962 HEPATOCELLULAR CARCINOMA DOES NOT SIGNIFICANTLY CONTRIBUTE TO THE RISK OF HEPATOBILIARY MALIGNANCY IN CIRRHOTIC PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS

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    for detoxication and elimination by glucuronidation, which

    is also regulated via the xenobiotic-activated arylhydrocarbon

    receptor (AhR) and the oxidative stress sensor nuclear factor

    erythroid 2-related factor 2 (Nrf2). Aim of this study was

    to elucidate transcriptional UGT1A regulation in vivo during

    obstructive cholestasis and the effects of exposure to the potentially

    benecial FXR agonist GW4064.

    Methods: TgUGT1A WT mice were subjected to BDL for 5 days,

    4 days intraperitoneal (i.p.) injection of GW4064, or 4 days

    i.p. GW4064 injection after BDL. Liver histology, serum bilirubin

    levels and aminotransferase activities (AST, ALT) as well as UGT1A

    gene expression (TaqMan-PCR in liver, jejunum and colon) were

    determined. Additionally, hepatic AhR-, Nrf2-, FXR-, IL6- and

    TNFa-mRNA-expression was quantied.Results: In BDL/BDL+GW4064 mice, upregulation of hepatic IL6

    and TNFa expression (2.7-, 2.4-fold) was observed in additionto signicantly increased bilirubin and AST/ALT levels correlating

    with increased histological injury. While no effect on hepatic Nrf2

    expression was seen in BDL/BDL+GW4064 mice, AhR expression in

    the liver was profoundly reduced. In GW4064 treated mice, UGT1A

    gene expression was signicantly activated in the liver (25-fold)

    and colon (2.445-fold). After BDL, hepatic UGT1A genes showed

    a 24-fold increase, contrasting intestinal activation observed only

    for UGT1A3 (37-fold) and UGT1A4 (227-fold). In BDL+GW4064

    mice, only UGT1A4 (6-fold) and UGT1A6 (1.4-fold) were signicantly

    induced in colon; no further signicant induction was observed in

    liver or jejunum.

    Conclusion: Unexpectedly, administration of the putative

    protective FXR agonist GW4064 during cholestasis resulted in an

    increased inammatory response (IL6, TNFa), increased liver injury(ALT/AST, histology) and inhibition of hepatic AhR expression,

    rather than FXR-mediated UGT1A upregulation. As previously

    shown (Kalthoff et al. JBC, 2010), transcriptional UGT1A activation

    requires coactivation of both Nrf2 and AhR, which is impaired

    by eliminating an AhR response demonstrated in this study. This

    inhibits a protective UGT1A response. Therefore, the development of

    more specic candidate substances for the treatment of cholestatic

    liver diseases is needed.

    961

    EFFECT OF URSODEOXYCHOLIC ACID WITHDRAWAL IN PATIENTS

    WITH PRIMARY SCLEROSING CHOLANGITIS

    E. Wunsch1, J. Trottier2, O. Barbier2, P. Milkiewicz1. 1Liver Unit,

    Pomeranian Medical University in Szczecin, Szczecin, Poland;2Laboratory of Molecular Pharmacology, CHU-Quebec & Faculty of

    Pharmacy, Laval University, Quebec, QC, Canada

    E-mail: ewa.wunsch@gmail.com

    Background and Aims: Recent AASLD Guidelines recommend

    against the use of ursodeoxycholic acid (UDCA) in adult patients

    with PSC. In this study we investigated the effect of UDCA

    withdrawal on liver biochemistry, bile acids (BA) proles and

    health-related quality of life (HRQoL) in a group of well

    characterized subjects with primary sclerosing cholangitis (PSC).

    Methods: Twenty six patients with PSC (16 males/10 females, mean

    age 3310.5 years) were included. They have all been treated fora period of at least 12 months with a low dose of UDCA (range

    1015mg/kg b.w.). Paired blood samples for liver biochemistry and

    BA were collected one day before UDCA withdrawal and 3 months

    after. Liquid chromatography coupled with mass spectrometry (LC-

    MS/MS) was used for the identication and quantication of 18

    plasma BA metabolites. VAS score was applied for the assessment

    of pruritus and PBC-40 questionnaire for evaluation of HRQoL.

