Crohn s disease, a chronic transmural inflammation of the

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: Endoscopic Skipping of the Distal Terminal Ileum in Crohn s Disease Can Lead to Negative Results From Ileocolonoscopy SUNIL SAMUEL,*, DAVID H. BRUINING,* EDWARD V. LOFTUS JR,* BRENDA BECKER,* JOEL G. FLETCHER, JAYAWANT N. MANDREKAR, ALAN R. ZINSMEISTER, and WILLIAM J. SANDBORN *Division of Gastroenterology and Hepatology, Department of Radiology, and Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota; Nottingham University Hospital NHS Trust, Nottingham, United Kingdom; and Division of Gastroenterology, University of California San Diego, La Jolla, California See editorial on page BACKGROUND & AIMS: Crohn s disease often involves the terminal ileum (TI), but skipping of the distal TI can occur. This can lead to negative results from ileocolonoscopy. We analyzed advanced cross-sectional images to determine how frequently this occurs. METHODS: We analyzed data from 189 consecutive patients (55% women) with Crohn s disease, evaluated in 2009 by computed tomography enterography (CTE) and ileocolonoscopy. The discharge impression of the gastroenterologist who treated the patients was used as the reference standard for Crohn s disease activity. RESULTS: Of the patients evaluated, 153 underwent TI intubation during endoscopy; 67 of these (43.8%) had normal results from ileoscopy, based on endoscopic appearance. Despite their normal results from ileoscopy, 36 of these patients (53.7%) had active, small-bowel Crohn s disease. The ileum appeared normal at ileoscopy because the disease had skipped the distal ileum of 11 patients (30.6%), developed only in the intramural and mesenteric distal ileum of 23 patients (63.9%), and appeared only in the upper gastrointestinal region of 2 patients (5.6%). These patients had a shorter duration of disease (61.1% for less than 5 years) compared with those found to have Crohn s disease based on ileoscopy (41.1% for less than 5 years; P.05). CTE detected extracolonic Crohn s disease in 26% of patients; 14% of patients were found to have disorders unrelated to inflammatory bowel disease that warranted further investigation or consultation (including 4 cancers). CONCLUSIONS: Ileoscopy examination can miss Crohn s disease of the TI because the disease can skip the distal ileum or is confined to the intramural portion of the bowel wall and the mesentery. CTE complements ileocolonoscopy in assessing disease activity in patients with Crohn s disease. Keywords: Diagnosis; Accuracy; Intestine; Inflammation. Crohn s disease, a chronic transmural inflammation of the human gastrointestinal (GI) tract, may progress over time to complications of fistula, abscess, and stricture formation. 1 Symptoms of early disease are often nonspecific, and accurate assessment of disease location, activity, and presence of diseaserelated complications is necessary before instituting or modifying a treatment plan. Computed tomography enterography (CTE) is increasingly used to evaluate the small bowel for Crohn s disease. This advanced imaging modality, in addition to detecting luminal disease, can identify extraluminal complications of Crohn s disease, and might aid in the distinction between inflammatory and fibrostenotic strictures. 2 5 Abnormalities detected on CTE scans in patients with active Crohn s disease showed very good correlation for stricture, fistula, abscess, and inflammatory mass at the time of surgery. 6 In a prospective, blinded 4-way comparison study of diagnostic modalities for active small bowel Crohn s disease, the combination of CTE and ileocolonoscopy had a sensitivity of 84% and specificity of 94%. 7 Because the terminal ileum (TI) is the most common site affected by Crohn s disease, 8 it has been reported by some that a normal ileoscopy during colonoscopy may render further radiological assessment of the small bowel unnecessary. 9,10 However, previous studies have suggested that Crohn s disease could skip the distal TI while affecting the more proximal small bowel, and a normal ileocolonoscopy would be falsely reassuring. 11 In children there is a tendency for Crohn s disease to be distributed more proximally than the TI, beyond the reach of a standard colonoscope. 