only three cases of celiac disease were found among people of other races. However, the results were not confirmed by biopsy of the small intestine.

The rarity of celiac disease among the Hispanic and African-American populations presents a puzzle. The highest incidence of celiac disease ever found occurred in northwest Africa among Saharawi refugees in Algeria: 5 to 6 percent. According to several studies, Caucasian Americans and African Americans have similar genetic predisposition to the disease. Authors of the Mayo Clinic study argue that an as-yet-unidentified gene might protect non-Hispanic blacks against celiac disease.

Other contributing factors

In some parts of the world, poor economic conditions seem to protect people against celiac disease. A 2008 study focused on people from the same genetic and cultural backgrounds in Finland and Russian Karelia. Celiac disease was less common on the poverty-ridden Russian side of the border. However, other studies have refuted the theory that communities with lower socioeconomic status are less vulnerable.

Some experts suspect celiac disease may be hidden among African Americans because they are less likely to get diagnosed. Lebwohl worked on a 2012 study that found disparities in the way endoscopies are conducted. Gastroenterologists use endoscopy to look inside the small intestine. Based on what he or she observes, the specialist may decide to take tissue samples for a biopsy, which is essential for diagnosis.

“African Americans and Hispanics were less likely to have a biopsy of the small intestine during the procedure, even if it was done to investigate signs of celiac disease such as iron-deficiency anemia or diarrhea,” Lebwohl reports. “In other words, celiac disease might have been missed.”

Fasano agrees that more research needs to look at the prevalence of celiac disease in certain cultural groups: “What is totally missed in my humble opinion is a systemic survey in African Americans and Native Americans.”

“Even though our latest study found a lower rate of celiac disease in Hispanics, we should not assume that celiac disease is out of the question based on a patient’s ethnic or racial background alone,” says Lebwohl. “Symptoms that are suggestive of celiac disease should be fully evaluated.”

Results of the latest study, he adds, “underscore the notion that celiac disease is not a condition that only or predominantly affects those of European ancestry.” GF

Van Waffle is research editor for Gluten-Free Living. He blogs about nature, gardening and local food at vanwaffle.com.

People with celiac disease are more likely to suffer from mental health problems. A study at University Hospital of Cagliari, Italy, found 30% of celiac disease patients had experienced major depression during their lives, 18% had panic disorder and 4% had bipolar disorder. In contrast, a control group showed a prevalence of 8%, 5% and 0.4%, respectively.

The study included 60 celiac disease patients and 240 randomly selected controls. The volunteers took computerized interviews and questionnaires to assess psychiatric disorders and quality of life.

Patients with celiac disease scored lower than normal on quality of life. This finding agreed with other research showing patients report impaired quality of life similar to that for serious chronic diseases such as end-stage liver disease. However, in this study celiac disease patients without psychiatric disorders did not score low on quality of life.

This indicates a key to the burden of treatment for people with celiac disease. The authors recommend screening celiac disease patients for mood and anxiety disorders, particularly if they show symptoms or have a family history. Appropriate treatment could reduce the burden of living with celiac disease.

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Carta MG, Conti A, Lecca F, Sancassiani F, Cossu G, Carruxi R, Boccone A, Cadoni M, Pisanu A, Moro MF and Demelia L, “The burden of depressive and bipolar disorders in celiac disease,” Clinical Practice & Epidemiology in Mental Health, 2015, 11:180-185.

It sounds like two scenes from the same science fiction thriller. With celiac disease, the body’s immune system attacks its own gut lining. With cancer, cells grow abnormally and invade other parts of the body.

But real science indicates people with celiac disease face increased risk for certain types of cancer. Fortunately they’re rare forms, and the risk declines when the gut lining heals.

“One [cancer] is called enteropathy-associated T-cell lymphoma. It’s a kind of lymphoma of the small intestine,” says Benjamin Lebwohl, M.D., assistant professor of medicine in epidemiology at the Celiac Disease Center at Columbia University in New York City. Another is small intestinal cancer, or small intestinal adenocarcinoma. These cancers are not seen very often in the general population but occur at an increased rate in people with celiac disease.

“These findings underscore the fact that celiac disease and the intestinal inflammation that is involved in this condition are a health hazard,” Lebwohl says. “The evidence is very good that healing in the intestines reduces the excess risk [for cancer], and there’s also evidence that following a gluten free-diet leads to healing of the intestines.”

It’s one more argument for why people with symptoms or risk factors should be tested for celiac disease and, if diagnosed, stick to a strict gluten-free diet.

Haunted by memory

Ken Kilgore, Ph.D., director of partnered pharmacology at Janssen Pharmaceutical Companies of Johnson & Johnson in Pennsylvania, has an especially good reason not to cheat.

“It doesn’t honor my dad,” Kilgore explains. “He was my greatest friend in the world, and that just taints the sacrifice he made if I go and cheat.”

In 2002 Kilgore’s father, Donald, had been suffering from severe weight loss when in September he was diagnosed with B-cell lymphoma. Despite chemotherapy his condition continued to decline. He could no longer pursue his passions for golfing or watching University of Michigan football with his son.

“We had season tickets for decades, and football Saturdays were a much-loved fixture of our family,” Ken Kilgore recalls. “However it became clear mid-way through the 2002 season that he was not strong enough to continue going to games. He and I had watched Michigan football together for 35 years and rarely missed a game until then.”

