By Amy Ratner, Medical and Science News Analyst
Some beliefs about celiac disease have been “upended” by increasing scientific research according to a broad review of the condition in the latest edition of the journal Gastroenterology Clinics.
The review is designed to keep physicians and researchers current on clinical findings and make it easier for them to put these findings into practice. For patients, articles on a variety of topics help explain the latest developments in celiac disease.
Peter Green, M.D., and Benjamin Lebwohl, M.D., of the Celiac Disease Center at Columbia University served as editors of the publication and wrote the introduction. A number of other celiac disease experts wrote articles on specific topics.
“From the mid-twentieth century forward, celiac disease was understood as an illness primarily affecting children, exclusively affecting the small intestine, and treated by life-long gluten restriction, with no other therapies on the horizon,” they wrote. “In recent years, these aspects of celiac disease have been upended.”
Celiac disease is now recognized as developing at any age, affecting many systems in the body, according to the editors. Research is finding breakthroughs in the diagnosis and treatment of refractory celiac disease, the more severe type, they note. Additionally, more is understood about the interplay between celiac disease and the microbiome and scientists are paying attention to the increase in incidence of celiac disease in Asia.
Meanwhile, a broad range of potential treatments are in various stages of development, including the critical clinical trials needed before any drug to treat celiac disease can be approved. In addition to celiac disease, the review includes an update on non-celiac gluten sensitivity, which Green and Lebwohl wrote is still largely a mystery but is being studied with increased scientific rigor.
Following are key points made in articles in the review issue.
The review presents a changing picture of patients being diagnosed with celiac disease.
The condition is increasingly being diagnosed in adults, including the elderly, according to the review. Additionally, it is being found both in those who have symptoms and those who don’t. When symptoms are present, they can be gastrointestinal or affect another part of the body.
More than half of adults with celiac disease have gastrointestinal symptoms and weight loss. While diarrhea is the most common symptom, it has been decreasing in frequency.
In fact, those who have no symptoms now make up 30 percent of newly diagnosed cases, while those with symptoms outside the digestive system, including anemia, osteoporosis, neuropathy, headaches and reproductive problems, make up more than 40 percent.
Overall, women continue to be diagnosed more often than men and at a younger age, but as the incidence of celiac disease diagnosis grows among those older than 65, elderly men are being diagnosed more than women. Anemia is the most common symptom and nutritional deficiencies might be the only presenting feature. Gastrointestinal symptoms are less prevalent in the elderly and, if present, tend to be mild.
About 35 percent of celiac disease patients have another autoimmune condition, and they are more likely to have more than one autoimmune disease, according to the review. Hashimoto’s thyroiditis is the most commonly associated autoimmune disorder, found in roughly 20 to 30 percent of patients. However, its frequency in celiac disease has been decreasing.
Follow-up of celiac disease
A lot of scientific discussion about celiac disease has focused on diagnosis, but follow-up care has generated less interest and needs more attention, according to the review article on the topic. The authors conclude that those who have uncomplicated cases of celiac disease should get annual follow-up with their physician and a dietitian, but they note that 20 to 40 percent of adult celiac disease patients have persistent symptoms and changes in the lining of the intestine.
A 2017 study by Beyond Celiac and other researchers found that more than one out of four celiac disease patients diagnosed at least five years ago had not had follow-up healthcare for the condition over a five year period.
The review authors also look at some of the complexities of celiac disease follow-up, including the role of repeat biopsies, testing stool and urine for gluten immunogenic peptides (GIP), the limitations of anti-tissue transglutaminase immunoglobulin A (tTG IgA) testing for monitoring celiac disease and the current state of knowledge regarding how strict a gluten-free diet needs to be.
“The relationship between the quantity of gluten ingested and the development of symptoms and histologic abnormalities is not clearly defined and the exact amount of gluten that people with celiac disease can tolerate on a daily basis without suffering any deleterious effects has not been fully established,” the authors wrote.
GIP testing needs to be made more sensitive so it detects smaller amounts of gluten but could provide a sensitive and specific option for monitoring how well someone is adhering to the gluten-free diet whether the tests are used by researchers, physicians in their offices or patients at home, according to the article.
The authors also look at the differences in follow-up for children, adolescents and adults. Although children generally do well on the gluten-free diet, those who do not get follow-up care do not follow the diet as well as children who do. Young adults often don’t get any follow-up and are the group with the greatest need, according to the article.