12,13 Of children with negative ileoscopy, approximately 20% had evidence of proximal small bowel Crohn s disease on small bowel follow-through when compared with 6.5% in adults. 13 In a study from St Mark s Hospital, London, 13% of adult patients with small bowel Crohn s disease had skipping of distal TI on barium studies. 14 The prevalence of TI skipping in patients with small bowel Crohn s disease undergoing CTE may vary from that previously reported with small bowel follow-through (as seen in children), and we therefore sought to study this phenomenon in a larger retrospective cohort of adolescent and adult patients with Crohn s disease. Methods Study Population and Design An electronic search of Mayo Clinic databases was employed to identify all patients with a diagnosis of Crohn s disease who were evaluated at Mayo Clinic, Rochester, Minnesota, during the year We identified 189 consecutive patients who had both CTE and ileocolonoscopy (with or without TI intubation) as part of their work-up for Crohn s disease. The Abbreviations used in this paper: CT, computed tomography; CTE, computed tomography enterography; GI, gastrointestinal; IBD, inflammatory bowel disease; MRE, magnetic resonance enterography; TI, terminal ileum by the AGA Institute /$

2 1254 SAMUEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 11 Figure 1. Representation of the findings in the retrospective cohort of 189 patients with small bowel CD. 2 tests had to be completed within 30 days of each other. The CTEs were performed according to a previously reported protocol. 11 The presence or absence of radiological features suggestive of small bowel inflammation in the form of mural hyperenhancement (segmental increased attenuation of the bowel wall compared with the attenuation of normal-appearing ileum), mural thickening ( 3 mm), mural stratification (visualization of 2 or 3 layers within the bowel wall), increased mesenteric fat attenuation, and the Comb sign (prominent vasa recta) were recorded for every patient in the study. 11,15,16 Patients with isolated colonic Crohn s disease were excluded. Demographic and clinical characteristics were abstracted retrospectively. These included age, sex, smoking history, duration of the disease, previous Crohn s-related bowel surgery, and current therapy for Crohn s disease. The length of the TI examined at the time of ileocolonoscopy and the presence of inflammation both endoscopically and histologically was recorded. The activity of Crohn s disease radiologically (as ascertained by the reporting radiologist) and biochemically (C-reactive protein), the anatomic locations within the GI tract affected, and the presence of Crohn s disease related complications were documented. Both clinically important and unimportant extraintestinal radiological abnormalities detected incidentally were also recorded. The discharge impression of the treating gastroenterologist (who specialized in inflammatory bowel disease [IBD]), which took into account all the clinical manifestations and test results, was used as the reference standard for Crohn s disease activity. All patients had provided written authorization for review of their medical records for research purposes and the study was approved by Mayo Clinic Institutional Review Board. Data Analysis Descriptive statistics in the form of mean, median, and range were calculated for baseline characteristics. Comparisons between 2 groups were performed using 2 test, Fisher exact test, or Wilcoxon rank-sum test as appropriate. For continuous variables, the 2-sample t test was used. All statistical analyses were performed using Microsoft Excel 2010 (Microsoft, Redmond, WA) and Statistical Analysis Software, SAS version 9.1 (SAS Inc, Cary, NC). Results A total of 189 consecutive patients with Crohn s disease who had both CTE and ileocolonoscopy as part of their evaluation were identified (Figure 1). Eighty-five were men (45%) (median age, 45 years; range, years) and 104 were women (55%) (median age, 41 years; range, years). Nearly a quarter of the Crohn s disease patients were current smokers (22.8%) and almost an equal number were former smokers (23.3%). Most patients had disease duration of more than 5 years (61.0%). Disease was classified according to the Montreal classification (Table 1). The ileum was the most common site involved with Crohn s disease (L1, L3), and most of the patients had nonstricturing and