Serological markers of extracellular matrix remodeling predict transplant-free survival in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. METHODS: Serum samples were available from 138 large-duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008-2012 and 52 ulcerative colitis patients (controls). The median follow-up time was 2.2 (range 0-4.3) years. Specific biomarkers of type III and V collagen formation (PRO-C3 and PRO-C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid was assessed for comparison. RESULTS: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO-C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO-C3 and PRO-C5 the odds ratio for predicting transplant-free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. CONCLUSIONS: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO-C3 was identified as a potent prognostic marker and an independent predictor of transplant-free survival in primary sclerosing cholangitis.

Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

Serum microRNAs as novel biomarkers for primary sclerosing cholangitis and cholangiocarcinoma.

The diagnosis of primary sclerosing cholangitis (PSC) is difficult due to the lack of sensitive and specific biomarkers, as is the early diagnosis of cholangiocarcinoma (CC), a complication of PSC. The aim of this study was to identify specific serum miRNAs as diagnostic biomarkers for PSC and CC. The levels of 667 miRNAs were evaluated in 90 human serum samples (30 PSC, 30 CC and 30 control subjects) to identify disease-associated candidate miRNAs (discovery phase). The deregulated miRNAs were validated in an independent cohort of 140 samples [40 PSC, 40 CC, 20 primary biliary cirrhosis (PBC) and 40 controls]. Receiver operating characteristic (ROC) curves were established and only miRNAs with an area under the curve (AUC) > 0·70 were considered useful as biomarkers. In the discovery phase we identified the following: 21 miRNAs expressed differentially in PSC, 33 in CC and 26 in both in comparison to control subjects as well as 24 miRNAs expressed differentially between PSC and CC. After the validation phase, miR-200c was found to be expressed differentially in PSC versus controls, whereas miR-483-5p and miR-194 showed deregulated expression in CC compared with controls. We also demonstrate a difference in the expression of miR-222 and miR-483-5p in CC versus PSC. Combination of these specific miRNAs further improved the specificity and accuracy of diagnosis. This study provides a basis for the use of miRNAs as biomarkers for the diagnosis of PSC and CC.

Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis.

BACKGROUND: Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies. AIMS: To critically review controversial aspects of the scientific basis for common clinical practice in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and to discuss key ongoing challenges to improve patient management. METHODS: We performed a literature search using PubMed and by examining the reference lists of relevant review articles related to the clinical management of PBC and PSC. Articles were considered on the background of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) practice guidelines and clinical experience of the authors. RESULTS: Ongoing challenges in PBC mainly pertain to the improvement of medical therapy, particularly for patients with a suboptimal response to ursodeoxycholic acid. In PSC, development of medical therapies and sensitive screening protocols for cholangiocarcinoma represent areas of intense research. To rationally improve patient management, a better understanding of pathogenesis, including complications like pruritis and fatigue, is needed and there is a need to identify biomarker end-points for treatment effect and prognosis. Timing of liver transplantation and determining optimal regimens of immunosuppression post-liver transplantation will also benefit from better appreciation of pre-transplant disease mechanisms. CONCLUSION: Controversies in the management of PBC and PSC relate to topics where evidence for current practice is weak and further research is needed.

Colectomy for patients with ulcerative colitis and primary sclerosing cholangitis - what next?

BACKGROUND AND AIMS: 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). PATIENTS: 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. RESULTS: 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). CONCLUSIONS: 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.

Cost and health consequences of treatment of primary biliary cirrhosis with ursodeoxycholic acid.

