Refractory Celiac Disease
Refractory Celiac Disease Hani Abdallah, MD, Daniel Leffler, MD, Melinda Dennis, RD, and Ciarán P. Kelly, MD
Corresponding author
Ciarán P. Kelly, MD
The Celiac Center, Division of Gastroenterology,
Beth Israel Deaconess Medical Center, Harvard Medical School,
330 Brookline Avenue, Boston, MA 02215, USA.
E-mail: ckelly2@https://www.sodocs.net/doc/361728803.html,
Current Gastroenterology Reports 2007, 9:401–405
Current Medicine Group LLC ISSN 1522-8037
Copyright ? 2007 by Current Medicine Group LLC
Celiac disease (CD) is a small intestinal in?ammatory dis-order characterized by an immune-mediated enteropathy triggered by the ingestion of wheat gluten or related rye and barley proteins in genetically predisposed individu-
als carrying the human leukocyte antigens (HLA)-DQ2 or
-DQ8. Nonresponsive CD (NRCD) is a clinical diagnosis
de?ned 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), de?ned as the persistence
of severe villous atrophy on small intestinal biopsy despite strict gluten withdrawal for at least 6 months with no evi-dence 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 signi?cant 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 pos-sibly 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. Introduction
Celiac disease (CD) is a small intestinal inflammatory dis-ease characterized by malabsorption associated with small intestinal villous atrophy, crypt hyperplasia, and increased numbers of intraepithelial lymphocytes (IELs). The immune-mediated injury of CD is triggered by the inges-tion of wheat gluten or related rye and barley proteins in genetically predisposed individuals who carry the human leukocyte antigens (HLA)-DQ2 or -DQ8 [1,2]. Diagnosis of CD is based on the presence of circulating anti-tissue transglutaminase (tTG) autoantibodies and the finding of typical abnormalities on small intestinal biopsy. Classi-cally, CD diagnosis was based on clinical and histologic improvement upon withdrawal of gluten from the diet and relapse when dietary gluten is reintroduced, as occurs in the majority, but not all, celiac patients.
Clinical improvement is usually evident in the first few weeks after gluten withdrawal, but it can take up to 2 years for complete histologic resolution of the enteropathy [3]. Most individuals with CD have a complete resolution of associated signs and symptoms after withdrawal of gluten from their diet and remain well for as long as they continue on that regimen. However, between 7% and 30% of CD patients experience persistent or recurrent signs and symp-toms at some point after diagnosis despite their remaining on a gluten-free diet [4,5].
Nonresponsive celiac disease (NRCD) is a clinical diag-nosis defined by the persistence of signs, symptoms, and/or laboratory abnormalities typical of active CD despite treat-ment with a gluten-free diet for at least 6 months [6]. Primary NRCD is defined as an initial lack of response to 6 months of gluten withdrawal, whereas secondary NRCD refers to a recurrence of symptoms, signs, or laboratory abnormalities despite continued maintenance of a glu-ten-free diet in individuals who initially responded [7,8]. There are multiple causes of NRCD that may present simi-larly; however, the most serious is refractory celiac disease (RCD). RCD is defined as the persistence of severe vil-lous atrophy on small intestinal biopsy despite at least 6 months of strict gluten withdrawal and with no evidence of another cause [8]. Differentiating RCD from other causes of NRCD is of paramount importance because treatment and prognosis are very different. RCD can be complicated by significant morbidity and mortality and carries a poor prognosis due to severe malabsorption, malnutrition, and development of ulcerative jejunitis or enteropathy-associ-ated T-cell lymphoma (EATL) [4,9,10]. Pathogenesis
In CD, gluten ingestion is required for T-cell activation and immune-mediated enteropathy to occur. Specific
402Small Intestine
genetic factors, HLA-DQ2 or -DQ8, are also required. Approximately 95% of patients with CD have a DQ2 gene comprised of DQA1*0501/DQB1*0201 or DQA1*0505/DQB1*0301. Most of the remaining 5% have a DQ8 heterodimer comprised of DQB1*0302/DQA1*0301 [11,12]. A small number of individuals lacking either of those heterodimers have DQA1*05 or DQB1*05 alone. Homozygous individuals who carry DQA1*05 and DQB1*02 in cis on both chromosomes have a greater risk of complicated CD [13]. Other non-HLA modifying genes are also thought to contribute but are not yet identified. The reason why some indi-viduals develop RCD is also unclear at this time but may relate to prolonged stimulation and the develop-ment of autonomous immune cell populations that are no longer dependent on antigen-specific stimulation by gluten peptides [14].