nonpenetrating disease (B1) (Table 1). Eighty-two patients (43.4%) had colonic Crohn s disease in addition to small bowel involvement. Terminal ileal intubation at the time of ileocolonoscopy was achieved in 153 patients (81%), and in more than 50% of these patients, 10 cm or more of the TI was endoscopically assessed. The TI was macroscopically normal in 67 of the patients (43.8%). Despite normal ileoscopy in these cases, 36 (53.7%) had active Crohn s disease based on the reference standard. Fortyeight of these 67 patients had biopsies taken of their normalappearing TI, and 13 (27%) of these patients had microscopic evidence of chronic inflammation. Among the 36 active Crohn s disease patients with endoscopically normal-appearing TI, 24 (66.7%) had biopsies taken from the TI. Fourteen (58.3%) had normal TI histologically, and the remaining 10 (41.7%) had microscopic chronic inflammation on histologic assessment. In the 36 patients with normal ileoscopy but active small bowel disease based on the reference standard, the CTE findings were suggestive of active disease (eg, contrast enhancement, thickening, dilated vasa recta, fat proliferation/stranding, and/or stratification) in all but 2 patients. Among these 2 patients, 1 had evidence of duodenal Crohn s disease on upper GI endoscopy and the other had widespread small bowel ulcerations noted on capsule endoscopy. In both these patients, CTE was suspected to be falsely negative. Normal ileoscopy in the other 34 patients with active Crohn s disease was due to sparing ( skipping ) of the distal TI in 11 (30.6%), with evidence of active Crohn s disease beyond the reach of the colonoscope seen

3 November 2012 DISTAL TERMINAL ILEUM AND CROHN S DISEASE 1255 Table 1. Demographic Data of the 189 Crohn s Disease Patients Who Were Included in This Retrospective Study Demographic parameters Frequency Median age (range), y 44 (10 80) Sex Male 85 (45.0) Female 104 (55.0) Smoking history Current 43 (22.8) Nonsmoker 99 (52.4) Former smoker 44 (23.3) Unknown 3 (1.6) Montreal classification of Crohn s disease Age at diagnosis a A1 21 (11.3) A2 120 (64.5) A3 45 (24.2) Disease location L1 91 (48.1) L2 1 (0.5) L3 82 (43.4) L4 1 (0.5) L1 and L4 8 (4.2) L2 and L4 2 (1.1) L3 and L4 4 (2.1) Behavior B1 91 (48.1) B1p 7 (3.7) B2 47 (24.9) B2p 6 (3.2) B3 29 (15.3) B3p 9 (4.8) Previous Crohn s disease surgery Yes 86 (45.5) No 103 (54.5) Duration of disease b 5 y 73 (39.0) 5 y 114 (61.0) Crohn s disease treatment at presentation No treatment 66 (34.9) Oral mesalamine 23 (12.2) Oral steroids 40 (21.2) Immunomodulators 43 (22.8) Biologic agents 46 (24.3) Combined immunomodulators and 12 (6.3) biologic agents NOTE. Data are n (%) except where otherwise noted. a Data not available for 3 patients. b Data not available for 2 patients. on their CTE (Figure 2A and B). Eight of these 11 patients had TI biopsies and only 2 had evidence of microscopic inflammation (18%). In the remaining 23 patients (63.9%), the normal ileoscopy was the result predominantly of intramural and/or mesenteric Crohn s disease as evidenced by mural enhancement, wall thickening, dilated vasa recta (Comb sign), stratification, and/or fat stranding on CTE affecting the distal TI (Figure 3A and B). Histologically half of the 14 patients in this group with TI biopsies had evidence of chronic inflammation (Figure 1). We compared the 36 active Crohn s disease patients with normal ileoscopic examinations with those patients with abnormal ileoscopy (n 74). Table 2 shows the various parameters compared for these 2 groups of patients. There were no significant differences in the median age (range) [48.5 (14 80) years vs 41.5 (10 78) years; P.1] or cigarette smoking status [ever smoked: 15 (42.9%) vs 32 (43.9%); P.92] between these 2 groups of patients. There were possible trends with the normal ileoscopy group consisting of more females (24 [66.7%] vs 36 [48.7%]; P.07) and more likely to have perianal disease (6 [16.7%] vs 4 [5.4%]; P.08) in comparison with the abnormal TI group. Crohn s disease duration of 5 years or less was more common in patients with normal ileoscopy compared with the abnormal ileoscopy group (22 [61.11%] vs 30 [41.10%]; P 0.05). In the subgroup of 23 patients with normal TI but intramural/mesenteric disease, the majority (65%) had disease duration of 5 years or less in contrast to