BACKGROUND: Long-term use of ursodeoxycholic acid (UDCA) is the recommended therapy in primary biliary cirrhosis (PBC). The lifetime effectiveness and cost-effectiveness of UDCA in PBC have, however, not been assessed. AIM: To estimate the health outcomes and lifetime costs of a Norwegian cohort of PBC patients on UDCA. METHODS: Norwegian PBC patients (n = 182) (90% females; mean age 56.3 ± 8.9 years; Mayo risk score 4.38) who were included in a 5-year open-label study of UDCA therapy were subsequently followed up for up to 11.5 years. The lifetime survival was estimated using a Weibull survival model. The survival benefit from UDCA was based on a randomised clinical trial from Canada, comparing the effect of non-UDCA and UDCA. Survival and costs of standard care vs. standard care plus UDCA were simulated in a Markov model with death and liver transplantation as major events, invoking transition of a patient's state in the model. RESULTS: The gain in life expectancy for a PBC patient on UDCA compared with standard care was 2.24 years (1.19 years discounted). The lifetime treatment costs were EUR 151,403 and EUR 157,741 (EUR 102,912 and EUR 115,031 discounted) for patients with and without UDCA respectively. A probabilistic sensitivity analysis indicated an 82% probability that UDCA entails both greater life expectancy and lower costs than standard care. CONCLUSIONS: The results of this study indicate that UDCA therapy is a dominant strategy as it confers reduced morbidity and mortality, as well as cost savings, compared with standard therapy.

High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia.

BACKGROUND: 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. AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease.

Current consensus on the management of primary sclerosing cholangitis.

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).

Validation of a cholangiographic prognostic model in primary sclerosing cholangitis.

BACKGROUND AND STUDY AIMS: We previously developed a prognostic model for primary sclerosing cholangitis (PSC), which was primarily based on a cholangiographic classification of the intra- and extrahepatic biliary tree lesions. The aim of the present study was to validate the performance of this model in an external cohort. PATIENTS AND METHODS: The validation dataset consisted of patients with PSC from a single referral center in Oslo, Norway. The patients' cholangiograms were scored according to the Amsterdam classification. We then examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the original model in the validation cohort. In addition, we evaluated calibration (closeness between observed and expected survival) and discrimination using the concordance index. RESULTS: A total of 111 patients (mean age 35 +/- 13 years; 76 % male) were included in the validation study. Baseline clinical characteristics were comparable between the two cohorts. None of the coefficients that were re-estimated in the validation cohort differed significantly from the values of the original model. Observed and expected survival curves were in close agreement across different risk groups. Discrimination of the original model was preserved in the validation cohort: the concordance index was the same in both cohorts. CONCLUSIONS: The prognostic model showed adequate performance in an independent series of patients. Therefore, we updated the model using the data from both cohorts to provide more robust estimates of transplant-free survival for individual patients. A nomogram was constructed, which can be used to predict medium- and long-term prognosis in individual patients with PSC.

Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases.

We reported earlier that two mitochondrial gene polymorphisms, UCP2 -866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2 -866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2 -866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR)=0.91, 95% confidence interval (95% CI): 0.86-0.96), P=0.0003) or genotypes (OR=0.88, (95% CI: 0.82-0.95), P=0.0008), with the -866A allele associated with a decreased risk to diseases. As the -866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.

The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases.

BACKGROUND AND OBJECTIVES: The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs. METHODS: We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests. RESULTS: RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels. CONCLUSION: We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.

Different HLA class II associations in ulcerative colitis patients with and without primary sclerosing cholangitis.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have inflammatory bowel disease (IBD), the majority ulcerative colitis (UC). An inherent problem in interpreting positive findings in genetic association studies of PSC is thus to distinguish between factors associated with hepatobiliary versus intestinal pathology. We aimed to clarify to what extent human leukocyte antigen (HLA) class II associations in UC patients with and without PSC differ. High-resolution DRB1 and DQB1 typing was performed in 365 Scandinavian PSC patients, an independent cohort of 330 Norwegian UC patients and 368 healthy controls. HLA associations found in PSC were mostly distinct from those seen in UC, and no significant differences were noted between PSC patients with concurrent UC and PSC patients without IBD. This suggests different HLA associated genetic susceptibility to PSC and UC, and supports notions that UC in PSC may represent a distinct UC phenotype.

Primary sclerosing cholangitis is associated with extended HLA-DR3 and HLA-DR6 haplotypes.

Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.

The 32-base pair deletion of the chemokine receptor 5 gene (CCR5-Delta32) is not associated with primary sclerosing cholangitis in 363 Scandinavian patients.

