W1388

Does HLA Status Predict Risk for, Severity of or Age of Onset of Celiac Disease in an American Population Joseph A Murnay, Carol Van Dyke, Matthew Plevak, S Breanndan Moore, Cynthm Kroinng, Russ Dierkhising, Alan Zinsmeister, L Joseph Melton III

Celiac disease is strongly associated with H[.A DQ2 in northern European and DQ8 in a lew other locations where cehac disease is common disease. Essentially all of these studies have been done in elhincally homogenous populations. The rok of these genes may be different in a more m, xed population such as the US, A gene dosage effect has been suggested for copy mambers of the HI_A genotypes in some populations The aim of this study was o examine the contribution of HIA type to disease risk, onset and severity in a geographically restricted though ethnically mixed American population with a relativeIy tow prevalence of celiac disease. Methods: A population-based cohort of patients with celiac disease and controls underwent detailed I l i a genotyping by" PCR-SSOP. ]'he patients' presentations were classified as severe (diarrhea and weight loss or failure to thrive) or mild. The age of onset of symptoms and the age at diagnosis were available tot all. Logistic regression analysis was used for calcnhtion of ~he odds for celiac disease as function of copy number of DQ2 genotypes, Results: 74 su~ects with celiac disease were compared to 102 racially matched healthy controls drawn from the same geographic location, none ot whom had celiac disease. All sub}ects were Caucasian of mixed efirnic origin Virtually all patients with celiac disease had DQ2 as compared to 31% of the controls DQ2 was associated vvith a greatly incl~ased risk of celiac disease. DQ8 "#as not Apparent homozygosity for DQ2 was associated with a hmher increase in risk as compared to those with a single copy of DQ2. Apparent homozygos W was not associated with an earlier age of onset or severity, at presentation. Conclusions: [his American population shares the same HIA predisposition to celiac disease as European groups In this population there, appears to be a gene dosage effect for risk of • but not for seventy of age of onset The carriage of DQ2 is essentially required for disease in this Midwestem US population with celiac disease, The possession of 2 copies significantly increases the nsk as compared to one but does not afl}ct the late onset of disease

Gene Dosage Effect of DQBI.0201 for Celiac Disease

# DQBI.0201 Copies Col~ols Celiac Disease OR (95% Cl) 0 (,=72) 70 (69~) 2 (3%) 1 1 (n=71) 28 (27%) 43 (58%) 53,7* (1Z2-237,0) 2 (.=~) 4,(4%) 29 (agN r �9 1 co~ vs 0 ml~es "2 ~p.~a ~,s 1 copy

W1389

Alterations in Bile Formation and the Expression of HepatobiliaD~ Transportes in Human Orthotopic Liver Transplantation Er'~n Geuken Dorien Visser Hans Blokzljl, Henri Leuvenink, Rob De Knegt Folkert k'uipers, Maarten Sloofl, Peter Jansen, Robert Porte

Introduction Expression and ftmction of hepatobihaBr transporters is influenced by several pa hoIogical and experimental condinons, such as endotoxins, liver regeneration and bile duct Iigation. There are no data on changes in the expression of these transporters after (haman) orthotopic liwer transplantation (OLT). The aim of this study was to analyze changes in the expression of hepatobiliaB~' transporter genes and to correlate this with bile formation and composinon after human O[.1" Methods: Three sequential liver biopsies were taken from donor livers during and after OLT in 23 patients: at the end of cold storage, 2 hours alter reperfusion and 1 week postoperativdy Biopsies were immediately snap-frozen and stored at -80C Total RNA was isolated frmn biopsies and real-time PCR was performed on an AB1 PRISM 7700 sequence detector, using specific pnmers and probes tbr the tbllowing transporters: BSEP, NTCP, MDRI, MDR3, MRP2 and the bile salt receptor FXR 185 was used as endogenous control Bile samples were taken daily (between 8 and 9 am), during 3 weeks, from a bile drain. Concentration of total bile salts (BS), phosphobpids (PL) were measured in daily bile samples, using enzymatic assays Results: Compared to the pretrans- plant biopsies, the postreperfnsion biopsies showed a 3&40% reduction of all transporters, except MDR1 which remained stable Biopsies taken 1 week after O[X showed a significant upregulation of NTCP mRNA levels (2.7-fbld; p<0,O1) and of BSEP mRNA levels (2.3-tbld; p<0 01), whereas MP(P2 and MDR3 mRNA levels remained stable. Levels of FXR mRNA decreased further between these two time points. In parallel with the increase of NTCP and BSEP mRNA, concentrations of BS in bile increased during the first postoperative week, reaching a plateau thereafter In contrast with this, the concentration of PL in bile increased at a much 1ower ;.ate, resulting in a change of the BS/PL ratio from 8 3 +/- 0.01 immediately after OLI" to 4 0 +/- 004 one week later Conclusion: The expression of BSEP and NTCP increases sigmficantly during the fira~ week after OLT and this coincides with an increase o f the concentration of BS in bile. Restoration of bdiary PL excretion is much slower, resulting in an increased BS/PL ratio early aiter OIX We speculate that this may lead to cytotoxic bile Drmation and act as a potential rnechainsm of bile duct injury in patients after O1.T