    Results: Signicant elevation of ALP (from 249U/l to 439U/l,

    p < 0.0001); GGTP (from 301U/l to 656U/l, p < 0.0001); ALT

    (from 81U/l to 133U/l, p < 0.005) and total bilirubin (from

    1.6mg/dl to 2.4mg/dl, p < 0.05) was seen after UDCA withdrawal

    (all biochemistry data shown as mean). BA analysis has

    shown, as expected, a signicant decrease of UDCA and its

    taurine/glycine conjugates in BA pool. It also revealed that

    UDCA discontinuation causes a signicant decrease of lithocholate

    (p = 0.001), sulfolithocholate (p = 0.002), glycolithocholate (p = 0.01)

    but not taurolithocholate (p = 0.12). No effect on cholate,

    chenodeoxycholate, deoxycholate and their taurine/glycine

    conjugates, hyocholate and hyodeoxycholate concentrations was

    seen after UDCA withdrawal. Five (19%) patients experienced

    worsening of their pruritus in VAS score. Six (23%) and eight (31%)

    reported deterioration in fatigue and social/emotional domain of

    PBC-40 questionnaire respectively after UDCA withdrawal.

    Conclusions: Discontinuation of low-dose UDCA in patients with

    PSC causes signicant deterioration of liver biochemistry. It also

    affects concentrations of bile acids metabolites causing decrease of

    lithocholate and its sulfo- and glyco-conjugates. Furthermore UDCA

    discontinuation exerts a negative effect on HRQoL in a proportion

    of patients with PSC.

    962

    HEPATOCELLULAR CARCINOMA DOES NOT SIGNIFICANTLY

    CONTRIBUTE TO THE RISK OF HEPATOBILIARY MALIGNANCY IN

    CIRRHOTIC PATIENTSWITH PRIMARY SCLEROSING CHOLANGITIS

    R. Zenouzi1, T. Weismuller2, P. Hubener1, K. Schulze1,

    M. Bubenheim3, M.P. Manns4, A.W. Lohse1, C. Schramm1. 11st

    Medical Clinic and Polyclinic, University Clinic Hamburg-Eppendorf,

    Hamburg, 2Medical Clinic and Polyclinic I, University Clinic Bonn,

    Bonn, Germany; 3Biostatistics Department, Rouen University

    Hospital-Charles Nicolle, Rouen, France; 4Clinic for Gastroenterology,

    Medical University Hannover, Hannover, Germany

    E-mail: rzenouzi@uke.de

    Background and Aims: Primary sclerosing cholangitis (PSC)

    is associated with an increased risk of hepatobiliary and

    gastrointestinal malignancy. There are few studies evaluating the

    risk of hepatocellular carcinoma (HCC) in PSC cirrhosis and a

    frequency of HCC in PSC patients of 2% has been suggested. The aim

    of this study was to determine the risk of HCC in PSC cirrhosis and

    to compare it to the risk of cholangiocarcinoma (CCA), gall bladder

    cancer (GBC) and colorectal cancer (CRC).

    Methods:We included 509 patients with well dened PSC receiving

    a regular surveillance program with ultrasound and/or MRI of the

    liver into this retrospective study. Liver cirrhosis was assumed if

    ascites, oesophageal varices, a transient elastography value >14kPa

    or a positive liver histology were present. Survival and risk analyses

    were performed using the KaplanMeier method and the Cox

    proportional hazard model. As no HCC was observed, the upper

    limit of the 95% condence interval (CI) for its instantaneous risk

    was estimated as the ln(0.05)/patient-years.

    Results: A total of 3954 patient-years were analyzed. 67% of

    patients were male. In 119 patients (23%) liver cirrhosis was

    diagnosed at rst presentation or during follow-up. Not a single

    HCC was detected in 245 patient-years with cirrhosis. Therefore

    the estimated upper limit of the 95% condence interval for the

    instantaneous risk of HCC in cirrhotic-stage PSC was 1.2%. CCA

    (n =35) was the most frequent malignancy followed by CRC (n =9)

    and GBC (n =3). 20% of CCA developed within the rst year of

    diagnosis. Excluding these cases the cumulated risk of CCA after

    10 and 20 years was 4.7% and 14.4%. The development of CCA

    was independent from sex and smoking and there was a trend

    towards a lower risk for CCA of patients treated with azathioprine

    (HR 0.16, 95%CI 0.021.17, p = 0.07, versus no azathioprine). Median

    transplantation-free survival in the whole cohort was 15 years

    (95%CI 13.716.3 years).

    Conclusions: Whereas we here conrm that the risk of

    hepatobiliary malignancy is high in PSC, the risk of HCC in PSC

    cirrhosis was low. A surveillance strategy for HCC in PSC cirrhosis

    may not be warranted.

    S396 Journal of Hepatology 2013 vol. 58 | S229S407

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