At the time, Ken Kilgore was an adjunct professor at University of Michigan Medical School, Ann Arbor. A gastroenterologist friend there suggested his father should get tested for celiac disease. The results came back positive.

In hindsight, Ken Kilgore believes his father’s celiac disease had been active for at least 10 years before the cancer diagnosis. Donald Kilgore had some nutritional problems, particularly low levels of vitamin B₁₂.

Recent research shows increased cancer risk declines when celiac disease is diagnosed and treated effectively, a fact that still haunts Ken Kilgore. “We were definitely in the Dark Ages of celiac awareness,” he says.

Ken Kilgore had his father switch care to University of Michigan Medical Center because he thought physicians there were among the few who were up-to-date on celiac disease. “Unfortunately it was too late by that point,” he laments.

While getting tested for celiac disease, Donald Kilgore underwent an upper digestive tract endoscopy that revealed the cancer was actually T-cell lymphoma. For half a year his treatment had targeted the wrong form of cancer. It was too late to start over. Donald Kilgore died in September 2003, at the age of 67.

After Donald Kilgore was diagnosed, the whole family got tested for celiac disease. Ken Kilgore was the first to test positive in 2003, followed by his daughter, who also has Down syndrome, his nephew and, most surprisingly, his mother.

“We look for hidden blessings in this whole adventure,” says Ken Kilgore, now 50. “We feel in the long run that my dad did something great for all of us.”

Understanding the risk

Alice Bast, president and CEO of Beyond Celiac, a patient advocacy organization based in Pennsylvania, says people diagnosed with celiac disease are concerned about associated health problems, including cancer.

“In fact, in a recent survey that we will be submitting for publication later this year, more than 80 percent of adults in our community are specifically worried about their increased cancer risk,” she adds.

The risk came to light only recently. One of the first studies to suggest a link appeared in American Journal of Medicine (2003); it reviewed statistics from 381 celiac disease patients seen between 1981 and 2000 at New York-Presbyterian Hospital.

Researchers found a higher-than-expected incidence of non-Hodgkin lymphoma, cancer of the small bowel, esophageal cancer and melanoma in this group. B-cell lymphoma and enteropathy-associated T-cell lymphoma are two types of non-Hodgkin lymphoma. No elevated risk was found for colon, lung or breast cancer.

However, before raising alarm, Lebwohl points to weaknesses in this data.

The study was performed at a major referral center for celiac disease, he notes. There’s always concern that studies coming out of such settings don’t apply to celiac disease patients in general.

“Patients who come to our center might be different in important ways. They might be referred to our center because of particularly complex problems or difficult-to-manage disease. Their risk might be different from the typical celiac disease patient,” Lebwohl explains.

“Some of the confusion derives from the fact that cancer is often lumped into one outcome when cancer represents many different kinds of disease,” he continues. “In fact celiac disease might increase the risk of one cancer and decrease the risk of another. Studying them on the aggregate often leads to confusion. It’s important to evaluate each cancer with regard to its relationship with celiac disease.”

Early findings provoked a variety of further research. Several studies from Scandinavia have provided clarity. They’re important, Lebwohl says, because they’re population-based.

In other words they include essentially all celiac disease patients from a large population, rather than a few under special circumstances.

“In general studies coming out of population-based settings show lower risks and diminished increases of risk,” Lebwohl observes.

For example a 2014 study from University of Tampere, Finland, analyzed data on 32,439 celiac disease patients between 2002 and 2011. It is the largest study of its kind completed to date. It confirmed an increased risk for non-Hodgkin lymphoma and small intestinal cancer, though the rates were lower than in other studies.

“Patients should be aware that while the risk of these cancers is increased compared to the general population, the absolute risk is modest in size,” Lebwohl points out. For example one study found that over the course of 10 years, less than 1 percent of patients with celiac disease developed lymphoma.

That means it’s rare even for people with celiac disease.

Not all cancers ARE the same

The Finnish study didn’t support evidence for a link between other cancers and celiac disease. Overall scientific findings have been ambiguous on esophageal cancer, melanoma and colon cancer.

However the Finnish study also provided some good news. The overall risk of cancer for newly diagnosed celiac disease patients was no higher than for the general population.

“There are a couple of cancers that appear to be less common in patients with celiac disease,” explains Lebwohl. “Lung cancer and breast cancer are the two that have been studied most. For some reason celiac disease appears to be protective against these cancers.”

One possible reason is that research has shown celiac disease patients are less likely to be smokers. But even with smoking habits removed from the equation, celiac disease appears to protect against lung cancer, Lebwohl says.

Similarly celiac disease patients may have less body fat, which could reduce the risk for breast cancer. Also some studies have shown that women with celiac disease “have later onset of menstruation and earlier onset of menopause compared to the general population,” Lebwohl explains. “It could be that these hormonal factors are influencing breast cancer risk.”

While these protections remain a puzzle, Lebwohl says he is most interested in research “honing in on lymphomas,” because these cancers seem to be the ones celiac disease tracks with most closely.

“It makes a sort of logical sense that patients with celiac disease who have inflammation in their small intestine would have cancers in their small intestine,” he points out, but research has not yet proven a cause-and-effect relationship.

The link with cancer helped scientists realize celiac disease is not only an intestinal condition but rather an autoimmune disorder, he adds.

