Primary sclerosing cholangitis (PSC) is a chronic, cholestatic

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: Progressive Primary Sclerosing Cholangitis Requiring Liver Transplantation Is Associated With Reduced Need for Colectomy in Patients With Ulcerative Colitis UDAYAKUMAR NAVANEETHAN,* PREETHI G. K. VENKATESH,* SAURABH MUKEWAR,* BRET A. LASHNER,* FEZA H. REMZI, ARTHUR J. MCCULLOUGH,* RAVI P. KIRAN, BO SHEN,* and JOHN J. FUNG *Department of Gastroenterology, Department of Colorectal Surgery, and Department of Transplant Surgery, Digestive Disease Institute, The Cleveland Clinic, Cleveland, Ohio BACKGROUND & AIMS: We investigated the association between the severity of primary sclerosing cholangitis (PSC) and clinical outcomes of patients with ulcerative colitis (UC) on the basis of need for colectomy. METHODS: We analyzed data from 167 patients with PSC and UC who were followed from 1985 to Patients with PSC and UC were divided into groups that received orthotopic liver transplantation (OLT) (n 86) or did not (non-olt, n 81). Clinical and demographic variables were obtained, and patients were followed until they received OLT or the date of their last clinical visit. RESULTS: The OLT group had significantly more subjects with less severe symptoms of UC (59, 68.6%) than the non-olt group (12, 14.8%; P.001). The subjects in the OLT group had a median of 0 UC flares compared with 3 in the non-olt group (P.001); fewer subjects in the OLT group required use of azathioprine or mercaptopurine (1, 1.2%), compared with the non-olt group (14, 17.3%; P.006). More subjects in the non-olt group required colectomies (61, 75.3%) than in the OLT group (23, 26.7%; P.001). On the basis of Cox regression analysis, OLT for PSC independently reduces the need for colectomy (hazard ratio [HR], 0.43; 95% confidence interval [CI], ; P.003), as does a high Mayo risk score at diagnosis (HR, 0.52; 95% CI, ; P.001). Development of colon neoplasia increased the risk for colectomy (HR, 2.47; 95% CI, ; P.001). CONCLUSIONS: Severe progressive PSC that requires liver transplantation appears to reduce the disease activity of UC and the need for colectomy. Keywords: Inflammatory Bowel Disease; Risk Factors; Prognostic; Liver Disease. Watch this article s video abstract and others at tiny.cc/bz9jv. Scan the quick response (QR) code to the left with your mobile device to watch this article s video abstract and others. Don t have a QR code reader? Get one at mobiletag.com/en/download.php. Primary sclerosing cholangitis (PSC) is a chronic, cholestatic hepatobiliary disorder affecting young and middle-aged people and is commonly seen in patients with underlying inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC). 1,2 Approximately 70% 80% of patients with PSC have underlying IBD, and 1.4% 7.5% of patients with IBD eventually develop PSC during their disease course. 3 Patients with UC with concomitant PSC might demonstrate a distinct clinical phenotype with a higher prevalence of backwash ileitis, pancolitis, colorectal neoplasia, and overall poorer survival than patients without concomitant PSC. 4 8 Patients with PSC-UC are also at an increased risk of pouchitis and prepouch ileitis after restorative proctocolectomy. 9,10 The risk for pouchitis does not appear to be related to the severity of PSC. 9 In clinical practice, we have seen that patients with PSC who required orthotopic liver transplantation (OLT) had clinically mild UC and vice versa. Also a recent study from England suggested that clinically progressive PSC requiring OLT was associated with a milder course of UC (reduced disease activity and less use of steroids, azathioprine, and surgery) and reduced incidence of dysplasia and colon carcinoma. 