Study Sessions

An Italian study shows that two-thirds of adult celiac disease patients who carefully followed a gluten-free diet showed complete recovery after one year. Patients with severe cases with more intestinal damage were likely to make only a partial recovery, but everyone who followed the diet improved. Patients who slipped up fared less well.

A gluten-free diet is the only known treatment for celiac disease, but experts disagree on how and when to measure its effectiveness in an individual. This study enrolled 65 newly diagnosed patients, providing follow-up interviews, blood tests and biopsies after one year.

Of the study’s participants, 53 patients, or 82 percent, followed the gluten-free diet better than expected. Most other research has found a lower rate of compliance. It is possible that patients were motivated to follow the diet because they knew they were participating in the study.  Of the 12 participants who did not stick with a strict diet, seven showed only partial intestinal recovery after a year, and the other five made no improvement.

 

Galli, G.; Esposito G.; Lahner, E.; Pilozzi, E.; Corleto, V.D.; Di Giulio, E.; Aloe Spiriti, M.A.; Annibale, B., “Histological recovery and gluten-free diet adherence: a prospective 1-year follow-up study of adult patients with coeliac disease,” Alimentary Pharmacology and Therapeutics, July 28, 2014, 40:639-47; doi:10.1111/apt.12893.

When ancient cultures started eating grain, people with the genes for celiac disease may have had better protection against tooth decay. Italian scientists think this finding might explain why the disease is so common today.

Many civilizations have depended on wheat since it was first cultivated in the Middle East 10,000 years ago. No one knew that wheat gluten caused celiac disease until the 20th century. But ancient bones and medical reports indicate that people suffered and died from it long ago. Theoretically, wheat-based diets should have killed more people who carried celiac disease genes, reducing their prevalence in later generations.

Paradoxically, these genes are most common in cultures with a long wheat-growing history, from the Middle East to Western Europe, parts of India and North Africa. The Italian study strengthened this connection and found that the most common celiac disease gene, HLA-DQ2, correlates with wheat consumption in 24 countries.

What advantage could favor its survival? Previous research found that tooth decay is the only thing the gene for celiac disease might prevent. A 2012 Brazilian study found that adolescents who carry HLA-DQ2 are less prone to tooth decay. Other research has found that, even though untreated celiac disease patients are prone to defective enamel, they are less likely than healthy people to have tooth decay.

The Italian authors speculate that the gene might provide code for a mechanism to clear the sticky protein from the mouth. This ability would have been a big advantage long ago. When people started consuming more carbohydrates, tooth decay for the first time became a serious problem. Cure and prevention were nonexistent, so people with natural tooth protection from gluten-fighting genes might have had an advantage for survival.

 

Lionetti, E. and Catassi, C. “Co-localization of gluten consumption and HLA-DQ2 and –DQ8 genotypes; a clue to the history of celiac disease,” Digestive and Liver Disease, 2014, doi:10.1016/j.dld.2014.08.002.

In a small Australian study, hookworms induced gluten tolerance in adult volunteers with celiac disease.

Before the advent of modern hygiene, many people tolerated intestinal parasites without experiencing serious health problems. Hookworms suppress the body’s immune response, so their hosts do not get sick as a result of harboring the parasites. This research followed eight celiac disease patients who were on a gluten-free diet. At the beginning of the study, researchers infected them with hookworms. Their gut tissue showed a subsequent drop in T-cells that provoke reaction to gluten and an increase in T-cells that reduce inflammation.

Over the course of a year, participants began consuming small amounts of wheat pasta, at first up to 50 mg of gluten daily to mimic accidental contamination. After returning to a gluten-free diet for 10 weeks, they undertook a more extreme challenge, gradually working up to 30 grams daily, or 60 to 75 spaghetti straws. The expected adverse reaction didn’t occur. Biopsies found no deterioration in the gut lining. Blood tests showed an unexpected decline instead of an increase in antibodies. The patients reported an improved quality of life.

