The prevalence and impact of cytomegalovirus infection in hepatitis C patients undergoing liver transplantation

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AASLD ABSTRACTS

943 THE PREVALENCE AND IMPACT OF CYTOMEGALOVIRUS INFECTION IN HEPATITIS C PATIENTS UNDERGOING LIVER TRANSPLANTATION. Kelly W Burak, Carlos V Paya, Walter K Kremers, Russell H Wiesner,

Charles B Rosen, Michael R Charlton, Mayo Clinic and Foundation, Rochester, MN Background: Cytomegalovirns (CMV) infection suppresses cell-mediated immunity and has been reported to be associated with more frequent development of cirrhosis in HCV infected liver transplant (LT) recipients. Aim: To prospectively determine the prevalence and impact of CMV infection on post2LT outcomes in HCV infected LT recipients. Methods: Consecutive HCV infected LT recipients (PCR positive) who had ->4 months post-LT follow-up were studied. The frequency of post-LT outcomes was determined in HCV infected recipients who developed CMV infection (CMV+, defined by the isolation of CMV from blood and treatment with ganciclovir) and compared to that of HCV infected recipients who did not develop CMV infection (CMV-). Measured outcomes included patient and graft survival, rejection and allograft histology. Data was collected prospectively with surveillance cultures for CMV infection and protocol liver biopsies. Results: Ninety-four consecutive HCV infected patients undergoing LT who met inclusion criteria were studied. Post-LT CMV infection requiring treatment occurred in 26/94 (26.6%). Graft failure (defined as cirrhosis, relisting for LT, re-LT or death) was more common in CMV+ than CMV- recipients (52% vs 18.8%, p=0.001). Fibrosis stage ->2 on liver biopsy 4 months post-LT was also more common in CMV+ recipients (45% vs 16.1%, p=0.009). The frequency of acute cellular rejection (64% vs 31.9%, p=0.005) and average daily steroid dose were also greater in the CMV+ group (69.3 vs 47.3 rag/day, p=0.04). OKT3 use was similar in both groups (4% vs 2.9%, p=0.79). Using a Cox proportional hazards model, the relative risk of graft failure in CMV+ patients was 3.53 (p=0.006) after accounting for rejection and average daily dose. Conclusions: CMV infection occurs in approximately one-quarter of HCV infected LT recipients and is art independent risk factor for graft failure in these patients. Whether HCV infected LT recipients will benefit from CMV prophylaxis requires further study.

HEPATOLOGYOctober 2001

944 LIVER CELL PROLIFERATION BY PCNA AND HCV RECURRENCE IN PATIENTS TRANSPLANTED FOR HCV-RELATED CIRRHOSIS W I T H OR W I T H O U T HEPATOCELLULAR CARCINOMA. Maria F Donato, Francesca

Agnelli, Eliana Arosio, Valentina Monti, Maria g Balestrieri, Div Hepatology, IRCCS Maggiore Hospital, University Milan, Milan Italy; Paolo Rizzi, Liver Unit, King's College Hospital, London United Kingdom; Massimo Colombo, Div Hepatology, IRCCS Maggiore Hospital, University Milan, Milan Italy Background andAim:. Natural history of hepatitis C is accelerated in the setting of liver transplantation and histological predictors of disease progression are still debated. Aim of the study was to evaluate if liver cell proliferation might predict the rate of disease progression in patients with HCV recurrence. Material and methods: 46 liver biopsies from 14 males patients (age 54+7 yrs) who underwent a liver transplant at King s College Hospital of London for HCVrelated cirrhosis with or without hepatocefiufar carcinoma were studied. 7 patients had CSA and 7 FK 506 immunosoppressive regimen. All were HCV RNA +, 71% with genotype lb, 12 (86%) with abnormal ALT (mean+SD: 151+91) at the time of baseline liver biopsy performed 7+5 months after transplant. All patients showed histological features of hepatitis C recurrence in the graft: 6 had mild portal and lobular hepatitis, 4 had acute hepatitis and 4 had chronic hepatitis with bridging necrosis. During fofiow-up, a mean of 3 liver biopsies for each patient were performed every 12-18 months. Ishak score was performed to evaluate grading and staging of liver disease. A progression of chronic hepatitis was classified as >2 increase of staging score. PCNA (proliferating cell nuclear antigen) was localized by immunoperoxidase (ABC, Vector) on microwave oven pre-treated formalin-fixed, paraffin-embedded sections using a monoclonal antibody to PC10 (Dako). PCNA labelling index (PCNA-LI) was expressed as percentage of hepatocytes with strong positive nuclei read by an automated imaging system (Immagini e Computers, Italy). Results Median baseline PCNA-LI was 1.4 (range: 0-5.6). 7 patients had baseline PCNA-LI >1.4 (group 1) and 7 patients had baseline PCNA-LI < 1.4 (group 2).The grading score was higher in patients with PCNA> 1.4 compared to those with PCNA <1.4 (7.9+2.2 vs 5.6+1.8, p < 0.01). Staging score was similar in the two groups (1.4+0.5 vs 1.0+0, p~NS). All patients of group 1 and 5/7 of the group 2 showed fibrosis progression during follow-up. However, fibrosis progressed more rapidly in patients with higher PCNA respect to those with lower PCNA (10.6+8.8 vs 50.0+31.1 months, p<0.01). Cirrhosis developed in 5/7 (71%) patients in group 1 as compared to none of 7 in group 2 within 4 years (p<0.01). Conclusions: In liver transplanted patients with HCV recurrence, PCNA assessment may help to identify patients prone to develop early fibrosis and cirrhosis during follow-up.

