ORIGINAL ARTICLES LIVER, PANCREAS, AND BILIARY TRACT

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6:62 68 ORIGINAL ARTICLES LIVER, PANCREAS, AND BILIARY TRACT Impact of Orthotopic Liver Transplant for Primary Sclerosing Cholangitis on Chronic Antibiotic Refractory Pouchitis KATHERINE FREEMAN,* ZHUO SHAO, FEZA H. REMZI,* ROCIO LOPEZ,* VICTOR W. FAZIO,* and BO SHEN* *Digestive Disease Center, Cleveland Clinic, Cleveland, Ohio; Department of Biliary Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China Background & Aims: The effect of orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) and post-olt immunosuppression on the disease course of pouchitis is not clear. The aims of this study were to compare the frequency of chronic antibiotic-refractory pouchitis (CARP) in PSC patients with or without OLT and to assess potential risk factors for CARP in these patients. Methods: Ulcerative colitis patients with PSC and ileal pouch anal anastomosis (IPAA) with or without OLT identified from our prospectively maintained pouch database were analyzed. CARP was diagnosed based on persistent symptomatic pouchitis after a 4-week single- or dual-antibiotic therapy. Results: A total of 63 PSC/IPAA patients were studied, including 19 patients with OLT and 44 patients without OLT. Fifty patients (79.4%) had CARP. In both univariable and multivariable analyses (adjusting for OLT status), none of the variables studied was associated significantly with CARP (P >.20). All 7 patients (100%) with IPAA-then-OLT were diagnosed as having CARP, of whom 4 developed CARP before OLT, which persisted after OLT, and 3 had CARP after OLT. Of 12 patients with OLT-then-IPAA, 7 (58.3%) developed CARP. The frequency of CARP in OLT-then-IPAA was statistically significantly lower than that in IPAA-then-OLT (58.3% vs 100%; P.047). Conclusions: CARP is common in patients with ulcerative colitis and PSC. OLT in these patients may not affect the frequency of CARP in general and appears not to alter the disease course of pre-existing CARP. However, in a subset of patients, OLT might reduce the risk for the development of de novo CARP. The surgical treatment of choice for the majority of patients with medical refractory ulcerative colitis (UC), UC with dysplasia, or familial adenomatous polyposis after total proctocolectomy is ileal pouch anal anastomosis (IPAA). 1 3 Pouchitis is the most common long-term complication of IPAA and one of its risk factors is the presence of concurrent primary sclerosing cholangitis (PSC). 3 PSC is a chronic inflammatory disease of the biliary system with idiopathic etiology that culminates in cirrhosis and can lead to mortality. 4,5 Approximately 70% to 80% of patients with PSC have concomitant inflammatory bowel disease (IBD). 4,5 Clinical features of concurrent IBD and PSC include rectal sparing, backwash ileitis, an increased frequency in colorectal neoplasia, and overall poorer survival. 6,7 In UC patients who underwent IPAA, the presence of PSC was associated with an increased risk for pouchitis (particularly chronic pouchitis), postoperative pelvic sepsis, and higher long-term mortality The treatment of choice for advanced PSC with cirrhosis is orthotopic liver transplantation (OLT). 15 Although OLT may be associated with a worse clinical course of IBD, 16 the impact of OLT for PSC on the natural history of pouchitis in IPAA patients is not clear. Based on the results of case reports, it appears that the disease course of pouchitis was not affected by OLT. 10,17 However, the limited sample sizes of these studies ( 7 cases) prevented the stratification of the disease categories of pouchitis and meaningful statistical analysis. Of various clinical phenotypes of pouchitis, management of chronic antibioticrefractory pouchitis (CARP) is most challenging. In fact, CARP is one of the most common causes for pouch failure, resulting in pouch resection or permanent diversion Our hypothesis was that OLT with concurrent antirejection immunosuppressant use may have an impact on the