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Mixed cryoglobulinemia after liver transplantation for HCV-positive liver cirrhosis
Liver transpluntaticm, surgery. acute lirer,failure
69
1 P/CO1/035 1
PREDICTION OF PROGNOSIS AFTER TRANSPLANTATlON IN PRIMARY SCLEROSING CHOlANGlTlS USING A COX MODEL J. Neuw
6. Gunson.
l
The Liverand HepatobiliaryUnit, The Queen Elizabeth Hospital, Birmingham, United Kingdom and ‘Department of Internal Medicine I, BispebjeroUniversity Hospttal. Copenhagen, Denrnati Background: Livertransplantationremainsthe only treatment for patients with end-stage primary sciemsing cholangitis (PSC) althoqth selectioncriteria for the procedureand its timing remains uncertain. Aims:To kientifypm-transplantvariablesassociatedwith survival after transplantationand to devise a Cox rt39ressionmodel for predictionof post-transplant survival. Methods:We studied 118 patients transplantedfor PSC at the Queen Elizabeth Hospital,Birminghambeing followedfor up to 9% years after the procedure.The asoclatlon betwen pm-transplant data and post-transplantsurvivalwas studied usingthe logranktest (univaftateanalyses)and Cox multipleregressionanalysis- bothfor the firstpost-transplant year and the total observationperiod. Results: Univariateanalysesshowedthe foHovvlng variablesto be associatedwith a decmased post-tmnspiantsutvlval: high serum creatinlne, hi9h serum bilirubin,blllarymalignancy,previousupper abdominal surgery, hepeuc encephaiopathy.ascites and Crohn’s disease,while ulcerativeoolitiswas assodated with increasedposttransplantsurvival (all psO.05). The final multiple Cox rsgmssion model lnckxied the following si@ficant variabies: Inflammatory bowel dkwse, ascites, previousupper abdominal surgery,serum creatinineand bliiary mai@wbcy (all pcO.03). Vhtually the same resultsWBIVJ obtainedcon&&win9the first post-transplantyear and the total observationperiod. Conclusions:These resultscan Improve!sebctionof patientswith PSC for liver transpiantation.Furthe~rmore. by comparlngprq~nosis withand withouttransplantaM (usifq pmviouslypublishedmodels) the timirg of the pmceduremay be improved. 1 P/CO1/034 1 MIXED CRYOGLOBULINEMIA AFTER FOR HCV-PUSITIVE LIVER CIRRHOSIS S Puliti’. C Fhv’. M Gieou’. F Giannelli’. Samuel’. P Gentilini’. AL Zinneno’. Institute of P. Browse Hospital, Villejuif, Francez~, Cisanello
IMMUNOGENETIC FACTORS, HCV GENOTYPE AND HCV RECURRENCEAFTER LIVER TRANSPLANTATfON MScalamomra.DFortiandtJJ& Uniti Trapiantid’orgaoo,Oqedale Nigmda. Milaa, Italy. Since HLA DRBl+ll has been associated with less advanced liver diseaseinPatients witllchronichepatitisc(1),wehaveim%stigatedthe distributionof HLA DRBlWkles in 81 HCV Positive liver mtsplam Patkntsaadtheirpossibleasseciationwithtbe frequency,timingand severity of recurmntdisease.TheroleofotherfMorssuchasHLA match,HCVgenotypeaodnumberofsteroid~ukeswasalsoevahuted. Ofthe 113 ~atkntswithHCVrelatedcirrhoGtmn@antedatour centerbetweenMay1990andJune1997,only81wboauvivedatleast3 monthsatkr 8raftiq wue consiin this stody. HLA-DRBl* typin8 (PCR-SSP), HLA-A,B (serologic technique) or DRBl* match between donorsand recipientsand HCV geno@ping(accordingto Okamoto)were availablein all cases. Liver bhqsies were Performedwheneverclinically indicatedand at yearly inter+&. . . uuvarmkandlogisticregeasionanalysisnoneofthefour seiected for investigation, ruunelypresenceof an HLAz DRBl*ll allele, of a HLA-DR-match,of geno@pe lb and number of steroidpllseswassi@icantlyasso&edeitherwiththeoaxrrenoeor theseverityofrlxWent hepatitS.Dif%fElUly,whenCOXlS&&thetime interval betwxea OLT and hepatitis by Kaplan Meyer analysis, patientscarryingHLA-DRB1* 11 allele, showed a significantly delayedl#xxrenthepatitiswhencomParedwithPatkntsauryingother DREl*alleks @co.019 by Log rank test). This finding was more evirkat whenbothBemtypemtlbandHLA-DRBl*llwerecoosideredtogether @=0.015) ThesereadtMll8gestthatbothimmunogeoeticaodviraifactors infloencethetimiogofdiseasenzcurrence. Alar8ersamplesizeis pmbably~tobetterdetinetbeexactrokoftheforementioned paramethersOXltheOCCUK%% atKlpfo@xSiondrhepntitiS. References 1) Zavagliaet al. J Hepatol1996;24:65&65
1 P/CO1/0361 LIVER
TRANSPLANTATION
E Marrowhi’. F Filiowni’. D Internal Medicine, Florence; Italy, Hospital, Piss’Italy.