11 However, there were very few patients with colectomy in their study, which limited their ability to analyze the inverse relationship between severe PSC (requirement for OLT) and severe UC (requiring colectomy). To our knowledge, there have been no studies about the inverse association between the severity of patients with PSC (requiring OLT or not) and the severity of outcome of UC (colectomy). The aims of our study were to evaluate the clinical and endoscopic features of PSC-UC with regard to treatment and to compare the course of PSC-UC in patients with nonprogressive liver disease not requiring liver transplantation (non-olt) and those with severe liver disease who required OLT. We also wanted to study risk factors for colectomy in patients with PSC-UC. Methods Patients The historical cohort study was approved by the Cleveland Clinic Institutional Review Board. A prospectively maintained Electronic Data Interface for Transplantation database has accrued information on all patients who underwent OLT at the Cleveland Clinic. Patients with PSC and IBD who required OLT were identified from the database. Patients with PSC and IBD who did not require OLT were identified by using the PSC and IBD database. A total of 312 patients (225 with UC, 10 with indeterminate colitis, and 77 with CD) with PSC and IBD were obtained from the database (Figure 1). Abbreviations used in this paper: CD, Crohn s disease; CI, confidence interval; HR, hazard ratio; IBD, inflammatory bowel disease; OLT, orthotropic liver transplantation; PSC, primary sclerosing cholangitis; UC, ulcerative colitis; UDCA, ursodexoxycholic acid by the AGA Institute /$36.00 doi: /j.cgh

2 May 2012 PSC AND UC 541 Figure 1. Patient selection algorithm for the study. Inclusion and Exclusion Criteria Inclusion criteria were as follows: (1) age older than 18 years, (2) UC, and (3) presence of PSC with or without OLT. Exclusion criteria were patients with CD, indeterminate colitis, and patients with UC who did not have follow-up at the Cleveland Clinic or were on the transplant list and did not receive a liver transplant. UC patients who underwent OLT for other liver diseases than PSC were excluded. Patients who underwent retransplantation for PSC recurrence were also excluded. Diagnostic Criteria PSC was defined as the presence of intrahepatic and/or extrahepatic bile duct abnormalities in the form of beading, duct ectasia, and stricturing of the intrahepatic or extrahepatic bile ducts documented in the medical record from endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, and/or liver biopsy. 1 Small-duct PSC was defined when there were histologic features consistent with PSC on liver biopsy in the absence of characteristic radiologic features, and clinical cholestasis with persistently elevated serum alkaline phosphatase levels for more than 6 months. The diagnosis of UC was confirmed with characteristic endoscopic examination of inflammation as well as from compatible histologic examination described before. 12 Demographic and Clinical Variables Demographic and clinical variables were studied from patient medical records including age; gender; smoking and alcohol history; and family history of IBD, PSC, or liver/colon cancer in first-degree relatives. The clinical variables were defined as follows: duration of UC, the time from diagnosis of UC to the time of last clinical follow-up; family history of IBD, CD or UC in first-degree relatives; smoking, smoking more than 7 cigarettes a week since the surgery; alcohol use, more than 2 drinks a day; extensive colitis, endoscopic, macroscopic, or microscopic evidence of disease proximal to the splenic flexure. We adopted the study design used in the study from England. 11 We assessed UC activity in the last 5 years of the follow-up period; type of UC treatment used during the whole follow-up period (steroids, azathioprine, biologics [infliximab and adalimumab], and surgery; severity of disease at last colonoscopy (before last follow-up or before OLT), assessed macroscopically and histologically; prevalence of colorectal dysplasia and/or carcinoma; PSC duration from diagnosis; severity of PSC at last follow-up or before OLT (serum albumin and bilirubin values and presence of ascites); and outcome (patient alive at last follow-up, dead, or had OLT). With regard to endoscopic assessment and histologic assessment of activity, we used the definition by Rutter et al. 13 For histologic assessment, no inflammatory cells or chronic inflammation only was termed as quiescent disease, whereas any evidence of inflammation on the biopsy