frequency and the disease course of pouchitis. This study s aim was to analyze the effect of OLT and posttransplant immunosuppression on the frequency of CARP in UC and PSC patients with IPAA. Patients and Methods Patients This historical cohort study was approved by the Cleveland Clinic Institutional Review Board. A prospectively maintained Pouch Database was reviewed with a total of 2510 patients with underlying UC or indeterminate colitis from 1983 to PSC patients with or without OLT were identified from the pouch database. In the database, demographic and clinical data (including clinical symptoms, pouch endoscopic and radiographic findings, presence of PSC, and OLT status) in each clinic visit were documented. The diagnosis of CARP initially was documented in the database or was made retrospectively Abbreviations used in this paper: CARP, chronic antibiotic refractory pouchitis; CD, Crohn s disease; IBD, inflammatory bowel disease; IPAA, ileal pouch anal anastomosis; OLT, orthotopic liver transplantation; PSC, primary sclerosing cholangitis; UC, ulcerative colitis by the AGA Institute /08/$34.00 doi: /j.cgh

2 January 2008 POUCHITIS AND LIVER TRANSPLANT 63 after reviewing the database and patients medical charts. A total of 63 patients with UC and IPAA were identified with documented PSC with or without OLT. Of the 63 patients, 19 patients had OLT (the OLT group) and the remaining 44 patients did not have OLT (the non-olt group). Detailed information on post-olt immunosuppressant use was obtained from medical chart review. Diagnostic Criteria CARP was diagnosed in patients with and without OLT based on persistent symptomatic pouchitis (with Modified Pouchitis Disease Activity Index scores 5 points 21 ) with symptoms lasting for more than 4 weeks and a failed 4-week singleor dual-antibiotic (ciprofloxacin and/or metronidazole) therapy. PSC was defined as the presence of intrahepatic and/or extrahepatic bile duct abnormalities documented in the medical record from endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, and/or liver biopsy. 22 OLT was performed for the indication of advanced PSC with or without other concurrent liver diseases. Inclusion and Exclusion Criteria Inclusion criteria were as follows: (1) age older than 18 years, (2) IPAA for UC, and (3) presence of PSC with or without OLT. Exclusion criteria were as follows: (1) IPAA for familial adenomatous polyposis, and (2) patients with IPAA for UC who were not diagnosed as having PSC. 22 Demographic and Clinical Variables Nineteen demographic and clinical variables were studied from patient medical records including age, sex, ethnicity, smoking and alcohol history, and family history of IBD, PSC, or liver/colon cancer in first-degree relatives. Also, UC history, including precolectomy and postcolectomy diagnosis of indeterminate colitis, extent of colitis at time of proctocolectomy, and indication for proctocolectomy, was evaluated. Extra-intestinal manifestations of IBD were evaluated such as eye and skin diseases and thromboembolic events. Pouchitis history was assessed including response to antibiotic therapy and disease course. The use of antibiotics, 5-aminosalicylates, immunosuppressants, corticosteroids (including budesonide), and infliximab was documented. Other disease conditions of the pouch such as cuffitis, irritable pouch syndrome, and Crohn s disease Table 1. Descriptive Statistics in 19 Patents With PSC and OLT Factor N Statistics Years between OLT and proctocolectomy 19 5 (3, 8) (25th, 75th quartiles) Duration of IPAA, y (25th, 75th quartiles) 19 8 (6, 11) Sequence of surgeries OLT first Proctocolectomy first OLT indication PSC PSC- and hepatitis B associated cirrhosis Long-term antibiotic use Yes No Table 2. CARP and OLT Status CARP No CARP P value No OLT (N 44) 36 (81.8%) 8 (18.2%).51 OLT (N 19) 14 (73.7%) 5 (26.3%) (CD) of the pouch were documented, but not statistically analyzed. Outcome Measurement The primary outcome of the study was the prevalence of CARP in patients with or without OLT and risk