Mubarak, A.*; Oudshoorn, J.H.†; Kneepkens, C.M.F.‡; Butler, J.C.§; Schreurs, M.W.J.||; Mulder, C.J.¶; Houwen, R.H.J.*
*Department of Paediatric Gastroenterology, University Medical Center, Utrecht
†Department of Paediatrics, Gelre Hospitals, Apeldoorn
‡Department of Paediatric Gastroenterology, VU University Medical Centre, Amsterdam
§Department of Paediatrics, Deventer Hospital, Deventer
||Department of Pathology, VU University Medical Centre
¶Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.
Address correspondence and reprint requests to Amani Mubarak, Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital, KE 01.144.3, PO Box 85090, 3508 AB, Utrecht, The Netherlands (e-mail: A.Mubarak@umcutrecht.nl).
Received 20 September, 2010
Accepted 27 January, 2011
The authors report no conflicts of interest.
Refractory coeliac disease (RCD) is a severe and often life-threatening complication of coeliac disease (CD), which is estimated to affect 7% to 8% of adult patients with CD (1). Although several definitions have been stated previously, it is now generally defined as persisting (primary RCD) or recurring (secondary RCD) villous atrophy with crypt hyperplasia and an increased number of intraepithelial lymphocytes (IELs) in spite of a strict gluten-free diet (GFD) for >12 months, or when severe persisting symptoms necessitate intervention independent of the duration of the GFD (2). RCD is considered to occur exclusively in adults because no cases in children have been reported.
Although the complex pathophysiological background of RCD is not completely understood, it is thought to be a diffuse gastrointestinal disease in which the small intestinal IELs play a major role (3). Why these elevated IELs do not disappear upon gluten withdrawal, as in responsive CD, remains unclear, but genetic factors may be at least partially responsible (4,5). On the basis of the phenotype of the IELs, RCD can be subdivided into 2 immunophenotypical categories (6). In type I (RCD I), phenotypically normal IELs showing expression of surface CD3, CD4 or CD8, CD103, and T-cell receptor (TCR) with polyclonal TCR gene rearrangement are present. The IELs in this subgroup are indistinguishable from those seen in active CD. By contrast, IELs in type II (RCD II) have been demonstrated to demonstrate an abnormal phenotype: expression of intracytoplasmatic CD3 and surface CD103, but lack of surface CD3, CD4 or CD8, and TCR. These aberrant IELs mostly show a monoclonal rearrangement of the TCR on the genomic level (6–8). Aberrant IELs, identical to those seen in RCD II, have also been reported in ulcerative jejunitis (UJ) and enteropathy-associated T-cell lymphoma (EATL), conditions that may coexist with or evolve from RCD, especially type II, and may suggest that these disorders form a continuous spectrum with RCD (8,9).
RCD is a diagnosis of exclusion. If this condition is suspected, then all of the other causes of unresponsiveness to the GFD must be eliminated before the diagnosis of RCD can be made (2,10). Most commonly, patients are intentionally incompliant with the diet, or yet more frequently, inadvertently ingest gluten (1,10). Measuring antiendomysium and anti-transglutaminase antibodies (EMA and tTGA, respectively) along with a thorough dietary review is essential in selecting this specific group of patients (11).
Furthermore, all of the other causes of nonresponsive CD, particularly collagenous sprue, UJ, and EATL, must be ruled out (12,13). These conditions are significantly associated with RCD, and the latter 2 especially with type II, but they may also develop in CD without a preceding diagnosis of RCD, mainly if a GFD is not maintained (14).
Finally, it should be taken into consideration, especially if primary RCD is suspected, that the initial diagnosis of CD may have been incorrect. Many disorders such as autoimmune enteropathy, tropical sprue, common variable immunodeficiency, and intolerance to nongluten dietary proteins may show histological findings that are virtually similar, but not necessarily identical with CD and therefore should be reconsidered and excluded (1).
Once the diagnosis of RCD is established, a flow cytometric analysis of IELs should be performed to distinguish between the 2 subtypes of RCD because both treatment and prognosis are mainly determined by the subtype (15). Patients with RCD I belong to the prognostically more favourable subgroup and seem to benefit from immunosuppressive treatment (15). Although benign in its course, RCD I is associated with an increased risk of developing concomitant autoimmune diseases in addition to infectious and thromboembolic complications (2). In RCD II a therapeutically more aggressive approach is necessary because the presence of aberrant IELs, as seen in this group, is highly associated with the development of overt lymphoma and carries a poor prognosis (15). Chemotherapeutics are therefore recommended as the first-line treatment in RCD II, although no treatment has been found to be curative (16). To our knowledge, no paediatric cases of RCD have been reported previously. Here we report a paediatric patient with RCD.
