NORD gratefully acknowledges Ciarán P. Kelly, MD, Professor of Medicine at Harvard Medical School and Director of the Celiac Center at Beth Israel Deaconess Medical Center in Boston, for assistance in the preparation of this report.
Refractory celiac disease (RCD) is a complex autoimmune disorder much like the more common celiac disease but, unlike celiac disease, it is resistant or unresponsive to at least 12 months of treatment with a strict gluten-free diet. Gliadin, a component of the wheat storage protein gluten, together with similar proteins in barley and rye, are the villains that trigger the immune reaction in celiac disease. The diagnosis of RCD is made by exclusion, especially of any other disorder that can affect the huge number of thread-like projections that line the interior of the intestine (intestinal villi), such as intestinal lymphoma, Crohn’s disease, small intestinal bacterial overgrowth or hypogammaglobulinemia.
The intestinal villi are the means by which the gut absorbs fluids and nutrients. In celiac disease and refractory celiac disease, these villi shrink and shrivel (atrophy) affecting the absorption of nutrients via the intestines. In celiac disease, treatment by means of a strict gluten-free diet is usually sufficient to overcome the disorder. However, refractory celiac disease is just that: refractory or stubbornly resistant to treatment. Only a small percentage (1-2%) of the people with celiac disease will develop RCD, and these patients are almost always 50 years of age or older. However, as yet, it is impossible to predict which of the tiny (1.5%) minority of patient of those with celiac disease will develop RCD.
The symptoms of refractory disease are not unlike those of untreated celiac disease except that they are usually more severe and more disabling. The more common symptoms include weight loss, diarrhea, abdominal pain, malnutrition and anemia.
Occasionally, examination of the intestine of an RCD patient, by means of a swallowed, picture taking, camera-like device (intestinal endoscope) reveals evidence of inflammation and ulceration of the middle portion (jejunum) of the small intestine (ulcerative jejunitis). This may be a significant warning that refractory celiac disease may progress to form an enteropathy-associated T-cell lymphoma (EATL). Thus, there is an intimate link between refractory disease and celiac-associated intestinal lymphoma.
The exact series of events that leads to refractory celiac disease remains unresolved. Involved are the body’s immune system, especially T lymphocytes and intraepithelial lymphocytes (IEL), cytokines, and antigens. Lymphocytes make up about 25% of a person’s white blood cells and include the B-cells (mature in bone marrow) and T-cells (mature in the thymus), each of which play key roles in the development of immunity. Intraepithelial lymphocytes (IELs) are T-cells that exist in the lining (intraepithelial) of the intestine. A protein on the surface of T lymphocytes called the T-cell receptor (TCR) serves as a “docking bay” for specific antigens. In celiac disease, T-cells that recognize gluten proteins are activated and proliferate. When gluten is removed from the diet, these T-cells become inactive and the intestinal damage heals. In refractory celiac disease, intestinal T cells are activated without gluten stimulation and intestinal injury persists despite the removal of dietary gluten.
Cytokines are small proteins that help to regulate communication among the cells of the immune system or between cells of the immune system and cells of another tissue. Some researchers suggest that patients with refractory celiac disease show a remarkable increase in the “proinflammatory cytokine” known as interleukin-15 (IL-15). IL-15 appears to stimulate the secretion of another cytokine known as interferon-gamma (INF-gamma) that seems to increase the toxicity of the IELs against the cells lining the surface of the intestine. As more and more cells from the lining of the intestine are damaged, symptoms and signs of refractory celiac disease develop. The alterations in the balance of intestinal T-cell activation that are induced by IL-15 may be instrumental in the development of RCD and its transition to intestinal lymphoma.
Disorders that are characterized by atrophy of the villi of the intestine are known, generally, as enteropathies (meaning damaged small intestine). There is a link between some enteropathies such as refractory celiac disease and lymphoma. That link is not completely understood, but it is thought that RCD may be just one step along a path of increasingly severe intestinal damage that may culminate in a special form of lymphoma known as “enteropathy-associated T-cell lymphoma” (EATL). RCD is sometimes divided into Type I and Type II. Type I RCD has a better prognosis and a lower risk for EATL. In Type II RCD, abnormal, immature IELs are found on intestinal biopsy and the risks for severe complications of malnutrition and EATL are greater.
Refractory celiac disease is rare among adults and is almost never seen in children. Data regarding the true incidence and prevalence of RCD are unreliable, but some have estimated that there might be 20,000 patients in the USA. However, those estimations are based on incomplete data. In one recent study, 1.5% of patients diagnosed with celiac disease at a single US center developed RCD. Of those with RCD 85% had the less severe Type I RCD.
Virtually all clinicians studying refractory celiac disease emphasize that the diagnosis is based on eliminating all other possible sources of the symptoms and intestinal injury. One article lists more than 10 conditions that must be considered and eliminated before a convincing diagnosis of refractory celiac disease may be made. As noted above, examination of the interior wall of the intestine (upper and lower) by means of an enteroscope or colonoscope as well as obtaining intestinal biopsies to be examined under a microscope is useful, especially to determine if the symptoms are the result of intestinal disorders other than RCD. Capsule endoscopy, which examines the small intestinal lining using a camera mounted on a swallowed pill, may also be useful in evaluating the degree of small intestinal inflammation and injury. Some specialized centers are able to offer sophisticated examinations of the biopsy materials that in many cases will assist in the diagnosis. These studies emphasize the presence of abnormal populations of T lymphocytes in the tissue indicating a diagnosis of the more aggressive Type II RCD. Other imaging studies (barium X-ray, CT scan, capsule enteroscopy and MRE) may be undertaken, especially if there is concern for the presence of a lymphoma.
Several therapies for RCD have been tried in uncontrolled tests with inconclusive results. Among the therapies tested in this way are: elemental diet (an elemental diet is a liquid diet consisting of nutrients that require no digestion, including amino acids, carbohydrates, vitamins, minerals, and triglycerides); and total parental nutrition (TPN) that is defined as nutrition maintained entirely by intravenous injection or by some other nongastrointestinal route. Steroid therapy is a mainstay of treatment but its beneficial effect is short-lived in patients of lymphoma. Treatment involving other immunosuppressive drugs such as azathioprine, cyclosporine, enteric-coated budesonide, 5-aminosalicylic acid (5-ASA), or inflixamab has been used with a limited number of patients. More recently chemotherapy with cladribine with or without autologous stem cell transplantation has also been reported to be useful.
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Contact for additional information about refractory celiac disease:
Ciarán P. Kelly, MD
Director Celiac Center
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
Office: (617) 667 1272
Patient Scheduling: (617) 667 2135
email: [email protected]
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