factors associated with CARP. The secondary outcomes were the prevalence of CARP in patients with PSC in general and the disease course of pouchitis in patients with IPAA-then-OLT and in patients with OLT-then-IPAA. Statistical Analysis Descriptive statistics were computed for all factors. These included medians, 25th and 75th percentiles for continuous factors, and frequencies for categoric factors. The Wilcoxon rank-sum test for continuous factors and the Pearson chi-square or the Fisher exact test for categoric factors were used to study associations between CARP and the following factors: age; sex; OLT; post-olt immunosuppressant use; durations of UC, IPAA, and OLT; tobacco consumption; and the presence of other extra-intestinal manifestations. Logistic regression analysis was performed to study multivariable associations. OLT and duration of IPAA were kept in the final model because of clinical importance. A significance level of 0.05 was used for all analyses. SAS version 9.1 software (SAS Institute, Cary, NC) was used to perform all analyses. Results We identified a total of 63 PSC patients who had restorative proctocolectomy with IPAA including 19 patients with OLT and 44 patients without OLT. The mean follow-up period after ileostomy take-down was (SD) years. The median follow-ups for the OLT and non-olt groups were 8.5 and 7.0 years, respectively (P.84). CARP was common in patients with underlying UC and PSC: 50 of the 63 patients (79.4%) with PSC had CARP, and of these 50 subjects, 14 (28.0%) had OLT. The clinical and demographic data of the 19 patients with OLT are listed in Table 1. The association between the status of OLT and the status of CARP is listed in Table 2. CARP was common in patients with PSC with or without OLT: 14 of 19 patients with OLT (73.7%) developed CARP; and 36 of 44 patients without OLT (81.8%) had CARP (Table 2). There was no statistical difference in the frequency of CARP between patients having OLT and those patients having no OLT (P.51). Of the 19 patients with OLT and IPAA, 7 had IPAA first, and 12 underwent OLT first. All the 7 IPAA-then- OLT patients were diagnosed as having CARP: 4 developed CARP before OLT, which persisted after OLT, and 3 had CARP after OLT. The frequency of CARP in patients with OLT-then- IPAA was statistically significantly lower than that in patients with IPAA-then-OLT (58.3% vs 100%, P.047); and the frequency of CARP appeared to be lower in the OLT-then-IPAA

3 64 FREEMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 1 Table 3. CARP and Posttransplant Immunosuppressant Use (N 19) Patients CARP Cyclosporine use Tacrolimus or sirolimus use Long-term prednisone 1 Yes Yes No Yes 2 Yes No No No 3 Yes Yes Yes Yes 4 Yes No Yes Yes 5 Yes No Yes No 6 Yes No Yes No 7 Yes No Yes Yes 8 Yes No Yes Yes 9 No No Yes No 10 Yes Yes Yes No 11 Yes Yes Yes Yes 12 Yes No Yes No 13 No No Yes No 14 No No Yes No 15 No No Yes Yes 16 Yes No Yes No 17 Yes No Yes Yes 18 Yes No No No 19 No No Yes Yes group than that in the non-olt group, but the difference was not statistically significant (58.3% vs 81.8%, P.22). As expected, all patients with OLT were on immunosuppressive agents, including cyclosporine (N 4), tacrolimus/sirolimus (N 16), and/or long-term corticosteroids (N 9). Detailed information on post-olt immunosuppressant use and its association with CARP in the 19 patients is listed in Table 3. In univariable analyses there was no evidence to suggest a significant association between CARP and OLT status or any of the factors under study. Although not statistically significant, subjects with CARP tended to consume more alcohol, had a family history of CD or UC, and had a history of thromboembolic events (Table 4). In multivariable analyses adjusting for OLT, there was no evidence to suggest that any of the factors were associated significantly with CARP (P.20) including age, sex, OLT, posttransplant immunosuppression, duration of UC, duration of IPAA, and duration of OLT, sequence of OLT and IPAA, tobacco consumption, and the presence of other extra-intestinal manifestations (Table 5). Discussion Pouchitis almost exclusively occurs in patients with underlying UC and rarely is seen in patients with familial adenomatous polyposis. 