Call for prevention

Because non-Hodgkin lymphoma and cancer of the small intestine are rare even in celiac disease patients, the risk calls for vigilance more than alarm.

“With cancer, early diagnosis is key,” Bast says. “Those diagnosed with celiac disease should also be monitored annually by their physician.” The Beyond Celiac website identifies the tests patients should receive yearly.

Lebwohl says screening for preventable cancers should be the same for those with celiac disease as for the general public, including colonoscopy and mammography at the appropriate ages.

“As for additional screening measures, none are routinely advised,” he says. “But patients with celiac disease should have regular medical follow ups because of the association with these cancers, including lymphoma.” This will help with early detection of any complications requiring investigation for cancer.

Given the evidence that treating celiac disease can reduce the risk of lymphoma, a follow-up biopsy might provide “important prognostic information,” he adds. A study of Swedish patients who underwent a second biopsy at an interval after starting the gluten-free diet showed the relationship between intestinal healing and risk of lymphoma.

“We compared those whose intestines had healed to those whose intestines failed to heal. Those who had healed no longer had an increased risk of lymphoma” Lebwohl says. This raises concern for celiac disease patients who do not heal despite following a strict gluten-free diet.

“These are the patients who we like to follow the closest,” Lebwohl says. “This is a substantial proportion of patients, some of whom have persistent symptoms but others [who] actually feel quite well,” despite poor healing.

Patients who have persistent intestinal damage meet with the celiac center’s dietitian more frequently than those who heal. “We try to drill down ways in which they might be exposed to gluten unintentionally,” Lebwohl explains. “This is a population that might benefit from [drug] therapy, if such therapy were to be developed in the future.”

But the absolute risk even for these patients is low.

“Those with persistent abnormalities on their intestinal biopsy have an increased risk compared to those who heal, but it’s still only about 1 percent risk of lymphoma over the course of 10 years,” Lebwohl says. “The risk should be treated the way other risk factors are generally treated, for an example having high cholesterol.”

Lurking feeling

Still Bast says cancer is a common concern for people with celiac disease, particularly those with family members who have been diagnosed with lymphoma or cancers of the gastrointestinal tract, blood, thyroid or pancreas.

“For many of us there’s always that lurking feeling that these instances may be connected to celiac disease,” she says. “My own mom died from pancreatic cancer at the age of 52. There’s no way to know for sure, but looking back, I think she had undiagnosed celiac disease. Many of us have stories like this.”

Patients with a family history of cancer are often concerned that it will increase their personal risk, Lebwohl says. In some cancers this is true; for example colon cancer. However family history doesn’t appear to increase the risk for lymphoma in celiac disease.

The lack of a genetic link only emphasizes the importance of effective, timely treatment for people with celiac disease.

“Celiac disease disrupts and devastates lives,” Bast says, but the recognition of increased cancer risk makes it “undeniable that celiac disease is serious and needs research for a cure.” She also points out an estimated 83 percent of people with celiac disease remain undiagnosed. “Their increased health risks are unrecognized and unmonitored by their healthcare professionals. It doesn’t get more serious than an increased cancer risk,” Bast says.

She encourages anyone diagnosed with celiac disease to talk to their relatives and encourage them to get tested. “We’ve found that once educated on the long-term health risks of undiagnosed and untreated celiac disease, people are more likely to get tested,” she notes.

Ken Kilgore looks back at the impact undiagnosed celiac disease had on his family.

“Celiac-associated cancer takes things, even beloved things, away long before one actually passes away. Within a few months of his diagnosis, my dad was unable to do the things he loved. [T-cell lymphoma] is a totally unforgiving and merciless disease,” he says. “It is also preventable.

“This last point is what haunts me the most. All the signs of celiac disease were there long before he got cancer, and we missed it. It is the survivors like me who have to carry that burden for the rest of our lives.”

He says he hasn’t watched a University of Michigan game since his father died. GF

Van Waffle is research editor for Gluten-Free Living. He blogs about nature, gardening and local food at vanwaffle.com.

Maggie McCombs had been gluten free for about five years without a celiac disease diagnosis, when at age 23, with the rest of her life and big changes ahead, she needed answers.

“I realized how much work I was already putting into the diet, but I needed to know if it was for a good reason,” she says.

Traditionally, a biopsy would be key to getting an answer. For decades specialists have considered a biopsy the gold standard for diagnosing celiac disease. But debate about the absolute need for a biopsy is emerging among experts, with some saying there are times when the invasive test is not needed.

Blood tests have become more accurate in identifying antibodies associated with the autoimmune reaction. Until recently tests could only provide preliminary evidence, needing confirmation of celiac disease from a biopsy. But some celiac disease researchers say there are cases when blood tests provide enough proof.

 

No biopsy

McCombs had adopted the diet at 17 when her brother was diagnosed with Type 1 diabetes and celiac disease, the autoimmune disorder triggered by gluten protein in wheat, barley and rye. McCombs’ brother had undergone a biopsy to look for characteristic tissue damage in his small intestine prior to getting a final celiac disease diagnosis.

“I feel as though my brother was a guinea pig in many ways,” says McCombs, now 25 and a content marketer in Lexington, Kentucky. “He had the multiple blood tests, the follow-up visits, the endoscopy.

“After his diagnosis, my mother immediately suspected that I also had the disease due to my stomach pain complaints and itchy rashes spreading across my hands and face,” McCombs says. She started to research celiac disease and felt all her symptoms suddenly made sense.

