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INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.

BACKGROUND AND AIM: Patients with liver cirrhosis and ascites have a poor prognosis with increased risk of infection related death, as advanced stages of cirrhosis are associated with immunodeficiency. We aimed to investigate immunologically active molecules in ascitic fluid and blood and their potential association to survival.MATERIALS AND METHODS: In an exploratory pilot study; blood and ascitic fluid from 34 patients with liver cirrhosis of different etiology were analyzed for pattern recognition molecules (ficolin-1, ficolin-2, ficolin-3 and MBL) and complement proteins (C4 and C3). An observational follow-up study (minimum 17 months) was conducted to assess the association to all-cause mortality or liver transplantation.RESULTS: Ficolin-1, ficolin-2, MBL, C4 and C3 in ascitic fluid and ficolin-1, C4 and C3 in blood were significantly (p = .001-.027) lower in patients with Child-Pugh stage C (n = 16, 47%) compared to Child-Pugh stage B cirrhosis (n = 18, 53%). In multivariate COX-regression analysis low levels of ficolin-1(p = .036) and C3 (p = .025) in ascitic fluid and C4(p = .005) and C3 (p = .032) in serum were associated with all-cause mortality or liver transplantation independent of Child-Pugh score.CONCLUSION: Levels of lectin-complement pathway molecules in ascitic fluid and blood are lower in patients with more advanced stage of cirrhosis. Low C4 and C3 in serum and C3 and ficolin-1 in ascitic fluid are risk factors for all-cause mortality or liver transplantation independently of liver function in patients with cirrhosis and ascites.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) may be complicated by primary sclerosing cholangitis (PSC). We aimed to assess the characteristics of Danish PSC-IBD patients and to compare their prognosis with IBD patients without PSC.METHODS: A retrospective nationwide population-based cohort of 257 PSC-IBD patients was assessed through Danish national registries and manual scrutiny of patient files.RESULTS: For all PSC-IBD patients diagnosed after 1976 (n = 222) and 8231 IBD controls (ie, without PSC), the cumulative probability of resective surgery, liver transplantation, cancer, and survival from 1977 through 2011 was estimated and compared by log-rank test and Cox regression. PSC-IBD patients primarily had ulcerative colitis (UC) (72%), were diagnosed in young adulthood (median age at IBD diagnosis, 23 years), and 9% were smokers. Among PSC-UC patients 78% had pancolitis at diagnosis. Among patients with PSC and Crohn's disease (CD) 91% had colonic involvement. The PSC-IBD patients had a significantly higher probability of receiving resective surgery (HR; 2.13, 95% CI: 1.50-3.03); of developing colorectal cancer (CRC) (HR; 21.4, 95% CI: 9.6-47.6), of cholangiocarcinoma (HR; 190, 95% CI: 54.8-660), and of dying (HR; 4.39, 95% CI: 3.22-6.00) as compared to non-PSC-IBD controls. The 25-year cumulative risk of liver transplantation was high (53%).CONCLUSIONS: This unselected population-based study shows that PSC-IBD patients not only have an extensive phenotype of IBD, they are also treated more intensively than other patients with IBD. However, the prognosis remains poor and without any apparent improvement over calendar time.

OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors of poor outcome.MATERIALS AND METHODS: We identified all patients diagnosed with DILI at the Department of Hepatology, Rigshospitalet, from March 2007 to November 2012. The following parameters were registered from patient files: drug causing DILI, symptoms, comorbidity, biochemistry, treatment and outcome.RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent biochemical findings included bilirubin elevated to above 3.2 × ULN, ALT elevated to above 9 × ULN in 86%, INR above 1.4 in 70%. Twenty two patients needed treatment in the liver intensive care unit. Fifteen patients developed acute liver failure with a severe outcome. Six patients were liver transplanted and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome.CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome.

Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are central components of the MBL pathway of complement activation, and may have potential as clinical biomarkers in colorectal cancer (CRC). Prior to clinical usage, knowledge of the biological variations of the molecules is needed. We here investigate variations of MBL and MASP-2 in healthy persons over time and in relation to gender, age and physical activity. MBL and MASP-2 concentrations were determined in serum from healthy adults over a 3-week period and this was repeated 6 months later (n = 32); during a 24-h period (n = 16); and in relation to physical exercise (n = 14). Concentrations in serum and plasma were compared (n = 198). No significant variation over 6 months and no circadian variation was found for MBL (P = 0.39 and P = 0.34 respectively) or MASP-2 (P = 0.54 and P = 0.55). Physical exercise did not affect the levels (P > 0.8). Serum and plasma levels were only marginally different, and were independent of age and gender. Circulating levels of MBL and MASP-2 are stable over time in healthy individuals, which is advantageous for their potential application as biomarkers. Udgivelsesdato: oktober, Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are central components of the MBL pathway of complement activation, and may have potential as clinical biomarkers in colorectal cancer (CRC). Prior to clinical usage, knowledge of the biological variations of the molecules is needed. We here investigate variations of MBL and MASP-2 in healthy persons over time and in relation to gender, age and physical activity. MBL and MASP-2 concentrations were determined in serum from healthy adults over a 3-week period and this was repeated 6 months later (n = 32); during a 24-h period (n = 16); and in relation to physical exercise (n = 14). Concentrations in serum and plasma were compared (n = 198). No significant variation over 6 months and no circadian variation was found for MBL (P = 0.39 and P = 0.34 respectively) or MASP-2 (P = 0.54 and P = 0.55). Physical exercise did not affect the levels (P > 0.8). Serum and plasma levels were only marginally different, and were independent of age and gender. Circulating levels of MBL and MASP-2 are stable over time in healthy individuals, which is advantageous for their potential application as biomarkers.

