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Refractory Sprue

NORD is very grateful to 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.

Synonyms of Refractory Sprue

  • intractable celiac sprue
  • refractory celiac disease

Disorder Subdivisions

  • type II refractory sprue
  • type I 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.

Related Disorders

Disaccharidase Intolerence
Disaccharide intolerance I is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. This enzyme complex (sucrase-isomaltase) assists in the breakdown of certain sugars (i.e., sucrose) and certain products of starch digestion (dextrins). The sucrase-isomaltase enzyme complex is normally found within the tiny, finger-like projections (microvilli or brush border) lining the small intestine. When this enzyme complex is deficient, nutrients based on ingested sucrose and starch cannot be absorbed properly from the gut.

Symptoms of this disorder become evident soon after sucrose or starches are ingested by an affected infant. Breast-fed infants or those on lactose-only formula manifest no symptoms until such time as sucrose (found in fruit juices, solid foods, and/or some medications) is introduced into the diet. Symptoms are variable among affected individuals but usually include watery diarrhea, abdominal swelling (distension) and/or discomfort, among others. Intolerance to starch often disappears within the first few years of life and the symptoms of sucrose intolerance usually improve as the affected child ages. Disaccharide intolerance I is inherited as an autosomal recessive genetic trait.

Enteropathy-associated T-cell lymphoma (EATL)
This is an aggressive lymphoma of the small intestine that almost always arises in association with celiac disease. Rarely, the lymphoma may arise in extraintestinal sites. The most common location is the jejunum, and the lymphoma presents as single or multiple tumors or as a diffusely infiltrating intestinal malignancy. EATL typically presents with tumor involvement of the middle or lower thirds of the small intestine leading to obstruction (blockage), bleeding, pain from ulcer formation or perforation (puncture).

Irritable bowel disease
Irritable bowel syndrome (IBS), previously known as spastic colon or mucous colitis, is a digestive disorder characterized by abnormal movement (motility) of the intestines (both small and large) and altered intestinal sensation (visceral hypersensitivity). Symptoms vary widely and include abdominal pain, bloating, constipation, and diarrhea. IBS is very common; about 50 percent of all patients referred to a gastrointestinal specialist have IBS. There is no obvious organic disease present; only the function of the intestines is affected. However, based on the symptoms, this disease can be confused easily with other bowel diseases including celiac disease.

Microscopic colitis (collagenous colitis, lymphocytic colitis)
Microscopic colitis is not a single disease but comprises two related entities, collagenous colitis and lymphocytic colitis, both characterized by chronic watery diarrhea. Lymphocytic colitis is distinguished primarily by intraepithelial lymphocytic (IEL) infiltration and collagenous colitis by an abnormal layer of fibrous tissue (collagen) beneath the surface layer of the intestine. The cause of microscopic colitis is unknown.

Pancreatic insufficiency
Pancreatic insufficiency is the inability of the pancreas to produce and/or transport enough digestive enzymes to break down food in the intestine and allow its absorption. It typically occurs as a result of chronic pancreatic damage, which may be caused by a variety of conditions including cystic fibrosis (in children and young adults), excessive alcohol intake, gallstone disease and medications (in older individuals). It is less frequently but occasionally associated with pancreatic cancer or celiac disease.

Pancreatic insufficiency usually presents with symptoms of malabsorption, malnutrition, vitamin deficiencies, and weight loss (or inability to gain weight in children) and is often associated with steatorrhea (fatty, loose, bulky and foul-smelling stools).

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

Refractory Sprue Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

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.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2013/02/07 00:00:00 GMT+0

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