Anti-neutrophil cytoplasmic antibody 50%-80% Anti-nuclear antibody 7%-77% Anti-smooth muscle antibody 13%-20% Anti-endothelial cell antibody 35% Anti-cardiolipin antibody 4%-66% Thyroperoxidase 7%-16% Thyroglobulin 4% Rheumatoid factor 15%

BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21–30 years old, 9.0 per 100 patient-years for patients 31–40 years old, 14.0 per 100 patient-years for patients 41–50 years old, 15.2 per 100 patient-years for patients 51–60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn’s disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; P =.001 and HR, 0.90; P = .03, respectively) and malignancy (HR, 0.68; P = .008 and HR, 0.77; P = .004, respectively). Small-duct PSC was associated with a lower risk of LTD or malignancy compared with classic PSC (HR, 0.30 and HR, 0.15, respectively; both P < .001). Female sex was also associated with a lower risk of LTD or malignancy (HR, 0.88; P = .002 and HR, 0.68; P < .001, respectively). In multivariable analyses assessing the primary endpoint, small-duct PSC characterized a low-risk phenotype in both sexes (adjusted HR for men, 0.23; P < .001 and adjusted HR for women, 0.48; P = .003). Conversely, patients with ulcerative colitis had an increased risk of liver disease progression compared with patients with Crohn’s disease (HR, 1.56; P < .001) or no IBD (HR, 1.15; P = .002). CONCLUSIONS In an analysis of data from individual patients with PSC worldwide, we found significant variation in clinical course associated with age at diagnosis, sex, and ductal and IBD subtypes. The survival estimates provided might be used to estimate risk levels for patients wi...

In our series, 28% of HCCs contained cells expressing CK7 and/or CK19. They potentially derive from HPCs. The higher recurrence rate of CK19+ HCC after transplantation suggests a worse prognosis for these HCCs compared with CK19- HCC.

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Bilirubin is an endogenous compound that can be toxic under certain conditions but, on the other hand, mild unconjugated hyperbilirubinaemia might protect against cardiovascular diseases and tumour development. Serum bilirubin levels are often enhanced under a variety of clinical conditions. These are discussed and the mechanisms are outlined.Bilirubin is an endogenous compound that can be toxic (1), especially in neonates. However, it has recently been recognized that unconjugated bilirubin (UCB) exerts a strong anti-oxidant activity, and that mild hyperbilirubinaemia might have positive health effects. Bilirubin is the ultimate breakdown product of haemoglobin and serves as a diagnostic marker of liver and blood disorders. It has a complex metabolism, which is important in relation to several processes involved in drug metabolism. Bilirubin: chemical structure and formationAt first glance, bilirubin appears to be a simple molecule. However, the UCB IXa 4Z,15Z molecule, the major compound in mammals, has a peculiar stereo-chemical structure (Fig. 1). Indeed, all hydrophilic groups are involved in strong hydrogen bonds, and this turns the molecule into a closed molecule with a ridge-tile conformation (2, 3). These hydrogen bonds render UCB hydrophobic and they also shield the central -CH 2 -, which thus becomes inaccessible for the diazo-reagent (see further). Depending on the pH of the plasma, bile or urine, UCB can be present as uncharged diacid, as a monoanion or as a dianion (3). The uncharged diacid is by far the dominant species at low and physiological pH (4 80%) but the ionized fractions become more important in an alkaline milieu, because the pK'a values have been determined to be 8.12 and 8.44, respectively, for the first and for the second anion (3).Bilirubin is formed from haem by opening of the haem ring at the a carbon bridge. This cleavage is catalysed by the enzyme haem-oxygenase, and results in liberation of iron, and in the formation of carbonmonoxide and biliverdin IXa (Fig. 2). The latter is reduced by a cytosolic enzyme biliverdinreductase to bilirubin IXa. The haem-oxygenase can temporarily be inhibited by mesoporphyrins, and this suppression results in a decreased UCB production as was shown in neonates (4). Cleavage at non-a sites is possible; it is probably non-enzymic and occurs