“I’d experienced severe depression, anxiety, confusion: all hidden neurological symptoms of celiac disease. Admittedly I was both in denial of the possibility and deathly afraid of needles. So I evaded the blood tests and started adapting to the diet,” she says.

Though her health improved, she had trouble maintaining the gluten-free diet at college.

“Initially part of my problem was not knowing for sure that I had celiac disease, so I’d talk myself into sneaking some gluten-filled meals and snacks,” she admits. “Naysayers insisted that the disease was all in my head.”

After graduation she wanted to know for sure and decided to take the blood test recommended years earlier by her brother’s doctor. Celiac disease cannot be diagnosed in someone when they’re on a gluten-free diet, so McCombs had to start eating gluten again—called a gluten challenge.

“Instead of looking forward to eating anything I wanted, I actually dreaded cramming my body with my favorite foods,” she recalls. “My stomach ached. I had itchy red rashes spreading all over my hands and face. Although the doctor asked for a full month of eating as much gluten as I could tolerate, I was so sick that I had to get the test a week early.”

When McCombs’ tests came back, her doctor told her the antibody levels were the highest he had seen since her brother’s. “Any other tests would be superfluous. I had celiac disease,” she says.

Unlike her brother, McCombs received a diagnosis without undergoing an endoscopy and biopsy, a procedure in which a gastroenterologist inserts a narrow tube down the throat, through the stomach and into the small intestine, allowing a visual inspection. But more importantly, small samples taken from the lining are examined to determine if there is damage from celiac disease.

RoByn Thompson, 51, of Paterson, New Jersey, was also recently diagnosed with celiac disease after a blood test. Her doctor didn’t suggest a biopsy, but Thompson says she probably would have decided against it.

“I’m a cancer survivor and have had too much surgery already,” she explains, adding she’s confident in the diagnosis. “I’m symptom free when I avoid gluten.”

 

Gold standard?

A few specialists believe it’s time to move beyond the biopsy as the gold standard. Geoffrey Holmes, M.D., emeritus consultant gastroenterologist at Royal Derby Hospital in Derby, U.K., is advancing the case for blood tests.

“Endoscopic biopsy is generally safe, but it is invasive and unpleasant and often requires sedation, so why do it if it is unnecessary?” he asks.

Holmes was seeing patients with high antibody levels and started to ask the question, “What could this be other than celiac disease and why do I need to perform a biopsy which is certain to confirm it?”

Though many doctors were already making diagnoses without biopsy and putting patients on gluten-free diets, Holmes says he wanted to address the question from a scientific basis.

The most valuable blood test relies on tissue transglutaminase (TTG), an enzyme that occurs in the gut and interacts normally with gluten protein. Meanwhile the immune system produces a class of antibodies called immunoglobulin A (IgA) to fight infection. But people with celiac disease produce particular IgA antibodies that bind with their own TTG.

Holmes thought there must be a high level of IgA anti-TTG that could predict celiac disease 100 percent of the time. His research found that antibody levels at least 10 times the upper limit of normal were sufficient, so a biopsy was unnecessary to confirm diagnosis. He and his colleague published these findings in 2008.

Previous research has suggested that 20 to 30 percent of patients with celiac disease can safely be diagnosed without biopsy. However recent work by Holmes and colleagues pushes the number much higher, to 78 percent. In practice, he claims about half of celiac disease patients in Derby are diagnosed without biopsy.

In 2012 the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) published new guidelines for diagnosis, based partly on Holmes’ work. The society affirmed that in a child showing 10 times the normal anti-TTG, an additional test for IgA endomysial antibodies (EMA) could be used in follow-up. If this second test was positive, the child could be placed on a gluten-free diet. If this produced beneficial results and the child’s antibodies returned to normal, celiac disease could be considered proven.

The EMA test was discovered when researchers were studying a painful skin form of celiac disease, dermatitis herpetiformis. Certain IgA antibodies appeared in connective tissue under the skin. This led to the revelation that EMAs also occur in celiac disease without the skin manifestation. In fact almost 100 percent of people who test positive for EMA have celiac disease.

But the EMA test gives a few false negatives, not showing up in 5 to 10 percent of patients. TTG doesn’t miss as many. EMA is also more difficult and expensive to perform, demands specialized training for the pathologist, and is not widely available in North America.

 

Critical component

Not everyone agreed with the ESPGHAN’s protocol and movement away from biopsy.

In 2013 the American College of Gastroenterology (ACG) weighed in, recommending that an endoscopy with biopsy is a “critical component” in evaluating patients and should be used to confirm the diagnosis. While affirming the value of blood tests, the group does not recommend use of EMA. British Society of Gastroenterology guidelines published in 2014 also insist that a biopsy is always necessary.

Joseph Murray, M.D., of the Mayo Clinic in Minnesota, is a strong proponent of biopsy. He acknowledges the ESPGHAN guidelines can lead to an accurate diagnosis, but only if followed correctly.

“Unfortunately what we’re seeing is people not following the guidelines,” says Murray.

Clinical antibody tests are recommended as a starting point by physicians, but some patients don’t take that step before starting a gluten-free diet.

Jill Wirth’s daughter Kaiya is an example. At 2 years old, Kaiya was “almost at the failure-to-thrive weight,” says Wirth, 38, a technical sales professional in Cambridge, Ontario, Canada.