The patient, a HLA-DQ2.5–positive and HLA-DQ8–negative boy, presented with symptoms of abdominal distension, vomiting, anorexia, fatigue, and failure to thrive (weight for height had declined from around 0 standard deviation [SD] to −2 SD, height for age had declined from around 0 SD to around −1 SD). At the age of 13 months, CD was diagnosed, suggested by positive serological markers (EMA) and confirmed by small intestinal biopsy, which showed the classical triad of villous atrophy: subtotal in this patient, increased IELs, and crypt hyperplasia (Marsh IIIb). A GFD was introduced shortly after the diagnosis and the patient showed an excellent clinical response to the diet: he showed catch-up growth while all other symptoms disappeared. During the following years, symptoms remained absent and weight for height was between −1 and 0 SD and height for age around 0 SD). In addition, EMA normalised and tTGA, which was not done initially, was repetitively negative. Both remained so during the subsequent 8 years.
A follow-up small intestinal biopsy was performed 1, 2, and 3.5 years after diagnosis. The first follow-up biopsy was performed as part of the routine (at that time) diagnostic approach for CD, which necessitated a gluten challenge in children diagnosed before age 2 years. Subsequent biopsies were done as a follow-up of the villous atrophy during a GFD. These follow-up biopsies repeatedly showed total villous atrophy consistent with active CD. Crypt hyperplasia was demonstrated in all biopsies, but an increased number of IELs was only found in the first 2. No biopsy showed any histological evidence of other gastrointestinal disorders. Giardiasis was excluded by repeated and direct evaluation of faecal and small intestinal biopsy specimens. Additionally, common variable immunodeficiency was excluded because immunoglobulin levels in the blood were repeatedly normal. Also, this patient never experienced recurring infections, making an immunodeficiency syndrome less probable. The lack of dense lymphocytic infiltrate in the lamina propria, the marked increase in IELs count, and the absence of anti-enterocyte antibodies, in combination with the good clinical response to the diet, ruled out autoimmune enteropathy.
Although serology (tTGA and EMA) remained negative, a dietary assessment was performed to rule out minor gluten contamination that may not have been detected serologically. The assessment showed a strict compliance to the diet and no signs of inadvertent gluten ingestion.
Because RCD was increasingly suspected at this time, 5 years after diagnosis, a small intestinal biopsy was performed for histopathological and flow cytometric IELs analysis (Fig. 1A). Once again, there was no histological improvement; flow cytometry revealed IELs with a normal phenotype (surface CD3 and CD8 positive). Conclusively, the patient was diagnosed as having RCD I. Because of the lack of symptoms, it was decided not to start with immunosuppressive treatment but to await further progression. Therefore, a small intestinal biopsy for histopathological and flow cytometric IELs analysis, now approximately 7 years after diagnosis, was repeated (Fig. 1B). Although aberrant IELs were still not present, in accordance with the diagnosis of RCD I, histopathology showed no signs of improvement and treatment with azathioprine (2 mg/kg) was therefore commenced. After approximately 1 year of treatment, a final small-intestine biopsy was performed. Histological evaluation at this point revealed a completely normal small-intestine architecture (Marsh 0) (Fig. 2) while flow cytometry still showed phenotypically normal IELs.
We report on a pediatric patient with RCD. The CD in this patient showed an excellent clinical response, but no histological response to the GFD. Serological markers remained undetectable over the years and dietary assessment showed the patient to be strictly adhering to the diet. Because there were no signs of other gastrointestinal diseases, he was diagnosed as having RCD; flow cytometry demonstrated the RCD to be type I. Subsequently, immunosuppressive therapy (azathioprine) was started and a small-intestine biopsy after approximately 1 year of treatment showed a complete normalisation of the intestinal architecture.
The first step in the diagnosis of RCD is to question whether patients are fully compliant with the GFD. The absence of EMA and tTGA in this patient strongly opposes the presence of any gluten contamination. Although intermittent gluten ingestion has been reported to cause histological abnormalities without being detected serologically, we have no reason to believe that this is the case in this patient because no signs of gluten contamination were detected by a thorough dietary review (17). Therefore, it is possible to rule out gluten ingestion as a cause for the persistent total villous atrophy in this case.