W1390

Refractory Ascites Identifies Cirrhotics with Low MELD \ ~ o Are at Risk of Decompensation and Death Douglas M Henman, Souhed G. Abou-Assi, Adfl Habib Leslie M Williams, Anastasios A Mihas

Background: The Model for End Stage Liver Disease sco~ (MELD) predicts early death in cin'hosis and is used by UNOS to assign pnonty ti/r liver transplantation (LT). Some patients with low MELD decompensate rapidly and die before LT can occur. Aim: To identify predictors of early morlality in cirrhotics with low MELD scores. Methods: Data (demo- graphic, etiologic, laboratory, clinical) were compiled prospectively fi'om records of 375 cirrhotics referred for 1~ m the U.S. Dept, of Veterans Affairs, 1/97 to 8/02.98% were male; cause of cirrhosis was ethanol and/or hepatitis C in 87% Predictors of mortality (censored at LT) were identflied by univariate, multivariate (logistic regression), and lite table analysis.

Results: 46/375 patients (12%) died ,~,qthout LT within 90 days and 73/338 (22%) vathin 180 days, Factors associated with 90 day mortality at p < 0,05 included MELD, hemoglobin, albumin, creatinine INR, bflimbin, aseites severity, encephatopathy severity, AST/ALT ratio and hyponatremia By logistic regression, MELD, refractory" ascites and hyponatremia were independent predictors of death at 90 or 180 days Initial MELD was < 21 in 313 (84%); 24% of all deaths within 90 days, and 47% of deaths within 180 days, occurred in patients with initial MELD < 21. For patients with MELD >- 21, MELD was the only independent predictor of death at 90 m- 180 days. in contrast, m patients with MELD < 21, MELD did not differ significantly between early deaths and survivors (p>O 05) Multivariate analy'sis in patients with MELD < 21 identified refractory ascBes and hyponatremia as independent predictors of mortality at 90 and 180 d, but neither MELD nor arty of its components was found to be an independent predictor at either time point. Hepatocellular carcinoma was the only other factor independently" associated with death at 180 days, but was not predictive at 90 days, For MELD < 21, the correlation between MELD and time to death over a 2 year follow-up was poor (R = 0.04), whereas presence of refractory, ascites or hyponatremm increased 180 day mortality from 4% to 23% (p < 0.001). Conclusions: In cirrhotic veterans referred for transplantation, MELD scores >- 21 accurately predict early mortality. However for patients with MELD scores < 21, differences in MELD were poorly indicative of mortality risk; instead refractory ascites was the key predictor. Subject to additional validation, we propose that the presence and dm'ation of refi'aaory ascites shot~ld be considered in assigmng priority for LT in cirrhotic patients with MELD < 21.

