lipids peroxidation which resuh in deterioration of energy production in the liver. Apocynin fbr the inactivation of KCs. As a result, PP SEC is more resistant to the attack of activated may become a cbnicaI tool to lacilitate liver regeneration afier liver resection KC through ROS, which can be compensated tbr KC's concentrated distribution in PP.

S1558

Morbidity and Mortality of Elderly Patients After Surgery of Liver Metastases Uwe Pohlen, H. Ringer, G. Bmger, i{ J. Buhr

Introduction and oblective: Colorectal carcinomas are the second most common cause of death irt western industrialized natiorks Liver metastases develop in 50% of the patients. About 5% of the population is >75 years Thus, the question increasingly arises as to whether an elderly patient should undergo liver resection. The aim of this study was to compare the nmrNdity, mortality and survival of patmnts >75 years to that of patients <75 years aker curative surgery of colorectal liver metastases. Patients and methods: From 1988- 1998, 158 patients with colorectal liver n'tetastases underwent R0 surgery in our department. ]'wenty~one panents (I3%) were >75 years and 137 (67%) <75 years. Results: Lister in the table. Conclusion Liver resection has become an intervention with a calculable risk due to improved surgical techniques and intensive caw med*cine This intervention can even be pertbrmed in patients >75 years with a mortal W of 5% and a major morbidity of 10% There was no sigmflcant difference between the morbidity, mortality and survival of patients <75 ?~ars and those >75 years

,=75 years n=137 (67%) >75 years n=21 (13%) 'DJajor resections 59 (43%) 4 (19%) Minor resections 78 (57%) 17 (81%) aajor morbidity 8 (6%) 2 (t0%) Minor morbidity 25 (18%) 5 (24%) ~ 4 (3%) 1 (s%) Median survival 38 months 33 months 5.~ar-survival 40% 2~0

S1559

Endothelin A Receptor Blockade Improves Postischemic Hepatic Microhemodynamics Dirk Uhlmann, Sebastian Glasser, Stetan I.udwlg, Gabor Gaehel, Frederick Serr, Helmut Witaigmann, Johann Hauss

Aim: Endothelin (El") contributes to disturbances of hepatic microcirculation after warm ischemia/reper fusion (t/R) by causing vasoconstriction and enhancing leukocyte- and platelet- endothelium interactions. The aim of this study" was to invesugate a possible protective role of a selective endothelin A receptor antagonist (EP&) in this setting. Material and Methods: In au in viva model (42 Wistar mrs), ischemia of the kh lateral liver lobe was induced for 90 rain under ether anesthesia Sham operated (so.) (i), untreated ischemic (ll) and treatment (llI) group with BSF208075 (5 mg/kg bw i v ) were investigated. The effect of the ERA in I/R was assessed by" in viva microscopy (30-90 rain after reperfusion), measurement of local tissue pO2 and of AST, ALT, aoGST levels (2 h to 14 d after reperfusion). Results: In the untreated group, sinusoidal constriction to 59,4 • 117 % of so. diameters was observed, leading to a significant decrease in perfusion rate (77.4 + 8.2 % of s o ) and liver tissue pO2 (435 • 32 % at s.o) (p<O 05). in addition, we tbund an increased percentage of stagnant leukocytes (1425 ~: 145 %) and platelets (163.5 • 12.3 %) in sinusoids and in postsinusoidal venules (p<005). Nepatocellular damage (AST/ALT increase to 4306 • 477 U/I / 2002 • 23.8 U/I, pro: 274 • 2.7 U/I / 282 + 27 UA) was detected 6 h afier n.'pertusion (p<O 05?. Administration of the ERA betom t~perfi.lston significantly reduced I/R inju U Sinusoidat diameters were maintained (1085 + 6.6 %), perthsinn rate (931 • 1.8 %) and tissue pO2 (953 • 5.7 %) signiiicandy increased (p<O.05). Hepatocellular damage was decreased (AST/ALI ~ levels after 6 h of reperfusion: 166.6 • 26.3 U/I / 1324 • 225 U/I, p<O05) and leukoc>:e- and platelet-eudothelinm interactions in sinnsoids and venules reduced (p<0 05) Conclusion: Our results provide evideuce that the new therapeutic approach with an ERA is eltective in reducing hepatic I/R injury

