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Background & aimsPrimary 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.MethodsWe 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.ResultsOf 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).ConclusionsIn 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 with PSC and select patients for clinical trials.

Induction of NF-[kappa]B-mediated gene expression has been implicated in the pathogenesis of alcoholic liver disease (ALD). Curcumin, a phenolic antioxidant, inhibits the activation of NF-[kappa]B. We determined whether treatment with curcumin would prevent experimental ALD and elucidated the underlying mechanism. Four groups of rats (6 rats/group) were treated by intragastric infusion for 4 wk. One group received fish oil plus ethanol (FE); a second group received fish oil plus dextrose (FD). The third and fourth groups received FE or FD supplemented with 75 mg. [kg.sup.-]*[day.sup.-] of curcumin. Liver samples were analyzed for histopathology, lipid peroxidation, NF-[kappa]B binding, TNF-[alpha], IL-12, monocyte chemotactic protein-I, macrophage inflammatory protein-2, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitrotyrosine. Rats fed FE developed fatty liver, necrosis, and inflammation, which was accompanied by activation of NF-[kappa]B and the induction of cytokines, chemokines, COX-2, iNOS, and nitrotyrosine formation. Treatment with curcumin prevented both the pathological and biochemical changes induced by alcohol. Because endotoxin and the Kupffer cell are implicated in the pathogenesis of ALD, we investigated whether curcumin suppressed the stimulatory effects of endotoxin in isolated Kupffer cells. Curcumin blocked endotoxin-mediated activation of NF-[kappa]B and suppressed the expression of cytokines, chemokines, COX-2, and iNOS in Kupffer cells. Thus curcumin prevents experimental ALD, in part by suppressing induction of NF-[kappa]B-dependent genes. antioxidants; cyclooxygenase; nitric oxide

Nanji, Amin A., Kalle Jokelainen, Maryam Fotouhinia, Amir Rahemtulla, Peter Thomas, George L. Tipoe, Grace L. Su, and Andrew J. Dannenberg. Increased severity of alcoholic liver injury in female rats: role of oxidatire stress, endotoxin, and chemokines. Am J Physiol Gastrointest Liver Physiol 281: G1348-G1356, 2002.--Alcoholic liver injury is more severe and rapidly developing in women than men. To evaluate the reason(s) for these gender-related differences, we determined whether pathogenic mechanisms important in alcoholic liver injury in male rats were further upregulated in female rats. Male and age-matched female rats (7/group) were fed ethanol and a diet containing fish oil for 4 wk by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. We analyzed liver histopathology, lipid peroxidation, cytochrome P-450 (CYP)2E1 activity, nonheme iron, endotoxin, nuclear factor-KB (NF-[kappa]B) activation, and mRNA levels of cyclooxygenase-1 (COX-1) and COX-2, tumor necrosis factor-[alpha] (TNF-[alpha]), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2). Alcohol-induced liver injury was more severe in female vs. male rats. Female rats had higher endotoxin, lipid peroxidation, and nonheme iron levels and increased NF-[kappa]B activation and upregulation of the chemokines MCP-1 and MIP-2. CYP2E1 activity and TNF-[alpha] and COX-2 levels were similar in male and female rats. Remarkably, female rats fed fish oil and dextrose also showed necrosis and inflammation. Our findings in ethanol-fed rats suggest that increased endotoxemia and lipid peroxidation in females stimulate NF-[kappa]B activation and chemokine production, enhancing liver injury. TNF-[alpha] and COX-2 upregulation are probably important in causing liver injury but do not explain gender-related differences. cytokines; cyclooxygenase-2; tumor necrosis factor-[alpha]

Objective: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to bile duct strictures and fibrosis, and predisposing to cholangiocarcinoma (CCA). Biliary dysplasia is a known precursor of CCA. In our unit, PSC patients undergo regular surveillance with ERC and brush cytology (BC), and liver transplantation is an option in case with biliary dysplasia. We evaluated the risk factors for biliary dysplasia and CCA based on ERC imaging, BC and liver function tests. Patients and methods: Seven hundred and eighty-eight ERCs were performed with BC for 447 PSC patients. ERC images were evaluated using the modified Amsterdam score, neutrophilic inflammation was assessed in BC, and liver function tests were collected. Ploidy analysis with DNA flow cytometry was performed in cases with advanced PSC or previous suspicious BC/aneuploidy. The endpoint was either a benign disease course (follow-up for ≥2.4 years after the latest ERC), benign histology, biliary dysplasia or CCA. Results: Benign disease course was seen in 424/447 (including 23 cases with biliary dysplasia), and CCA in 17 (3.8%) patients. Gallbladder carcinoma/carcinoma in situ was diagnosed in three patients. Advanced ERC findings, male gender, suspicious BC, aneuploidy in flow cytometry, inflammation, and elevation of ALP, bilirubin, ALT, AST, GGT, CEA and CA19-9 represented significant risk factors for CCA in univariate analysis. Conclusions: PSC patients with advanced bile duct disease and elevated liver enzymes, CEA or CA19-9, inflammation or suspicious BC are most likely to develop CCA. These patients may benefit from surveillance with BC if early liver transplantation is possible. [ABSTRACT FROM AUTHOR]

Background and study aims  Endoscopic retrograde cholangiopancreatography (ERCP) procedures may result in remarkable radiation doses to patients and staff. The aim of this prospective study was to determine occupational exposures in gastrointestinal endoscopy procedures, with a special emphasis on eye lens dose in ERCP. Methods  Altogether 604 fluoroscopy-guided procedures, of which 560 were ERCPs belonging to four American Society for Gastrointestinal Endoscopy procedural complexity levels, were performed using two fluoroscopy systems. Personal deep-dose equivalent H p (10), shallow-dose equivalent H p (0.07), and eye lens dose equivalent H p (3) of eight interventionists and H p (3) for two nurse dosimeters were measured. Thereafter, conversion coefficients from kerma-area product (KAP) for H p (10), H p (0.07), and H p (3) were determined and dose equivalents per procedure to an operator and assisting staff were estimated. Further, mean conversion factors from H p (10) and H p (0.07) to H p (3) were calculated. Results  The median KAP in ERCP was 1.0 Gy·cm 2 , with mobile c-arm yielding higher doses than a floor-mounted device ( P  < 0.001). The median H p (3) per ERCP was estimated to be 0.6 µSv (max. 12.5 µSv) and 0.4 µSv (max. 12.2 µSv) for operators and assisting staff, respectively. The median H p (10) and H p (0.07) per procedure ranged from 0.6 to 1.8 µSv. ERCP procedural complexity level ( P  ≤ 0.002) and interventionist ( P  < 0.001) affected dose equivalents. Conclusions  Occupational dose limits are unlikely to be exceeded in gastrointestinal endoscopy practice when following radiation-hygienic working methods and focusing on dose optimization. The eye lens dose equivalent H p (3) may be estimated with sufficient agreement from the H p (10) and H p (0.07)., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)