Information on the following diseases can be found in the Related Disorders section of this report:

• Celiac disease
• Disaccharidase deficiency
• Enteropathy-associated T-cell lymphoma (EATL)
• Inflammatory bowel disease
• Microscopic colitides (collagenous colitis, lymphocytic colitis)
• Pancreatic insufficiency

The symptoms of refractory sprue are not unlike those of 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.

Not infrequently, 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 the area of damaged intestine 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.

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-?) that seems to increase the toxicity of the IELs against the cells lining the interior 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).

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 center, for instance, more than 100 new cases of celiac disease are seen each year but only 1 or 2 cases of RS. Since RS patients are far more likely to be referred to a specialized center, it is likely that only 0.1% of celiac disease patients develop RS. Since there are approximately 2 million individuals with celiac disease in the US, the estimate of 20,000 RS patients seems reasonable.

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). 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 specific disease but comprises two distinct 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).

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 or abnormal populations of T lymphocytes in the tissue. 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, or inflixamab has been used with a limited number of patients.

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

TEXTBOOKS
Farrell RJ, Kelly CP. Celiac sprue and refractory sprue. In: Feldman, Friedman, and Sleisenger, eds. Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 7th ed. W.B. Saunders Co. Philadelphia, PA. 2002:1817-41.

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.

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.

JOURNAL ARTICLES
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.

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.

Accomando S, Albino C, Montaperto D, Amato GM, Corsello G. Multiple food intolerance or refractory celiac sprue. Dig Liver Dis. 2005 Sept 15; [Epub ahead of print].

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. 2005 Aug 16; [Epub ahead of print].

Schuppan D, Dennis MD, Kelly CP. Celiac disease: epidemiology, pathogenesis, diagnosis, and nutritional management. Nutr Clin Care. 2005;8:54-69.

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