report was taken as evidence of active disease. For endoscopic assessment, a normal-appearing mucosa or chronic changes without acute inflammation was termed as quiescent disease on endoscopy, whereas the rest were termed as active disease. In the individual patient, the highest degree of inflammation on the biopsies was defined as the degree of inflammation. The use of ursodeoxycholic acid (UDCA) and its dose were obtained from the database. UDCA was defined by the use of this medication for at least 50% of the follow-up period. Activity of UC (in the last 5 years before last follow-up or colectomy or OLT) was defined as quiescent in the absence of UC-related symptoms (eg, diarrhea or hematochezia), requiring drugs when drugs other than maintenance acetylsalicylic acid agents were required to control disease activity (steroid or immunosuppressant), and surgery when colectomy was required. UC flare was defined by the presence of clinical symptoms requiring a short course of corticosteroids. We collected information on UC flares available from the paper charts and electronic medical records during the last 5 years of follow-up. The follow-up period was obtained from the date of diagnosis and the time of the last clinical visit, date of OLT, or death. The Mayo risk score was calculated at entry by using the revised PSC Mayo risk score. 14 This score was developed to assess 1-year to 4-year probability of survival of patients with PSC, and its advantage is that there is no requirement for liver histology. 14 Definitions of Severity of PSC and UC The severity of PSC was defined in terms of requirement of OLT. The severity of UC was defined in terms of requirement of colectomy. Outcome Measurement The primary outcome of interest was to evaluate the clinical and endoscopic/histologic features of PSC-UC with regard to treatment and outcome (colectomy) and to compare the course of PSC-UC and the Mayo PSC risk score in patients with and without OLT. The secondary outcome was to identify the risk factors to predict colectomy during follow-up in patients with PSC-UC. Statistical Analysis Descriptive statistics were computed for all factors. These include medians, 25th and 75th percentiles, range, or mean and standard deviation for continuous factors and frequencies and percentages for categorical factors. Wilcoxon rank sum tests for continuous factors and Pearson 2 or Fisher exact tests for categorical factors were used. Kaplan Meier curve for patient survival in patients with PSC-UC and OLT/with colectomy/with OLT and colectomy and neither OLT nor colectomy was compared. A significance level of.05 was used for all analyses. Cox logistic regression model was constructed by including variables that had significant univariable associations with colectomy and then perform-

3 542 NAVANEETHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 ing backward stepwise selection with a removal criterion of P.05. R software (The R Foundation for Statistical Computing, Vienna, Austria) was used to perform all analyses. Results Demographic and Clinical Characteristics The basic demographic and clinical information including age, sex, race, UC duration from diagnosis, PSC duration from diagnosis, and colonoscopic extent of UC are summarized in Table 1. Patients with PSC-UC were divided into 2 groups; 81 did not need OLT (non-olt), and 86 required OLT. There were no significant differences with regard to duration of UC between the 2 groups, whereas the duration of PSC was longer in the OLT group (median, 13.5 [interquartile range, 10, 20] vs 11 [7.5, 17]; P.01) than in the non-olt group. The median follow-up was longer for the OLT group (13.5 vs 11 years, P.009). Four of the patients developed UC after their OLT. These patients had colonoscopy before OLT, which did not show any evidence of UC. Patients in the OLT group with available laboratory values to calculate the severity of PSC at the time of initial referral to our center had much higher serum bilirubin, aspartate aminotransferase, and lower serum albumin levels than patients in the non-olt group (Table 1). The initial Mayo PSC risk score was also much higher in patients who