The effect wasn’t strong enough to allow patients to resume a normal gluten-containing diet but could protect against the effects of small amounts that patients might accidentally consume through cross-contamination at home or at a restaurant. This approach may benefit refractory patients who respond poorly to conventional treatment. But a larger study will be required to assess the approach’s safety and effectiveness. Although the treatment might provoke squeamishness, the authors claim that participants with celiac disease consistently choose to keep their hookworms.

 

Croese, J.; Giacomin, P.; Navarro, S.; Clouston, A.; McCann, L.; Dougall, A.; Ferreira, I.; Susianto, A.; O’Rourke, P.; Howlett, M.; McCarthy, J.; Engwerda, C.; Jones, D.; and Loukas, A., “Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease,” Journal of Allergy and Clinical Immunology, Sept. 20, 2014, doi:10.1016/j.jaci.2014.07.022.

A three-year study³ followed 700 newborns genetically at risk for celiac disease in seven European countries and Israel. From 4 to 6 months of age, the children were randomly assigned to receive either 100 milligrams (mg) of gluten daily or a placebo. Parents reported their breastfeeding practices, and they were advised to introduce the infants to a normal gluten-containing diet after six months. At 3 years of age, 5.2 percent of all these at-risk children had been diagnosed with celiac disease. Neither early gluten nor breastfeeding affected the outcome.

In another U.S. and Italian study⁴, 500 children at risk of developing celiac disease started eating a full gluten-containing diet at different times during their first year of life. Researchers assigned half to receive normal gluten-containing foods, such as pasta, beginning at 6 months and assigned the rest to wait until they were 12 months old. Researchers periodically screened the children for five years. At age 2, the children in the first group showed a higher risk for celiac disease, but the late starters soon caught up. By age 5, 16 percent of children in both groups had celiac disease.

The authors suggest that postponing gluten could reduce development issues associated with earlier onset of celiac disease. However, these findings overturn previous speculation that introducing gluten at a certain time in infancy could reduce a person’s long-term risk of developing celiac disease. Genetics is the most important factor, so physicians should screen children with a family history of the disease.

3  Vriezinga, S.L.; Auricchio, R.; Bravi, E.; Castillejo, G.; Chmielewska, A.; Crespo Escobar, P.; Kolaček, S.; Koletzko, S.; Korponay-Szabo, I.R.; Mummert, E.; Polanco, I.; Putter, H; Ribes-Koninckx, C; Shamir, R.; Szajewska, H.; Werkstetter, K.; Greco, L.; Gyimesi, J.; Hartman, C.; Hogen Esch, C.; Hopman, E.; Ivarsson, A.; Koltai, T.; Koning, F.; Martinez-Ojinaga, E.; te Marvelde, C.; Mocic Pavic, A.; Romanos, J.; Stoopman, E.; Villanacci, V.; Wijmenga, C.; Troncone, R.; and Mearin, M.L., “Randomized feeding intervention in infants at high risk for celiac disease,” The New England Journal of Medicine, Oct. 2, 2014, 371:1304-15.; doi:10.1056/NEJMoa1404172.

 

4 Lionetti, E.; Castellaneta, S.; Francavilla, R.; Pulvirenti, A.; Tonutti, E.; Amarri, S.; Barbato, M.; Barbera, C.; Barera, G.; Bellantoni, A.; Castellano, E.; Guariso, G.; Limongelli, M.G.; Pellegrino, S.; Polloni, C.; Ughi, C.; Zuin, G.; Fasano, A.; and Catassi, C., “Introduction of gluten.; HLA status.; and the risk of celiac disease in children”.; . The New England Journal of Medicine, Oct. 2, 2014, 371:1295-303; doi:10.1056/NEJMoa1400697.

Most foods labeled “gluten free” are meeting new Food and Drug Administration (FDA) labeling requirements; however, some improvement is called for.

Recently published studies from the FDA and an independent testing company found that most products sampled were complying with new gluten-free labeling rules even before they went into effect in the United States last August. Manufacturers can label foods gluten free only if they contain less than 20 parts per million (ppm) of gluten or are inherently gluten free.

