3 Effects of celecoxib and naproxen on renal function in patients with cirrhosis and ascites: A double-blind randomized controlled trial

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Thursday, April 15, 2004 Opening & General Session 1: Clinical Hepatology & Transplantation 1 USE OF FATTY LIVERS: CLINICAL EXPERIENCE FROM 1000 TRANSPLANTATIONS

A. Franchello, A. Brunati, G. Liddo, D. Cocchis, F. Lupo, A. Giacardi, M. Salizzoni. Liver Transplantation Unit - Molinette Hospital, Turin, Italy Aims: To optimise the use of fatty livers, we evaluated the influence of several donor and recipient characteristics on the outcome of LT. Methods: 1000 consecutive LT performed in 912 patients between 19902002 were considered. The analysed variables were: donor-recipient age and sex, donor hepatic enzymes, bilirubin, total and warm ischemia time, macro-microvesicular steatosis, serum sodium levels, ICU stay, UNOS, Child, indication for LT. Liver biopsies were fixed in buffered formalin, paraffin embedded and stained with hematoxilin-eosin. Statistical analysis was performed using SPSS. Univariate survival was analysed by KaplanMeier method; variables with univariate significance were analysed using Cox multivariate regression model. Results: Multivariate analysis identified three variables independently associated with a worse outcome: macro-steatosis >15% (p=.0007, RR=1.37), donor age >65 yrs (p=.03, RR=1.16), HCV+ pts (p=.005, RR=1.18). Graft survival significantly decreased according to a continuous increment of macro-steatosis; a value >15% resulted already relevant for patient and graft survival (p=.0001, p=.0002). Total ischemia time, considered as continuous variable, significantly influenced patient and graft survival in the group of >15% macrosteatotic livers (p<.05, RR=1.13; p<.05, RR=1.34). In fatty livers group, donor age >65 years significantly influenced patient and graft survival (p=.016, RR=2.1; p=.001, RR=2.5). A significant worse prognosis of patient and graft was documented if>15% macrosteatosis was associated with HCV+ recipients (p=.0056, p=.013). In conclusion, macro-steatosis involving >15% of the hepatocytes identifies marginal livers. Such livers should be used, but we must be aware of the major risk when total ischemia time >8 hours, or donor age >65 years or HCV+ recipients are associated.

2 HEPATITIS C VIRUS (HCV) RECURRENCE IS AN EARLY AND SEVERE EVENT IN LIVING DONOR LIVER TRANSPLANTATION (LDLT)

M. Garcia-Retortillo 1 , X. Forns 1 , J.M. LLovet 1 , M. Navasa 1 , A. Massaguer 1 , A. Feliu 1 , M. Bruguera 1 , J. Fuster 2 , J.C. Garcia-Valdecasas 2 , A. Rimola 1 . 1 Liver Unit, IDIBAPS/Hospital Clinic, Barcelona, Spain; 2 Liver Transplantation Unit, IDIBAPS/Hospital Clinic, Barcelona, Spain The outcome of HCV recurrence in LDLT remains controversial. Aim: To assess prognostic factors associated with severe HCV recurrence (SR) after LT. Patients: A cohort of 117 consecutive HCV-infected patients undergoing LT from 3/2000 to 7/2003 were followed-up prospectively. LDLT was performed in 22 (19%) patients. SR was defined as the presence of cirrhosis in a liver biopsy and/or clinical decompensation. All variables potentially associated with SR were prospectively recorded. Protocol liver biopsies were performed at 3, 12 and 24 months, and when clinically indicated.

The association of these variables with SR was assessed by univariate and multivariate analysis. Results: Pre-transplantation viral load, genotype and indication for LT were similar between recipients of a cadaveric organ and LDLT. However, the latter had younger donors (p < 0.001), less graft steatosis (p=0.06), more biliary complications after LT (p < 0.001) and earlier and more severe acute hepatitis (higher ALT at 1 and 3 months; p < 0.001 and p=0.016). After a follow-up of 664 days (77-1319), 26 (22%) patients developed SR (clinical decompensation in 12). SR occurred in 17 (18%) of 95 patients receiving a cadaveric organ and in 9 (41%) of 22 undergoing LDLT. SR was associated (Kaplan-Meier) with LDLT (p=0.019) and ALT>76 U/L 3 months after LT (p=0.023). The only variable independently associated with SR was LDLT (p=0.042; OR=2.39, 95%CI:1.02-5.60). Conclusions: HCV disease recurrence is more aggressive in LDLT compared to cadaveric transplantation. This should be considered in LDLT programs, since may ultimately compromise graft and patient survival.