later required OLT ( vs , P.001). Clinical Activity of Ulcerative Colitis The clinical activity of UC in the 2 groups is shown in Figure 2A. UC activity (in the last 5 years before OLT or last follow-up) was significantly more quiescent in the OLT group (68.6% vs 14.8%, P.001) endoscopically and histologically. Table 1. Comparison of Demographic and Clinical Variables Between PSC-UC Patients With or Without Underlying Liver Transplantation (OLT) Variable PSC-UC without OLT, n 81 (48.5%) PSC-UC with OLT, n 86 (51.5%) P value Age (end of follow-up or OLT), y (mean standard deviation) Male gender 53 (65.4%) 57 (66.3%).91 Median body mass index (kg/m 2 ) (range) ( ) ( ).30 Smoker.11 Yes 4 (4.9%) 2 (2.3%) Ex-smoker 2 (2.5%) 10 (11.6%) Alcohol.61 Yes 8 (9.9%) 8 (9.3%) Ex-alcohol use 1 (1.2%) 4 (4.7%) Median follow-up time, mo (range) 132 (0 456) 156 (12 456).009 Median UC duration, mo (range) 240 (24 576) 228 (36 588).71 Median PSC duration, mo (range) 132 (0 480) 162 (12 456).01 Median PSC-UC duration, mo (range) 132 (0 456) 156 (12 456).018 Small-duct PSC 0 1 (1.2%) Extensive colitis 72 (88.9%) 81 (94.2%).005 Median initial albumin, mg/dl (range) a 3.8 ( ) 3.1 ( ).001 Median initial bilirubin, mg/dl (range) a 0.9 ( ) 3.2 ( ).001 Median initial INR (range) a 1.0 ( ) 1.0 ( ).003 Median initial PSC Mayo risk score (range) a 0.07 ( 2.33 to 3.12) 1.54 ( 1.62 to 5.20).001 Median initial AST, IU/L (range) a 40 (16 206) 68.5 (9 380).001 Median final albumin, mg/dl (range) b 3.5 ( ) 2.9 ( ).001 Median final bilirubin, mg/dl (range) b 0.3 ( ) 6.3 ( ).001 Ascites (end of follow-up or OLT) 4 (4.9%) 57 (66.3%).001 Colectomy during follow-up 62 (76.5%) 30 (34.9%).001 UDCA use 65 (80.2%) 68 (79.1%).85 Median UDCA dose, mg/d (range) 900 (0 1800) 900 (0 3000).06 Median age at colectomy, y (interquartile range) 30 (19.3, 44.8) 45 (40, 61).001 Indication for colectomy c.001 Steroid refractory 20 (32.3%) 7 (23.3%) Steroid dependent 10 (16.1%) 5 (16.6%) Dysplasia/colon cancer 32 (51.6%) 18 (60%) Dysplasia.01 Low-grade 12 (14.8%) 4 (4.7%) High-grade 15 (18.5%) 10 (11.6%) Colon carcinoma 10 (12.3%) 4 (4.7%).09 Dysplasia and/or colon carcinoma 37 (45.7%) 18 (20.9%).001 Cholangiocarcinoma 5 (6.2%) 2 (2.3%).19 AST, aspartate aminotransferase; INR, international normalized ratio. a Laboratory values were not available on 11 patients without liver transplant and 5 patients with liver transplantation. b Laboratory values were not available on 12 patients without liver transplant and 7 patients with liver transplantation. c Five patients who underwent colectomy for steroid refractory/dependent disease had dysplasia in their colectomy specimen.

4 May 2012 PSC AND UC 543 Figure 2. (A) Activity of UC in patients with and without OLT classified as quiescent, requiring medications, and requiring surgery. (B) Comparison of the number of UC flares in patients with and without OLT. During the last 5 years of follow-up, UC flares requiring treatment with steroids were significantly more frequent in the non-olt group than in the OLT group (Figure 2B). The use of azathioprine/mercaptopurine was significantly more frequent in the non-olt group than in the OLT group (17.3% vs 1.2%, P.006), whereas there was no difference in the use of biologics between the 2 groups (3.7% vs 5.8%, P.72). Surgery for Ulcerative Colitis The non-olt group required colectomy significantly more frequently than the OLT group (62, 76.5% vs 30, 34.9%; P.001). The median age at colectomy was significantly higher in the OLT group (45 vs 30 years, P.001) than in the non-olt group. Among the 92 patients who underwent colectomy, the mean time from UC diagnosis to colectomy was years. The mean time from PSC diagnosis to colectomy was years, and the mean time from the combined PSC and UC diagnosis to colectomy was years. There was significant difference between the 2 groups regarding the indication for surgery. More patients in the non- OLT group underwent colectomy for steroid dependent/refractory disease (30 of 62, 48.4% vs 12 of 30, 39.9%) than patients in the OLT group (Table 1). Among all the patients who underwent colectomy, 7 of 92 (7.6%) underwent total proctocolectomy with