Refractory coeliac disease / celiac disease
Refractory Celiac Disease is the deadly rare version of Celiac Disease
Early research into Celiac disease suggested that it was caused by the gluten in certain grains and that the disease would subside by strict adherence to a gluten free diet.
While this occurs for the majority of the people diagnosed as being Celiac or gluten intolerant, there has always been a very small number of people who do not get better by abstinence alone. These people are said to have celiac sprue or refractory Celiac Disease (RCD).
SUMMARY
The following is the abstract of a paper written in 2007 at The Celiac Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School. It provides a very succinct summary of RCD.
"Celiac disease (CD) is a small intestinal inflammatory disorder characterized by an immune-mediated enteropathy triggered by the ingestion of wheat gluten or related rye and barley proteins in genetically predisposed individuals carrying the human leukocyte antigens (HLA)-DQ2 or-DQ8. Nonresponsive CD (NRCD) is a clinical diagnosis defined by the persistence of signs, symptoms, and/or laboratory abnormalities typical of CD despite adherence to a gluten-free diet for at least 6 months. One cause for NRCD is refractory CD (RCD), defined as the persistence of severe villous atrophy on small intestinal biopsy despite strict gluten withdrawal for at least 6 months with no evidence of other pathology.
Although rare, RCD should be suspected in individuals with an established diagnosis of CD who fail to respond primarily or secondarily to a strict gluten-free diet, particularly if they manifest significant weight loss. A thorough evaluation must be performed to distinguish RCD from other causes of NRCD. RCD may be categorized into type I or type II. Type I RCD has a more favorable prognosis compared with type II and can often be managed with nutritional supplementation and possibly low level immunosuppressive therapy. Type II RCD carries a poor prognosis and is more likely to progress to life-threatening malnutrition or intestinal T-cell lymphoma. Immunosuppressive agents and, more recently, autologous stem cell transplant have been used to treat type II RCD." Ref A
The following information is often highly technical in nature, however it provides a good explanation of the current state of RCD and the future of diagnosis and treatment.
DEFINITION OF RCD
One of the most quoted definitions of this version of the disease was given by Severin Daum and colleagues. True RCD is considered to be "villous atrophy with crypt hyperplasia and increased IELs persisting for more than 12 months in spite of a strict gluten-free diet." Ref 1
Villi = hair-like projections that cover the lining of the small intestine. In a celiac, ‘blunting' of the villi occur which reduces their ability to absorb nutrients.
"Crypt hyperplasia" refers to the appearance of the villi in a biopsied celiac. The crypt is the base of the villi. In a celiac "the crypts can become enlarged (crypt hyperplasia) in response to stimulus of injury or perceived threat of invasion to the body. White blood cells called lymphocytes are activated and sent up from the crypt areas to the tips of the villi. This results in what is termed intra-epithelial lymphocytosis or increased intra-epithelial lymphocytes (IELs). This is the hallmark of celiac disease and the earliest sign of gluten sensitivity. It is not however specific for celiac disease or gluten sensitivity." Ref 7
Another articles states that "Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict gluten free diet and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy." Ref 2
RULING OUT REFRACTORY CELIAC DISEASE
"Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made." Ref 4
It is theorized that "if a patient is not responding well to a gluten-free diet, three considerations are necessary: (1) the initial diagnosis of celiac disease must be reassessed; (2) the patient should be sent to a dietician to check for errors in diet or compliance problems, because problems with the gluten-free diet are the most important cause for persisting symptoms; (3) other reasons for persisting symptoms (eg, pancreatic insufficiency, irritable bowel syndrome, bacterial overgrowth, lymphocytic colitis, collagenous colitis, ulcerative jejunitis, protein-losing enteropathy,T-cell lymphoma, fructose intolerance, cavitating lymphadenopathy, and tropical sprue) should be considered. Other causes for villous atrophy are Crohn's disease, collagenous sprue, and autoimmune enteropathy." Ref 1
THE TWO TYPES OF RCD
And no the following paragraph is not full of ‘typo's, RCD research typically involves the discussion of complex medical concepts which while informative can reduce the understanding of non-medical people - the majority of the population. Where possible this article will attempt to simplify these complexities.
Refractory Celiac Disease is classified into two types. "RCD type I is characterized by normal expression of T-cell antigens and polyclonal TCR gene rearrangement. RCD type II is characterized by an abnormal IEL phenotype with the expression of intracytoplasmic CD3e, surface CD103, and the lack of classic surface T-cell markers such as CD8, CD4, and TCR-alpha/beta." Ref 1
Definitions:
T cell: A type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body's immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders. T cell are also known as T lymphocytes. (ref www.medterms.com)
Antigens: A substance that when introduced into the body stimulates the production of an antibody. Antigens include toxins, bacteria, foreign blood cells, and the cells of transplanted organs. (ref http://www.answers.com/topic/antigen)
IEL = intestinal intraepithelial lymphocytes. Intestinal intraepithelial lymphocytes (also known as iIELs) play an important role in intestinal innate immunity and oral immune tolerance.
Phenotype = The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences. (ref http://www.answers.com/topic/phenotype). This is the "outward, physical manifestation" of the organism. These are the physical parts, the sum of the atoms, molecules, macromolecules, cells, structures, metabolism, energy utilization, tissues, organs, reflexes and behaviors; anything that is part of the observable structure, function or behavior of a living organism. (ref http://www.brooklyn.cuny.edu/bc/ahp/BioInfo/GP/Definition.html)
Intracytoplasmic = Located or occurring within the cytoplasm of a cell. Cytoplasm is a general term that refers to all the material found in the interior of a living cell, except for the nucleus.