A striking association has been shown between HCV infection and B-cell lymphoproliferative disorders (LD) including mixed cryoglobulinemia (MC) and Bcell non-Hodgkin’s lymphoma. Post-transplant LD has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. We studied six pts. undergoing trasplantation (OLT) for HCVrelated cirrhosis in whom mixed cryoglobulinemia (MC) with vasculitis was observed after OLT. In one case, MC was also detected before OLT, even if with mild clinical manifestations. In the remaining pts., the mean time interval behveen OLT and the first expression of vasculitis was I7 m. (range 3-27 m.). All but one pt. developed cutaneous vasculitis (c.v.). 4/6 pts. (including the case without c.v.) were shown to be affected by membrane-proliferative glomendonephritis. 2/6 pts. developed a frank B-cell lymphoma I8 and 29 tn. after OLT, respectively. Clinical MC-related manifestations were generally relevant and frequently invalidating. This was particularly tlue for the patient in which MC was also evident before OLT, this patient died 62 m. after OLT due to renal impairment and multiorgan failure. All patients were HCV RNA positive. Semiquantitative analysis of HCV viremia (Amplicor HCV MonitorTM) performed in 4 pts. showed no significant differences with respect to viraemia levels detected in IO transplanted pts. without MC. Serological markers of EBV infection were negative in 4/4 pts. In two pts. in whom MC appeared aller OLT, molecular genetic analysis identified the t(14;lS) translocation in peripheral B cells. This study suggests that OLT may significantly worsen or manifest MC in HCVpositive pt.% In addition, malignant evolution of MC seems to be accelerated. Consequently, the possibility of MC should be taken into account in HCV+ OLT pts. both before and after intervention. This behaviour of HCV reinfection seems to be essentially related to a predisposition to LD in post-transplant pts probably on the basis of constitutional and/or HCV infection-induced conditions. These latter may possibly include anti-apoptotic mechanisms. High levels of viral replication generally observed after OLT may also play a role.
POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) IN LIVER RECIPIENTS. Z. Ben-An P. Amlot’. S. Lachmanan’, R. Tur-Kaspa, K. Rolles’, A.K. Burrouahs’ Liver Institute, Rabin Medical Center, Petah Tikva, Israel and ‘Hepatobil 8 Liver Transplantation Unit, Royal Free Hospital, London, UK. PTLD is a well recognized complication of organ transplantion but its significance in Orthotopic liver transplantation (OLT) needs to be ellucidated. Over a period of 9 years 7 adults (prevalence of 1.6%) mean age 53 years; liver allograft recipients developed PTLD, 1 to 36 months (m) post OLT (mean 6 m). Four patients (pts) received ATG/OKT3 for steroid resistant cellular rejection. Four pts had localized hepatic tumor, 2 had extralymphoreticular disease and 1 had spleen involvement, All tumors were B cell lymphomas. Three polymorhic, 3 monomorphic and 1 immunoblastic. Four pts had monoclonal and 3 had polyclonal tumors. All patients were seropositive for Epstein Barr virus (EBV) and had IgG anti-VCA. EBNA or EBER were demonstrated in all 6 tumors tested. lmmmunosuppressive therapy was decreased in all patients and the polyclonal tumors were treated either with acyclovir or excision. Monoclonal tumors were treated with systemic chemotherapy or in one case with monoclonal Ab’s (CD20). Mortality was 46% (all with monoclonal tumors). The median survival for the PTLD patients is 21 months (range 1 42 months). PTLD is presenting earlier post-OLT. EBV plays a special role in the pathogenesis combined with immunosuppressive therapy. The outcome is poor and newer therapeutic approaches are needed.