While a strictly gluten-free diet is effective in treating celiac disease, the reality is that the diet is challenging and difficult to maintain, according the authors of an article on non-dietary treatments for celiac disease. For those who have nonresponsive and refractory celiac disease, symptoms and intestinal damage can continue even with a very strict diet.
The authors note that the sequential steps in the development of celiac disease are well understood, giving researchers well defined targets for drugs being investigated. Since 2005 when the first clinical trial in celiac disease was registered with the National Institutes of Health, 192 trials have been conducted, with 43 focused on treatment alternatives to the gluten-free diet, according to the review.
They identify the following treatment possibilities: degrading gluten with enzymes before or after food is ingested, binding and sequestering gluten in the intestine, restoring tight junction barrier function in the intestine, preventing tissue transglutaminase from modifying gluten in the cell, inducing tolerance to gluten and reducing intestinal inflammation with anti-inflammatory treatments.
Although enzymes that break down gluten are one of the treatments being investigated, the article warns against patients using digestive enzyme supplements currently on the market. The authors point to a study of five commercially available products that found the supplements do not detoxify gluten as claimed. In particular the authors were concerned that celiac disease patients are very interested in the supplements and perceive them as proven remedies.
While treatments currently under study would be used along with the gluten-free diet the article authors look toward “the ultimate goal,” a future where patients could eat a diet without gluten restrictions.
“This life-changing advance for patients with celiac disease could also act as the pivotal event in the prevention and management of other autoimmune disorders for which the environmental activators of disease are not well characterized,” they wrote.
Bifidobacterium: microbes that are among the first to colonize the human gastrointestinal tract and are believed to exert positive health benefits on their host.
Lactobacillus: a type of bacteria that lives in the intestines and converts sugars to lactic acid and is considered a friendly bacterium
Gram negative bacteria: bacteria that cause infections including pneumonia, bloodstream and wound infections and are resistant to multiple drugs and antibiotics as the bacteria have built-in abilities to find new ways to be resistant and can pass along genetic materials that allow other bacteria to become drug-resistant as well.
As the role of the microbiome in celiac disease has been increasingly studied, researchers have seen differences in the population of Bifidobacterium and lactobacillus in study participants, according to the review. Celiac disease patients also seem to have an increased number of gram-negative bacteria, specifically proteobacteria. This imbalance of bacteria, called dysbiosis, can lead to modification of the intestinal barrier and persistent activation of the immune system by the harmful protein in gluten, leading to symptoms.
Studies related to the microbiome have shown that the gluten-free diet alone does not normalize this condition, and probiotic therapy is being investigated, the authors wrote. More research is needed in relationship to celiac disease and the microbiome, they conclude.
Refractory celiac disease
Refractory celiac disease continues to need investigation as it is the more severe form of the condition, in particular type 2, which brings the risk of malnutrition and lymphoma. Recent advances in understanding the pathogenesis of refractory celiac disease open the possibility of targeted therapy, according to the review.
Treatment with the medication open-capsule budesonide has shown some promise, with one study by the Mayo Clinic finding that study participants had improvement clinically and in biopsy results, including those for whom immune-suppressive medications failed.
Celiac disease in Asia
Although the number of celiac disease patients in Asia is small, it is expected to grow significantly in coming years as a result of more awareness and increased diagnosis, according to the review.
The medical community across Asia should define the extent of the problem now and be prepared to handle the “impending epidemic of celiac disease,” the authors wrote.
Non-celiac gluten sensitivity
Scientific interest in non-celiac gluten sensitivity, also called non-celiac wheat sensitivity, has increased and is reflected by the growing number of original papers, reviews, and trials published on this topic in the past 10 years, authors of an article in the review found.
“The initial skepticism surrounding this disorder has gradually given way to a progressing awareness of [its] existence,” they wrote. The exact triggers of symptoms among the various components of wheat and related cereals remain unclear, but gluten, amylase/trypsin inhibitors (ATIs), fructan and other components may play a role.
Fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) have been reported to contribute to certain intestinal symptoms in some patients, but other components of wheat and related cereals are believed to trigger immune activation or dysfunction of the intestinal barrier that could explain intestinal and other symptoms.
Biomarker: a distinct cellular, biochemical or molecular indicator of a process, event or condition that can be measured reliably in tissues, cells or fluids to detect early changes in a person’s health.
The search for biomarkers for gluten sensitivity has intensified because they would enable diagnosis without the need for a time-consuming food challenge, which is currently used but not well-accepted by patients, the authors note.