The Usefulness of Defining Rapid Virological Response by a Very Sensitive Assay (TMA) during Treatment of HCV Genotype 2/3 Infection.

The aim of this study was to determine in patients with HCV genotype 2 or 3 the performance at week 4 of two assays with different sensitivities for HCV RNA detection, for the prediction of SVR and stratification for treatment duration (14 and 24 weeks). Recruitment was from two trials comparing 14 and 24 weeks treatment to patients with rapid virological response (RVR) (n = 550). RVR was originally defined as HCV RNA <50 IU/ml at week 4. Patients with an available frozen plasma sample drawn at week 4 and with follow-up data week 24 post-treatment were included (n = 429). HCV-RNA was prospectively measured with COBAS Amplicor V2, Roche (CA) (lower detection limit 50 IU/ml) and retrospectively assessed with VERSANT HCV-RNA Qualitative Assay, Siemens (TMA) (lower limit detection 10 IU/ml). Genotype 3 was present in 80% and genotype 2 in 20%. A SVR was achieved in 82%. At week 4 HCV-RNA was undetectable in 74.8% and 63% of serum samples tested with CA and TMA, respectively. CA undetectable/TMA positive was observed in 61/341 (18%) of the samples. In genotype 3 patients a relapse was seen in 9% of the patients with both CA and TMA undetectable and in 25% of the patients who were CA undetectable/TMA positive (p = 0.006). In patients allocated to 14 weeks treatment a relapse was observed in 11% of TMA undetectable patients and 26% of TMA positive (p = 0.031). In genotype 2 patients treated for 14 weeks relapse was observed in 6% of the patients with both CA and TMA undetectable week 4. Assays with high sensitivity for HCV RNA identifies patients at week 4 with high risk of virological relapse. We recommend that patients with genotype 3 and detectable HCV RNA at levels below 50 IU/ml do not receive truncated therapy with pegIFN and ribavirin.

Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013.

AIM AND BACKGROUND: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. MATERIALS AND METHODS: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. RESULTS: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. CONCLUSION: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Low use of surveillance and early diagnosis of hepatocellular carcinoma in Norway--a population-based cohort study.

BACKGROUND AND AIMS: Curative treatment of hepatocellular carcinoma (HCC) is dependent on early diagnosis. Surveillance of patients at high risk for HCC is a key determinant to achieve this goal, but may be an underutilized tool. The aim of this study was to determine the rate of pre-diagnosis surveillance in patients with HCC in a large population-based cohort and to assess to what extent cirrhosis was known prior to the diagnosis of HCC. METHODS: All patients diagnosed with HCC during 2000-2009 in The South-Eastern Regional Health Authority, representing 56% of the Norwegian population, were identified from The National Cancer Registry and the medical records were reviewed. RESULTS: Fifteen out of 486 patients (3%) were diagnosed by surveillance. Potential curative treatment was offered to 58% of the patients who underwent surveillance as opposed to 15% in the non-surveillance group. Only age ≤ 65 years was an independent predictor of screening in a multivariate model. Almost two thirds of the patients with cirrhosis were unrecognized prior to the HCC diagnosis. Two hundred and fourteen patients (44%) were non-cirrhotics. CONCLUSION: Regular HCC surveillance in at-risk populations is virtually not applied in Norway and this may contribute to inferior overall survival. Failure to recognize cirrhosis and a high rate of HCC in non-cirrhotic patients will be limiting factors for the overall effectiveness of a potential surveillance program.

Genetic variants at the ITPA locus protect against ribavirin-induced hemolytic anemia and dose reduction in an HCV G2/G3 cohort.

