[show abstract][hide abstract] ABSTRACT: Primary sclerosing cholangitis (PSC) occurs in 2%-8% of patients who suffer from ulcerative colitis (UC). For patients who require colectomy, ileal pouch-anal anastomosis (IPAA) or ileorectal anastomosis (IRA) is employed to preserve continence.We evaluated the outcomes after IPAA and IRA for patients with UC-PSC, using patients with UC but without PSC as controls (UC-only group).
In a case-control study conducted at Sahlgrenska University Hospital, Sweden, patients with UC-PSC (N=48; 31 IPAA and 17 IRA) were compared to patients with UC only (N=113; 62 IPAA and 51 IRA). Functional outcomes (Öresland score), pouchitis, surgical complications, and failure were evaluated.
For patients with IPAA, the median Öresland scores were similar for the two groups: 5 (range, 0-13) for the UC-PSC group and 5 for the UC-only group (range, 0-12; p>0.05). However, the IRA scores were significantly different at 7 (range, 2-11) and 3 (range, 0-11) for the respective groups (p=0.005). Pouchitis was more frequent in patients with UC-PSC. Complication rates did not differ. For patients with IPAA, the failure rate was 16% for those in the UC-PSC group versus 6% for those in the UC-only group (p>0.05); the corresponding results for IRA were 53% versus 22% (p=0.03).
For cases of IPAA, pouchitis seems to be more common in patients with UC-PSC. However, the functional outcomes and failure rates are unaffected by concurrent PSC. For patients with UC-PSC, functional outcome is poor and the failure rate is high after IRA.
Journal of Crohn s and Colitis 11/2013; · 3.39 Impact Factor
[show abstract][hide abstract] ABSTRACT: Little is known about nongenetic risk factors for primary sclerosing cholangitis (PSC), except a possible protective effect of smoking. We investigated the relationship between environmental risk factors and susceptibility to PSC.
A questionnaire was distributed to patients with PSC, recruited from Oslo University Hospital Rikshospitalet in Norway through 2011, and randomly chosen individuals from the Norwegian Bone Marrow Donor Registry (controls). Data were analyzed from 240 patients with PSC and 245 controls, matched for sex and age.
A lower proportion of patients with PSC were daily coffee drinkers than controls, both currently (76% vs 86%; odds ratio [OR], 0.52; 95% confidence interval [CI], 0.32-0.82; P=.006) and at the age of 18 y (35% vs 49%; OR, 0.58; 95% CI, 0.40-0.83; P=.003). The associations were mainly attributed to differences observed in men. Twenty percent of the patients were ever (current or former) daily smokers compared with 43% of controls (OR, 0.33; 95% CI, 0.22-0.50; P<.001). Ever daily smoking before PSC diagnosis was associated with older age at diagnosis (42 y vs 32 y, P<.001). Ever daily smoking (P<.001) and being a coffee drinker at the age of 18 y (P=.048) were independently and negatively associated with PSC. Fewer female patients with PSC than controls reported ever use of hormonal contraception (51% vs 85%, P<.001). Among female patients, there was a strong correlation between increasing number of children before the diagnosis of PSC and increasing age at diagnosis (r=0.63; P<.001).
Coffee consumption and smoking might protect against development of PSC. In women, the disease might be influenced by hormonal factors.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 09/2013; · 5.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Allelic variants of fucosyltransferases 2 and 3 (FUT2/3) influence serum levels of CA19-9, a screening parameter commonly used for detection of biliary malignancy in PSC. We aimed to improve diagnostic accuracy of CA19-9 by determining the impact of FUT2/3 genotypes.
CA19-9 levels were measured in 433 PSC patients, 41 of whom had biliary malignancy. Genotypes for FUT3 and FUT2 were used to assign patients to one of three groups: A, no FUT3 activity regardless of FUT2 activity; B, both FUT2 and FUT3 activity and C, no FUT2 activity without loss of FUT3 activity. Group-specific cut-off values were determined by Youden's index.