3 EFFECTS OF CELECOXIB AND NAPROXEN ON RENAL FUNCTION IN PATIENTS WITH CIRRHOSIS AND ASCITES: A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL

J. Claria 2 , J.D. Kent 7 , M. Lopez-Parra 2 , G. Escolar 3 , L. Ruiz-del-Arbol 5 , P. Gines 1 , W. Jimenez 4 , B. Bucelic 6 , V. Arroyo 1 . 1 Liver Unit - Institut De Malalties Digestives, Hospital Clínic, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Univerisity of Barcelona, Barcelona, Spain; 2 DNA Unit, Hospital Clínic, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Univerisity of Barcelona, Spain; 3 Hemotherapy and Hemostasis Laboratory, Hospital Clínic, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Univerisity of Barcelona, Spain; 4 Hormonal Laboratory, Hospital Clínic, Institut D’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Univerisity of Barcelona, Spain; 5 Department of Gastroenterology, Hospital Ramón Y Cajal, Madrid, Spain; 6 Department of Gastroenterology, Clinical Hospital Center Rebro, Zagreb, Croatia; 7 Pfizer Global Pharmaceuticals, Stokie IL, USA Non-selective inhibition of cyclooxygenase (COX) by nonsteroidal antiinflammatory drugs frequently induces renal failure in decompensated cirrhosis. Studies in experimental cirrhosis suggest that selective inhibitors of the inducible isoform COX-2, which posses anti-inflammatory activity, do not adversely affect renal function. However, there are no studies in human cirrhosis using these compounds. This investigation was a double-blind, randomized, placebo-controlled trial aimed at comparing the effects of the selective COX-2 inhibitor celecoxib (200 mg every 12 hours for a total of 5 doses) on platelet and renal function, and the renal response to furosemide (40 mg i.v.) with those of naproxen (500 mg every 12 hours for a total of 5 doses), and placebo in 26 patients with cirrhosis and ascites. A significant reduction (p<0.05) in glomerular filtration rate (113±27 to 84±22 ml/min), renal plasma flow (592±158 to 429±106 ml/min), urinary prostaglandin E2 excretion (3430±430 to 2068±549 pg/min), and suppression of the diuretic (urine volume: 561±128 to 414±107 ml/h) and natriuretic (urine sodium: 53±13 to 34±10 mEq/h) responses to furosemide were observed in naproxen-treated patients compared with celecoxib and placebo. Naproxen, but not celecoxib or placebo, significantly inhibited platelet aggregation (72±8 to 47±8%, p<0.05) and ex-vivo thromboxane B2 production (41±12 to 14±5 pg/ml, p<0.05). These results suggest that selective COX-2 inhibition with celecoxib does not impair platelet and renal function or the response to diuretics in decompensated cirrhosis.

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Thursday, April 15, 2004

Celecoxib may be the anti-inflammatory option of choice in patients with this condition.

4 INHIBITION OF VEGF RECEPTOR-2 (VEGFR-2) SIGNALING

sion in the placenta. In patients with ICP who received UDCA a significant increase in MRP2 expression was observed (p<0.03). Conclusions: MRP2 protein expression is induced by the administration of UDCA in ICP. This may account, at least partially, for the efficacy of UDCA in ICP

PREVENTS PORTAL-SYSTEMIC COLLATERAL (PSC) VESSEL FORMATION IN RATS WITH PORTAL HYPERTENSION (PH)

M. Fernandez, M. Mejias, B. Angermayr, J.C. Garcia-Pagan, J. Rodes, J. Bosch. Hepatic Hemodynamic Laboratory, Liver Unit, IDIBAPS, Hospital Clinic, Barcelona, Spain Background & Aim: The development of PSC vessels in PH is highly relevant since these vessels are responsible for the most serious clinical consequences of PH, including hepatic encephalopathy and massive bleeding from ruptured gastroesophageal varices. To test whether the development of PSC vessels in PH involves angiogenesis, we determined the effects of an anti-angiogenic therapy in rats with PH induced by partial portal vein ligation (PPVL). Methods: PH rats were treated with a specific inhibitor of VEGFR-2 (SU5416; 20 mg/kg/day, i.p.) or vehicle from PPVL to day 5. The extent of PSC vessel formation, as well as systemic and splanchnic hemodynamics were determined using radioactive microspheres. Results: A marked inhibition in the formation of PSC vessels was observed in SU5416-treated PPVL rats, compared with those receiving vehicle (52% inhibition; 61.4±6% vs. 29.3±6%; P<0.01). Blockade of VEGFR-2 in PPVL rats was also associated to a significant decrease in portal venous inflow (7.1±0.9 vs. 3.9±0.5 ml/min 100g,P<0.05) and increased splanchnic arteriolar resistance (13.9±1.7 vs. 23.4±2.2 mmHg/ml/min 100g, P<0.05) and portal venous resistance (2.2±0.3 vs. 4.3±0.4 mmHg/ml/min 100g, P<0.01), without modifying portal pressure (14.1±1.13 vs. 15.4±1.23 mmHg). The effects of SU5416 were specific for the splanchnic vascular area, since no significant changes were observed on systemic hemodynamics: mean arterial pressure (103.9±6.7 vs. 98.6±5.9 mmHg), cardiac index (66.2±22.0 vs. 46.9±7.0 ml/min 100g), and systemic vascular resistance (2.2±0.4 vs. 2.7±0.6 mmHg/ml/min 100g). Conclusion: This study demonstrates that formation of PSC vessels and splanchnic vasodilation in PH rats are angiogenesis-dependent processes that can be markedly inhibited by blockade of VEGF signaling.

