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Background
Refractory celiac disease (RCD) is a clinical, serologic and histologic failure to improve after 6-12 months of a gluten free diet (GFD). RCD may occur as an initial failure of strict diet over this time course (primary RCD) or as a subsequent recurrence of previously controlled disease despite continued gluten avoidance (secondary RCD).1 Interestingly, the frequency of diagnosis of RCD is approximately 15% in poorly responsive celiac patients2, attesting to the difficulty in the majority to maintain an adequate GFD or initial misdiagnosis. This complicated form of celiac disease has been subdivided in the laboratory by sophisticated techniques into two types with different pathophysiologies and prognoses.
Type I refers to those with normal expression of T cell antigens and polyclonal T cell receptor (TCR) gene rearrangements of the intra-epithelial lymphocytes (IELs) on duodenal biopsies as assessed by polymerization chain reaction (PCR), usually responds to immunosuppression and has a reasonable prognosis. Type II is a much more aggressive form of RCD with loss of classic T cell antigens and a monoclonal expansion of the IEL’s TCR gene rearrangements with a high propensity for advancement to T cell lymphoma (40-60%) and an extremely poor prognosis. This high grade form of non-Hodgkin’s lymphoma is most commonly found in the jejunum as circumferential, discrete or confluent ulcerations and is referred to as enteropathy-assosciated T-cell lymphoma (EATL) with a 30 month survival of only 13%.3 Therefore, an accurate distinction between the 2 types of refractory disease is crucial for risk stratification, as screening of Type II RCD patients could possibly lead to an earlier diagnosis of lymphoma and improved survival. Type I RCD patients would benefit treatment with immunosuppressive agents such as azathioprine, steroids or even anti-TNF agents.
Genetic assessments, such as the finding of HLA DQ2 homozygosity or variants of the MYO9B gene on chromosome 19, have been demonstrated to be strong risk factors for the development of Type II RCD and EATL.4-5 Recently, the group from Amsterdam reported on the use of clonality by PCR in comparison with flow cytometric determination of aberrant IELs for accuracy in prediction of the development of EATL in patients with RCD6. A total of 31 patients with RCD, ulcerative jejunitis and EATL were compared by both techniques and against normal controls. EATL was found exclusively in RCD with greater than 20% aberrancy on flow cytometry (median 52%, range 27-94%). The negative predictive value and sensitivity were both 100% for the development of EATL by flow cytometry as compared to 75% and 78%, respectively for PCR clonality.
The case report presented in this paper exemplifies the clinical dilemma due to our present ability to efficiently stratify refractory celiac patients at high risk for a strongly lethal lymphoma while addressing the critical issue of screening. It raises controversial, and as yet unanswered, questions regarding the details of whether to screen Type II refractory disease, the modality and appropriate intervals.
Case Report
JR is a 71 year old woman who initially presented in November 2005 with upper abdominal pain, diarrhea and bloating. The bowel movements were described as soft, foul smelling and greasy appearing. She denied any melena, hematochezia, nausea, vomiting or significant weight loss. Past history included coronary artery disease requiring PTCA in the remote past, gastroesophageal reflux and osteoporosis. Family history was only significant for heart disease. Lab studies exhibited an iron deficiency anemia, dyslipidemia and a strongly positive IgA tTG at 51 U/ml (positive > 10 U/ml). An endomysial antibody was positive. EGD was performed for biopsy confirmation revealing duodenitis with features of scalloping and fissuring (Figure 1). Colonoscopy with ileoscopy was negative. Histology from the duodenum was described as acute and chronic duodenitis with epithelial atrophic changes, lymphocytic infiltrate in the lamina propria and abundant intraepithelial lymphocytes (Figure 2). A gluten free diet (GFD) was initiated with excellent adherence and she improved dramatically over a 3-4 week period. However, soon the symptoms returned as before and a capsule endoscopy was performed (Video 1). The capsule reveals typical scalloping, cobblestoning, villous atrophy and fissuring.