W1391

Adult Living Donor Liver Transplantation: Donor Characteristics And Outcomes Tbalia Mayes, Parvez Mantu, Uma Sundaram

Background: The characteristics of donors of living related liver transplantation and their outcomes after sm'gery have not been studied on a large scale We report a study on 80 successftd living donor liver transplantations performed over the last two years. Objective: To determine the outcomes of donors of living donor liver transplantation. Methods: We studied the records of 80 consecutive donors of right lobe liver tbr operative and post operative course, operative blood loss, operating time, liver fi.mction abnormaiities, length of hospital stay and liver pathology from the liver biopsies. Results: Of 80 donors 37 were men and 43 women 70 donors were Caucasian, 3 African American, 6 Latin American, and 1 Asian. The age distribution was as follows :21-30 years 33%; 31-40 years 33% and 4654 years-33% 36 donors were children of the recipients, 24 were siblings and 2 were 2nd degree relatives. The remaining donors were unrelated and consisted of spouses, friends and sons and daughters in law.9 out of the 80 patients suffered ft'om depression/anziety and 8 were on medications for the same. In 41/80 patients the pre-operative liver biopsies were normal, Thirty-seven donors had less than 15% steatosis Two patients were found to have more than 15% steatosis on the liver biopsy. There was no difference in surswal of these liver grafts in the recipients or a W effect on the donors after right hepatectomy. The actual time required for partial hepatectomy was 10 hours (range-8*ll hours), The estimated blood loss was less than 500 mi in 55% of the patients and less than 1 liter in 85% of cases. The mean length of stay in the hospital was 7 days(range4-12 days). 5 of the donors were readmitted in the next one year after the sm~gery, One patient was re-admitted 1 month after discharge for pneumonia and discharged m stable condition after 2 days. Two patients were readmitted for fleus 1 and 4 days after discharge respectively. They were both treated wlth conservative measures and discharged uneventfully after 48 hours. The other 2 donors were readmitted tot reasons unrelated to their surgery" (diverticulitis and renal stones), Discussion: We report the largest study of the donor outcomes of living donor liver transplanta- tion up-to-date. Living donor transplantation appears to be a sale procedure from the donor's perspective. It carries a low burden of blood loss, post-operative morbidity and a reasonably short hospital stay, With the increasing shortage of cadaveric liver donors it presents an mvaluable resource with minimum morbidity to the donors.

w1392

Cyclosporin A Inhibits Bile Salt Synthesis Rate and Increases Plasma Triglycerides after Liver Transplantation in Children Christian V. Hulzebos, Frans Stellaard, Folkert Kuipers, Vaclav Fidler, Maarten j. S]ooff, Paul M Peeters, Pieter J Sauer, Charles M Bijleveld, Henkjan J Verkade

Background: CycIosporin A (CsA) is widely" u ~ d after ortbotopic liver transplantation (OLT) and is associated with hyperiipidemia CsA treatment markedly reduces bile salt synthesis rate in rats (]PET, in press). It is not known whether CsA aftects bile salt synthesis in humans. We discontinue CsA treatment several years after pediatric OLT, provided that there are no signs of cholestasis or reiection (liver biopsy,) ~rh~s regimen allows to determine whether CsA alfects synthesis rate of bile salts, or is associated with disturbances in lipid metdbdism. ObJective: To assess the eft;ects of CsA on synthesis rate and pool size of the pnmary bile salts cholate (C) and cbenodeoxycholate (CDC) and on plasma hpid levels in children after OLT. Desigtl/Methods: Before and after discontinuation of CsA m pediatric OLT patients, pool size and synthesis rate of C and CDC were measured using a stable isotope dduuon technique (JLR 2001;42:1923-9; 3-4 measurements per pauent), and related to plasma lipids. To test the null hypothesis (no effect of CsA discontinuation) we used as test staUstic the number of patients whose measm'ements without CsA all exceeded those ,,wth CsA. Exact one-sided P~values of this test are presented. Results: in 6 children (age: 3-16A years; 4M/2F) CsA Ireatlnent was discontinued at a mean of 3.5 years (sd: 2 5 y) after OLT (biliary atresia n = 5; choledochal cyst, n = 1). Discontinuation of CsA increased synthesis rote of CDC from 0.7 + 0.2 to 1.0 +_ 0.5 ~*ntol. 100g*.day * (p<0.001) and tended to increase that of C ( + 25%, p = 0,05). Discontinu- ation of CsA increased the pool size oi CDC (from 2.3 • 1.3 to ;3.6 • 19 ~mol,100g ~, p<0.001), but not that of C (from 2.4 -+ 10 to 2.5 • 1.2 gmol. lO0g, NS). Discontinuation of CsA decreased plasma levels of cholesterol (-6 %, p=0.05) and trigiycerides (-26%,

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