5 MRP2 IS UPREGULATED BY UDCA IN CHOLESTASIS OF PREGNANCY

F. Azzaroli, V. Feletti, C. Mazzeo, P. Simoni, S. Giovanelli, G. Nigro, A. Miracolo, F. Lodato, A. Roda, E. Roda, G. Mazzela. Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy Introduction: Increased bile acids (BA) in the foetal compartment is one of the factors involved in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP) a disease that may be harmful for the foetus. Recently, the presence of BA transporters in the placenta, among which MRP2, has been described. The treatment of choice is UDCA whose effects on human placenta are still undefined. Aim of our study was to evaluate whether UDCA could induce MRP2 expression in the placenta. Materials and Methods: 30 pregnant women were enrolled. 10 were controls with physiologic pregnancies and 20 with ICP. The latter were divided in two groups: 1) UDCA (20 mg/kg/day), 2) untreated. Routine liver test and BA in serum, cord blood and amniotic fluid were determined in each subject. Placentas were collected at the time of delivery for subsequent evaluation, by immunoblotting and immunofluorescence, of MRP2 protein expression. Statistical differences between groups were calculated with t test for paired and unpaired data. Results: UDCA induced a significant improvement in transaminases and serum BA compared to untreated patients with ICP as well as a reduction in bile acids in all compartments. No significant difference was observed between controls and untreated ICP with regard to MRP2 protein expres-

6 GENETIC AND ENVIRONMENTAL INFLUENCES FOR GALLSTONE DISEASE-RELATED DIAGNOSES: A SWEDISH TWIN STUDY OF 43,141 TWIN PAIRS

D. Katsika 1 , A. Grjibovski 2 , F. Lammert 3 , C. Einarsson 1 , P. Lichtenstein 4 . 1 Karolinska Institutet, Dept. of Medicine, Div. of Gastroenterology and Hepatology, Huddinge University Hospital, Stockholm, Sweden; 2 Karolinska Institutet, Unit For Preventive Nutrition At NOVUM, Stockholm, Sweden; 3 University Hospital, Dept. of Internal Medicine III, University of Technology, Aachen, Germany; 4 Karolinska Institutet, Dept. of Medical Epidemiology and Biostatistics, Stockholm, Sweden Background: The pathogenesis of gallstone disease still is unclear. We aimed to estimate the relative importance of genetic and environmental factors by analyzing a large twin population. Methods: The Swedish Twin Registry was linked with the Inpatient Registry and Causes of Death Registries for gallstone disease and gallstone surgery-related diagnoses (ICD 8, 9, 10) in twin pairs with known zygosity (n=43141) born between 1900 and 1958. Concordance, relative risk and correlations were calculated for males, females, MZs and DZs, as well as for twins with opposite gender. Structural equation modelling techniques were used to decompose the phenotypic variance into genetic effects (additive A and/or dominant D) as well as common (C) and unique environmental factors (E). A series of models was analysed to find the model that had the best fit to data. Results: Correlations were in all cases higher in MZs compared to DZs, both for males and females. There were no significant gender-related differences in heritability. In a full model, genetic effects (A) accounted for 25% (9%-40%) of liability, common environmental effects (C) for 13% (1%25%) and unique environmental effects for 62% (56%-68%); In the best fitting model A was estimated 41% (36%-46%); and E 59% (54%-64%). Conclusion: Our results show heritability, along with unique environmental factors, to be a major factor (25-41%) determining gallstone disease, which is consistent with previous much smaller studies. FOOTNOTE: The Swedish Twin Registry is supported by grants from the Swedish Research Council and the National Institute of Health, USA, grant AG 08724.

Parallel Session 1: Liver Transplantation

7 LIVER TRANSPLANTATION AFTER NON HEART BEATING MULTI-ORGAN DONATION, FIRST RESULTS OF A NEW TECHNIQUE IN THE NETHERLANDS

J. Dubbeld 1 , B. Hoek 2 , R.J. Porte 3 , M.J. Slooff 3 , J.N.M. IJzermans 4 , H.W. Tilanus 4 , A.F.M. Schaapherder 1 , A. Baranski 1 , J. Ringers 1 . 1 Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands; 2 Department of Hepatology, Leiden University Medical Centre, Leiden, The Netherlands; 3 Department of Surgery, University Hospital Groningen, Groningen, The Netherlands; 4 Department of Surgery, Erasmus University Medical Centre Rotterdam, Rotterdam, The Netherlands Background: Growing waiting lists and shortages of donor organs have led to an increased morbidity and mortality on the waiting lists for liver