The median CA19-9 values of cancer-free patients were significantly different (p < 0.001) in Groups A (2.0 U/mL), B (17.0 U/mL), and C (37.0 U/mL). Biliary malignancy patients in Groups B and C had significantly higher CA19-9 values than cancer-free patients (p < 0.001). The optimal cut-off, as determined by ROC analysis, for all patients was 88.5 U/mL. Optimal cut-off values in Groups A, B, and C were 4.0 U/mL, 74.5 U/mL, and 106.8 U/mL, respectively. Use of these values improved sensitivity of CA19-9 in Groups B and C. Further, use of group-dependent cut-off values with 90% sensitivity resulted in a 42.9% reduction of false positive results.
Use of FUT2/3 genotype-dependent cut-off values for CA19-9 improved sensitivity and reduced the number of false positive results.
Journal of Hepatology 08/2013; · 9.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Liver abnormalities are often seen in bowel diseases. Whether these represent aspects of two separate diseases, or if one is causing the other, is not always easy to decide. Extraintestinal manifestations of inflammatory bowel disease (IBD) or coeliac disease are frequently observed. Of these extraintestinal manifestations, hepatic disorders are among the most common. Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis are the most frequent hepatic disorders in IBD and coeliac disease, respectively. Genetic studies have lately elucidated the associations between IBD and PSC, but there is still a long way until we have complete understanding of the molecular aetiology and pathophysiology of these conditions. There is no curative treatment available for PSC, besides liver transplantation. Steatosis and cholelithiasis are also common in IBD, as are signs of hepatic injury due to IBD treatment. Less common liver abnormalities include liver abscesses, hepatic thromboembolic events, granulomatous liver disease and hepatic amyloidosis.
Best practice & research. Clinical gastroenterology 08/2013; 27(4):531-542. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Primary sclerosing cholangitis (PSC) is a severe liver disease of unknown etiology leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. We compared 3,789 PSC cases of European ancestry to 25,079 population controls across 130,422 SNPs genotyped using the Immunochip. We identified 12 genome-wide significant associations outside the human leukocyte antigen (HLA) complex, 9 of which were new, increasing the number of known PSC risk loci to 16. Despite comorbidity with inflammatory bowel disease (IBD) in 72% of the cases, 6 of the 12 loci showed significantly stronger association with PSC than with IBD, suggesting overlapping yet distinct genetic architectures for these two diseases. We incorporated association statistics from 7 diseases clinically occurring with PSC in the analysis and found suggestive evidence for 33 additional pleiotropic PSC risk loci. Together with network analyses, these findings add to the genetic risk map of PSC and expand on the relationship between PSC and other immune-mediated diseases.
[show abstract][hide abstract] ABSTRACT: OBJECTIVE:: The objective of this pilot study was to investigate the potential for long-term overall survival (OS) after liver transplantation for colorectal liver metastases (CLMs). BACKGROUND:: Patients with nonresectable CLMs have poor prognosis, and few survive beyond 5 years. CLMs are currently considered an absolute contraindication for liver transplantation, although liver transplantation for primary and some secondary liver malignancies shows excellent outcome in selected patients. Before 1995, several liver transplantations for CLMs were performed, but outcome was poor (5-year survival rate: 18%) and liver transplantation for CLMs was abandoned. Since then, the survival rate after liver transplantation in general has improved by almost 30%. On the basis of this, a 5-year survival rate of about 50% after liver transplantation for CLMs could be anticipated. METHODS:: In a prospective pilot study, liver transplantation for nonresectable CLMs was performed (n = 21). Main inclusion criteria were liver-only CLMs, excised primary tumors, and at least 6 weeks of chemotherapy. RESULTS:: Kaplan-Meier estimates of the OS rate at 1, 3, and 5 years were 95%, 68%, and 60%, respectively. Metastatic recurrence of disease was common (mainly pulmonary). However, a significant proportion of the recurrences were accessible for surgery, and at follow-up (after median of 27 months; range, 8-60), 33% had no evidence of disease. Hepatic tumor load before liver transplantation, time from primary surgery to liver transplantation, and progressive disease on chemotherapy were identified as significant prognostic factors. CONCLUSIONS:: OS exceeds by far reported outcome for chemotherapy, which is the only treatment option available for this patient group. Furthermore, OS is comparable with liver resection for resectable CLMs and survival after repeat liver transplantation for nonmalignant diseases. Selection strategies based on prognostic factors may further improve the outcome (ClinicalTrials.gov: NCT01311453).