OBJECTIVES: Two functional genetic variants in the inosine triphosphatase (ITPA) gene have been shown to be strongly associated with protection from ribavirin (RBV)-induced hemolysis. We aimed at evaluating this finding in a chronic hepatitis C genotype 2/3 cohort with a predominance of genotype 3 patients where available data are scarce. A second objective was to determine whether a protective association translated into the need for RBV reduction and hence a possible impact on treatment response. METHODS: Overall, 457 patients were recruited from two trials of genotype 2/3 patients treated with pegylated interferon α-2b and weight-based RBV. rs1127354 and rs7270101 were genotyped and a composite ITPAase deficiency variable was graded according to the two single nucleotide polymorphisms. The primary endpoints were hemoglobin (Hb) decline from baseline and Hb decline of more than 3 g/dl at week 4. RESULTS: Both single nucleotide polymorphisms and the composite ITPAase deficiency variable were strongly and independently associated with protection from a decline in Hb at week 4 in multivariate linear regression models (Prs1127354=7.0×10, Prs7270101=0.0036, PITPase deficiency variable =6.3×10). Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced (odds ratio 0.39, 95% confidence interval 0.16-0.96, P=0.040), although this did not translate into increased rapid viral response or sustained viral response (Prvr=0.93, Psvr=0.22). CONCLUSION: We have confirmed a strong association between functional ITPA variants and RBV-induced hemolysis and showed protection from RBV dose reduction, although this did not translate into increased rapid viral response or sustained viral response.

IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection.

UNLABELLED: Polymorphisms near the IL28B gene, which code for interferon (IFN)-λ3, predict response to pegylated interferon-α (PEG-IFN) and ribavirin treatment in hepatitis C virus (HCV) genotype 1 infected patients. Follow-up studies of the effect of IL28B gene in HCV non-genotype 1 infected patients have almost always used predominantly HCV genotype 2-infected or mixed genotype 2/3-infected cohorts with results partly conflicting with HCV genotype 1. We performed a retrospective analysis of 281 patients infected with HCV genotype 3 for association of response to therapy with IL28B polymorphisms. We found that the HCV genotype 1 responder genotypes at rs12979860 and rs8099917 did not associate with sustained virological response to PEG-IFN/ribavirin therapy. However, the responder genotypes of both SNPs showed association with rapid viral response measured at 4 weeks (rs12979860, P = 3 × 10(-5) ; rs8099917, P = 3 × 10(-4) ). In multivariate analysis, age (<40 years), baseline viral load (<4 × 10(5) IU/mL) and the responder genotypes of SNPs rs12979860 or rs8099917 remained significant independent predictors of rapid viral response to therapy. Furthermore, we show that IL28B polymorphisms are associated with relapse in patients who achieve rapid viral response to PEG-IFN/ribavirin therapy. The responder genotypes also showed association with markers of stage and activity of liver disease, namely high aspartate aminotransferase platelet ratio index (APRI, rs12979860, P = 0.018; rs8099917, not significant) and high alanine aminotransferase (ALT, rs12979860, P = 0.002; rs8099917, P = 0.001), in addition to a high baseline viral load (rs12979860, P = 1.4 × 10(-5) ; rs8099917, P = 7.3 × 10(-6) ). CONCLUSION: Polymorphisms near the IL28B gene show association with rapid viral response but not sustained viral response to PEG-IFN/ribavirin therapy in HCV genotype 3-infected patients.

Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western and non-Western countries, but its pathogenesis is not fully understood. OBJECTIVE: Based on the role of nicotinamide phosphoribosyltransferase (NAMPT) in fat and glucose metabolism and cell survival, we hypothesized a role for NAMPT/visfatin in the pathogenesis of NAFLD-related disease. DESIGN AND SETTING: We conducted clinical studies at a referral medical center in well-characterized NAFLD patients (n = 58) and healthy controls (n = 27). In addition we performed experimental in vitro studies in hepatocytes. MAIN OUTCOME MEASURES: We examined 1) the hepatic and systemic expression of NAMPT/visfatin in patients with NAFLD and control subjects, 2) the hepatic regulation of NAMPT/visfatin, and 3) the effect of NAMPT/visfatin on hepatocyte apoptosis. RESULTS: Our main findings were as follows. 1) Patients with NAFLD had decreased NAMPT/visfatin expression both systemically in serum and within the hepatic tissue, with no difference between simple steatosis and nonalcoholic steatohepatitis. 2) By studying the hepatic regulation of NAMPT/visfatin in wild-type and peroxisome proliferators-activated receptor (PPAR)alpha(-/-) mice as well as in hepatocytes, we showed that PPARalpha activation and glucose may be involved in the down-regulation of hepatic NAMPT/visfatin expression in NAFLD. 4) Within the liver, NAMPT/visfatin was located to hepatocytes, and our in vitro studies showed that NAMPT/visfatin exerts antiapoptotic effects in these cells, involving enzymatic synthesis of nicotinamide adenine dinucleotide. CONCLUSION: Based on these findings, we suggest a role for decreased NAMPT/visfatin levels in hepatocyte apoptosis in NAFLD-related disease.

