June 04, 2014
Celiac disease is a chronic inflammatory condition that results in immune-mediated damage to the mucosal lining of the small intestine. It occurs in genetically predisposed people who consume gliadin — a protein in gluten-containing foods such as wheat, rye and barley. Diagnosis is made by small intestinal biopsy, which shows characteristic inflammation and flattening of the mucosal lining.
A gluten-free diet is the only effective treatment for celiac disease, and most adherent patients experience substantial clinical improvement within two weeks, with varying degrees of mucosal healing over time. But a small percentage of patients have malabsorptive symptoms (abdominal pain, diarrhea, weight loss) and histologic abnormalities that persist or recur, despite their best efforts to follow dietary recommendations.
Lucinda A. Harris, M.D., a Mayo Clinic gastroenterologist in Scottsdale, Arizona, notes that inadvertent gluten contamination is often the main reason patients fail to improve on a gluten-free diet. "Gluten can sneak in through sources you wouldn't expect, such as lipstick, lip gloss and medications. And many foods that people aren't aware of contain some type of gluten. My first recommendation for patients who don't seem to respond is to see a dietitian. Unfortunately, not all dietitians are equal in teaching about celiac disease," she says.
Joseph A. Murray, M.D., president of the North American Society for the Study of Celiac Disease and director of Mayo Clinic's Celiac Disease Research Program in Minnesota, agrees, noting that many patients are never referred to a dietitian and, according to a 2012 study in Clinical Gastroenterology and Hepatology, don't receive consistent or adequate follow-up.
Still, not all gluten ingestion is accidental. "If you ask patients how many times gluten has passed their lips, they tell you what you want to hear," Dr. Murray says. "Now I approach it differently. I say, 'This diet is tough. There's gluten everywhere.' If you make it passive, not active, it's amazing what people will tell you. You have to evaluate for gluten in the most nonconfrontational, collaborative way, and enable people to tell the truth."
When gluten isn't the issue, Dr. Murray says part of the evaluation should include a review of the original diagnosis — even if it means going back decades. "You have to have a very robust diagnosis. Some patients don't have adequate blood testing and some never had a biopsy because their gastroenterologist told them they didn't need it. Or there could have been an overcall on the biopsy; you have to review the pathology because something else may be damaging the small intestine, such as tropical sprue, which looks like celiac. There may also be drug-induced injury to the small intestine, collagenous sprue or, more rarely, autoimmune enteropathy. It can be very laborious to get the original data, but it may unmake the diagnosis."
Other disorders that may be associated with nonresponsive celiac disease include:
- Lactose or fructose intolerance
- Small bowel bacterial overgrowth
- Exocrine pancreatic insufficiency
- Microscopic colitis
- Irritable bowel syndrome
When these and other reasons for treatment failure have been excluded, Drs. Harris and Murray say refractory celiac disease, also called refractory sprue, should be considered. Affecting no more than 1 in 50 people with celiac disease, refractory sprue is defined as malabsorptive symptoms and villous atrophy that persist or recur after six to 12 months on a strict gluten-free diet.
Refractory disease is divided into two types based on flow cytometric analysis of small bowel biopsies. Type I is characterized by a normal intraepithelial lymphocyte phenotype and type II by aberrant or premalignant lymphocytes. Patients with type I usually respond well to intense nutritional support, a gluten-free diet and pharmacologic therapies such as steroids.
Patients with type II disease have more-severe symptoms, frequently require intravenous nutrition, respond poorly to steroids and can experience complications such as ulcerative jejunitis, which may progress to enteropathy-associated T-cell lymphoma. Type II patients are vulnerable to infection, diarrhea and wasting, and have a mortality approaching that of cancer patients.
Dr. Murray and Alberto Rubio Tapia, M.D., a Mayo Clinic celiac disease researcher in Minnesota, published their findings on management of refractory celiac disease in the April 20, 2010, issue of Gut.
On the horizon
New therapeutic interventions are being studied for use in refractory and standard celiac disease. At Mayo Clinic's campus in Minnesota, an anti-interleukin-15 monoclonal antibody is under investigation as a potential therapy to reverse gluten-induced damage to the small intestine in patients with severe refractory symptoms.
In Arizona, Dr. Harris and colleagues took part in a multicenter study of the zonulin antagonist larazotide acetate. Zonulin, a protein involved in intestinal permeability, is highly expressed in the guts of celiac disease patients. Larazotide acetate, taken immediately before a meal, may reduce exposure of the gluten antigen to the immune system. Results of the study appeared in the American Journal of Gastroenterology in 2012.
Of other potential therapies Dr. Harris says, "People who think the rapid increase of celiac disease since 1950 is the result of modern wheat hybrids want to develop cultivars that have less toxic gluten fragments. Other researchers are trying to develop a celiac disease vaccine, which is promising, but in all areas, a great deal of work remains to be done."
For more information
Herman ML, et al. Patients with celiac disease are not followed up adequately. Clinical Gastroenterology and Hepatology. 2012;10:893.
Rubio Tapia A, et al. Classification and management of refractory coeliac disease. Gut. 2010;59:547.
Leffler DA, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. American Journal of Gastroenterology. 2012;107:1554.