The FDA conducted its study¹of products found in grocery stores, testing 275 foods labeled gluten free. More than 98 percent had less than 20 ppm of gluten, and only three products, or about 1 percent, tested to 20 ppm or higher. Researchers also evaluated 186 foods that were not marked gluten free but did not contain wheat, barley or rye based on the ingredients list. In this group of 36, nearly 20 percent contained 20 ppm or higher.

The foods sampled included a variety of products, from soup to breakfast cereal to beverages. In the group without a gluten-free label, products containing oats were most likely to have unsafe levels of gluten. The FDA study calls for better protocols to prevent contamination of oats.

Researchers also looked at the gluten content of foods with advisory labels such as “manufactured in a facility that also processes wheat” or “manufacturer on equipment that also processes wheat.” Of the 29 products that were labeled gluten free and had one of these warnings, only one contained 20 ppm or more of gluten and would be considered misbranded.

However, among products that were not labeled gluten free, half of the 36 that contained 20 ppm or more of gluten had warning statements. Consumers should take seriously any wheat or gluten advisory on a product that does not have a gluten-free label, the study notes.

An independent U.S. study² by Gluten Free Watchdog, a private testing company in Boston, sampled 158 products labeled gluten free, of which 46 were certified gluten free by an independent third-party organization. This assessment found that 5 percent of all gluten-free products and 4 percent of certified gluten-free foods contained 20 ppm or more gluten, underlining a need for greater quality control.

1 Sharma G.M., Pereira M. and Williams, K.M, “Gluten detection in foods available in the United States—A market survey,” Food Chemistry, Feb. 15, 2015, 169:120-6, doi:10.1016/j.foodchem.2014.07.134.

 

2  Thompson, T. and Simpson, S., “A comparison of gluten levels in labeled gluten-free and certified gluten-free foods sold in the United States,” European Journal of Clinical Nutrition, Oct. 1, 2014, doi:10.1038/ejcn.2014.211.

Summary: Despite the rise of celiac disease, it remains widely under-diagnosed. An American and Lebanese study found that certain readily available medical information could help endoscopists improve the diagnosis rate.

Endoscopy is a procedure used to investigate a variety of digestive problems such as indigestion, nausea, ulcers and celiac disease. The stomach and small intestine are visually inspected during an endoscopy. Diagnosis of celiac disease requires endoscopy plus an additional, more expensive and invasive procedure, called a biopsy, during which tissue samples are taken.

Most patients referred for endoscopies do not receive prior blood tests that could indicate celiac disease. Lacking evidence of celiac disease, the endoscopist may not recognize the importance of also performing a biopsy. So endoscopies often overlook celiac disease, delaying diagnosis. Performing a biopsy on every patient sent for endoscopy would significantly increase the cost of diagnosis and subject many people to an unnecessary procedure. On the other hand, undiagnosed celiac disease also leads to long-term health care costs.

To find a cost-effective strategy, researchers associated with American University of Beirut followed 1,000 Lebanese volunteer patients scheduled for endoscopy who had not already received blood tests. Each participant answered a questionnaire, provided blood samples, and underwent endoscopy. The interview included questions about ethnicity, chief complaint, and details of family and medical history that may be associated with celiac disease, such as diabetes, skin diseases and anemia. Based on medical information available on referral, the endoscopists were asked whether they suspected celiac disease prior to the procedure, and whether they observed any tissue damage leading to a suspicion during the procedure.

Biopsies were then performed on all patients to ensure accurate diagnosis. Labs tested the blood samples for several indicators and analyzed tissue samples for features of celiac disease. To avoid bias, specialists looking at either blood or tissue samples received no other information about the patients.

Celiac disease was common in patients referred for endoscopy; 15 cases were diagnosed. But prior suspicion was not always an accurate predictor. Many of the 50 patients the endoscopists suspected might have celiac disease actually did not. Meanwhile, half the diagnosed cases of celiac disease had not been suspected beforehand.

Conclusion: Patient medical information available to endoscopists can help predict diagnosis of celiac disease with greater accuracy.