In patients with HCV genotype 2 or 3 infection and RVR 14 weeks treatment is noninferior to 24 weeks. Pooled analysis of two Scandinavian trials.

AIM: To compare 14 and 24 weeks treatment to patients with HCV genotype 2 or 3 infection and rapid virological response (RVR). MATERIALS AND METHODS: Patients included in two Scandinavian trials, one nonrandomized pilot trial (n=122) and one randomized controlled trial (RCT) (n=428) were entered into a pooled database. In both trials treatment naïve patients with genotype 2 or 3 were treated with pegylated interferon alpha 2b (1.5 microg/kg, subcutaneous) weekly and ribavirin (800-1400 mg, orally) daily. Primary endpoint was sustained virological response (SVR). RVR was defined as HCV RNA less than 50 IU/ml after 4 weeks of treatment. In the pilot trial all patients with RVR were treated for 14 weeks and in the RCT patients with RVR were randomised to either 14 or 24 weeks treatment. Patients treated per protocol were included in the primary analysis. The noninferiority margin was set to be 10% between the two groups with a one-sided 5% significance level. RESULTS: In patients with RVR and genotype 2 or 3 SVR was obtained in 181 of 199 (91.0%) and 93 of 98 (94.9%) after 14 and 24 weeks treatment, respectively. The observed difference in SVR rates was 3.9% (90% confidence interval: +1 to -8.8). The relapse rate was highest among those older than 40 years and those with genotype 3 and high viral load, but prolongation of treatment from 14 to 24 weeks did not reduce the relapse rate substantially in any of these groups. CONCLUSION: In patients with HCV genotype 2 or 3 infection and RVR 14 weeks treatment is noninferior to 24 weeks.

[Liver transplantation in Norway through 25 years]. / Levertransplantasjon i Norge gjennom 25 år.

BACKGROUND: In Norway, liver transplantation has been the treatment of choice for irreversible acute and chronic liver failure for 25 years. The aim of this article is to present a summary of the results obtained. MATERIAL AND METHODS: All liver transplants performed in Norway in the period 25.02.84-31.12.08 have been reviewed retrospectively with respect to patient and donor epidemiology, survival and recurrence. RESULTS: 651 transplants have been performed in this period. The annual number of transplants increased gradually up to the year 2000 (31), and more steeply afterwards - to 79 in 2008. Also the number of organ donations has increased and reached 98 (20 pr. million inh.) in 2008. 5-year patient survival was 53 % in the period 1984-1994. In the period 2001-2008, 1-year survival was 90 % and 5-year survival was 83 %. INTERPRETATION: The gradual improvement of results should be interpreted in light of improvements within transplant surgery, medicine and anaesthesiology and the increased local experience due to the increasing number of transplants performed. The transplant centre at Rikshospitalet has developed into being among the largest of its kind within the Nordic Countries and the results compare well with the best international data.

Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial.

OBJECTIVE: The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease. MATERIAL AND METHODS: Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers. RESULTS: No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p<0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p<0.001), glucose (p=0.032) and on HbA1c (p=0.020). CONCLUSIONS: Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537).