S1560

Zone-dependent Susceptibility to Anoxia Reoxygenation of Sinusoidal Endothelial Cell through Interactions with Kupffer Cell Hisashi Taniai, Yuli Nimura Laura Con, Aw Tak Yen

Iscbemia/Reperfusion (I/R) injury is a critical pathologic issue in nmjor liver operatimrs. While apoptosis o[ smusoidal endothelial cell (SEC) plays an important role m the following parenchymal liver iqu U in I/R. little is aw~ilable on its underlying mechanisms. Meanwhile, t/R-related hepatic damage m late phase seems more severe in perivenous zone (PV) although the morn Kuptter cells (KCs) in penpor~al zone (PP) may poweflhlly attack SEC or hepatocyte in PP with reactive oxTgen species (ROSa in early phase. However, no account has been illustrated to discuss with the zo~ution of SEC sensitivity against I/R Therefore, this study was aimed to investigate the zonation of SEC susceptibility to apoptosis and the zonation of KC harmfulness induced by I/R. An in vitro cell culture mac/el was adopted for this study because it is too complex to analyze the interaction between parenchymal and nonparenchy- real cells as well as a varmty of mediators with an in viva system. Liver cells were collected after the zone-specitfc destruction by digitonin inluston as we reported belbre. They were indirectly co-cuhured through instals with 0.2 I.~m of pores; those enabled them to interact each other with soluble tactors as ROS ghey were incubated for 4 hours or tbr 2 hours of reoxygenation aIter 2-hour anoxia The extent of apoptnsis was counted with DAPI staining. I/R induced more apoptosis in PV SEC in presence of KC (15 x 10/insert) than in PP SEC, whereas tDice more KCs elicited as nmch apoptosis in PP SEC as seen in PV SEC co- culturing with the anginal dense at KC Tim origin (PP or PV) of KC gave no difkrence in the etiect m~ SEC apoptosis. These apoptotic eftects were cancelled out by the administration of anti-oxidizers (N-acetyl-L-cysteine and catalase) or the pre-iNection of GdCI3 to donors

$1561

Mycophenolate Mofetil Metabolism in Pediatric Liver Transplantation: A Pharmacokinetic Analysis based on Plasma Myeophenolic Acid Metabolite Levels Carmen Cuffari, Thomas M Attard Paul Colombani

Background: Although Mycophenolate Mofetil (MMF) affords demonstrably lower rates of rejection when used in combination with calcinurin-based immunosuppression, gastrointesti- nal and hematological side effects often interrupt or preclude its use in children post liver transplantation. Since there are no standardized dosing guidelines that have been shown to effectively prevent allograft rejection or avoid toxic W, MMF therapy in children has been largely' based on the adult experience Aim: This study aims to perform a pharmacokinetic analysis of MMF metabolism in pediatric liver transplant recipients based on the measure of plasma Mycophenolic acid (MPA) metabolite levels, and to correlate levels with one institution's current dosing practices. Methods: Seventeen pediatric liver transplant recipients with a median (range) age of 61 (8-238) months had plasma MPA levels measured via HPLC by UV detection at 254 n m Samples were drawn at time 0, 20, 40, 75 rain, 2, 4, 6, and 8 hours after a mean (SEM) oral dose of 335 (95) mg/day of MMF (600rag/m2). Resnhs: The median (range) plasma MPA level was 325 (10.1-145.6) mg~. There was a wide inter- patient variability in plasma MPA levels that correlated (p<0.03) directly with MMF dosing based on body weight (mg/kg), but not with total mg dose or rag/m2 body" surface area, based on the Spearman Rank Correlation Cocfliciem. The ibmml area under the curve (AUC) also correlated well with the extrapolated AUC (r=0.99) based on a limited sampling strategy'. Conclusions: The wide inter-patient variability in plasma MPA levels would suggest that the current dosing (600mg/m2) strategies in children post liver transplantation may render patients at risk of MMF induced toxicity. The correlation between plasi:;m MPA levels and dosing based on conventional body weight measurements (mg/Kg) would suggest a potential treatment suategy that could reduce the" risk of toxicity. Further studies are war- ranted m order to establish a therapeutic window of treatment efficacy and toxicity' based on the measurement of plasma MPA metabolite levels