Diagnostic Approach
Confirm diagnosis
The diagnostic approach to NRCD is depicted in Figure 1. The initial step in the evaluation of NRCD is confirmation that the patient does have CD and not one of the many dis-orders that can mimic this diagnosis clinically, histologically, or in both ways such as peptic duodenitis, small intestinal bacterial overgrowth (SIBO), disaccharide intolerance (eg, lactose intolerance), microscopic colitis, pancreatic insuffi-ciency, food allergies, common variable immune deficiency, and irritable bowel syndrome [3,15–19]. A definite diagnosis of CD requires positive serology for anti-tTG autoantibod-ies or antiendomysial antibodies (EMA) at some point in the clinical course and histologic changes consistent with CD. In patients with NRCD in the absence of documented anti-tTG autoantibodies the histologic diagnosis of CD should be
carefully reevaluated. The diagnostic small intestinal biopsies
Review initial diagnosis of celiac disease
Weight loss present
Dietary treatment
Persistently abnormal SI histology
Refractory sprue
Normal or near normal SI histology Consider:IBS 22%
Microscopic colitis 6%SIBO 6%
Eating disorders 4%Food intolerances ~1%Peptic ulcer disease ~1%Gastroparesis ~1%
Pancreatic insuf?ciency
Consider:SIBO
Peptic duodenitis
Immunode?ciency states, including CVID Tropical sprue Giardiasis
Post-gastroenteritis Eosinophilic enteritis Autoimmune enteropathy Consider:
Imaging studies (SBFT, capsule endoscopy, CT) to evaluate for UJ or EATL T -cell clonality and aberrant IEL markers to differentiate type I from type II refractory sprue
Con?rmed
No gluten exposure
No response to GFD/LFD
Excluded
Search for gluten exposure by history, nutritionist evaluation, lgA-tTG
Trial of lactose restriction
if primary NRCD
EGD with biopsy
(plus colon, if diarrhea prominent)
Figure 1. Diagnostic approach for treatment for treatment of nonresponsive celiac disease (NRCD). CVID—common variable immune de?ciency; EATL—enteropathy-associated T-cell lymphoma; EGD—esophagogas-troduodenoscopy; GFD—gluten-free diet; IBS—irritable bowel syndrome; IEL—intra-epithelial lymphocyte; LFD—lactose-free diet; SBFT—small bowel follow-through; SI—small intestine; SIBO—small intestinal bacterial overgrowth; tTG—tissue transglutaminase; UJ—ulcerative jejunitis.
Refractory Celiac Disease Abdallah et al.403
should be reviewed by an experienced pathologist. Two to 5% of patients with CD have coexisting IgA deficiency and may not demonstrate elevated IgA antibody to tTG. Thus, if an elevated IgA tTG or endomysial antibody was never documented in the past, a total IgA measurement should be obtained. IgG anti-tTG can be helpful in this situation. In cases of continued uncertainty, genotyping for HLA-DQ2 and -DQ8 can be used to exclude CD, as the test has a very high negative predictive value [20].
Assess degree of adherence to gluten-free diet
In multiple studies, the most common cause of persis-tence of clinical and/or histologic features of CD is lack of adherence to the gluten-free diet resulting from either intentional or inadvertent ingestion of gluten [21–23]. Abdulkarim et al. [3] reported a 50% prevalence of glu-ten exposure in 55 patients with NRCD. More recently, Leffler et al. [24??] found that 36% of 99 patients with NRCD had inadvertent gluten exposure. Thus, a thorough evaluation of the patient’s diet is the second critical step and should be performed by a nutritionist skilled in CD and knowledgeable about the specifica-tions of the gluten-free diet. The evaluation should include a search for potential sources of hidden glu-ten (eg, medications and oral body care products) and cross contamination (in the home kitchen, restaurants, work cafeterias, and other locations). The presence of an elevated IgA tTG is strongly suggestive of gluten exposure [25]; in one study an elevated IgA tTG was associated with an 11-fold increased likelihood that inadvertent gluten intake would be identified [24??]. Thus, if IgA tTG remains persistently elevated after an initial nutritional evaluation, the probability of occult gluten exposure is high enough to warrant a second nutritional evaluation prior to more invasive diagnostic study. Conversely, a normal IgA tTG titer does not rule out minor gluten ingestion, whereas persistent eleva-tions in IgA tTG can be seen in both RCD and SIBO [26] despite strict gluten avoidance. If primary NRCD presents with gastrointestinal symptoms alone without elevated IgA tTG or other laboratory abnormalities, a trial of disaccharide restriction (eg, lactose-free diet) is worthwhile. Disaccharide intolerance, like lactose intolerance and in some cases fructose intolerance, is an unlikely cause for secondary NRCD [24??]. Establish the presence or absence of continued histologic abnormality
An important next step in the investigation of NRCD is to obtain a small intestinal biopsy to determine whether there is severe ongoing enteropathy. In patients with diarrhea a colonoscopy with colonic biopsies should be performed also to exclude microscopic colitis. Individu-als with persistent severe villous atrophy despite apparent gluten avoidance should be evaluated for conditions that can cause a celiac-like enteropathy, including SIBO, infec-tions (eg, giardiasis or tropical sprue in the appropriate clinical settings), Crohn’s disease, autoimmune enter-opathy, common variable immune deficiency, and peptic duodenitis [15,27,28]. Work-up should include a glucose hydrogen breath test for SIBO, small bowel imaging, and, depending upon the clinical circumstances, stool sample for giardiasis, measurement of serum immunoglobulin, and gastrin levels.