Another paper describes explains that the "two types of refractory celiac disease are differentiated by the type of T-cell populations in the intestinal mucosa (The innermost membrane of the four coats of the intestinal wall), which are polyclonal in type I disease and clonal in type II disease. Although the presence of this clonal T-cell population is termed "cryptic intraepithelial lymphoma," this finding does not imply a diagnosis of a malignant process, although enteropathy-associated T-cell lymphoma develops in a subset of these patients. Ref 3
Definitions:
Polyclonal = Derived from different cells. As opposed to monoclonal or clonal.
Lymphoma = Any of various usually malignant tumors that arise in the lymph nodes or in other lymphoid tissue.
PROGNOSIS
"Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy (A rare disease in which certain cells in the intestine are destroyed by a patient's immune system. It causes severe, chronic, diarrhea and usually occurs in children), characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology." Ref 4
"Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma." Ref 4
Another paper states that "The 5-year survival for type II refractory celiac disease is <50%, with the most common causes of death being T-cell lymphoma and infection. Treatment options include corticosteroids and immunosuppressive agents such as thiopurines and infliximab. There is concern that immunosuppressive therapy promotes progression to lymphoma, but no data confirm this risk. Therapies under investigation include antibody to IL-15, a cytokine that leads to enhanced enterocyte killing in celiac disease (10), and stem cell transplantation. " Ref 3
CAUSES OF TYPE 2 RCD
In a healthy body "a certain type of IELs called TCRγ/δ+ IELs may play an important role in repairing mucosa, maintaining homeostasis, and guarding against tumor development. TCRγ/δ+ IELs in the human intestine have recently shown promise in the regulation of uncomplicated (non RCD) celiac disease." Ref 5 "In one study, the research team wanted to see if patients with RCD II had fewer TCRγ/δ+ IELs than either RCD I, or celiac disease, and thus provide a possible explanation for ongoing mucosal damage and inflammation, and the development of abnormal T cells that tend to morph into EATL. The negative relationship between TCRγ δ+ and abnormal IELs, together with their known role in regulating uncomplicated celiac disease, suggests that TCRγ δ+ IELs may play a crucial role in helping the body to repair mucosa, maintain homeostasis and possibly even guard against tumor development." Ref 5These cells may serve as important markers, along with the abnormal T cells, to help distinguish between types of celiac disease, and to gage the effectiveness of treatment efforts. Ref 5
THE FUTURE
An article in 2001 found that "there are no clear clinical or biological markers that predict the development of RCD. The disorder manifests in adulthood and all reported cases have been in individuals over 20 years of age. The current hypothesis is that refractory sprue represents a transition state to intestinal lymphoma. The true prevalence of this disease entity is unknown. Future multicenter trials are therefore warranted to estimate its prevalence and establish clear therapeutic guidelines." Ref 6
Obviously with such high death rates, this is a form of celiac disease that should really grab the attention of the press and deserve research funding. Although it appears that due to the difficulty in diagnosing CD in the first place, and the low certainty of financial gain in return for research from pharmaceutical companies, that a cure for standard or refractory CD has not been a priority. Although a celiac disease vaccine is being trialed in Melbourne Australia in 2009, it is unclear whether the RCD version will be as easy to cure.
TYPICAL RCD DIAGNOSIS FLOWCHART - Ref 9
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References
Ref A Refractory celiac disease. By HaniAbdallah, DanielLeffler, MelindaDennis and CiaránP.Kelly The Celiac Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA02215, USA Published online: 3 October2007
Ref 1 Monitoring nonresponsive patients who have celiac disease. By Krauss N, Schuppan D. 2006 Apr
Ref 2 Best Pract Res Clin Gastroenterol. 2005 Jun by Daum S, Cellier C, Mulder CJ. (http://www.ncbi.nlm.nih.gov)
Ref 3 (Clinical Chemistry. 2008;54:441-444.) by Leann M. Mikesh1, Sheila E. Crowe2, Grant C. Bullock1, Nancy E. Taylor1 and David E. Bruns1 (http://www.clinchem.org/cgi/content/full/54/2/441 )
Ref 4 Gastroenterology. 2000 Jul;119(1):243-51, By Ryan BM, Kelleher D. (http://www.ncbi.nlm.nih.gov/pubmed/10889175 )
Ref 5 Small Intestinal Intraepithelial Gamma/Delta T-Lymphocytes Occur Inversely to Lymphomas in Refractory Celiac Disease (http://www.celiac.com/articles/21727/1/Small-Intestinal-Intraepithelial-GammaDelta-T-Lymphocytes-Occur-Inversely-to-Lymphomas-in-Refractory-Celiac-Disease/Page1.html )
Ref 6 Management of Refractory Celiac Disease Dr. Horvath is Professor of Pediatrics, and Dr. Fasano is Professor of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland. (ref http://www.medscape.com/viewarticle/414940 ) Published 2001
Ref 7 Celiac Disease Biopsy Explained - Part II. By Dr. Scot Lewey (http://ezinearticles.com/?Celiac-Disease-Biopsy-Explained-Part-II&id=315579 )
Ref 8 Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. By Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, Macintyre E, Cerf-Bensussan N, Brousse N. (http://www.ncbi.nlm.nih.gov/)
Ref 9 Diagram A diagnostic algorithm is shown to confirm the diagnosis of RCD. http://medgenmed.medscape.com/viewarticle/414940_print |