S1562

Does Severe Morbid Obesity Compromise Results in Liver Transplantation? Jonathan S. Fisher, Claudia R. Tombazzi, Osama Gaber, Santiago R. Vera, Nosratollah Nezacatgoo, A. Bashar Abdulkarim, M Hosein Shokouh-Amiri

The incidence of morbid obesity has increased to more than a third of the population in the US. That shift is reflected in the population awaiting liver transplantation In fact, a greater number of patients with severe morbid obesity (BM1 >40 kg/m2) accompanying end-stage liver disease are now being referred for liver transplantation. Prevmus reports have suggested increased early' postoperative morbidity and mortality" for obese patients undergoing liver transplantation Purpose: To evaluate a single center experience transplanting livers into patients with severe morbid obesity (BMI >40 kg/m2). Methods: A retrospective chart review tbr first transplant, cadaveric liver recipients at a single center from 1998 to 2002. Three groups were examined: BM1 >40 (n = 10), BM130-40 (n = 39), and BM1 <30 (n = 67). The first two groups were compared to a third concurrent cohort similar to the first two with respect to age, race, etiology of liver disease, MELD scorn, preoperative creatinine clearance and incidence of diabetes mellitus. Outcomes measmvd included length of stay, need for re-exploration, patient and grafi survival, rejection episodes, development of new onset diabetes post-transplant (PTDM), and serologic markers of organ function at 12 months post-transplant. Results: There was no statistically significant change in length of stay m intensive care unit and bospital, need fbr moperation, incidence of rejection, and graft, and patient survival with increasing degree of obesity ]'here was a trend toward an increased incidence of post-transplant diabetes mellims in the group with BMI >40 (60%) versus BMI<30 (31%). Liver tunction (measured by serum albumin and alanine transaminase) and renal function (measured by serum creatmine) were not statistically difterent between groups as well. Conclusions: One-year results at liver transplantation are not adversely affected by severe morbid obesity Therdbre, morbid obesity should not be considered a risk tactor tar liver transplantation.

Body Mass Index and Outcome after Liver Transplantation

Indde~e BMI Hospital IGU Incidence of of Rejec- Graft Patient

Stay stay ~ i o n tion Survival Survival PTDM

(kg/m2) (days) (days) (% at 1 year) (% at 1 (% at I (% at 1 (% at 1

>40 10.8+/-4 3,1+I-1.2 20 30 ~00 90 60 30-40 13,5+/-6 3.7+/-2.2 18 13 95 90 28

14/I +/- 10.8 3.5+/-2.9 18 25 94 91 31

No statistical difference (p value > 0,1) between 8MI <30 an other groups for all outcomes

$1563

Liver Transplantation For Cryptogenic Cirrhosis~A Single Center Study Of 71 Patients Arthi Sanjeevi, Ramesh Asbwathnarayan, Sandeep Mukherjee, Elizabeth kyden, Becky Weseman, Brandy Sunderman

Background Cryptogenic hver disease is as an important cause of cirrhosis that can require liver transplantation (OLT). Nonalcoholic steatohepatitis (NASH) may be an important risk tactor in the development of cryptogenic liver disease. The aim of this stud}' was to evaluate outcomes for OLT for cryptogenic cirrhosis from a single transplant center including presence of risk factors traditionally associated with NASH