The GFD continued with only minor improvement in the symptomatology and another EGD was undertaken in June 2006 revealing persistent fissuring in the 2nd and 3rd segment of the duodenum (Figure 3). Biopsies from this area continued to demonstrate focal villous atrophy, dense chronic inflammatory infiltrate and intraepithelial lymphocytosis (Figure 4). Consultation with a nutritionist again confirmed that she was following the GFD with excellent compliance. Some improvement followed but the diarrhea and abdominal discomfort waxed and waned with worsening fatigue, weakness and back pain. She was lost to follow up after suffering a myocardial infarction in August 2007 but presented again in April 2008 for further evaluation still strongly symptomatic while maintaining the GFD. Another capsule endoscopy was performed which demonstrated less fissuring but more severe scalloping of the mucosa (Video 2), ( Figures 5,6,7). Refractory disease was therefore diagnosed and concern regarding Type II IEL was further raised by the finding of HLA DQ2 homozygosity. Biopsies of the duodenum were then evaluated by flow cytometry, revealing 60% aberrancy of the IEL’s, a strongly positive result in favor of Type II RCD and risk for EATL. The decision was made to follow this patient by capsule endoscopy every 6 months for evidence of early lymphoma since the cumulative radiation dose from CT enterography was considered problematic for screening, although there is no safety data in these patients using this approach. The efficacy of capturing early lesions with less frequent cross-sectional enterographic imaging techniques is unknown.
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Discussion
Recent developments in our ability to distinguish aggressive RCD in poorly responsive celiac patients at risk for EATL, offer a unique opportunity to focus on available small bowel imaging technologies as potential screening modalities.
The use of capsule endoscopy (CE) for the screening of lymphoma and other associated complications of celiac disease has been proposed in developing algorithms for refractory celiac disease and incorporated into evidence-based consensus opinion by expert committees such as occurs at the International Conference on Capsule Endoscopy (ICCE)7. This potentially important application of CE in complicated celiac patients is based on the ability to easily visualize, in a non-invasive fashion, the entire small bowel, making screening of lymphoma, adenocarcinoma or ulcerative jejunitis a more sensitive exercise than previously available by radiologic studies or push enteroscopy. Suspicious findings can then be defined histologicaly by more invasive techniques such as double balloon enteroscopy (DBE), other forms of enteroscopy or surgery. However, no data exists supporting the effectiveness of such an approach. Empirically, survival should improve if lesions are found early since EATL is often widespread at the time of diagnosis with a poor response to therapy. Patients with RCD Type II would therefore likely benefit from a screening program, although this would have to be assessed prospectively in a well designed study comparing other modalities such as cross sectional enterography or enteroclysis in addition to balloon-assisted enteroscopy. There are no present guidelines regarding the most effective technique or interval between exams to maximize capture of early neoplasm and remain cost efficient.
Although capsule endoscopy appears to be an appealing choice for screening these patients, there are significant drawbacks to this modality such as the inability for tissue sampling, inadequate localization, incomplete studies and missed lesions. The overall miss rate foe CE in small bowel disease is 10% as compared to isolated mass lesions which is high at 18.6%8. The difference may be related to variable capsule velocity, tumbling, blood obscuring visualization and the propensity for tumors to cincture the bowel wall. On the other hand, EATL often presents as ulcers, nodularity or white plaques9. These findings may not be as focal and isolated as an adenocarcinoma or other mass lesions and less likely missed.
Double-balloon enteroscopy has been reported to detect small bowel tumors missed on CE and can also allow for biopsy and tattoo localization. In a large U.S. multicenter study of mass lesion detection by DBE in 183 patients with obscure bleeding, 10 of 15 patients who underwent prior CE had their tumors found only on DBE10. Hadithi et al. reported on the usefulness of DBE in detecting EATL and ulcerative jejunitis in patients with RCD and was able to exclude EATL in 4 patients who had CT evaluations suggesting its presence11. However, the drawbacks of this technology include its invasive nature, need for deep sedation, lack of availability, time consumption and frequent incomplete panenteroscopy.
Radiologic investigation of the small bowel holds promise for a minimally invasive screening tool. Conventional double contrast enteroclysis has been rapidly replaced by cross-sectional imaging methods such as CT and MRI utilizing specialized enterographic contrast and workstations that allow multiplanar or 3-D evaluation with or without enteroclysis technique. CT enterography or enteroclysis has been reported to demonstrate the best visualization of small bowel neoplasms and offers additional findings such as obstruction, mural and extra-mural extent of disease, lymphadenopathy, peritoneal seeding and liver metastasis12.
Summary
In summary, although unproven, it is expected that patients with Type II RCD will likely benefit from early detection of associated complications such as EATL by engaging in a preventative screening program. However, the modality utilized and the interval between exams has not been adequately investigated and could possibly include a combination of techniques. Randomized prospective trials comparing available endoscopic and radiologic procedures to determine a cost-effective and practical screening algorithm are strongly desired for these patients.
References:
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11. Hadithi M, Al-toma A, Oudejans J, vanBodegraven AA, Mulder CJ, Jacobs M. The value of double-balloon enteroscopy in patients with refractory celiac disease. Am J Gastroenterol 2007; 102(5):987-96.
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