In many instances small bowel biopsies will be nor-mal or show a marked improvement compared with those obtained prior to starting a gluten-free diet. This sug-gests that the patient’s CD has responded to treatment and that the ongoing symptoms and signs are caused by a second disorder. Common diagnoses in this setting include irritable bowel syndrome, SIBO, disaccharide intolerance (in primary NRCD), microscopic colitis, or pancreatic insufficiency.
Refractory celiac disease
Unlike NRCD, RCD is a rare complication of celiac disease affecting less than 1% of patients with CD and should be considered a diagnosis of exclusion. Weight loss at initial evaluation for NRCD was found to be highly associated with an ultimate diagnosis of RCD, being 30 times more common in patients with RCD com-pared with all other causes of NRCD [24??]. However, RCD varies widely in severity, ranging from relatively mild type I RCD to fatal type II complicated by EATL [29,30]. RCD can be separated at diagnosis into type I and type II based on mucosal T-cell clonality and IEL immunophenotyping [10,31,32]. Cellier et al. [14] showed that in uncomplicated CD and in type I RCD, similar numbers of IELs will express the common T-cell marker CD3 together with CD4 or CD8 surface T-cell markers. The finding of a predominance of CD3-posi-tive IELs that lack CD4 and CD8 is indicative of type II RCD and is associated with a poor prognosis [14]. Polymerase chain reaction for T-cell receptor monoclo-nality or oligoclonality may be performed on intestinal biopsies [14,33]. The finding of an expanded monoclo-nal or oligoclonal intestinal T-cell population is also a marker for type II RCD and greater risk for progression to overt lymphoma. The prognosis of RCD varies greatly based on the existence of the markers for type II RCD or lymphoma, with 5-year survival recently reported by Al-Toma et al. [13] to be 96% for type I RCD, 58% for type II RCD, and 8% for EATL. The cause of death in type II RCD is typically progression to EATL, and, less commonly, complications of malnutrition [14]. Thus, patients with RCD should be offered immunophenotyp-ing and evaluation of T-cell clonality, and patients with type II RCD or lymphoma should be cared for at centers experienced in managing these disorders.
The initial treatment of RCD patients should be directed toward nutritional assessment and support. Fluid, electrolytes, and acid base balance should be assessed and
404Small Intestine
managed as a priority, especially in the presence of severe malabsorption, weight loss, muscle wasting, and edema.
Complete blood count, vitamin B
12, folate, albumin, cal-
cium, and vitamin D levels should also be measured and corrected. Oral supplements should be encouraged, and medium-chain triglycerides can be used to boost calorie intake. Although often poorly tolerated, elemental diets may also be beneficial in RCD [34]. In the presence of severe malnutrition, total parenteral nutrition should be initiated and a more thorough search made for fat soluble vitamin, mineral, and trace element deficiencies.
Evidence supporting the use of immunosuppressive therapy for RCD is based on anecdotal reports, and no controlled trials have been performed. For treatment of type I RCD, systemic and topical steroids (budesonide) have been used with varying degrees of response [35?,36–38]. Evidence of effectiveness for azathioprine, cyclosporine, infliximab, and tacrolimus has been cited in individual case reports [37,39–41]. G oerres et al. [42] recommend induction of remission by steroids followed by maintenance therapy with azathioprine. The use of these immunosuppressive agents is associated with signifi-cant side effects and increased risk of infection. Given the good prognosis of type I RCD, systemic immunosuppres-sive agents may not be necessary.
No therapy has been reported to be safe and effective in type II RCD. Alemtuzumab, an anti-CD-52 mono-clonal antibody, has been used in a number of reported cases with varied results [43]. Cladribine, a synthetic purine nucleoside with cytotoxic activity, has also been used, with improvement in some cases, although concern has been expressed regarding the precipitation of latent EATL [44?]. Recently a series of seven patients with type II RCD treated with autologous stem cell transplant has been reported, with promising results [45?]. Patients with EATL or monoclonal T-cell populations should be referred for evaluation by an oncologist and, whenever possible, enrolled in a clinical trial aimed at identifying effective treatment of this very morbid disease. Conclusions
NCRD is a clinical diagnosis defined by the persistence of signs, symptoms, and/or laboratory abnormalities typical of CD despite treatment with a gluten-free diet for at least 6 months [6]. One specific cause of NRCD is RCD, which is defined as the persistence of severe villous atrophy on small intestinal biopsy despite dietary gluten withdrawal and with no evidence of another cause. Although rare, RCD should be suspected in individuals with CD who fail to respond primarily or secondarily to a strict gluten-free diet and particularly in those with significant malabsorp-tion and weight loss. Individuals with RCD should be categorized into type I or type II RCD. Type I RCD has a favorable prognosis compared with type II and can often be managed with low-level immunosuppressive therapy. Type II RCD carries a dismal prognosis and is more likely to progress to intestinal lymphoma. Autologous stem cell transplant has been reported for treatment of type II RCD. References and Recommended Reading
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