A-737 AASLD Abstracts

Methods: A retrospective chart review was perle:reed on patients transplanted for cwptogenic cirrhosis at the University oi Nebraska Medical Center between October 1993 and September 2002 Chronic viral hepatitis, alcoholic, autoimmune, metabolic and drug-induced liver disease were excluded in all patients prior to OLT Results: 7I patients underwent 75 OLT's dmmg the study period Median follow was 3.9 years Tbere were 37 males (53%) and 34 temahes (47%) Average age at OLT was 53.5 years 58 patients (817%) were Caucasian. Cyclosporine was used in 51 patients (73%5, EK506 in 27 patients (23%) and Rapamycin in 3 patients (4%) 47 patients (66%) were maintained on low dose prednisone There was an average of 05 episodes of rejection of which 583% occurred in the first 6 months. Mean total cholesterol increased from 174.8 to 222.3nig/dl and mean triglyceride increased hom 1626 to 279.66mg/dL Prevalence of' diabetes melfims increased kent 37 [4% to 5493% and the prevalence ot insulin-requiring diabetes increased fi'om 25.71 to 3239%. Deterioration in diabetic control, defined as a new prescription of, or increase in anti-diabetic therapy occurred in 14 patients (55 07%). Mean BMI did not change significantly (28.5 in pm-OIT versus 28.64 in post-OLr patients), but prevalence el morbid obesity (BMI >35 kg/m 2) increased frran 13.34% to 22%. Steato- hepatitis occu~red in 8 (11 3%) post-transplant patients. Recurrent cryptogenic [wer disease developed m 4 (5.6%3 patients, of whom 1 t~eqinred retran@antation. Cumulative incidence of grail failuee at 1 year was 4% (95% conhdeuce interval CI 0-10%5 and at 5 years was 7% (95% CI 0-18%5 I yea: overall survival was 85% (95% CI 77-94%) and at 5 years was 73% (95% Ci between 61-86%) Conchasion: OLT tur cryptogeinc fiver disease has mo:lafity rates comparable to other liver tranaptant recipients. A siguincant traction of the patiems have r:sk factors tor NASH of whom a subset dereloped steatohel)atitis "treatment of these risk Iactors may reduce the incidence of post-OLT NASH and recurrent disease

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Pattern o f Progress ion o f the MELD score in pat i ent s l i s ted for OLT Halim O Muslu, Nun Ozdeu Vharat Saruc Kamran Safdar, Douglas Meyer, Marzia Monta]bano Guy W Neff, Andreas Tzakis, Christopher B. O'Brien, Eugene R. Sehiff

Background: MELD score was a&~pted as the criteria for organ allocation tot liver transplanta- tion since Febluary 2002 However the minimal listing criteria based on MELD seem has not been dehned Aint: We analyzed the rate of progression of MELD score of our patients prior :o OIT to determine a minimal ME1.D to initiate OI.T evaluation Methods: All adult patients transplanted at jackson Memorial Hospital between March 2002 and November 2002 were rerqewed {or this :~trospective cohort study Of the three possible curves, linear, sigmoid, and logarithmic; aigmoid curve had the higbest R value Theretore it was used to plot the MELD progression curve Resuhs: A total ot 89 adult patients have undergone OLT during the study period 16 patients with HCC and 5 patients wnh tulminant hepatitis were initially excluded hem the study Tfie mean age ot study participants were 47.7, 124 yrs (mean, SD) There were 18F/50M The indications for OLT wet~ HCV in 37%(n=25), Chohes:atic (PBC/PSC) in 15%(n= 10), EtOH in 10%(n = 7), HCV+ EtOH in 15%(n= 10), HBV in 7%(n = 55, HBV + EtOH iu 3%(n = 2), HBV + HCV in l%(n= 1), and the odrm-s 12%(n = 8) Meat: MELD s,.ore at the time of transplant was 18, 9 (mean, SD). Progression oI the MELD score was applied to 4 rnam groups (Viral Hepatitis, Cholestanc, EtOH, and the overall group), ffiere was *to statistical dilterence among three groups according to age, vender and racial background. The progression of the MELD scores of the pauents who had a mioimum MELD value of 18 wnhin 30 days prior to OLT in the overall group are represented in the attached hgu:*' below Conclusion: In persons with advanced liver disease listed tor transplant, MELD score progression rate is similar according m 3 main indications L,r OLT. We conclude that the MELD score of 13 seems the ideal minimal listing score since tile >alien s stay with this score toi at least 6 months before they rapidly deteriorate