The mannan-binding lectin (MBL) pathway of complement activation is important in host defence against pathogens and possibly against cancer. We investigated the effect of major surgery on two central components of the MBL pathway; MBL and the MBL-associated serine protease MASP-2, and for comparison also measured the interleukin (IL)-6 and C-reactive protein (CRP) levels. Serial blood samples were obtained from patients belonging to two different cohorts. Cohort 1 comprised 60 patients undergoing open or laparoscopic colectomy for benign disease (n = 12) or colon cancer (n = 48). Cohort 2 comprised 27 patients undergoing elective, open surgery for colorectal cancer, and was included in order to cover blood sampling between days 2 and 6. As expected, the surgical stress induced a marked acute phase response, as evidenced by a large increase in IL-6 (18-fold) and CRP (13-fold) levels with maximum at 12 h and 2 days, respectively. However, in both cohorts the levels of MBL and MBL-associated serine protease 2 (MASP-2) were largely unaffected, except for a minor but significant increase around day 8 in cohort 1. The preoperative levels of IL-6 and CRP were correlated significantly in both cohorts (r = 0.71, P < 0.0001 and r = 0.65, P = 0.005, respectively). Preoperative MASP-2 correlated with preoperative CRP (r = 0.59, P = 0.001) and IL-6 (r = 0.55, P = 0.02) in cohort 2 only. In contrast to the marked effects on the levels of IL-6 and CRP, the surgery influenced only marginally the two proteins of the MBL pathway.

OBJECTIVE: Sixty to 70% of upper gastrointestinal bleeding episodes in patients with cirrhosis are caused by oesophageal varices. Prophylaxis is indicated in patients with varices and a hepatic venous pressure gradient (HVPG) above 12 mmHg. The study of the natural history of patients with lower HVPG has been sparse. In this study, long-term survival and the risk of complications in mild portal hypertension were analysed. MATERIAL AND METHODS: Sixty-one patients with cirrhosis and HVPG below 10 mmHg were included in the study. Data were collected from medical files and National Patient Registries. Variceal bleeding, hepatic encephalopathy and death related to cirrhosis were registered. Thirty-nine patients were graded as Child class A, 19 as class B and 3 as class C. Median survival time was 11 years. RESULTS: Twenty-eight patients (46%) developed one or more complications: variceal bleeding in 10 (16%) and hepatic encephalopathy in 18 patients (30%). Twenty-three patients (38%) died from complications of cirrhosis. Two patients (3%) died from variceal bleeding, another two (3%) from gastrointestinal bleeding of unidentified source. Survival rate was significantly decreased compared with that in the background population. CONCLUSIONS: The frequency of complications in patients with mild portal hypertension is considerable, and guidelines for follow-up or medical prophylaxis are warranted. The risk of bleeding from oesophageal varices is low and bleeding-related deaths rare.

PURPOSE: Mannan-binding lectin-associated serine protease 2 (MASP-2) is a plasma protein involved in inflammatory processes. MASP-2 circulates in complex with the protein mannan-binding lectin (MBL) or ficolins, and is activated to recruit the complement system when MBL binds to its targets. The level of MASP-2 is genetically determined, and the aim of the present study was to evaluate the effect of MASP-2 levels on postoperative infection, recurrence and survival. EXPERIMENTAL DESIGN: MASP-2 concentrations were determined in serum from 605 patients collected before elective resection for primary colorectal cancer. The primary end points were postoperative infection, time to any recurrence, and time to death. The median time of follow-up was 7.9 years. RESULTS: MASP-2 levels were not correlated to postoperative infections (P = 0.49). High MASP-2 levels significantly correlated with recurrent cancer disease [P = 0.03; hazard ratio (HR) = 1.4; 95% confidence interval (CI), 1.0-2.0] and with poor survival (P = 0.0005; HR = 1.4; 95% CI, 1.2-1.7). Multivariate statistical analysis, including age, gender, Dukes' stage of disease, tumor localization, and postoperative pneumonia, showed that the MASP-2 level had an independent prognostic value in the patients (P = 0.0001; HR = 1.5; 95% CI, 1.2-1.8). CONCLUSION: In the cohort of patients with colorectal cancer investigated, MASP-2 concentration in serum proved to be an independent prognostic marker with high MASP-2 levels predicting recurrence and poor survival. Postoperative infection could not be shown to be associated with MASP-2 levels