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IS LIVER DAMAGE DUE TO HCV RECURRENCE AFTER TRANSPLANTATION ASSOCIATED W I T H HISTOLOGICAL FEATURES OF DONOR GRAFT ?. Francesco P Rnsso, Liver Transplantation Unit-Gastroenterology

PATIENTS TRANSPLANTED FOR HEPATITIS C SHOULD NOT RECEIVE LIVERS FROM OLDER DONORS. J Pirenne, H Decaluwe, R Aerts, F Van

Section, Padova Italy; Alessandra Galligioni, Department of Pathology, Padova Italy; Stefano Targhetta, Liver Transplantation Unit-Gastroenterology Section, Padova Italy; Mario Ermani, Department of Neurology, Padova Italy; Stefano Fagiuoli, Liver Transplantation Unit-Section of Gastroenterology, Padova Italy; Umberto Cillo, Liver Transplantation Unit-Surgical Section, Padova Italy; Massimo Rugge, Department of Pathology, Padova Italy; Remo Naccarato, Liver transplantation Unit-Gastroenterology Section, Padova Italy; Patrizia Burra, Liver Transplantation Unit- Gastroenterology Section, Padova Italy Despite numerous factors have been described to be associated with the recurrence of HCV-infection and histological damage after liver transplantation, the problem is stiU open. The aim of the study was to evaluate whether a) the early liver function and b) the late liver damage due to HCV recurrence after transplantation were associated with histological features of donor graft 195 liver transplantations were performed in 182 patients, 16 of whom were antiH CV(+), HBsAg(-) and with negative history of alcohol consumption before surgery. In 195 liver biopsies, obtained after donor hepatectomy and before implantation, hepatocyte fatty infiltration (0-3), hydropic degeneration (0-3), glycogen content (0-3) and lipofnscin/haemnsiderin deposition (0-3) were assessed. The score of early liver function after transplantation was based on AST, Factor V and PT serum levels (primary non function=PNF, initial poor function=IPF, good function=GF). At 6 and 12 months after liver transplantation histological features of HCV recurrence were assessed by liver biopsy in all anti-HCV(+) patients and classified according to Ishak's score (grading 0-18; staging 0-6). The outcome of liver transplantation was as follows: 5 PNF, 41 IPF, 149 GF. The early liver function significantly correlated with the donor graft fatty changes (Mann Whitney U test p<0.05). The grading score of HCV recurrence significantly correlated with the donor graft fatty changes (p=0.028) at 12 months after liver transplantation. In conclusion hepatocyte fatty changes in the donor graft seem to be associated with both the early liver function and the late HCV-related hepatic inflammation after transplantation.

Gelder, W Van Steenbergen, C Verslype, P Yap, T Roskams,J Fevery, F Nevens, Univ Hospitals Leuven, Leuven Belgium Background. Hepatitis C (HepC) is the major cause of liver disease requiring Liver transplamation (Ltx). HepC recurrence in the tx liver is almost universal and is clinically significant (Sign) in a large proportion of patients. The exact impact of various risk factors {viral load-genotype, rejection, immunosuppression (steroids) etc.} remains controversial and no strategy has been able to prevent clinically Sign HepC recurrence. On the contrary, a few centers report an increased % and severity of Sign HepC recurrence in the recent years (J Hepato100,32:673). Aim. T'o identify risk factors that account for increased % of Sign HepC recurrence. Methods. Retrospective single-center study of 25 consecutive Ltx (HepC +) done between 2/96-7/00. Sign HepC recurrence was defined by abnormal liver function tests (ALT>2x nl) and biopsy proof. The following risk factors were studied: donor/recipient age, % donor with hypotension, % donor on high dose vasopressor, cold ischemia time (CIT), operative time (OT), blood transfusion, reperfnsion injury score, Child score, rejection requiring steroid bolus, type of immunosuppression (IS): azathioprine vs mycophenofate mofetil, cyclosporine vs tacrolimus. Results. Incidence of Sign HepC recurrence was 56% (14/25). Sign HepC recurrence correlated with increased donor age: mean donor age was 45.1 - 15.3 in Sign HepC-recurrent vs 33.6--.13.4 in HepC-non-recurrent patients (p=.03). Mean donor age increased during the study period: 36--16 (1995-1996); 43+-17.5 (1997-1998), 45 ± 17 (1999-2000), (p=.001). Donor age correlated not only with % but also with severity of HepC recurrence: 3 of 4 Ltx done > 1999 with donors >60 had Sign HepC recurrence; 2 of them had rapidly lethal cholestatic HepC, a form of recurrence not seen <1999 when using donors <60. Further comparing HepC-non-recurrent vs Sign HepC-recurrent patients, % rejection requiring steroid bolus was 9% vs 57% (p=.017). No other risk factor was identified: donor with hypotension: 20% vs 33% (p=.5); donor on vasopressor: 14% vs 25% (p=.3); CIT: 9.2±3.15h vs 8--1.4h (p=.2); OT: 6.3±2.4h vs 6.3±1.2h (p=.8); blood transfusion: 3.8+-3.8 vs 3.5±3 units (p=.7); reperfusion injury score (ns); Child score (us); type of IS (us) and recipient age: 53.8-+10.6 vs 52.8+-9.9 (p=.4). Conclusion. In addition to confirming the impact of steroid bolns-rejection, this study unmasks the deleterious effect of donor age on HepC recurrence after Ltx. This observation is consistant with the natural history of HepC in the non-transplant setting and its more rapid progression in older patients. We hypothesize that the recent liberalization of donor criteria and the utilization of older donors account for the increased % and severity of HepC recurrence seen at many centers. Patients transplanted for HepC should receive livers from younger donors (at least <60).