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...

Chronic ethanol ingestion leads to an enhanced risk of upper gastrointestinal tract cancer. Although many hypotheses for the tumor promoting effect of alcohol exist, the pathogenetic mechanisms remain unclear since alcohol in itself is not carcinogenic. Acetaldehyde, the first metabolite of ethanol, has been shown to have multiple mutagenic effects and to be carcinogenic to animals. Previous research has revealed that acetaldehyde can be formed from ethanol via microbial alcohol dehydrogenase. Thus, at least part of the proposed tumorigenic effect of ethanol may be linked to local production of acetaldehyde from ethanol by oral microflora. In this study we demonstrate the production of marked amounts of acetaldehyde in saliva after ingestion of moderate amounts of ethanol. Considerable inter individual variation in acetaldehyde production capacity is also shown. In vivo acetaldehyde production is significantly reduced after a 3-day use of an antiseptic mouthwash (chlorhexidine). In vitro acetaldehyde production was shown to be linear in time, inhibited by 4-methylpyrazole and it could not be saturated under ethanol conditions that are relevant in vivo. There was a significant positive correlation between salivary acetaldehyde production in vitro and in vivo. We conclude, that the microbial formation of acetaldehyde in saliva could be one explanation for the tumor promoting effect of ethanol on the upper gastrointestinal tract. Moreover, this may support the epidemiological finding, that poor oral hygiene is an independent risk factor for oral cavity cancer.

Induction of NF-kappaB-mediated gene expression has been implicated in the pathogenesis of alcoholic liver disease (ALD). Curcumin, a phenolic antioxidant, inhibits the activation of NF-kappaB. 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(-1). day(-1) of curcumin. Liver samples were analyzed for histopathology, lipid peroxidation, NF-kappaB binding, TNF-alpha, IL-12, monocyte chemotactic protein-1, 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-kappaB 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-kappaB 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-kappaB-dependent genes.

Alcoholic liver injury is a complex process involving several injury mechanisms and multiple cellular targets. 1