Refractory Sprue

Refractory Sprue

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Refractory Sprue is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • refractory celiac disease
  • intractable celiac sprue

Disorder Subdivisions

  • type I refractory sprue
  • type II refractory sprue

General Discussion

Refractory sprue (RS) is a complex autoimmune disorder much like the more common celiac sprue but, unlike celiac sprue, it is resistant or unresponsive to six 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 sprue. The diagnosis of RS 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 sprue and refractory sprue, these villi shrink and shrivel (atrophy) affecting the absorption of nutrients via the intestines. In celiac sprue, treatment by means of a strict gluten-free diet is usually sufficient to overcome the disorder. However, refractory sprue is just that: refractory or stubbornly resistant to treatment. Only a small percentage of the people with celiac sprue will develop RS, and these patients are almost invariably 30 years of age or older. However, as yet, it is impossible to predict which patient of those with celiac sprue will develop RS.

Symptoms

The symptoms of refractory sprue are not unlike those of untreated celiac sprue 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 RS 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 sprue may progress to form an enteropathy-associated T-cell lymphoma (EATL). Thus, there is an intimate link between refractory sprue and celiac-associated intestinal lymphoma.

Causes

The exact series of events that leads to refractory sprue 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 sprue, 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 sprue, 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 sprue 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 sprue develop. The alterations in the balance of intestinal T-cell activation that are induced by IL-15 may be instrumental in the development of RS 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 sprue and lymphoma. That link is not completely understood, but it is thought that RS 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). RS is sometimes divided into Type I and Type II. Type I RS has a better prognosis and a lower risk for EATL. In Type II RS, abnormal, immature IELs are found on intestinal biopsy and the risks for severe complications of malnutrition and EATL are greater.

Affected Populations

Refractory sprue is rare among adults but even rarer in children. Data regarding the true incidence and prevalence of RS are unreliable, but some have estimated that there might be 20,000 cases 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 RS. Of those with RS 85% had the less severe Type I RS.

Standard Therapies

Diagnosis

Virtually all clinicians studying refractory sprue 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 sprue 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 RS. 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 RS. Other imaging studies (barium X-ray or CT scan) may be undertaken, especially if there is concern for the presence of a lymphoma.



Treatment

Several therapies for RS 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 cases 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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Contact for additional information about refractory sprue:



Ciarán P. Kelly, MD

Director Celiac Center

Beth Israel Deaconess Medical Center

Dana 601

BIDMC

330 Brookline Avenue

Boston, MA 02215

Office: (617) 667 1272

Patient Scheduling: (617) 667 2135

email: ckelly2@bidmc.harvard.edu

References

TEXTBOOKS

Farrell RJ, Kelly CP. Celiac Disease and Refractory Celiac Disease. Feldman, Friedman, and Brandt, editors. Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 9th edition. W B Saunders Co., Philadelphia. 2010:1797-1820.



Kasper, DL, Fauci AS, Longo DL, et al., eds. Harrison's Principles of Internal Medicine, 16th ed. McGraw-Hill Companies. New York, NY; 2005:1772.



Yamada T, Alpers DH, Kaplowitz N, Laine L, et al., eds. Textbook for Gastroenterology. 4th ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2003:1594-95; 2922-23.



JOURNAL ARTICLES

Abdallah H, Leffler D, Dennis M, Kelly CP. Refractory celiac disease. Curr Gastroenterol Rep. 2007;9:401-5.



Heine GD, Hadithi M, Groenen MJ, Kuipers EJ, Jacobs MA, Mulder CJ. Double-balloon enteroscopy: indications, diagnostic yield, and complications in a series of 275 patients with suspected small-bowel disease. Endoscopy. 2006;38:42-48.



Accomando S, Albino C, Montaperto D, Amato GM, Corsello G. Multiple food intolerance or refractory celiac sprue. Dig Liver Dis. 2006 ;38(10):784-5.



Di Sabtino A, Ciccocioppo R, Cupelli F, et al. Epithelium-derived interleukin-15 regulated intraepithelial lymphocyte Th1 cytokine production, cytotoxicity and survival in coeliac disease. Gut. 2006;55(4):469-77.



Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:413-24.



Olaussen RW, Lovik A, Tollefsen S, et al. Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease. Clin Gastroenterol Hepatol. 2005;3:875-85.

Resources

Association of Gastrointestinal Motility Disorders, Inc.

12 Roberts Drive

Bedford, MA 01730

Tel: (781)275-1300

Fax: (781)275-1304

Email: gimotility@gmx.com

Internet: http://www.agmd-gimotility.org



Gluten Intolerance Group of North America

31214 124th Ave SE

Auburn, WA 98092

Tel: (253)833-6655

Fax: (253)833-6675

Email: info@gluten.net

Internet: http://www.gluten.net



Crohn's and Colitis Foundation of America

386 Park Avenue South

17th Floor

New York, NY 10016-7374

USA

Tel: (212)685-3440

Fax: (212)779-4098

Tel: (800)932-2423

Email: info@ccfa.org

Internet: http://www.ccfa.org



Celiac Sprue Association

P.O. Box 31700

Omaha, NE 68131-0700

USA

Tel: (402)558-0600

Fax: (402)643-4108

Tel: (877)272-4272

Email: celiacs@csaceliacs.org

Internet: http://www.csaceliacs.org



NIH/National Institute of Diabetes, Digestive & Kidney Diseases

Office of Communications & Public Liaison

Bldg 31, Rm 9A06

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Tel: (301)496-3583

Email: NDDIC@info.niddk.nih.gov

Internet: http://www2.niddk.nih.gov/



International Foundation for Functional Gastrointestinal Disorders

700 W. Virginia St., 201

Milwaukee, WI 53217

USA

Tel: (414)964-1799

Fax: (414)964-7176

Tel: (888)964-2001

Email: iffgd@iffgd.org

Internet: http://www.iffgd.org



Celiac Disease Foundation

20350 Ventura Blvd

Ste 240

Woodland Hills, CA 91364

USA

Tel: (818)716-1513

Fax: (818)267-5577

Email: cdf@celiac.org

Internet: http://www.celiac.org



Academy of Nutrition and Dietetics

120 South Riverside Plaza, Suite 2000

Chicago, IL 60606-6995

Tel: (312)899-0400

Fax: (312)899-4899

Tel: (800)877-1600

Email: knowledge@eatright.org

Internet: http://www.eatright.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



National Foundation for Celiac Awareness

P.O. Box 544

224 South Maple Street

Ambler, PA 19002

Tel: (215)325-1306

Fax: (215)643-1707

Email: info@celiaccentral.org

Internet: http://www.CeliacCentral.org



For a Complete Report

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