[show abstract][hide abstract] ABSTRACT: BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) has not been shown to stop progression of primary sclerosing cholangitis (PSC). However, patients with primary biliary cirrhosis treated with UDCA whose levels of alkaline phosphatase (ALP) decrease have longer survival times than patients whose levels do not decrease. We compared survival times between patients with PSC treated with UDCA or placebo, with and without decreased levels of ALP. METHODS: We collected data from patients enrolled in the Scandinavian PSC UDCA trial. Patients were randomly assigned to groups given UDCA (17-23 mg/kg/day, n=97) or placebo (n=101) from 1996 to 2001 and were followed until 2010. Endpoints were death, liver transplantation, or cholangiocarcinoma. They were considered to be biochemical responders if they had serum levels of ALP that were normal or reduced by ≥40% after 1 year in the trial (regardless of whether they received UDCA or placebo). Numbers of patients surviving until the study endpoint were compared using the Kaplan-Meier method. RESULTS: There were no differences in survival at the end of the study between patients given UDCA or placebo (P =.774 log rank); 26 patients in the UDCA group and 29 in the placebo group reached an endpoint. Based on ALP levels, there were 79 responders and 116 nonresponders, overall. Of patients given UDCA, significantly more biochemical responders survived for 10 y than non-responders (P =.03, log rank). However, difference remained significant regardless of group assignment-overall, patients with reductions in ALP level survived longer than patients without reductions in ALP (P =.0001, log rank). CONCLUSIONS: There is no significant difference in long-term survival between patients with PSC given UDCA (17-23 mg/kg/day) or placebo for 5 y. However, patients who have reduced or normal levels of ALP have longer survival times, regardless of whether they receive UDCA or placebo.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2013; · 5.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND & AIMS: Previous studies have shown conflicting results regarding the course of inflammatory bowel disease (IBD) after liver transplantation in patients with primary sclerosing cholangitis (PSC). We studied the development of IBD in patients with PSC who have undergone liver transplantation, risk factors for IBD, and the effects of treatment on disease activity. METHODS: In a longitudinal, multicenter study, we analyzed data from the Nordic Liver Transplant Group on 439 patients with PSC who underwent liver transplantation from November 1984 through December 2006; 353 had IBD at the time of transplantation. We compared IBD activity before and after liver transplantation. Data from 218 patients who had an intact colon and had undergone pre- and post-transplant colonoscopies were further characterized. RESULTS: Macroscopic colonic inflammation was more frequent after than before liver transplantation (153 vs 124 patients; P <.001). The degree of inflammation decreased in 37 patients (17%), was unchanged in 93 (43%), and increased in 88 (40%) (P <.001). The rate of relapse after transplantation was higher than that before transplantation (P <.001); overall clinical IBD activity also increased (P<.001). Young age at diagnosis of IBD and dual treatment with tacrolimus and mycophenolate mofetil (MMF) were significant risk factors for increased IBD activity after transplantation, whereas combination treatment with ciclosporine A and azathioprine had protective effects. CONCLUSIONS: Immunosuppression affects IBD activity after liver transplantation in patients with PSC; a shift from present standard maintenance treatment of tacrolimus and MMF to ciclosporine A and azathioprine should be considered for these patients.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2013; · 5.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cholangiocarcinoma is notoriously difficult to diagnose, and the mortality rate is high due to late clinical presentation. CpG island promoter methylation is frequently seen in cancer development. In the present study, we aimed at identifying novel epigenetic biomarkers with the potential to improve the diagnostic accuracy of cholangiocarcinoma. Microarray data analyses of cholangiocarcinoma cell lines treated with epigenetic drugs and their untreated counterparts were compared with previously published gene expression profiles of primary tumors and with non-malignant controls. Genes responding to the epigenetic treatment that were simultaneously downregulated in primary cholangiocarcinoma compared with controls (n = 43) were investigated for their promoter methylation status in cancer cell lines from the gastrointestinal tract. Genes commonly methylated in cholangiocarcinoma cell lines were subjected to quantitative methylation-specific polymerase chain reaction in a total of 93 clinical samples (cholangiocarcinomas and non-malignant controls). CDO1, DCLK1, SFRP1 and ZSCAN18, displayed high methylation frequencies in primary tumors and were unmethylated in controls. At least one of these four biomarkers was positive in 87% of the tumor samples, with a specificity of 100%. In conclusion, the novel methylation-based biomarker panel showed high sensitivity and specificity for cholangiocarcinoma. The potential of these markers in early diagnosis of this cancer type should be further explored.