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t h e 13C-M ethace t ine Breath "rest: a N e w T o o l for Moni tor ing H e p a t i c Func t io n in Cirrhot ic Patients Be lore and After Liver Transp lanta t ion Aiessandra Petrolati, Davide Eesti, Giovanni De Berardinis Daniele Di Paolo, Luca Colaiocco-Ferrante, Oiuseppe fisone, Marie Angdico

Quantitative measmvrnent of liver functional reserve is critical to monitor progression, determine prognosis and control thr therapeutic efficacy in patients with advanced liver diseases "Phis can can be obtained from breath tests employing labeled substrates metabolized within the hepatocyte The 13C-ntethacetine breath test (MBT) is a new, simple, breath test based on a relatively inexpensive, non-toxic substance undergoing selective microsomal hepatic nmtabolisnl In the p~e'sent study we investigated the usefulness of 13C- methacetine breath test to monitor hepatic function in cirrhotic patients before and alter liver transplanta- tion Methods. The study included 28 cirrhotic patients (20 males, 8 females; age range 38- 60 years, 8 Ctnld-Pugh A, 13 B and 7 C) listed tk~r orthotopic liser transplantation and I0 healthy controls 13C-me hacetine (75 rag) was adn:inistered orally afier an overnight fasting

Samples of expired air svere collected at baseline and at fl:ree 15-minute intervals [br mass spectrometric analysis. Tn all patients and controls MBT was perf).~rmed at baseline and at successive 12-week intervals. Eleven patients who underwent iiver transplantation during the study period were also evaluated intra-operatively and in the early post-transplant period Results are expressed as n:ean 13C-methacetine cumulative oxidation percentage 45 minutes after substrate ingestion Results. Meat: baseline 13C-methacetine cumulative oxidation a 45 minutes was 5.4%+/4.2% in cirrhotic patients at time of listing and I7.5+/2 8% m controls (p<0 001). Percent oxidation was strictly dependent on the Chfld-Pugh score (87% in group A; 3.7% in group B; 27% in group C) in patients who underwent successfial liver transplantation, mean oxidation increased fi'om 3.3 +/1.6% immediately betore transplant to 8.0+/2 1% at week 1, to 15.1 +/54% at month 1 and to 17.0+/5.2% at month 6 niter transplant (p<0 0001). Mean intra-operative 13Cmlethacetine cumulauve oxidation changed fi-om 1.5 +/06% at time ot first surgical recision to 0.1% dunng tire anhepatic phase, to 3.7+/2.0% 120 minutes after graft reperfusion Conclusion. MTB is a reliable tool tilt measuring functional hver mass in the pre- and post transplant setting. MTB could not only be ficlpful in monitoring hepatic function in patients on the transplant list bur also to assess the recovery of hepatic function during surge D , and after transplantation

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Analys i s o f H e p a t o b i l i a r y Sc int igraphy In Evaluat ing Early Bil iary Leaks After Adul t Liver Transp lanta t ion Ritesh Shah, Roshan Shrestha