23,24 Although the etiology and pathogenesis of pouchitis are not entirely clear, the bulk of the evidence suggests an abnormal mucosal immune response (innate and adaptive) to altered microflora in the pouch leading to acute and/or chronic inflammation. 2,25 30 Genetic polymorphisms such as those of interleukin-1 receptor antagonist and NOD2/CARD15 34 may increase the risk for pouchitis. Purported risk factors for pouchitis also include extensive UC, 35 backwash ileitis, 35 preproctocolectomy thrombocytosis, 36 extraintestinal manifestations, especially PSC, 8 13,37,38 the presence of perinuclear antineutrophil cytoplasmic antibodies, 39,40 being a nonsmoker, 22,41 and the use of nonsteroidal anti-inflammatory drugs. 42 It appears that acute and chronic pouchitis may be associated with different risk factors. 43 In PSC patients, the risk of pouchitis seemed not related to the severity of liver disease, despite the fact that PSC is a risk factor for pouchitis. 3 In the current study, the majority of PSC patients (79.4%) with or without OLT had CARP, supporting the notion that the presence of PSC increases the risk for chronic pouchitis. Interestingly, there are similarities in terms of clinical presentations and immunologic abnormalities between pouchitis (particularly CARP) and UC, suggesting that in a subset of patients pouchitis actually may represent the recurrence of a UC-like condition in the ileal pouch. The theory of recurrent UC is supported by several lines of evidence. With the presence of fecal stasis in the pouch, exposure to luminal contents of the pouch and the increased microbial load could be the initiating event that allows for the onset of inflammatory changes. Colonic metaplasia of the pouch mucosa seems to be a nonspecific adaptive response to the new luminal environment, which may favor the development of a UC-like condition. 49 A similar alteration in mucin glycoproteins was observed in pouchitis as in UC. 50 It is possible that the altered glycoproteins are more susceptible to enzymatic degradation by bacteria, making the mucus barrier less resistant. 51 In addition, some patients with pouchitis have the same extra-intestinal manifestations as those occurring in UC. As in UC, smoking tends to have a protective effect against the development of pouchitis. 52 Furthermore, corticosteroids, immunosuppressants, and even biological agents have been used in patients with CARP with some success. 53,54 Therefore, dysregulated immune response, as seen in UC, may play an important role in the pathogenesis of pouchitis. One would expect that in patients with UC and PSC, OLT may be beneficial by reducing the risk for pouchitis with the routine use of antirejection immunosuppressants. Although it has been documented that pouchitis is more prevalent in IPAA patients with concurrent PSC, little is known about the effects of previous OLT for PSC with immunosuppression on the development of pouchitis in patients with UC undergoing restorative proctocolectomy with IPAA. Zins et al 17 reported 7 patients with previous IPAA for UC who subsequently underwent OLT for PSC. Five of the 7 patients had pouchitis before transplant (3 recurrent acute pouchitis and 2 chronic pouchitis), and in 5 of the 7 patients pouchitis continued after OLT (4 chronic pouchitis). Of the 2 patients without pouchitis before transplant, 1 developed an episode of acute pouchitis after transplant. 17 In another report of 4 patients with IPAA and PSC who had OLT, 1 patient developed chronic pouchitis requiring long-term metronidazole. 10 The results of these studies support the notion that OLT and post-olt immunosuppressant use may not have significant impact on the course of pouchitis in these patients. Our current investigation showed no evidence to suggest that any of the factors under study including age, sex, OLT, post-olt immunosuppressant use, durations of UC and IPAA, tobacco consumption, or extraintestinal manifestations were associated with CARP in general. However, in a subset of patients (OLT-then-IPAA patients in particular), OLT with posttransplant immunosuppression might decrease the risk for the development of de novo CARP (see later). Interactions between OLT with posttransplant immunosuppression and the disease course of IBD can be assessed from the