A complex role of activin A in non-alcoholic fatty liver disease.

OBJECTIVES: Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes. RESULTS: Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A-follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-beta(1), promoted matrix metalloproteinase activity, induced mitochondrial beta-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs. CONCLUSIONS: Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation.

Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.

UNLABELLED: A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment-naïve HCV RNA-positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon alpha-2b (1.5 microg/kg) subcutaneously weekly and ribavirin (800-1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one-sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention-to-treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7-17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, -0.1 to +13.9). CONCLUSION: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks.

Incidence rates and causes of cirrhosis in a Norwegian population.

OBJECTIVE: To investigate the incidence rate and causes of cirrhosis in a Norwegian population. We also sought to assess the degree of underreporting of cirrhosis to the Norwegian Death Registry. MATERIAL AND METHODS: All 1264 patients treated at Aker University Hospital in the period January 1999 to March 2004 who were given a diagnosis indicating cirrhosis, chronic liver disease or symptoms possibly attributable to cirrhosis were screened retrospectively. A search in the registry of histological diagnoses at Department of Pathology was also carried out. Based on the results of histological examinations and non-histological criteria, cirrhosis was confirmed in 194 patients. Calculations of the incidence rate of cirrhosis and frequencies of the various etiologies were based on 93 patients living in the catchment area of the hospital. Causes of death were retrieved from the Norwegian Death Registry. RESULTS: The incidence rate of cirrhosis was 134 per million per year. The majority of cases were due to alcoholic liver disease (53%), followed by viral liver disease (12%), various autoimmune liver diseases (12%), hemochromatosis (4%) and non-alcoholic steatohepatitis (NASH) (3%). No etiology was established in 16%, a group with a high prevalence of diabetes mellitus, indicating that some of these cases were possibly caused by NASH. Among 105 deaths in this cohort of 194 cirrhotic patients, the diagnosis of cirrhosis was absent in the Norwegian Death Registry in 30% of cases. CONCLUSIONS: The incidence of cirrhosis in Norway is relatively low, with alcohol as the most important etiologic factor. Significant underreporting to the Norwegian Death Registry was observed.

Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma.

BACKGROUND/AIMS: Liver transplantation (LTX) is the only curative treatment for end-stage liver disease caused by hepatitis C (HCV). Hepatocellular carcinoma (HCC) is common in patients with HCV cirrhosis. METHODS: Two hundred and eighty-two HCV patients listed for LTX in the Nordic countries in a 17-year period were included. For comparison a group of patients with non-viral chronic liver disease (n=1552) was used. RESULTS: Two hundred and fifty-three (90%) patients received a first liver allograft. HCC was found in 38% of the explanted livers. Survival at 1, 3 and 5years was 82%, 69% and 61% vs. 85%, 80% and 76% for the comparison group (p<0.0001), this survival difference was also evident when excluding patients with HCC (p=0.007). HCV patients with HCC had 1, 3 and 5year survival of 73%, 52% and 46% compared with 88%, 80% and 71% for the HCV patients without HCC (p=0.0005). In an intention-to-treat analysis (from time of acceptance to the waiting list) HCV was also associated with an impaired survival. CONCLUSIONS: HCV cirrhosis, which is now also an important indication for LTX in the Nordic countries, and significantly impairs survival following LTX. Concomitant HCC and donor age are the two most important factors contributing to an impaired survival.

Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2.