“As a baby she cried more often than what I would consider normal. She didn’t want to be held or fed. She had very little interest in food. She was not what I would call a happy baby by any means,” Wirth recalls. “Our general practitioner had suggested [putting] 35 percent cream in her bottle and to put sugar on her food to try to entice her to eat it.”

After dissatisfying results, Wirth took Kaiya to a holistic nutritionist who tested her for food sensitivities and celiac disease. Results from an over-the-counter test for celiac disease were positive so Wirth immediately put Kaiya on a gluten-free diet.

Murray says store-bought tests like the one used to diagnose Kaiya are available in Canada but have not been approved by the U.S. Food and Drug Administration. The tests can give accurate results, according to Murray, but that depends on the test and who does it. And patients are advised to seek further testing to confirm results before undertaking a gluten-free diet.

Kaiya’s doctor did order a blood test, which also came up slightly higher than normal. Finally Wirth asked for a referral to a gastroenterologist.

“We decided with the specialist that we would not put our daughter through having to be glutened for an extended period of time in order to go for a measurable biopsy,” she says. “Since we had seen such a positive change in weight, behavior and mental wellness, we would not put her back on a diet that included gluten.”

Kaiya, now 5, “responded incredibly,” Wirth says, “a complete transformation.” She adds that she and her husband are completely confident in the diagnosis.

“If there is any doubt about the celiac disease, there is certainly no doubt that this sweet young girl should not be consuming gluten. I guess the biopsy would only confirm the extent of the damage the gluten creates in Kaiya’s body, not whether or not she should consume gluten,” Wirth explains.

Blood tests

Blood tests for diagnosis include several alternatives suited for specific circumstances. IgA deficiency, a rare condition affecting a few people with celiac disease, causes undetectable IgA anti-TTG. This can call for an IgA deficiency test and alternate tests for celiac disease based on immunoglobulin G (IgG). However, their accuracy is less well known.

Genetic tests for celiac disease are now being commonly used. The human leukocyte antigen (HLA) gene codes for an agent in the immune system. Two forms, HLA-DQ2 and HLA-DQ8, occur in about 40 percent of the population. Only people who carry these genes can develop celiac disease: Still, the vast majority never will.

Some celiac disease experts have found the problem with HLA tests is that patients and many doctors interpret a positive result as strong evidence for a diagnosis, which it is not. It indicates only that the patient has a higher risk for celiac disease. The ESPGHAN guidelines recommend including it with other blood tests in reaching diagnosis, even though genetic testing is inconclusive and relatively expensive to perform.

A negative HLA result is helpful in ruling out celiac disease in the majority of cases. The ACG recommends this as a first step for patients who have already adopted a gluten-free diet without diagnosis. A negative result indicates the diet is unnecessary. However the genetics of celiac disease are not entirely understood, and about 1 percent of patients have none of the gene types so far identified. These rare individuals would get a negative HLA result.

The ACG strongly recommends that people with a positive HLA seek appropriate diagnosis beginning with a gluten challenge and appropriate antibody tests, instead of continuing a gluten-free diet.

Some doctors won’t understand these nuances, says Murray. He discourages the practice of sending patients for a panel of blood tests. “The problem when you combine tests is they reduce to the lowest common denominator of accuracy. I frequently have patients come to me who’ve had four tests, one out of the four was positive, and they were told they had celiac disease when it’s obvious they don’t.”

Murray says the first step after a positive anti-TTG test should always be referral to a gastroenterologist.

“One of the hardest things I do in my practice is, when someone comes to me who has been committed to being on a gluten-free diet for two or three years, I have to tell them, ‘You don’t have celiac disease.’ It is a life-long diagnosis with a life-long, life-altering treatment,” Murray says. “Many people choose to go gluten free, but that’s very different from the burden on a patient, who must go gluten free. It affects every time you eat, buy food, eat out or travel. That applies to children as well as adults, and with children it’s imposed on them, so I think there’s a higher bar for certainty.”

Ivor Hill, M.D., medical director of Nationwide Children’s Hospital Celiac Disease Center in Columbus, Ohio, says he has had cases where the symptoms were very typical, the TTG was very high, and the parents were reluctant to have their child undergo a biopsy.

“I’ve felt comfortable in those cases saying we’ll put them on the diet and monitor the response. They all had a good response and their [antibody] numbers came down, so in retrospect I’m pretty sure they have celiac disease,” Hill says. “Do we have the same level of confidence with a non-biopsy diagnosis? Hopefully we’ll get there someday but right at the moment, maybe not.”

He discusses the implications of making a positive diagnosis with the parents. “I want to be 100 percent sure that the child has celiac disease because if they’re going to go gluten free, it’s for life,” Hill explains.

Alessio Fasano, M.D., chief of the division of pediatric gastroenterology and nutrition at Massachusetts General Hospital for Children in Boston and director of the Center for Celiac Research and Treatment, says patients who have been diagnosed based on blood tests alone tend to comply poorly with the gluten-free diet over time, compared with people who have received a picture of their damaged intestine.

Previously a supporter of diagnosing without biopsy in some cases, Fasano says he now has reservations because endoscopy can reveal important information that would otherwise be missed. For example a patient may have other related conditions such as reflux.

“In a large number of people who go on the gluten-free diet, once their symptoms have gone and their antibodies go back to normal, after a year when we repeat the endoscopy, we see [a significant] number of these individuals that still have damage,” Fasano says. “So that’s another reason why we are skeptical at this point.”