4 January 2008 POUCHITIS AND LIVER TRANSPLANT 65 Table 4. Factors Associated With CARP: Univariable Analysis CARP No CARP Factor N Statistics a N Statistics a P value b Age, y (47, 59) (51, 61).34 Years between UC diagnosis and proctocolectomy (11, 20) 13 9 (4, 29).43 Duration of IPAA, y (6, 12) 13 7 (5, 11).84 Sex.72 Male Female Ethnicity.72 Caucasian Other Tobacco consumption.75 Yes No Alcohol consumption.23 Yes No Family history of IBD.42 CD or UC None Family history of PSC.99 Yes No Family history of colon cancer.99 Yes No Family history of liver cancer.99 Yes No Extent of UC.99 Proctitis Left-sided colitis Pancolitis Toxic megacolon.37 Yes No Type of colitis.99 UC Indeterminate colitis Indication for colectomy.27 Refractory disease Steroid dependency Dysplasia Cancer Uveitis or iritis.99 Yes No Skin.67 Yes No Thromboembolic events.31 Yes No Osteoporosis.99 Yes No Arthritis or arthralgia.56 Yes No a Statistics presented are median (25th, 75th quartiles) or %. b P values correspond to Wilcoxon rank sum tests for age and time variables, Pearson chi-square for alcohol consumption and arthritis, or Fisher exact test otherwise.

5 66 FREEMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 1 Table 5. Factors Associated With CARP: Multivariable Analysis Factor Reference OR (95% confidence interval) P value OLT No vs yes 1.6 ( ).48 Duration of 5-y increase 1.03 ( ).94 IPAA following perspectives: (1) does OLT with posttransplant immunosuppression for PSC affect the disease course of preexisting IBD, and (2) does OLT with posttransplant immunosuppression trigger the development of de novo UC- or CD-like bowel inflammation? In patients with IBD who underwent OLT for PSC, posttransplant standard immunosuppression may be beneficial for the disease course of IBD in some patients. 55 In contrast, OLT has been reported to exacerbate pre-existing IBD, and to be associated with a higher risk for development of colonic neoplasia. 58,59 It also was reported that OLT has no beneficial or detrimental effects on the disease course of pre-existing IBD. 59 Of our 7 patients with IPAA-then-OLT, 4 developed CARP before OLT, which persisted after OLT, and 3 had CARP after OLT. It appears that OLT with posttransplant immunosuppression did not alter the disease course of preexisting CARP as illustrated by the 4 patients. However, there were differences in the frequency of CARP between patients with OLT-then-IPAA and patients with IPAA-then-OLT or patients without OLT. The results suggest that in a subset of patients with PSC and IPAA, OLT with posttransplant immunosuppression may decrease the risk for the development of de novo CARP. The findings would provide some rationale for the use of immunomodulators in a subset of patients with CARP. 53,54 The impact of solid-organ transplantation and posttransplant immunosuppression on the initiation and development of de novo UC- or CD-like conditions or existing IBD has been investigated. De novo UC- or CD-like conditions have been reported in renal transplantation or liver transplantation for PSC as well as other liver disorders 57,64 67 with concurrent immunosuppression with mycophenolate mofetil, calcineurin inhibitor and azathioprine, 65 and tacrolimus or cyclosporine. 