end ileostomy, 1 of 92 (1.1%) underwent total proctocolectomy with Brooke ileostomy, and the remaining 84 patients (91.3%) underwent total proctocolectomy with ileal pouch anal anastomosis. The OLT group had significantly milder disease endoscopically and histologically, compared with the non-olt group (68.6% vs 14.8% of patients had quiescent colitis, P.001). Multivariable Analysis of Risk Factors for Colectomy Table 2 summarizes the univariable analysis of risk factors for colectomy. On Cox regression analysis, OLT for PSC (hazard ratio [HR], 0.43; 95% confidence interval [CI], ; P.003) and a higher Mayo risk score at diagnosis (HR, 0.52; 95% CI, ; P.001) independently reduced the need for colectomy, whereas the development of cancer or dysplasia increased the risk of colectomy (HR, 2.47; 95% CI, ; P.001). The use of UDCA did not have any impact on the risk of colectomy in these patients (Table 3). Discussion Our study showed the possible association between severity of PSC and the clinical outcome of UC and reported that requirement for OLT decreases the risk for colectomy. This study highlights that severe progressive PSC requiring OLT appears to be associated with a milder course of UC, reduced incidence of dysplasia and colon carcinoma, and decreased risk of colectomy. The requirement for OLT and a higher Mayo PSC risk score at PSC diagnosis seem to independently reduce the need for colectomy, whereas the development of Kaplan Meier Survival Analysis Figure 3 summarizes the Kaplan Meier curve of the survival analysis of patients with PSC/UC and OLT alone/with colectomy alone/with OLT and colectomy/with neither OLT nor colectomy. There was not a statistically significant difference among these groups (log rank, P.97). Dysplasia and Colon Cancer Risk in Ulcerative Colitis Colon carcinoma and dysplasia were more frequent in the non-olt group (37, 45.7% vs 18, 20.9%; P.001) than in the OLT group (Table 1). Figure 3. Comparison of Kaplan Meier survival curve for all patients with OLT only, colectomy only, with OLT and colectomy, and with no OLT and colectomy. We did not find any statistically significant differences between both groups (P.97, log rank test).

5 544 NAVANEETHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 Table 2. Comparison of Demographic and Clinical Variables Between PSC-UC Patients With or Without Colectomy Variable PSC-UC without colectomy, n 75 (44.9%) PSC-UC with colectomy, n 92 (55.1%) P value Age (end of follow-up or OLT), y (mean standard deviation) Male gender 51 (68.0%) 59 (64.1%).60 Median body mass index (kg/m 2 ) (range) ( ) ( ).77 Smoker.26 Yes 1 (1.3%) 5 (5.4%) Ex-smoker 8 (10.7%) 4 (4.3%) Alcohol.69 Yes 5 (6.7%) 11 (12.0%) Previous alcohol use 2 (2.7%) 3 (3.3%) Median follow-up time, mo (range) 144 (0 408) 156 (0 456).75 Median UC duration, mo (range) 210 (36 588) 252 (24 564).06 Median PSC duration, mo (range) 156 (0 420) 156 (0 480).78 Median PSC-UC duration, mo (range) 144 (0 408) 156 (0 456).80 Extensive colitis 67 (89.3%) 86 (93.5%).73 Liver transplantation 56 (74.7%) 30 (32.6%).001 Median initial albumin, mg/dl (range) a 3.3 ( ) 3.6 ( ).041 Median initial bilirubin, mg/dl (range) a 3.0 ( ) 1.0 ( ).001 Median initial INR (range) a 1.0 ( ) 1.0 ( ).026 Median initial PSC Mayo risk score (range) a 1.41 ( 1.62 to 5.20) 0.22 ( 2.33 to 4.69).001 Median initial AST, IU/L (range) a 67 (18 380) 43 (9 288).002 Median final albumin, mg/dl (range) b 3.0 ( ) 3.5 ( ).001 Median final bilirubin, mg/dl (range) b 5.2 ( ) 1.3 ( ).001 Ascites (end of follow-up or OLT) 37 (49.3%) 24 (26.1%).002 Azathioprine/6-mercaptopurine 1 (1.3%) 14 (15.2%).014 Biologics 3 (4.0%) 5 (5.4%).73 Steroid precolectomy 23 (30.7%) 69 (75.0%) Acetylsalicylic acid use 55 (73.3%) 76 (82.6%).15 UDCA use 59 (78.7%) 74 (80.4%).78 Median UDCA dose, mg/d (range) 900 (0 1800) 900 (0 3000).19 Alive at the end of follow-up period 67 (89.3%) 79 (85.9%).50 AST, aspartate aminotransferase; INR, international normalized ratio. a Laboratory values were not available on 11 patients without liver transplant and 5 patients with liver transplantation. b Laboratory values were not available on 12 patients without liver