the 45% in the 11 TI skipping patients. The serum C-reactive protein concentrations of patients with intramural/mesenteric Crohn s disease were not significantly different from those with active endoscopic disease (P.31). In addition to providing information on intestinal disease activity in Crohn s disease, CTE also detected abnormalities including extraintestinal IBD manifestations, complications, and incidental (non IBD-related) findings. Nearly a third of the Crohn s disease patients in our cohort (n 58; 30.7%) had findings that were a consequence of their underlying IBD (Table 3). The most common radiologic findings were internal penetrating disease in 10.5% patients. Other Crohn s disease associated conditions and complications including ankylosing spondylitis, thromoboembolic phenomena, and small bowel obstruction were seen in a minority of our patients (Table 3). Among the patients with incidental radiological findings (n 38), 28 (14.8%) had a clinically important abnormality that resulted in either a referral to a different specialty or additional testing. These findings included indeterminate pulmonary nodules, complex solid organ cysts, and malignancy. Six cancers were detected; 2 of these were already known while new diagnoses of pancreatic cancer, endometrial cancer, liver metastases, and leukemia (based on a finding of massive splenomegaly leading to hematology work-up) were made as a consequence of abnormalities detected on CTE. Discussion The results from this retrospective study indicate that up to 54% of patients with active small bowel or upper gut Crohn s disease may have a normal ileoscopy. This can be the result of either intramural and mesenteric disease or skipping of the distal TI. Patients with small bowel disease not detected by ileoscopy had a more recent onset ( 5 years) of disease duration and tended to have more perianal disease when compared with patients with small bowel Crohn s disease visualized by ileoscopy. In more than half of our Crohn s disease cohort, CTE also detected extraintestinal abnormalities (both related to and unrelated to Crohn s disease), which may lead to alterations in the management strategies. One of the major strengths of this study is that it adds to the sparse existing data regarding the prevalence of small bowel Crohn s disease that is missed by ileoscopy and the utility of CTE to supplement ileocolonoscopy in identifying and monitoring these patients. In addition, the study cohort was derived from a consecutive series of patients in clinical practice undergoing both colonoscopy and CTE, and thus reflects the utility

4 1256 SAMUEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 11 Figure 2. CTE images of a patient with skipped distal TI (arrow in A) but active disease more proximally (arrowheads in A and B) as evidenced by mural enhancement, wall thickening, Comb sign, and fat stranding affecting the TI beyond the reach of a standard colonoscope. of CTE to detect small bowel Crohn s disease in patients with negative ileoscopy in a real-world clinical setting. The yield of ileoscopy with biopsies remains a topic of debate in clinical practice. It is invaluable in patients with IBD when the disease is localized to the TI. 9,10,17,18 Among the patients in our cohort who underwent ileoscopy, only 13 patients (8.5%) with normal-appearing TI had histologic evidence of inflammation. This finding of microscopic inflammation in the setting of normal TI endoscopy could partly be due to variations in the different endoscopist s assessment of the TI. However, the vast majority of patients with normal endoscopic TI had normal ileal histology suggesting good concordance between the different endoscopists. Among the 36 patients with active Crohn s disease despite normal ileoscopy, 14 cases had active Crohn s disease despite normal TI both endoscopically and histologically. Therefore, a normal ileocolonoscopy and TI histology would neither completely exclude a diagnosis of Crohn s disease nor fully assess intestinal disease activity. We therefore, in Figure 3. CTE images of another patient with active Crohn s disease but normal ileoscopy owing to inflammation affecting exclusively the intramural and mesenteric portion of the TI as evidenced by mural enhancement, wall thickening, Comb sign, and fat stranding (arrowheads in A and B).