A positive blood test for tissue transglutaminase (tTg), an enzyme that appears in most patients with celiac disease, was a powerful predictor and should prompt a biopsy, say the authors. However, one-quarter of the celiac disease patients in this study tested tTg-negative. Consequently, endoscopists should not require a positive tTg test when deciding to perform a biopsy.

The study found three other factors that strongly predict celiac disease in the absence of blood test results. Besides a positive tTg test, the authors recommend that endoscopists take tissue samples if the patient has anemia or history of eczema or if the endoscopy reveals tissue damage suggesting flattening of the villi. This protocol could improve diagnosis rates while limiting the number of costly, unnecessary biopsies.

 

[1] “Prediction of celiac disease at endoscopy”, Barada K, Habib RH, Malli A, Hashash JG, Halawi H, Maasri K, Tawil A, Mourad F, Sharara AI, Soweid A, Sukkarieh I, Chackachiro Z, Jabbour M, Fasano A, Santora D, Arguelles C, Murray JA, Green PH, #Endoscopy# (2014) 46:110-119, doi: 10.1055/s-0033-1359200.

Summary: Celiac disease may be on the rise because people’s immune systems are losing the jobs they evolved to perform. The hygiene hypothesis suggests the human body is used to hosting bacteria, and infections protect them from autoimmune disorders.

Helicobacter pylori, a bacterium commonly found in the stomach, may play a role. Its declining prevalence in North America coincides with an increase in celiac disease. To examine this relationship, a team of American and Swedish scientists studied stomach and intestinal tissue samples collected together from 136,000 patients and submitted to an American pathology lab. Stomach tissue was tested for H. pylori while intestinal tissue indicated celiac disease.

Conclusion: H. pylori was significantly more common in people with healthy intestinal tissue (8.8 percent) than in people with celiac disease (4.4 percent). The large study size, including 2,689 celiac disease patients, found the same effect regardless of age, gender, socioeconomic status and location within the United States. The study could not show whether the infection occurred first, but people usually acquire H. pylori during the first few years of life. The authors suggest it provides some protection against celiac disease.

Although this study provides no evidence how this might happen, previous research in mice suggests the immune system’s defense against H. pylori prevents asthma and other diseases involving hypersensitivity, so it might also reduce any reaction to gluten. Further research is needed to determine whether the bacterium could be used therapeutically to prevent celiac disease in patients at risk.

 

[1] “Decreased risk of celiac disease in patients with #Helicobacter pylori #colonization”, Lebwohl B, Blaser MJ, Ludvigsson JF, Green PHR, Rundle A, Sonnenberg A, Genta RM, #American Journal of Epidemiology# (2013) 178(12):1721-1730.

By Van Waffle

Summary: This was the first study to investigate the risk for celiac disease in children whose mothers took iron supplements during pregnancy. Iron plays an important role in immune system development and in excess may have negative impact.

This 10-year study in Norway tracked the development and health of 79,000 children. Their mothers answered a series of questionnaires during pregnancy, infancy and childhood about iron supplements, diet, anemia and more. Information from a national patient register was also included to track their medical histories up to 8 years of age, identifying 314 children with celiac disease.

Conclusion: Children whose mothers took iron supplements during pregnancy were 33 percent more likely to be diagnosed with celiac disease. The association was similar for pure iron or multivitamins containing iron.

The effect did not appear in mothers who consumed more iron in their food or took other supplements including folic acid, fish oil, multivitamins and minerals not containing iron. The risk was not associated with maternal anemia.

The authors speculate excess iron may play a role in the development of celiac disease. They recommend against routine use of iron supplements during pregnancy, pointing out many women in the study used them without any evidence of anemia. In the United States, the recommended average daily intake of iron during pregnancy is 27 milligrams, achievable with a healthy food selection.

In response to this study^[i], three American celiac disease experts commented that the increased risk, while statistically significant and interesting, is small. It may provide insight but cannot account for the increasing epidemic of celiac disease. They state it is too soon to argue that women should avoid iron supplements during pregnancy even if the child is at risk for celiac disease.