transplant and 7 patients with liver transplantation. cancer or dysplasia increased the risk of colectomy for their underlying UC. Previous studies have shown that PSC-UC is a distinct clinical phenotype with a higher prevalence of backwash ileitis, pancolitis, colorectal neoplasia, and overall a worse survival than patients without concomitant PSC. 4 8 The relationship between the severity of PSC and UC activity was not studied until recently. In a study of 96 patients with PSC-UC from Royal Free Hospital, 50 patients who underwent OLT were compared with 46 patients with no OLT; both groups had similar length of follow-up and interval from diagnosis of both PSC and UC. 11 Patients with PSC-UC with severe disease activity requiring OLT had a less severe clinical outcome Table 3. Cox Logistic Regression Analysis for Colectomy Variable HR (95% CI) P value Requirement for liver transplant 0.43 ( ).003 Development of 2.47 ( ).001 cancer/dysplasia Revised Mayo risk score at 0.52 ( ).001 diagnosis, 1-unit increase UDCA use 1.09 ( ).56 of UC with fewer flares and less medication use in their last 5 years. Our results were similar to those in the study from London, with patients requiring OLT having clinically mild UC with decreased risk of cancer and/or dysplasia. We have also found that the requirement for OLT and a higher Mayo PSC risk score decreased the need for colectomy. Both studies reiterate the inverse relationship between the activity of UC and the severity of PSC. Also, patients in the OLT group had a longer period of follow-up than the non-olt group, highlighting the fact that the reduced frequency of colectomy in this group is not due to more limited follow-up. The median age at colectomy was also significantly high in the OLT group. Previous studies have investigated the clinical course of patients with PSC-UC. In a study evaluating the inflammatory activity by histologic grading, PSC-UC patients had a significantly lower grade of inflammation when compared with UC patients without PSC. 8 Similarly, studies have demonstrated that IBD in PSC patients might have a prolonged subclinical phase, leading to underestimation of the disease duration. 15 In a study of 76 PSC patients from Sweden, 11 patients did not have associated IBD symptoms; changes consistent with IBD were observed in 7 patients. 16 Similarly in pediatric patients, a

6 May 2012 PSC AND UC 545 study observed that 11% of PSC patients had asymptomatic IBD at the time of their diagnosis of PSC. 5 However, we demonstrated that among the PSC patients, the subset of patients with PSC requiring OLT had less inflammation than patients in the non-olt group, similar to the group from London. The relationship between PSC and UC appears to be enigmatic. However, our study findings highlight the role of progressive PSC, with development of cirrhosis as a protective factor against severe UC requiring colectomy. Studies have shown that cell-mediated and humoral immunity is impaired in patients with liver cirrhosis. 17 Thus, patients with PSC cirrhosis might have a compromised immune system, resulting in less severe colitis in these patients. Also, patients with PSC have recruitment of gut-homing lymphocytes into the liver. Marelli et al 11 suggested that because PSC and UC share the same pool of lymphocytes, these lymphocytes are sequestered in the liver in PSC cirrhosis, resulting in less severe colon inflammation. Immune mechanisms play an important role in the pathogenesis of both PSC and UC. Bacterial translocation or absorption of the bacterial endotoxins into the portal circulation through a chronically inflamed bowel as in UC with Kupffer cell activation has been proposed to play a role in the pathogenesis of PSC. 12,18 Thus, the presence of colon inflammation with bacterial translocation appears to be essential for the development of PSC. Our study is clinically significant for a number of reasons. The inverse relationship between the clinical activity of PSC and UC might provide a link to the pathogenesis of PSC and its relationship to UC. Newer therapeutic modalities for the treatment of PSC exploiting the lymphocyte trafficking between the liver