5 November 2012 DISTAL TERMINAL ILEUM AND CROHN S DISEASE 1257 Table 2. Comparison Between Patients Who Had Active Crohn s Disease With and Without Abnormal TI Clinical parameters Active Crohn s disease and normal TI (n 36) Active Crohn s disease and abnormal TI (n 74) P value Age, median (range), y 48.5 (14 80) 41.5 (10 78).10 Sex Male 12 (33.3) 38 (51.4).07 Female 24 (66.7) 36 (48.7) Smoking history Smoker or former smoker 15 (42.9) 32 (43.8).92 Nonsmoker 20 (57.1) 41 (56.2) Duration of Crohn s disease 5 y 22 (61.1) 30 (41.1).05 5 y 14 (38.9) 43 (58.9) Previous surgery for Crohn s disease 11 (30.6) 29 (39.2).38 Perianal Crohn s disease 6 (16.7) 4 (5.4).08 C-reactive protein, median (range), mg/l 3.1 ( ) 4.3 ( ).47 Small bowel Crohn s disease proximal to TI 14 (38.9) 0 (0).0001 NOTE. Data are n (%) except where otherwise noted. The 2 groups were compared using 2, Fisher exact test, or Wilcoxon rank-sum test as appropriate. contrast to earlier reports, 9,10 propose that in addition to endoscopic assessment, patients should also undergo imaging studies of small bowel to quantify the extent and activity of Crohn s disease. Newer imaging modalities for small bowel assessments such as magnetic resonance enterography (MRE) have a similar highlevel diagnostic performance compared with CTE in Crohn s disease. 11,19,20 Computed tomography (CT) images have higher image quality, less interobserver variability, 11 and are superior to MRE for detecting fibrofatty proliferation and mesenteric Table 3. The Extraintestinal Abnormalities Detected on CTE in the 189 Patients With Crohn s Disease Abnormality on CTE Frequency, n (%) IBD (Crohn s disease)-related findings 58 (31) Musculoskeletal (eg, sacroiliitis, ankylosing 11 (5.8) spondylitis) Vascular abnormalities (eg, thrombosis) 4 (2.1) Internal Crohn s fistulae 20 (10.6) Abscess/phlegmon 8 (4.2) Small bowel obstruction 5 (2.7) Nephrolithiasis 10 (5.3) Cholelithiasis 7 (3.7) Retained capsule 2 (1.1) IBD (Crohn s disease) unrelated findings 38 (20) Clinically unimportant Benign hepatic, kidney, or other cysts 7 (3.7) Hernias (abdominal wall) 3 (1.6) Anatomical variants 6 (3.2) Clinically important findings needing follow-up Indeterminate pulmonary nodules 8 (4.2) Complex solid organ and adnexal lesions 8 (4.2) Portal hypertension and varices 2 (1.1) GI (diverticulosis/diverticulitis, mesenteric 4 (2.1) vessel stenosis, pancreatic IPMN, and FNH Malignancy (gynecologic, GI, and 6 (3.2) hematologic) FNH, focal nodular hyperplasia of liver; IPMN, intrapapillary mucinous neoplasm of pancreas. lymphadenopathy. 20 However, CT involves ionizing radiation exposure, which might be associated with increased lifetime risk of malignancy. 21 The estimates of radiation-induced cancer risk from imaging studies has been generated using extrapolations from diverse data sets and various assumptions, 22,23 and hence the actual risk is unclear. Nonetheless, this concern with repeated CT examinations 23 will likely push forward the use of low-dose CTE and MRE in young patients or when serial imaging is performed. 24 Capsule endoscopy may be superior to CTE for detecting mucosal lesions, 25 but this advantage in Crohn s disease is offset by a decreased specificity when compared with CTE (53% vs 89%, respectively) and the risk of capsule retention. 7,26 Small bowel endoscopy including balloonassisted endoscopy is particularly useful in patients to obtain biopsies (confirm diagnosis) and perform therapeutic interventions such as stricture dilatation. 27 It is widely accepted that inflammation in Crohn s disease can be noncontiguous, leading to characteristic skip lesions, but the exact explanation for this behavior is unclear. Subanalysis in a recent study of 33 patients comparing CTE and MRE, which also included ileocolonoscopy as part of the reference standard, found almost a quarter (24.2%) of patients with active small bowel Crohn s disease had normal ileoscopy. 11 Half of these patients (11%) had skipping of terminal TI while the other half had intramural and mesenteric disease on crosssectional imaging. We noted similar findings in our study wherein 19% (n 36) of our patient cohort had normal ileoscopy but active Crohn s disease and 11 had no radiological or endoscopic disease noted in distal TI. This skipping of the distal TI probably represents the tendency of Crohn s disease to develop noncontiguous lesions and thereby skip the distal TI in these patients by chance. In the additional 23 patients, the activity of the disease was entirely intramural and/or mesenteric with thickening, hyperenhancement, and perienteric fat stranding. Current models of Crohn s disease invoke an initial disturbance of the epithelial interface between the GI mucosa and the intestinal microbiota. 28 This classic outside-in pathogenetic mechanism (wherein mucosal pathology is the initial event) fails to completely explain all the abnormalities encountered in patients with Crohn s disease, while an inside-out mechanism