Epigenetics: official journal of the DNA Methylation Society 09/2012; 7(11). · 4.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: Approximately 60-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the purpose of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases and 2,977 controls and followed up top association signals in additional 1,012 PSC cases, 4,444 UC cases and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at GPR35; P=3.0×10(-9) in the overall study population, combined odds ratio (OR; 95% confidence interval (CI)) of 1.39 (1.24-1.55)], and at 18q21 [rs1452787 at TCF4; P=2.61×10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, while TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2012.).
[show abstract][hide abstract] ABSTRACT: Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant.
In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis.
Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia.
The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.
Scandinavian journal of gastroenterology 05/2012; 8-9(47):1021-9. · 2.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS).
We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing.
Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients.
We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.
Journal of Hepatology 04/2012; 57(2):366-75. · 9.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study was performed to explore whether lactate, pyruvate, glucose, and glycerol levels sampled via microdialysis catheters in the transplanted liver could be used to detect ischemia and/or rejection. The metabolites were measured at the bedside every 1 to 2 hours after the operation for a median of 10 days. Twelve grafts with biopsy-proven rejection and 9 grafts with ischemia were compared to a reference group of 39 grafts with uneventful courses. The median lactate level was significantly higher in both the ischemia group [5.8 mM (interquartile range = 4.0-11.1 mM)] and the rejection group [2.1 mM (interquartile range = 1.9-2.4 mM)] versus the reference group [1.5 mM (interquartile range = 1.1-1.9 mM), P < 0.001 for both]. The median pyruvate level was significantly increased only in the rejection group [185 μM (interquartile range = 155-206 μM)] versus the reference group [124 μM (interquartile range = 102-150 μM), P < 0.001], whereas the median lactate/pyruvate ratio and the median glycerol level were increased only in the ischemia group [66.1 (interquartile range = 23.9-156.7) and 138 μM (interquartile range = 26-260 μM)] versus the reference group [11.8 (interquartile range = 10.6-13.6), P < 0.001, and 9 μM (interquartile range = 9-24 μM), P = 0.002]. Ischemia was detected with 100% sensitivity and greater than 90% specificity when a positive test was repeated after 1 hour. In 3 cases of hepatic artery thrombosis, ischemia was detected despite normal blood lactate levels. Consecutive pathological measurements for 6 hours were used to diagnose rejection with greater than 80% sensitivity and specificity at a median of 4 days before the activity of alanine aminotransferase, the concentration of bilirubin in serum, or both increased. In conclusion, bedside measurements of intrahepatic lactate and pyruvate levels were used to detect ischemia and rejection earlier than current standard methods could. Discrimination from an uneventful patient course was achieved. Consequently, intrahepatic graft monitoring with microdialysis may lead to the earlier initiation of graft-saving treatment.
[show abstract][hide abstract] ABSTRACT: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long-term data and larger trials are lacking.
To evaluate the effect of high dose (17-23 mg/kg/day) UDCA on colorectal neoplasia in a cohort of patients with PSC and IBD.
From our previous 5-year randomised controlled trial of UDCA vs. placebo in PSC, we performed a follow-up of 98 patients with concomitant IBD from entry of the trial 1996-1997 until 2009 for development of colorectal cancer or dysplasia.