and bowel can be explored by better understanding of this relationship. We also found that use of UDCA did not alter the risk of colectomy in these patients. We did not specifically address the risk of colon dysplasia and cancer to the use of UDCA in this study. There are, however, only limited data regarding the role of UDCA in colorectal neoplasia prevention in PSC patients with UC. 19,20 There are certain limitations of our study. The study population was recruited from a subspecialty tertiary care referral center. This contributes to a selection bias. This is highlighted by the fact that PSC patients who required OLT had a higher PSC risk score at the time of referral to our center. The retrospective nature of our cohort study limited our ability to obtain longitudinal data. We also did not have information on the dose and duration of corticosteroid use in these patients. Also information on endoscopy/histology data and UC flares was not available in all the patients. Most of the information on UC flares was obtained from the chart review as documented by the clinician seeing the patient, and this is subject to errors, and patients might have been seen in outside hospitals or emergency departments. Nevertheless, this is one of the largest studies on the natural history of PSC and UC in which PSC patients who underwent OLT had mild UC and vice versa. To conclude, severe PSC requiring OLT is associated with a milder course of UC, a relatively reduced incidence of dysplasia and colon carcinoma, and decreased risk of colectomy. The requirement for OLT and a higher Mayo PSC risk score at diagnosis appear to independently reduce the risk for colectomy, whereas the development of colonic dysplasia and/or cancer increased the risk for colectomy. The relationship between the pathogenesis of liver and gut inflammation needs further studies in the future. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at and at doi: /j.cgh References 1. Navaneethan U, Shen B. Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel disease. Inflamm Bowel Dis 2010;16: Olsson R, Danielsson A, Järnerot G, et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991;100: Broomé U, Bergquist A. Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis 2006;26: Loftus EV, Sandborn WJ, Lindor KD, et al. Interactions between chronic liver disease and inflammatory bowel disease. Inflamm Bowel Dis 1997;3: Faubion WA, Loftus EV, Sandborn WJ, et al. Pediatric PSC-IBD : a descriptive report of associated inflammatory bowel disease among pediatric patients with PSC. J Pediatr Gastroenterol Nutr 2001;33: Loftus EV, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut 2005;54: Heuschen U, Hinz U, Allemeyer E, et al. Backwash ileitis is strongly associated with colorectal carcinoma in ulcerative colitis. Gastroenterology 2001;120: Joo M, Abreu-e-Lima P, Farraye F, et al. Pathologic features of ulcerative colitis in patients with primary sclerosing cholangitis: a case-control study. Am J Surg Pathol 2009;33: Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut 1996;38: Shen B, Bennett AE, Navaneethan U, et al. Primary sclerosing cholangitis is associated with endoscopic and histologic inflammation of the distal afferent limb in patients with ileal pouch-anal anastomosis. Inflamm Bowel Dis 2011;17: Marelli L, Xirouchakis E, Kalambokis G, et al. 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7 546 NAVANEETHAN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 ative colitis and primary sclerosing cholangitis. Ann Intern Med 2001;134: Pardi DS, Loftus EV, Kremers WK, et al. Ursodeoxycholic acid as a chemopreventative agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124: Euclid Avenue, Cleveland, Ohio navaneu@ ccf.org; fax: (216) Acknowledgments The authors thank Jeffrey Hammel, MS, for doing the statistical analysis for the manuscript. Conflicts of interest The authors disclose no conflicts. Reprint requests Address requests for reprints to: Udayakumar Navaneethan, MD, Digestive Disease Institute-Desk A31, The Cleveland Clinic Foundation, Funding Supported by a research grant from the Inflammatory Bowel Disease Working Group (to U.N.).