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Background & Aims: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We aimed to identify novel protein biomarkers of disease severity and prognosis in primary sclerosing cholangitis (PSC)., Methods: Using a bead-based array targeting 63 proteins, we profiled a derivation panel of Norwegian endoscopic retrograde cholangiography bile samples (55 PSC, 20 disease controls) and a Finnish validation panel (34 PSC, 10 disease controls). Selected identified proteins were measured in serum from two Norwegian PSC cohorts (n=167 [1992-2006] and n=138 [2008-2012]), inflammatory bowel disease (n=96) and healthy controls (n=100)., Results: In the bile derivation panel, the levels of 14 proteins were different between PSC patients and controls (p<0.05); all were confirmed in the validation panel. Twenty-four proteins in the bile derivation panel were significantly (p<0.05) different between PSC patients with mild compared to severe cholangiographic changes (modified Amsterdam criteria); this was replicated for 18 proteins in the validation panel. Interleukin (IL)-8, matrix metallopeptidase (MMP)9/lipocalin (LCN)2-complex, S100A8/9, S100A12 and tryptophan hydroxylase (TPH)2 in the bile were associated with both a PSC diagnosis and grade of cholangiographic changes. Stratifying PSC patients according to tertiles of serum IL-8, but not MMP9/LCN2 and S100A12, provided excellent discrimination for transplant-free survival both in the serum derivation and validation cohort. Furthermore, IL-8 was associated with transplant-free survival in multivariable analyses in both serum panels independently of age and disease duration, indicating an independent influence on PSC progression. However, the Enhanced Liver Fibrosis (ELF®) test and Mayo risk score proved to be stronger predictors of transplant-free survival., Conclusions: Based on assaying of biliary proteins, we have identified novel biliary and serum biomarkers as indicators of severity and prognosis in PSC., Lay Summary: Prognostic biomarkers are lacking in primary sclerosing cholangitis, hampering patient care and the development of therapy. We have identified inflammatory proteins including calprotectin and IL-8 as important indicators of disease severity and prognosis in bile and serum from patients with primary sclerosing cholangitis., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Unlabelled: There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments., Conclusion: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score., (© 2015 by the American Association for the Study of Liver Diseases.)

Objective: 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., Material and Methods: In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis., Results: 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., Conclusion: 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.

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.

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.

Background/aims: Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) has been implicated in the aberrant homing of intestinal lymphocytes to the liver in primary sclerosing cholangitis (PSC). Intercellular adhesion molecule-1 (ICAM-1) has also been implicated in the pathogenesis of PSC and the E/E genotype of the K469E polymorphism has been reported to be associated with PSC susceptibility. The aims of this study were to determine if MAdCAM-1 polymorphisms or the K469E polymorphism of ICAM-1 are associated with PSC in Scandinavia., Methods: Seven single nucleotide polymorphisms (SNPs) in MAdCAM-1 and the G421R and K469E ICAM-1 SNPs were genotyped in 365 PSC patients from Norway and Sweden. 327 Norwegian ulcerative colitis (UC) patients and 368 Norwegian bone marrow donors served as controls., Results: No significant association with PSC was found for any of the MAdCAM-1 or ICAM-1 SNPs. Allele frequencies for these polymorphisms were not significantly different between PSC patients with UC, UC patients and healthy controls., Conclusions: Polymorphisms in MAdCAM-1 are not likely to significantly affect PSC susceptibility. In addition, the E/E genotype of the K469E in ICAM-1 does not influence PSC susceptibility in Scandinavia.

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.