The total follow-up time was 760 person-years. Dysplasia/cancer-free survival was compared between placebo- (n = 50) and UDCA-treated (n = 48) patients. There was a similar frequency of dysplasia or cancer after 5 years between patients originally assigned to UDCA or placebo (13% vs. 16%) and no difference in dysplasia/cancer-free survival (P = 0.46, log rank test). At the end of 2009 no difference in cancer-free survival was detected, 30% of the placebo patients compared with 27% of UDCA patients had developed colorectal cancer or dysplasia.
Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease.
[show abstract][hide abstract] ABSTRACT: Cholangiocarcinoma complicates primary sclerosing cholangitis (PSC) in approximately 10% of cases, but no risk factor that can identify this subgroup of patients is known. No imaging modalities or serum tumour markers that can diagnose early cholangiocarcinoma are available, but endoscopic retrograde cholangiography with brush cytology is recommended when clinically indicated. Liver transplantation with neoadjuvant therapy is carried out in specialist centres in cases of limited stage cancer. Transplantation should also be considered in patients with biliary dysplasia without evident tumour. Gallbladder polyps in PSC are often malignant, and liberal indication for cholecystectomy is recommended. Hepatocellular carcinoma develops in 2%-4% of patients with end-stage liver disease. Patients with inflammatory bowel disease are at risk of colorectal neoplasia. Surveillance colonoscopies are recommended, also after liver transplantation. Epigenetic markers represent one among several classes of potential biomarkers for early diagnosis of malignancies in PSC that should be further explored.
Best practice & research. Clinical gastroenterology 12/2011; 25(6):753-64. · 2.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Guidelines for the management of primary sclerosing cholangitis (PSC) have recently been published by both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD). The current review focuses on the management of PSC, based on these guidelines. There is no established medical therapy for PSC. The role for UDCA in slowing the disease progression and improving survival is as yet unclear, and there are no specific recommendations for the general use of UDCA in this condition. Guidelines recommend that dominant bile duct strictures with significant cholestasis should be treated with biliary dilatation, with or without stenting. Prospective studies to define type, duration, optimal frequency and long-term effects of endoscopic therapy are needed. Liver transplantation is recommended for end stage disease and has excellent results. PSC patients with dysplasia in biliary brush cytology specimens should also be considered for transplantation. There is no evidence-based algorithm for the follow-up of PSC patients, but some regular investigations are recommended (surveillance colonoscopies in patients with IBD and ultrasound to detect gallbladder mass lesions).
Gastroentérologie Clinique et Biologique 09/2011; 35(12):786-91. · 0.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10−4), 4q27 (P-value 4.10 × 10−5), and 9q34 (P-value 8.41 × 10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. Conclusion: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. (HEPATOLOGY 2011;)
[show abstract][hide abstract] ABSTRACT: Inflammatory bowel disease (IBD) in patients with primary sclerosing cholangitis (PSC) seems to differ from IBD without PSC, but a systematic, prospective study of IBD in PSC has until now not been reported. We aimed to describe the clinical, endoscopic, and histopathologic features of PSC-IBD in liver-transplanted and nontransplanted patients.
PSC patients (n = 184) were included and underwent ileocolonoscopy with assessment of segmental histopathology.
A total of 155 (84%) patients had IBD, of whom 39 (25%) had undergone colectomy. The patients with an intact colon and complete tissue samples (n = 110) were further investigated. Forty-two (38%) patients had undergone liver transplantation. The median IBD duration was 11 (range, 0-50) years. The majority (65%) had no or sparse IBD symptoms. Inflammatory findings were more frequent by histology than by endoscopy (89% versus 47%, P < 0.001). Histopathological signs of inflammation involved the right colon in 86% of patients and were purely right-sided in 23%. The findings of inflammation were higher in the right compared to the left colon (P < 0.001), but the general inflammatory activity was low. Backwash ileitis was demonstrated in 20% (17/87) of patients and rectal sparing in 65% (70/107). The liver-transplanted patients had lower clinical (P = 0.035) and histological (P = 0.013) IBD activity than the nontransplanted group.
PSC-IBD may represent a distinct entity of colitis in which low endoscopic activity may mask an active histologic inflammation that possibly contributes to an increased risk of malignancy. Circumstances related to liver transplantation seem to act favorably on colonic inflammation in PSC.