BACKGROUND/AIMS: To elucidate the role of systemic inflammation in nonalcoholic fatty liver disease (NAFLD). METHODS: Serum samples in 47 patients with histologically verified NAFLD (22 with simple steatosis and 25 with nonalcoholic steatohepatitis [NASH]), and in 30 age-, sex- and ethnicity-matched healthy controls, were assessed for (i) general markers of inflammation (C-reactive protein [CRP], tumor necrosis factor [TNF]-alpha, and interleukin [IL]-6), (ii) chemokines (CC-chemokine ligand [CCL] 2/monocyte chemoattractant protein [MCP]-1, CCL19 and CCL21), (iii) adipocytokines related to insulin resistance and inflammation (adiponectin and leptin) and (iv) a marker of oxidative stress (8-isoprostane-F2alpha). RESULTS: Serum levels of several inflammatory cytokines were increased in NAFLD as compared to controls, and IL-6 (P=0.017), CCL2/MCP-1 (P=0.008) and CCL19 (P=0.001), but not CRP (P=0.199), remained elevated also after correction for sex, body mass index (BMI) and age. Comparing NASH with simple steatosis, levels of TNF-alpha (P=0.024) and CCL2/MCP-1 (P=0.012) were elevated and adiponectin (in women) (P=0.001) were decreased also after adjustment for sex, BMI and presence of the metabolic syndrome. CONCLUSIONS: Our results indicate that patients with NAFLD are characterized by a low-grade systemic inflammation. The high CCL2/MCP-1 levels in NASH might be of importance for the conversion from simple steatosis to NASH.

Liver TX for hepatitis C cirrhosis in a low prevalence population: risk factors and status at evaluation.

OBJECTIVE: Hepatitis C virus (HCV) cirrhosis is the most common indication for liver transplantation (LTX) world-wide. The prevalence of HCV infections is much lower in Norway than in most other countries from which data on HCV infection and liver transplantation have been published. MATERIAL AND METHODS: Patients with HCV infection referred for evaluation of a possible LTX between 1990 and 2005 were included in the study. Their clinical status, biochemical parameters and risk factors were recorded. All patients were followed until 1 January 2005 irrespective of transplantation status. RESULTS: Fifty-one patients were included; 80% were males and 18% were non-Caucasians. Previous intravenous drug abuse (28%) and exposure to contaminated IgG products (15%) were the most common routes of infection. In 45/51 (88%) of the evaluated patients at least one risk factor for rapid progression of HCV disease was identified. Twenty-seven patients were accepted on the waiting list. The MELD (model for endstage liver disease) score for the accepted patients was significantly higher than that for the patients who were not listed because they were found to be too healthy (18.4 versus 12.1, p<0.01). Twenty-four patients (89% of those listed) received a liver allograft; their 1-, 3- and 5-year survival rates following LTX were 81%, 68% and 68%, respectively. Two patients needed a second transplantation. CONCLUSIONS: A low number of HCV-infected patients have so far been evaluated for LTX in Norway. The present study demonstrates that almost all of the HCV patients progressing to cirrhosis and being evaluated for LTX in Norway have additional risk factors for development of cirrhosis.

[Fulminant hepatic failure in malignant liver disease]. / Fulminant leversvikt ved malign leversykdom.

BACKGROUND: Fulminant hepatic failure is a rare disorder. Patients should be evaluated for liver transplantation. Malignant liver disease has been reported to cause the condition and this possibility should be excluded prior to listing the patient for transplantation. MATERIAL AND METHODS: We present four patients with this condition caused by malignant liver disease. INTERPRETATION: Fulminant hepatic failure may be caused by diffuse and massive infiltration of malignant cells in the liver. If a regular liver biopsy cannot be obtained due to severe coagulopathy, bone marrow aspiration and fine needle aspiration from the liver should be performed.

Liver transplantation in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) represents an important indication for liver transplantation. Selection for and timing of liver transplantation is difficult due to the disease course and the frequent occurrence of hepatobiliary malignancies. Pretransplantation screening of malignancies is difficult, but brush cytology of the biliary ducts seems to represent a possibility for early detection of some cholangiocarcinomas. Patient and graft survivals following liver transplantation are good, with 1 year patient survival exceeding 90%. Survival is also satisfactory in patients with early detected or highly limited cholangiocarcinomas. Recurrent PSC represents a particular problem, and affects as many as 20 to 40% in a long-term perspective. Few predictors of recurrent disease have been identified; severe rejections and their treatment may be of importance.