Holmes argues that while biopsy remains useful, its status as the gold standard is becoming hard to defend. Celiac disease may be the correct diagnosis if the intestinal lining is typically flattened, but some cases are more uncertain.

Reading the biopsy

Biopsy has its limitations. Damage from celiac disease may be spotty, with some tissue still appearing healthy. Specialists recommend collecting at least five or six samples from different parts of the small intestine of each patient. Studies have shown gastroenterologists performing the procedure do not always take enough samples to detect celiac disease in every patient.

The tissue samples must then be correctly preserved and oriented so the damage is visible. They are sent to a lab where trained pathologists look for telltale damage. The earliest sign of damage is an increase in a certain kind of white blood cells in the tissues. However this can occur in other conditions, too.

Next comes an increase in the number of cells in depressions lining the intestine, a condition called crypt hyperplasia. This is thought to occur in response to tissue damage.

The third and most significant change is flattening of the villi, minute hair-like projections that normally line the gut, increasing its surface area. Celiac disease blunts them or flattens them completely, so the body has a hard time absorbing enough nutrients. This is the damage pathologists look for to confirm a diagnosis. It may occur in a few other conditions, but they’re very rare.

Inconsistencies in how tissue samples are collected and prepared raise concerns even among biopsy advocates. Holmes says typical flattening may provide a clear diagnosis, but with moderate damage the cause is uncertain.

“Often the villi are reported as slightly shortened or blunted. Is this celiac disease? It may or may not be, and here serology can come to the rescue,” he says.

 

The right diagnosis

Meanwhile, McCombs says she is confident in her celiac disease diagnosis.

“I was determined to get a definitive answer, so I definitely would have gotten a biopsy if needed,” she reflects. “Honestly I would have undergone almost any procedure to get diagnosed and end the misery of the gluten challenge.”

Two years later she is learning to cook at home, asking more questions in restaurants and looking for a follow-up with a new doctor in the area where she moved to start a career.

“I’m still so thankful to know what’s wrong with me. Most days I don’t even mind the gluten-free diet because I see it as a cure,” she says. “Changing my diet improved my health, but changing my attitude improved my entire way of life.”

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What is Celiac Disease?

Gluten-Free Recipes

Diagnosis Dilemma

 

Van Waffle, who has a bachelor’s degree of science in biology, is research editor for Gluten-Free Living. A resident of Ontario, Canada, he also contributes regularly to Edible Toronto and blogs about nature, gardening and local food at vanwaffle.com.

 

 

This article was originally published in our March/April 2015 issue. All information was correct at time of publication.

Soon, when a baby is born, doctors will be able to inspect his or her genetic code and advise the parents how to avoid life-long disorders of the immune system such as celiac disease. Preventive measures might include introducing particular foods while breastfeeding or enlisting the child to help in the garden or raise chickens. So predicts Moises Velasquez-Manoff in An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases (Scribner, 2012). Velasquez-Manoff is also the author of a recent lead story in The New York Times Sunday Review that examined the role of breastfeeding and the development of celiac disease. He said he had noted the disease has been a hot topic recently in the media, but discussions seldom touched on establishing healthy microbiota in the gut.

So he chose to address it in a Feb. 23 piece, “Who Has the Guts for Gluten?” The story resonated among those who have celiac disease for its clear and reasoned description of the ways celiac disease might develop. It was the most emailed story on the paper’s website the day it appeared and as of press time it was the newspaper’s seventh-most emailed article in the past 30 days.

“Scientists are pursuing some intriguing possibilities. One is that breast-feeding may protect against the disease. Another is that we have neglected the teeming ecosystem of microbes in the gut-bacteria that may determine whether the immune system treats gluten as food or as a deadly invader,” Velasquez-Manoff wrote in the Times.

The story was based on findings in Velasquez-Manoff’s book, which highlights new ideas about the causes and rising prevalence of celiac disease. The book also details the role parasites play in combating immune disorders. Investigating the topic over two years, the author infected himself with hookworms, surveyed research and interviewed scientists from around the world.

He noticed parallel lines of research showing a rise in various diseases of the immune system, particularly in affluent countries. Some important insight turned up in obscure journals. To his knowledge, he said in an interview, some of the most surprising findings had never been reported in popular media.

“I do not know if I am able to articulate it any better than anyone else. I am just aware of a lot more science. I spent two years writing this book, so I did a lot of research,” he said. Many of the specialists he contacted for his research have expressed appreciation for the book, he said, and were happy to see it bring those “parallel lines of this science together.”

He argues that this trend in autoimmune diseases results from a declining biodiversity of germs and worms that normally live in our bodies, even the blood parasite that causes malaria.

Why the rate of celiac disease is increasing

A popular theory suggests celiac disease is becoming common because we are eating too much wheat or the wrong varieties, particularly genetically modified wheat. Velasquez-Manoff disputes this. Facts about wheat are the most essential point about celiac disease that readers should take from his book, he said.

“It is important to contextualize any autoimmune disease within the greater family of autoimmune diseases,” he said, “to recognize that sometimes at the individual level but especially at the population level, all these diseases increase together.”

People miss this pattern if they focus on just one disorder, he added. For example, he warns against jumping to the conclusion that celiac disease has arisen because of increased wheat consumption, changing molecular structure of the protein, or how we prepare it.