57,66,67 It was speculated that post-olt cytomegalovirus infection might contribute to the development of de novo IBD. 67 In the current study, we could not determine whether de novo CARP that developed after OLT resulted from the organ transplantation. There were some limitations to this study. The sample size was small, which only allowed for limited logistic regression analyses because only patients with well-documented PSC were studied. It is possible that patients with asymptomatic or mild PSC might have been missed. In addition, acute pouchitis as well as other disease conditions of the pouch, such as cuffitis, CD of the pouch, and irritable pouch syndrome, were not studied because of the small sample size. Furthermore, there might have been selection bias because the patients were from the tertiary care facility. Finally, the current study did not address the question of whether the presence of CARP affected the outcome of PSC or OLT. In conclusion, CARP is common in patients with UC and PSC with or without OLT. OLT and posttransplant immunosuppressant use in these patients may not affect the frequency of CARP in general and appears not to alter the disease course of pre-existing CARP. However, in a subset of patients with PSC and IPAA, OLT with posttransplant immunosuppression might decrease the risk for the development of de novo CARP. References 1. Fazio VW, Ziv Y, Church JM, et al. Ileal pouch-anal anastomosis; complications and function in 1005 patients. Ann Surg 1995; 222: Sandborn WJ. Pouchitis following ileal pouchitis-anal anastomosis: definition, pathogenesis, and treatment. Gastroenterology 1994;107: Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouchanal anastomosis for ulcerative colitis occurs with increase frequency in patents with associated primary sclerosing cholangitis. Gut 1996;38: Wiesner RH, Grampsch PM, Dickson ER, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 1989;10: Wiesner RH. Current concepts in primary sclerosing cholangitis. Mayo Clin Proc 1994;69: Loftus EV Jr, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005;54: Gorgun E, Remzi FH, Manilich E, et al. Surgical outcome in patients with primary sclerosing cholangitis undergoing ileal pouch-anal anastomosis: a case-control study. Surgery 2005; 138: Poritz LS, Koltun WA. 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6 January 2008 POUCHITIS AND LIVER TRANSPLANT Winther KV, Jess T, Langholz E, et al. Survival and cause-specific mortality in ulcerative colitis follow-up of a population-based cohort in Copenhagen County. Gastroenterology 2003;125: Prudhomme M, Dehni N, Dozois RR, et al. Causes and outcomes of pouch excision after restorative proctocolectomy. Br J Surg 2006;93: Nicholls RJ. Review article: ulcerative colitis-surgical indications and treatment. Aliment Pharmacol Ther 2002;16: Shen B, Lashner BA, Achkar J-P, et al. Modified pouchitis disease activity index: a simplified approach to the diagnosis of pouchitis. Dis Colon Rectum 2003;46: Shen B, Fazio V, Remzi F, et al. Risk factors for diseases of ileal pouch-anal anastomosis after restorative proctocolectomy for ulcerative colitis. Clin Gastroenterol Hepatol 2006;4: Penna C, Tiret E, Kartheuser A, et al. Function of ileal J pouchanal anastomosis in patients with familial adenomatous polyposis. Br J Surg 1993;80: Tjandra JJ, Fazio VW, Church JM, et al. Similar functional results after restorative proctocolectomy in patients with familial adenomatous polyposis and mucosal ulcerative colitis. Am J Surg 1993;165: Gosselink MP, Schouten WR, van Lieshout LMC, et al. Delay of the first onset of pouchitis by oral intake of the probiotic strain Lactobacillus rhamnosus GG. Dis Colon Rectum 2004;47: Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119: Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004;53: Komanduri S, Gillevet PM, Sikaroodi M, et al. Dysbiosis in pouchitis: evidence of unique microfloral patterns in pouch inflammation. Clin Gastroenterol Hepatol 2007;5: Duffy M, O Mahony L, Coffey JC, et al. Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis. Dis Colon Rectum 2002;45: Nasmyth DG, Godwin PGR, Dixon MF, et al. Ileal ecology after pouch anal anastomosis or ileostomy. Gastroenterology 1989; 96: Carter K, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. Gastroenterology 2001; 121: Brett PM, Yasuda N, Yiannakou JY, et al. Genetic and immunological markers in pouchitis. Eur J Gastroenterol Hepatol 1996; 8: Aisenberg J, Legnani PE, Nilubol N, et al. Are panca, ASCA, or cytokine gene polymorphisms associated with pouchitis? Longterm follow-up in 102 patients with ulcerative colitis. Am J Gastroenterol 2004;99: Meier C, Hegazi RA, Aisenberg J, et al. Innate immune receptor genetic polymorphisms in pouchitis: is NOD2/CARD15 a susceptibility factor? 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High level perinuclear antineutrophil cytoplasmic antibody (panca) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut 2001; 49: Kuisma J, Jarvinen H, Kahri A, et al. Factors associated with disease activity of pouchitis after surgery for ulcerative colitis. Scand J Gastroenterol 2004;39: Merrett MN, Mortensen N, Kettlewell M, et al. Smoking may prevent pouchitis in patients with restorative proctocolectomy for ulcerative colitis. Gut 1996;38: Shen B, Fazio VW, Remzi FH, et al. Risk factors for diseases of ileal pouch-anal anastomosis in patients with ulcerative colitis. Clin Gastroenterol Hepatol 2006;4: Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol 2005;3: Thomas PD, Forbes A, Nicholls RJ, et al. Altered expression of the lymphocyte activation markers CD30 and CD27 in patients with pouchitis. Scand J Gastroenterol 2001;36: Goldberg PA, Herbst F, Beckett CG, et al. Leukocyte typing, cytokine expression and epithelial turn over in the ileal pouch in patients with ulcerative colitis and familial adenomatous polyposis. Gut 1996;38: Patel RT, Bain I, Youngs D, et al. Cytokine production in pouchitis is similar to that in ulcerative colitis. Dis Colon Rectum 1995; 38: Schmidt C, Giese T, Ludwig B, et al. Increased cytokine transcripts in pouchitis reflect the degree of inflammation but not the underlying entity. Int J Colorectal Dis 2006;21: Gionchetti P, Campieri M, Belluzzi A, et al. Mucosal concentrations of interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor- in pelvic ileal pouches. Dig Dis Sci 1994;39: Shepherd NA, Healey CJ, Warren BF, et al. Distribution of mucosal morphology and an assessment of colonic phenotype change in the pelvic ileal reservoir. Gut 1993;34: Tysk C, Riedesel H, Lindberg E, et al. 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7 68 FREEMAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No Ho GT, Seddon AJ, Therapondos G, et al. The clinical course of ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis: further appraisal of immunosuppression post transplantation. Eur J Gastroenterol Hepatol 2005;17: van de Vrie W, de Man RA, van Buuren HR, et al. Inflammatory bowel disease and liver transplantation for primary sclerosing cholangitis. Eur J Gastroenterol Hepatol 2003;15: Al-Essa H, Organ Transplantation Centre and Faculty of Medicine, Kuwait. De novo Crohn s disease in a renal transplant recipient. Transplant Proc 2007;39: Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea. Transplantation 2003;75: Papadimitriou JC, Cangro CB, Lustberg A, et al. Histologic features of mycophenolate mofetil-related colitis: a graft-versus-host disease-like pattern. Int J Surg Pathol 2003;11: Dalle IJ, Maes BD, Geboes KP, et al. Crohn s-like changes in the colon due to mycophenolate? Colorectal Dis 2005;7: Riley TR, Schoen RE, Lee RG, et al. A case series of transplant recipients who despite immunosuppression developed inflammatory bowel disease. Am J Gastroenterol 1997;92: Ramji A, Owen DA, Erb SR, et al. Post-liver transplant Crohn s disease: graft tolerance but not self tolerance? Dig Dis Sci 2002;47: Worns MA, Lohse AW, Neurath MF, et al. Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation. Am J Gastroenterol 2006;101: Verdonk RC, Haagsma EB, Van Den Berg AP, et al. Inflammatory bowel disease after liver transplantation: a role for cytomegalovirus infection. Scand J Gastroenterol 2006;41: Address requests for reprints to: Bo Shen, MD, Department of Gastroenterology/Hepatology-A30, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio shenb@ccf.org; fax: (216)