Background/aims: Primary sclerosing cholangitis (PSC) is considered an immune mediated liver disease of multifactorial and multigenetic aetiology. Concomitant ulcerative colitis (UC) is seen in many PSC patients, but the pathogenetic link between these disorders is unknown. Due to association with inflammation, fibrosis, and cancer development, the matrix metalloproteinases MMP-1 and MMP-3 are candidate genes for predisposition to both PSC, UC and cholangiocarcinoma., Methods: We investigated the association of MMP-1 and MMP-3 promoter polymorphisms in 165 Norwegian PSC patients compared to 118 UC patients and 346 healthy controls., Results: There were no differences in MMP-1 and MMP-3 frequencies between PSC patients and UC patients or healthy controls. PSC patients with UC showed an increased frequency of the MMP-3 allele 5A compared to PSC patients without UC (60% vs. 45%; P(c)=0.01). All patients (100%) with cholangiocarcinoma carried MMP-1 allele 1G, compared to only 72% of PSC patients without cholangiocarcinoma., Conclusions: We found no general associations of the MMP-1 and MMP-3 genes to PSC or UC among Norwegian patients, but specific alleles were associated to subsets of PSC patients with UC and cholangiocarcinoma. The results support the theory of genetic heterogeneity among PSC patients.

Background: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation., Methods: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals., Results: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A., Conclusion: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

A total of 114 liver transplantations were performed in 106 patients in Norway during 1984-1994. Survival after one year was 65% and after three years 57%. The most frequent causes of death were infections and rejections. The survival rate improved considerably during the period, and after 1990 the 1 year survival was 70%. Approximately 2/3 of the patients return to work or education. Very few patients die later than 12 months after the transplantation. The most frequent indications were primary biliary cirrhosis, metabolic liver disease, primary sclerosing cholangitis, autoimmune cirrhosis and fulminant liver failure. The number of liver transplantations (approximately 4 per million inhabitants) is lower in Norway than in the other Nordic countries. The number should be increased to 7-8 per million inhabitants.

The number of orthotopic liver transplantations per year in Norway is smaller than in other countries of Northern Europe. Relatively fewer liver transplantations are performed both in the case of accepted indications such as primary biliary cirrhosis and acute liver failure, and for more arguable indications like post viral cirrhosis and alcoholic liver disease. The authors discuss priorities in health care in Norway. The efficacy of liver transplantation for selected groups of patients is compared with the efficacy of bone marrow transplantation for another selected group of patients. If indications and activity of bone marrow transplantation depict the threshold of prioritization, then more patients with chronic liver disease should be offered liver transplantation as therapy.

In a prospective study of 16,756 consecutive blood donors, we found 54 donors (0.3%) to be anti-hepatitis C virus (HCV)-positive by a first-generation enzyme-linked immunosorbent assay. After retesting, 18 donors were confirmed positive or indeterminate by a second-generation recombinant immunoblot assay. Sixteen of these donors were found positive by a second-generation enzyme-linked immunosorbent assay, and 15 of these were positive by HCV polymerase chain reaction with two primer sets. Nine donors (50%) had a history of drug abuse. In 15 donors found positive by a second-generation enzyme-linked immunoblot assay liver biopsy specimens were taken after at least 6 months' follow-up. In all except one hepatitis C RNA-negative donor, histologic abnormalities were observed, even when alanine aminotransferase (ALAT) levels were continuously normal or only moderately elevated. The abnormalities were less pronounced in these donors (n = 5) than in donors with ALAT levels increased more than twice the upper normal limit (p < 0.05). In conclusion, we found the proportion of previous drug abusers in anti-HCV-positive blood donors to be high. We confirm that the presence of anti-HCV (second generation) usually, and HCV-RNA always, seems to indicate ongoing infection--also when ALAT levels are normal. Our study further suggests that low-activity hepatitis, evaluated by ALAT levels, may indicate a milder disease.

The incidence of ulcerative colitis (UC) in the three counties that compose Western Norway was registered in a prospective study during the years 1984 and 1985. Both inpatients and outpatients were included. Five hundred and fifty general practitioners and 12 hospitals participated in the study. A total of 239 patients were diagnosed in this area with 807,000 inhabitants, giving a mean annual incidence of 14.8 per 100,000. For patients between 30 and 35 years of age the age-specific incidence rate was 31.2. The M/F sex ratio was 1.10. Familial occurrence of inflammatory bowel disease was found in 11% of the patients. Patients with rectal involvement only constituted 35% of the patients.