Second, repeated biopsies excluded the presence of collagenous CD, UJ, and EATL. Moreover, flow cytometry of small intestinal IELs did not demonstrate any aberrant T cells. In addition, this patient did not show any clinical symptoms that may suggest the presence of these disorders, and the long-term survival in this patient strongly opposes the existence of any of these complications. Therefore, we consider this group of diseases to be highly unlikely.
Finally, the diagnosis of CD should be questioned, especially in this patient because he never demonstrated a histological normalisation after commencing the GFD. He showed an unequivocal clinical response to the diet, and the presence of circulating EMA antibodies before the onset of the GFD in combination with the HLA-DQ2.5 genotype is strongly suggestive for CD (18). Furthermore, histological findings typical for CD were repetitively demonstrated, and even after reviewing the original slides, no signs of CD-mimicking diseases could be found. In particular, autoimmune enteropathy could be ruled out because this patient did not meet the criteria for this disease as proposed by Unsworth and Walker-Smith; he did not experience protracted diarrhoea, there was a good response to dietary gluten exclusion, and most important, this patient lacked evidence of predisposition to autoimmune diseases because of the absence of anti-enterocyte autoantibodies and associated autoimmune diseases (19). Finally, common variable immunodeficiency could be excluded with certainty because of the lack of symptoms indicating recurrent infections and repeatedly normal immunoglobulin levels in the blood. Also, the criteria for making a formal diagnosis of common variable immunodeficiency as defined by the European Society for Immunodeficiency and the Pan American Group for Immunodeficiency requires a late onset of this disease, which is defined as an onset after the age of 24 months (20). This was not the case in this patient because his villous atrophy manifested at age 13 months.
Thus, this patient appears to have an actual RCD I. We therefore conclude that RCD should be considered not only in adults but also in children presenting with persistent villous atrophy despite a strict GFD. In those patients thiopurines may be used as the first-line treatment.
1. O’Mahony S, Howdle PD, Losowsky MS. Review article: management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther 1996; 10:671–680.
2. Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol 2005; 19:413–424.
3. Verkarre V, Asnafi V, Lecomte T, et al. Refractory coeliac sprue is a diffuse gastrointestinal disease. Gut 2003; 52:163–164.
4. Wolters VM, Verbeek WH, Zhernakova A, et al. The MYO9B gene is a strong risk factor for developing refractory celiac disease. Clin Gastroenterol Hepatol 2007; 5:1399–1405.
5. Al-Toma A, Goerres MS, Meijer JW, et al. Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol 2006; 4:315–319.
6. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet 2000; 356:178–179.
7. Cellier C, Patey N, Mauvieux L, et al. Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology 1998; 114:471–481.
8. Bagdi E, Diss TC, Munson P, et al. Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population. Blood 1999; 94:260–264.
9. Daum S, Weiss D, Hummel M, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut 2001; 49:804–812.
10. Abdulkarim AS, Burgart LJ, See J, et al. Etiology of nonresponsive celiac disease: results of a systematic approach. Am J Gastroenterol 2002; 97:2016–2021.
11. Bazzigaluppi E, Roggero P, Parma B, et al. Antibodies to recombinant human tissue-transglutaminase in coeliac disease: diagnostic effectiveness and decline pattern after gluten-free diet. Dig Liver Dis 2006; 38:98–102.
12. Ho-Yen C, Chang F, van der Walt J, et al. Recent advances in refractory coeliac disease: a review. Histopathology 2009; 54:783–795.
13. Brousse N, Meijer JW. Malignant complications of coeliac disease. Best Pract Res Clin Gastroenterol 2005; 19:401–412.
14. Freeman HJ. Lymphoproliferative and intestinal malignancies in 214 patients with biopsy-defined celiac disease. J Clin Gastroenterol 2004; 38:429–434.
15. Al-Toma A, Verbeek WH, Hadithi M, et al. Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience. Gut 2007; 56:1373–1378.
16. Al-toma A, Verbeek WH, Mulder CJ. The management of complicated celiac disease. Dig Dis 2007; 25:230–236.
17. Vahedi K, Mascart F, Mary JY, et al. Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol 2003; 98:1079–1087.
18. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40:1–19.
19. Unsworth DJ, Walker-Smith JA. Auto-immunity in diarrheal disease. J Pediatr Gastroenterol Nutr 1985; 4:375–380.
20. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999; 93:190–197.