CCR5 is a chemokine receptor expressed on T-cells and macrophages. A 32-base pair deletion in the chemokine receptor 5 gene (CCR5-Delta32) leads to a non-functional receptor. Conflicting evidence exists whether this deletion is associated with primary sclerosing cholangitis (PSC). We genotyped the CCR5-Delta32 variant in 363 PSC patients and 366 controls. No significant increase in the Delta32 allele frequency was detected in the PSC patients compared to controls (12.7% vs 10.7% OR = 1.22, 95% CI [0.88, 1.68], P = 0.23). Survival analysis did not reveal any significant effects from CCR5-Delta32 genotypes on disease progression. Thus, in this study (power > 90%, given OR = 2, alpha = 0.05), we were unable to replicate previous findings and our results do not support an involvement of CCR5-Delta32 in either PSC susceptibility or progression.

ABO-incompatible deceased donor liver transplantation with the use of antigen-specific immunoadsorption and anti-CD20 monoclonal antibody.

In patients with fulminant liver failure requiring emergency liver transplantation, the only donor organ that becomes available may be ABO incompatible. The risk of graft failure because of antibody-mediated acute rejection is high, but can be reduced by various means. We reported a deceased donor ABO-incompatible liver allograft recipient who was treated with antigen-specific immunoadsorption in combination with anti-CD20 monoclonal antibody and conventional plasmapheresis and immunosuppression. The patient was a 33-yr-old male with blood group A who presented with subacute liver failure of unknown aetiology and received a blood group AB liver graft. Pretransplant he underwent plasmapheresis and received one dose of rituximab. The immunosuppressive regimen consisted of methylprednisolone, tacrolimus and mycophenolate mofetil. Despite regular post-operative plasmapheresis sessions, anti-B antibody titres increased. Antigen-specific immunoadsorption with depletion of anti-B antibodies was performed from day nine to day 17. Thereafter, anti-B IgM and IgG antibody titres remained low. After one month the patient was reoperated with hepaticojejunostomy because of bile duct necrosis and with reconstruction of a stenotic hepatic artery. A mild rejection was successfully treated with methylprednisolone four months post-transplant. At six months post-transplant there was a stricture of the biliary-enteric anastomosis, but the graft was well functioning. We conclude that antigen-specific immunoadsorption can be an important adjuvant therapy to control recipient anti-A/B antibody levels and prevent acute rejection in ABO-incompatible deceased donor liver transplantation.

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases.

A functional single nucleotide polymorphism, 1858C>T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR=1.41; P=0.04), not previously reported, and a tendency for an association with coeliac disease (OR=1.35; P=0.08). In primary sclerosing cholangitis, no association was observed (OR=0.95; P=0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR=1.58; P=0.001), but could not find support for an association with systemic lupus erythematosus (OR=0.94; P=0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C>T polymorphism in PTPN22.

Long-term effect of corticosteroid treatment in primary sclerosing cholangitis patients.

BACKGROUND: A beneficial effect of corticosteroids in primary sclerosing cholangitis (PSC) has been suggested, but characteristics of responding patients and long-term outcome have not been assessed. In this retrospective study, we aimed to characterize PSC patients selected for corticosteroid treatment at our centre and to identify potential factors associated with response. METHODS: We first compared groups of PSC patients treated (n = 47) and not treated (n = 88) with corticosteroids. Responding (n = 20) and non-responding (n = 27) patients were subsequently compared. Complete and partial responses were defined according to criteria established for autoimmune hepatitis. A third response category included improvement of symptoms and at least 50% reduction of transaminase and/or bilirubin levels during the first 6 months. RESULTS: At diagnosis of PSC, patients treated with corticosteroids were significantly younger, had higher serum levels of alanine transaminases, and more histological features of autoimmune hepatitis compared to the non-treated group. Complete treatment response was obtained in three patients and partial response in two, together comprising 3.7% of all PSC patients in this study. Fifteen patients fulfilled criteria of the third response category. Response to treatment was associated with higher serum levels of alanine transaminases and bilirubin and lower levels of alkaline phosphatases at treatment start. Responders had better long-term survival than non-responders (hazard ratio 6.28; 95% confidence interval 1.62 to 24.4; P = 0.008). CONCLUSIONS: A subgroup of PSC patients seems to respond favourably to corticosteroid treatment and may obtain improved long-term survival.

Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation.

BACKGROUND: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC. METHODS: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC. RESULTS: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis). CONCLUSIONS: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.