Wheat has increased in the American diet since the 1970s, but we actually ate more of it in the late 19th century. Despite this, celiac disease could not have been widespread then. We have no way to estimate its prevalence at the time except by noting that deaths were rare, even though celiac disease was frequently fatal in childhood cases before scientists recognized the connection to wheat and began eliminating it from their patients’ diets in the 1940s. Consumption of wheat does not seem to account for increasing incidence of celiac disease, but the argument persists, according to Velasquez- Manoff.

“You can log onto the Web and find a number of conspiracy theories in a second,” he added. “There is a lot of evidence that those are non-sequiturs. It is far more likely— at least this is the hypothesis I explore— that something has changed about us.”

The increasing prevalence of celiac disease has followed the same trajectory as other autoimmune diseases and in the same geographical locations, irrespective of how much or how little the culture relies on wheat as a staple. Velasquez-Manoff points instead to the changing ecology of our guts.

Cultivating the superorganism

An Epidemic of Absence explores how microbes and parasites build a healthy ecosystem within our bodies, particularly the gut. The genetic diversity of our microbiota helps us digest food and has long been recognized as essential to health. However, new studies add increasing evidence that affluent lifestyles are changing the bugs that inhabit our intestines. This in turn appears to be causing the rise of allergies and autoimmune diseases, still rare in most developing countries.

One corner of the world has provided a fertile laboratory for studying this phenomenon. Karelia, historically a province of Finland, became divided during World War II. Part remains in Finland, one of the richest countries in the world. The other part in Russia is one of the poorest regions in Europe.

“You have the same population genetically, culturally and linguistically on both sides,” Velasquez-Manoff said, “and a very, very different prevalence of celiac disease.”

A 2008 study published in Annals of Medicine tested schoolchildren for celiac disease and found in Russian Karelia, “a prevalence of 1 in 496 children compared to 1 in 107 children in Finland.” Finnish children with the same heritage and living in the same climate are almost five times more likely to have celiac disease. Not only that, Finland has one of the highest incidences of autoimmune disease in the world, ranking first for autoimmune Type I diabetes.

Velasquez was quick to point out that the celiac disease epidemic cannot be attributed to wheat: “We should be focusing on what is the difference there and why the immune system seems to work differently on the Russian side. Just looking at that example you can come away and say it is not the amount of wheat we come in contact with. If anything, the Russians are consuming more wheat, the same modern varieties.”

What is the difference? The average Russian Karelian family has a lower income, lives in more crowded conditions, and often keeps farm animals. Their children encounter a diversity of microbes and are more likely to experience infections such as hepatitis A. Studies show that this exposure seems to protect Russian Karelian children from autoimmune disorders and allergies.

Germs and worms have lived in us and our ancestors for millions of years. We are their home, so they have a vested interest in keeping us well. They interact with the complex human immune system, stimulating it just enough to fight off virulent pathogens while preventing the body from launching a massive, self-destructive attack. Velasquez-Manoff considers this balanced system, including an individual with all his inhabiting life forms, a superorganism.

A healthy start: breast milk

We used to depend on nature to populate our digestive tract with the right variety of bacteria. We spend the first nine months in a sterile environment and acquire our first microbes while passing through the birth canal.

According to research surveyed in An Epidemic of Absence, breast milk contains chemical messages from a mother’s body telling her baby what bacteria to expect, which species to accept, and when to turn on the immune reaction to fend off dangerous ones. If the mother has the right balance of bacteria in the gut and a healthy immune system, it helps the baby avoid developing allergies and autoimmune diseases.

The American Academy of Pediatrics recommends gluten be introduced to babies while breast-feeding to help prevent celiac disease. But Velasquez-Manoff pointed out it’s not clear exactly when during breastfeeding this should occur. This might confuse parents. Too early may be counterproductive, he said, and possibly cause celiac disease.

However, the society’s counterpart across the Atlantic, European Society for Paediatric Gastroenterology, Hepatology and Nutrition, provides specific guidelines. They recommend introducing gluten no earlier than four months and no later than seven.

“I think some of the ambiguity in the American Academy of Pediatrics may be intentional because they are not sure,” Velasquez-Manoff said. “There are ongoing prospective studies. Once we have the results we will know better.”

He also noted, as he did in the Times article, that “there is this added layer of complexity: all breast milk is not the same.”

A study last year in Pediatric Research reported breast milk from overweight mothers contained less bifidobacterium, a bacterial group beneficial to the baby’s developing microflora.

Velasquez-Manoff refers to a study by Yolanda Sanz of the Institute of Agrochemistry and Food Technology in Valencia, Spain, which found bifidobacteria were relatively depleted in children with celiac disease, while other microbes such as E coli. were over-abundant.

In the Times article, he explained, “In a test tube, (Sanz) found that those E. coli amplified the inflammatory response of human intestinal cells to gluten. But bifidobacteria switched the response from inflammation to tolerance.” E. coli also appears to provoke the leaky gut condition implicated in celiac disease while bifidobacteria protect the intestinal barrier.

Velasquez-Manoff suggested that there should be more focus on this where prenatal healthcare is available. Meanwhile, a 2010 paper in Pediatric Allergy and Immunology found better anti-inflammatory properties in breast milk from farm mothers than from women who lived in cities.