[i] “The unfolding story of celiac disease risk factors”, Lebwohl B, Judvigsson JF, Green PHR, #Clinical Gastroenterology and Hepatology# (2014) 12:632-635.

 

[1] “Association between maternal iron supplementation during pregnancy and risk of celiac disease in children”, Størdal K, Haugen M, Brantsæter AL, Lundin KEA, Stene LC, #Clinical Gastroenterology and Hepatology# (2014) 12:624-631.

[1] “The unfolding story of celiac disease risk factors”, Lebwohl B, Judvigsson JF, Green PHR, #Clinical Gastroenterology and Hepatology# (2014) 12:632-635.

By Van Waffle

Summary: Many patients would consider medication as an alternative to going gluten-free for life, according to a recent study.

The Celiac Disease Center at Columbia University recruited 352 adults with the disease to survey their interest in using a pharmaceutical drug. The study also asked about individuals’ symptoms and adherence to the diet. It included a detailed questionnaire about quality of life. All but 5 percent of participants reported some symptoms of the disease, but 72 percent said they had improved on a gluten-free diet.

Conclusion: Two-thirds of respondents said they would take medication to treat celiac disease. Older patients, men, people who frequent restaurants, those concerned about their weight or dietary costs, and patients reporting a decreased quality of life were more likely to say yes.

Length of time since diagnosis, education, ongoing symptoms and success of the gluten-free diet did affect people’s interest. Patients raised concerns about cost, side effects and safety of potential drugs. The survey did not ask how much they would be willing to pay or whether they could afford it. However, the relatively high cost and low availability of gluten-free foods might lead people to consider using medication.

A limitation of this study is that the Celiac Disease Center might have recruited interviewees who were more highly educated and receptive to medical treatment. The authors suggest a drug could benefit patients in particular situations when used alongside dietary therapy.

 

[1] “Interest in medical therapy for celiac disease”, Tennyson CA, Simpson S, Lebwohl B, Lewis S, Green PHR, #Therapeutic Advances in Gastroenterology# (2013) 6(5) 358-364, doi: 10.1177/1756283X13492580.

By Van Waffle

Summary: ALV003 is an experimental drug that can break gluten proteins into small particles. Alvine Pharmaceuticals, based in California, has investigated it to treat celiac disease patients who remain sick despite following a gluten-free diet. To determine the safety and effectiveness of ALV003, a team of Finnish and American scientists conducted a phase II clinical trial in 47 patients who had followed a gluten-free diet for at least a year.

Every day for six weeks they consumed up to 6 grams of normal breadcrumbs and doses of either ALV003 or a placebo. A small number withdrew due to intolerable symptoms from the gluten challenge. The study assessed the response of those who continued by looking at intestinal health before and after the challenge. Tissue samples were analyzed for flattening of the villi and immune T-cells produced in response to gluten.

Conclusion: Patients taking a placebo rather than ALV003 showed increased damage in their gut tissue over the six-week study, while those taking the drug showed no significant change.

The authors recommend tissue biopsy as the most effective tool to evaluate other potential celiac disease therapies.

They found no adverse reaction to the drug itself. This is the first study to identify a drug that breaks down ingested gluten, reducing intestinal injury in celiac disease patients who consume gluten.

Now that it has worked in healthy celiac disease patients, the authors recommend testing for safety and effectiveness in people who continue to have symptoms despite following the gluten-free diet. A larger study would be necessary to determine whether ALV003 actually makes patients feel better, because the small study size prevented finding any statistical difference in symptoms such as cramps reported between the two groups.

 

[1] “The glutenase ALV003 attenuates gluten-induced mucosal injury in patients with celiac disease”, Lähdeaho M-L, Kaukinen K, Laurila K, Vuotikka P, Koivurova O-P, Kärjä-Lahdensuu T, Marcantonio A, Adelman DC, Mäki M, #Gastroenterology# (2014), doi: 10.1053/j.gastro.2014.02.031.