Two hundred patients with liver disease were re-studied after six to eight years. The initial routine diagnosis (mainly based on morphological criteria) was confirmed in almost 80% of cases of chronic liver disease. In chronic active hepatitis, agreement was found in 86%. An alternative classification based on cluster analysis of clinical chemical results from the first admission was also to a great extent confirmed by the follow-up study. Discriminant analysis of clinical chemical data correctly allocated 94% of patients with alcoholic cirrhosis (who had low haptoglobin and albumin) into groups with different prognosis. Clinical chemical results differed between verified and non-verified cases of primary biliary cirrhosis. By retrospective examination , we found that 15 of 16 patients with this disease or chronic active hepatitis who were initially misclassified by biopsy findings could be correctly diagnosed by discriminant analysis of clinical chemical results.

The incidence of Crohn's disease in western Norway was estimated in a prospective epidemiologic study during the years 1984 and 1985. The total population in the area was 807,000. Both inpatients and outpatients were included. Five hundred and fifty general practitioners and 12 hospitals participated in the study. A total of 86 patients were diagnosed, giving a mean annual incidence of 5.3 per 100,000. For patients between 15 and 19 years of age-specific incidence rate was 16.0 The M/F sex ratio was 0.9. In the same period 240 patients with ulcerative colitis were diagnosed (mean annual incidence, 14.8 per 100,000), giving a ratio of 2.8 between ulcerative colitis and Crohn's disease and an annual incidence of 20.1 per 100,000 for inflammatory bowel disease. Familial occurrence of IBD was found for 12% of the patients.

During the 10-year period from 1 January 1975 to 31 December 1984, primary sclerosing cholangitis (PSC) was diagnosed in 45 patients. Twelve of the patients have died (26.7%), 10 of them of causes related to PSC. Inflammatory bowel disease was found in all patients; ulcerative colitis was found in 37, Crohn's disease in 6, and unclassified colitis in 2 patients. Of the patients alive, 27 were submitted to a follow-up study in 1985. At the follow-up examination no general progression of the liver disease, as measured on the basis of clinical examination and levels of transaminases, alkaline phosphatases, and bilirubin, was found. Cholangiographic evaluation in 24 patients showed that the stage of ductal changes progressed from mild to moderate in 3 patients; in the other patients the stage was not altered. Morphologic examination of liver biopsy specimens in patients with a benign clinical course usually showed portal inflammation, fibrosis, and minor signs of piecemeal necrosis, whereas widespread piecemeal necrosis was found in patients who deteriorated and died. The 50% survival since diagnosis of liver disease was calculated to be 17 years in patients with PSC and 50 years in a comparable group among the general population. The estimated survival curve in PSC was displaced to the left, indicating a reduced life expectancy of about 30 years.

Out of 421 patients who had partial gastrectomy 20-25 years ago for gastric or duodenal ulcer, 108 were examined by endoscopy with multiple biopsy. In no case were the endoscopic appearances of the mucosae interpreted as malignant, though in 2 patients the clinical history suggest malignant disease. Histological examination revealed infiltrating carcinoma in 4 patients, 3 of whom had intramucosal carcinoma only. 3 further patients had severe dysplasia (carcinoma-in-situ). Only 1 patient had a near-normal mucosa close to the anastomosis; in the remainder the gastric remnant showed various degress of dysplasia, metaplasia, or chronic atrophic gastritis. In the patients with carcinoma only 28 (12%) of the 226 biopsy specimens revealed the malignant lesion. Patients who have had partial gastrectomy for benign lesions are at high risk of gastric-stump carcinoma. If, 20 years after operation, they have an endoscopy with multiple biopsy, stump carcinoma may be detected early when the prognosis after operation is probably good.