“In some ideal future,” Velasquez-Manoff said, “doctors will proactively approach these problems.”

They will identify the genetic risk for celiac disease in a family and advise the mother, while still pregnant, to shift the microbiology of her breast milk using probiotics. This may seem to put additional pressure on mothers to do the right thing, but Velasquez-Manoff said we cannot escape the importance of a mother’s nutrition.

“The idea is not to blame women,” he said, responding to some comments after the Times story accusing his article of faulting women. “What we have to do is shift society to accommodate biology. I agree that the answer should not be, ‘Women need to leave work and go back to the kitchen.’ That is absurd. We need instead to make it possible for women to do the healthy thing without having to disrupt their lives.”

Velasquez-Manoff said his wife’s experience breast-feeding is an example of some of the difficulties women face. Her employer provided a pumping room in a converted closet. Using the space was a hassle for her, he said, but at least she had somewhere to go. Many women do not.

Hookworms and celiac disease

Velasquez-Manoff also refers to a different prospect for defense against celiac disease, intriguing but less palatable: hookworms.

As Velasquez-Manoff describes it, hookworms prevent their host from letting “loose with a higher fire power,” which might kill the parasite but also destroy the gut. Intestinal parasites are so ubiquitous that vertebrate animals now depend on them to help manage their immunity.

In people with celiac disease, the immune system recognizes gluten as an invading bacteria or virus and begins attacking the gut lining. It is theorized that hookworms can prevent this by inducing a more tightly reined response, preventing autoimmune attacks.

A clinical study, published last year in International Journal for Parasitology, infected celiac disease patients on gluten-free diets with hookworms. Although the parasites did not cure anyone, they reduced the immune reaction when subjects ate food containing gluten.

Velasquez-Manoff said, “It was not anywhere near qualifying as remission” from celiac disease. However, it was measurable and led to a less-adverse reaction. In particular it meant people with an intense sensitivity to wheat would not have to worry about encountering “a few miniscule grains of wheat flour somewhere along the way. Some patients ended up opting to keep their parasites, because they felt better,” he added.

A personal journey

As part of the research for his book, Velasquez-Manoff inoculated himself with hookworms. He wanted to see if the parasite would relieve his food allergies, asthma, eczema and alopecia areata, a condition in which the body’s own immune system attacks hair follicles, causing partial or complete hair loss.

He had put up with symptoms since childhood but became more concerned when faced with becoming a parent. Alopecia areata shares gene variants with more serious conditions such as celiac disease and Type 1 diabetes. Velasquez-Manoff was bound to pass some of those genes on to his children, and he wanted to learn all he could to ensure their health. He found some compelling evidence, from both scientists and an underground movement of patients treating themselves, that hookworms could mollify autoimmune diseases.

He decided to try it at the same time he decided to write about it. It seemed like a good way of making “a very science-rich book more accessible” to readers, he said. He was also intensely curious. The people he contacted told him parasite infections were not bad to live with, but he wanted to gauge negative side effects for himself.

Coincidentally, a certain gene is also known to be connected with curiosity and daring behaviour, but Velasquez-Manoff does not consider himself a risk-taker. “A number of scientists have self-infected with hookworm, including John Croese [an Australian gastroenterologist investigating hookworm as a treatment for celiac disease]. Once you learn that scientists, with their wealth of knowledge about the horrors of parasite infection, are willing to self-infect, well, it seems not so risky,” he said.

The results of the author’s personal experiment with hookworms were mixed. He experienced relief from hay fever and eczema. His eyebrows started to grow back and his grooved and pitted fingernails, another symptom of alopecia areata, began growing in normally. Asthma and food allergies were unaffected. However, side effects of the hookworm infection, including cramps, diarrhea and headaches, were initially intense. They eventually settled to a more acceptable level, but the cure did not justify the treatment. Velasquez-Manoff said that eventually, after writing the book, he took a deworming drug. He does not recommend using hookworms to prevent autoimmune disease or allergies in children.

“Given my symptoms,” he concludes in the book, “I would never deliberately administer them to my daughter, for example. On the other hand, if I knew with any certainty that she was destined to develop Crohn’s disease and debilitating allergies, I might think differently.”

The long view

Studies tend to focus on prevention and development of celiac disease in children. Velasquez-Manoff said he did not find much research about what triggers its onset in adults. However, celiac experts recognize it may develop after surgery, antibiotic treatment or even pregnancy, he added.

Our lives appear to be over-sanitized. Generally, the research indicates that autoimmune diseases are increasing because germs and parasites are missing, according to Velasquez-Manoff.

Specifically, with respect to celiac disease, certain bacteria may prevent it. Breast-feeding can foster the right bacteria to protect babies against the disease. Ongoing research promises new insights about how probiotics and other lifestyle choices may contribute to a healthier gut. If these studies hold, Velasquez-Manoff said, they will change the way doctors treat celiac disease.

Meanwhile, his own journey continues. His daughter is now 2 years old. At the time of the interview, he was preparing to move from New York City to California with his family the following day.

“I will continue to cover this topic and think about a next book,” he said.

Van Waffle, who has a bachelor of science in biology, is a freelance journalist based in Guelph, Ontario, Canada, and has cooked gluten free for five years. He writes frequently for Gluten-Free Living. His work has also appeared in Edible Toronto and on cottagelife.com. He blogs about urban nature, local food and environmental issues at vanwaffle.com.

 

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