6 1258 SAMUEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 11 may address some of these issues. 29 Central to the inside-out model is an aberration in the regional mesenteric lymphatic system, 30 which propagates the chronic inflammation; thus, the mucosal ulcerations observed at endoscopy may represent a late event in the disease pathway. 29,31 It therefore could be speculated that those patients in our cohort with only intramural and mesenteric disease (n 23) may have early Crohn s disease, where perienteric changes predate inflammatory mucosal changes. The recent disease onset in this particular subgroup lends further support to this hypothesis. Prospective follow-up of these patients is needed to fully understand the natural history of disease in this subgroup. Patients with active Crohn s disease but normal TI also had a higher proportion of perianal disease and on further analysis, 67% of these perianal Crohn s patients belonged to the TI-skipped group. Perianal disease and perforating phenotype are indicators of aggressive disease in Crohn s disease. 32,33 Whether Crohn s disease patients with TI skipping represent an aggressive phenotype will need to be addressed in a much larger study cohort. Analogous to extracolonic abnormalities detected on CT colonography during colon cancer screening, CTE has the unique feature of identifying extraintestinal IBD and non IBD-related abnormalities, which could potentially change the management strategy. In our study, 14% (Table 3) had IBD-unrelated radiologic findings that were significant enough to warrant further investigations or consultations. We believe that cross-sectional imaging in addition to ileocolonoscopy for patients with Crohn s disease provides a more comprehensive assessment of their disease activity and extent that is useful to clinicians in making decisions about the use of immunosuppressive therapy. Several limitations to this study exist. As the number of patients with TI skipping is small, a larger cohort of patients would help to further characterize this subset of patients. Also, patients in this study were from a tertiary center practice and may not reflect the patterns observed in population-based cohorts. 34 In conclusion, we have demonstrated that the Crohn s disease of distal TI can be missed by ileoscopy either because of the disease being confined to the intramural and mesenteric portion of the distal ileum, or skipping of the distal ileum. Follow-up studies on patients with TI skipping and intramural and mesenteric Crohn s disease may help in understanding the natural history of disease in this group of patients. This study adds to a growing body of evidence for the benefit of cross-sectional imaging in IBD diagnostic and management algorithms. References 1. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, et al. The natural history of adult Crohn s disease in population-based cohorts. 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7 November 2012 DISTAL TERMINAL ILEUM AND CROHN S DISEASE 1259 pected and established small-bowel Crohn s disease: a meta-analysis. Am J Gastroenterol 2010;105: Hansel S, Huprich J, Fletcher JG, et al. Retained capsule endoscopy in a large tertiary care academic center [abstract]. Inflamm Bowel Dis 2011;17(Suppl 1): Bourreille A, Ignjatovic A, Aabakken L, et al. Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED-ECCO consensus. Endoscopy 2009;41: von der Weid PY, Rehal S, Ferraz JG. Role of the lymphatic system in the pathogenesis of Crohn s disease. Curr Opin Gastroenterol 2011;27: Behr MA. The path to Crohn s disease: is mucosal pathology a secondary event? Inflamm Bowel Dis 2010;16: Van Kruiningen HJ, Colombel JF. The forgotten role of lymphangitis in Crohn s disease. Gut 2008;57: Rutgeerts P, Geboes K, Vantrappen G, et al. Natural history of recurrent Crohn s disease at the ileocolonic anastomosis after curative surgery. Gut 1984;25: Greenstein AJ, Lachman P, Sachar DB, et al. Perforating and non-perforating indications for repeated operations in Crohn s disease: evidence for two clinical forms. Gut 1988;29: Beaugerie L, Seksik P, Nion-Larmurier I, et al. Predictors of Crohn s disease. Gastroenterology 2006;130: Zankel E, Rogler G, Andus T, et al. Crohn s disease patient characteristics in a tertiary referral center: comparison with patients from a population-based cohort. Eur J Gastroenterol Hepatol 2005;17: Reprint requests Address requests for reprints to: David H. Bruining, MD, Division of Gastroenterology and Hepatology, 200 First Street SW, Rochester, Minnesota bruining.david@mayo.edu; fax: (507) Acknowledgments Presented in part at the Annual Meeting of the American Gastroenterological Association (Digestive Disease Week 2011), Chicago, Illinois, May 8 10, Conflicts of interest The authors disclose no conflicts.