Background- Bfliary leaks following liver transplantation are associated with significant morbidity and mortahty. Early detection and treatment is important m preventing further complications. Endoscopic retrograde cholangiogram remains a conrmon diagnostic study in detecting biliary leaks in this patient population. However, hepatobiliary seintigraphy (HBS) is less invasive and is being increasingly used as an initial sereemng tool prior to more invasive procedures. Our study retrospectively evaluates the accuracy" of HBS detecting biliary leaks in liver transplant patients at our institution. Methods- We reviewed medical records for all adult patienls who have undergone liver transpIantation at 0or institution fi-om 1/01/95 to 6/1/02 For patients who had HBS within one month of transplanl- alien, we searched for follow up evidence to evaluate the accuracy of the HBS perle:reed This included surgical, radiologic, or cholangiographic evidence of bifiary leaks. In addition, we Mt that patients that did not receive these studies could be followed clinically, up uno: discharge or thirty days after transplant, to determine if their HBS was correct. Results- During this period, we identified 272 patients who had undergone 307 liver transpta:tts Of these, a total of 118 patients underwent 122 HBS studies within one n:onth of transphn Six patients, representing 7 outcomes, were excluded due to death (n = 5) or therapeuuc biliary manipulation prior to HBS (n=2). We analyzed a total of 115 onteon:es and deter- mined that HBS had a sensitivity of 77%, specificity 97%, positive predicuve value of 85%, and a negative predictive value of 95% at our restitution. Conclusion- Hepatobitiary scmtigrapfiy is a moderately sensitive and very specific test for detecting bihag/leaks t ~s less invasive and cames less morbidity and mortality than either endoscopic or surgica: technNues. Given these results, we tvcommend using HBS as an initial screening tool to evaluate for bfliary leaks in post liver transplant patients

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D o n o r Arterial O x y g e n Pressure Is a Major D e t e r m i n a n t o f Early" Post-operative Adverse Events In Adul t Liver Transp lant Rec ip ient s Stefano Ginanni Corradini, Waiter Elisei, Rosanna De Marco, Maria Teresa Sicilian< Renzo Pretagostmi, Massimo lappellb Francesco Pngfiese, France Ruberto, Davide Stabde, Gianni Casciaro, Manuela Merli, Adofiio Franceseo Attih, Pasqnale gerloco, Massimo Ross[

Backgronnd & Aims: Pretreatment with hKperoxia attenuates hepatic ischemic-reperfosam inju D' in rats. It is not known whether arterial oxygen pressure (PQ) before liver harves:it:g from cadaveric donors influences the outcome of liver transplantation in humans "~e investigated the assodation of different variables, including donor P~O:,, with the sfiorblerm outcome of liver transplantation. Methods: Forty-six primary cadaveric orthotopic non-slants 1 whole liver adult transplantations were studied during the period 02/2001-9/2002 at a single institution Recipient age and MELD score, donor age, blood sodium, days of lOJ and pre-harvestmg PO2 and cold ischemia time were recorded. Patients were" pmspect:vdy studied tor bile flow, blood chemistry" and the occurrence of post-transplant short-term adverse events (AE). Results: in 18 patients the fbllo,,ving AE occurred during fire first postoperative week: pnmary non-function (5), prin:aey poor fhnction (6), hepatic arterj thrombosis (2), acute rejection (1) and altered mental status of a minimum of 3 days duratie~ without underlying structural brain or metabolic causes(4). Twenty-eight patients were f.~ of AE at least two months after transplantation. After n-ansplantation, the group w:th AE as compared with tire group free of AE was characterized by: a) a lower mean cumulative peal- operative three-day bile flow (213.6 +_ 57 5 vs 4368 +- 43 1 ML; p<0 005); b) a higher rt~. blood total bilirubin concentration at day 1 (6.0_+_ 07 vs 4 1 +- 0.5 mg/dl; p<0 05), at day 2 (7.0 +- 0.8 vs 4 1 _+ 0.6 mg/dI; p<0.01 ) and at day 3 (8.3 +- 0,9 vs 4 6 +- 0 7 mg/dL; p<0.005) Univariate analysis of pre- and mtra-transplantation variables (ANOVA) showed that the group with AE as compared with the group flee of AE was characterized only, by: 1) a 10wet mean donor P00:(102.7+-15.0 vs 157.1_ + l l .9 mngHg; p<0 01) and 2) a longer mear~ donor iCU stay (6.4 -+ 1. i vs 2.7 -+ 0.9 days; p<0.01). Muhivariate analysis confirmed result~ of univariate analysis. Conclusions: Failure to induce hyperoxia in cadaveric donors bet0~ liver harvesting has a negative impact on tire short-term liver tranplantation owcome Donor P00: helps to define marginal livers.

A A S L D A b s t r a c t s A - 7 3 8