69
1 P/CO1/035 1
PREDICTION OF PROGNOSIS AFTER TRANSPLANTATlON IN PRIMARY SCLEROSING CHOlANGlTlS USING A COX MODEL J. Neuw
6. Gunson.
l
The Liverand HepatobiliaryUnit, The Queen Elizabeth Hospital, Birmingham, United Kingdom and ‘Department of Internal Medicine I, BispebjeroUniversity Hospttal. Copenhagen, Denrnati Background: Livertransplantationremainsthe only treatment for patients with end-stage primary sciemsing cholangitis (PSC) althoqth selectioncriteria for the procedureand its timing remains uncertain. Aims:To kientifypm-transplantvariablesassociatedwith survival after transplantationand to devise a Cox rt39ressionmodel for predictionof post-transplant survival. Methods:We studied 118 patients transplantedfor PSC at the Queen Elizabeth Hospital,Birminghambeing followedfor up to 9% years after the procedure.The asoclatlon betwen pm-transplant data and post-transplantsurvivalwas studied usingthe logranktest (univaftateanalyses)and Cox multipleregressionanalysis- bothfor the firstpost-transplant year and the total observationperiod. Results: Univariateanalysesshowedthe foHovvlng variablesto be associatedwith a decmased post-tmnspiantsutvlval: high serum creatinlne, hi9h serum bilirubin,blllarymalignancy,previousupper abdominal surgery, hepeuc encephaiopathy.ascites and Crohn’s disease,while ulcerativeoolitiswas assodated with increasedposttransplantsurvival (all psO.05). The final multiple Cox rsgmssion model lnckxied the following si@ficant variabies: Inflammatory bowel dkwse, ascites, previousupper abdominal surgery,serum creatinineand bliiary mai@wbcy (all pcO.03). Vhtually the same resultsWBIVJ obtainedcon&&win9the first post-transplantyear and the total observationperiod. Conclusions:These resultscan Improve!sebctionof patientswith PSC for liver transpiantation.Furthe~rmore. by comparlngprq~nosis withand withouttransplantaM (usifq pmviouslypublishedmodels) the timirg of the pmceduremay be improved. 1 P/CO1/034 1 MIXED CRYOGLOBULINEMIA AFTER FOR HCV-PUSITIVE LIVER CIRRHOSIS S Puliti’. C Fhv’. M Gieou’. F Giannelli’. Samuel’. P Gentilini’. AL Zinneno’. Institute of P. Browse Hospital, Villejuif, Francez~, Cisanello
IMMUNOGENETIC FACTORS, HCV GENOTYPE AND HCV RECURRENCEAFTER LIVER TRANSPLANTATfON MScalamomra.DFortiandtJJ& Uniti Trapiantid’orgaoo,Oqedale Nigmda. Milaa, Italy. Since HLA DRBl+ll has been associated with less advanced liver diseaseinPatients witllchronichepatitisc(1),wehaveim%stigatedthe distributionof HLA DRBlWkles in 81 HCV Positive liver mtsplam Patkntsaadtheirpossibleasseciationwithtbe frequency,timingand severity of recurmntdisease.TheroleofotherfMorssuchasHLA match,HCVgenotypeaodnumberofsteroid~ukeswasalsoevahuted. Ofthe 113 ~atkntswithHCVrelatedcirrhoGtmn@antedatour centerbetweenMay1990andJune1997,only81wboauvivedatleast3 monthsatkr 8raftiq wue consiin this stody. HLA-DRBl* typin8 (PCR-SSP), HLA-A,B (serologic technique) or DRBl* match between donorsand recipientsand HCV geno@ping(accordingto Okamoto)were availablein all cases. Liver bhqsies were Performedwheneverclinically indicatedand at yearly inter+&. . . uuvarmkandlogisticregeasionanalysisnoneofthefour seiected for investigation, ruunelypresenceof an HLAz DRBl*ll allele, of a HLA-DR-match,of geno@pe lb and number of steroidpllseswassi@icantlyasso&edeitherwiththeoaxrrenoeor theseverityofrlxWent hepatitS.Dif%fElUly,whenCOXlS&&thetime interval betwxea OLT and hepatitis by Kaplan Meyer analysis, patientscarryingHLA-DRB1* 11 allele, showed a significantly delayedl#xxrenthepatitiswhencomParedwithPatkntsauryingother DREl*alleks @co.019 by Log rank test). This finding was more evirkat whenbothBemtypemtlbandHLA-DRBl*llwerecoosideredtogether @=0.015) ThesereadtMll8gestthatbothimmunogeoeticaodviraifactors infloencethetimiogofdiseasenzcurrence. Alar8ersamplesizeis pmbably~tobetterdetinetbeexactrokoftheforementioned paramethersOXltheOCCUK%% atKlpfo@xSiondrhepntitiS. References 1) Zavagliaet al. J Hepatol1996;24:65&65
1 P/CO1/0361 LIVER
TRANSPLANTATION
E Marrowhi’. F Filiowni’. D Internal Medicine, Florence; Italy, Hospital, Piss’Italy.
A striking association has been shown between HCV infection and B-cell lymphoproliferative disorders (LD) including mixed cryoglobulinemia (MC) and Bcell non-Hodgkin’s lymphoma. Post-transplant LD has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. We studied six pts. undergoing trasplantation (OLT) for HCVrelated cirrhosis in whom mixed cryoglobulinemia (MC) with vasculitis was observed after OLT. In one case, MC was also detected before OLT, even if with mild clinical manifestations. In the remaining pts., the mean time interval behveen OLT and the first expression of vasculitis was I7 m. (range 3-27 m.). All but one pt. developed cutaneous vasculitis (c.v.). 4/6 pts. (including the case without c.v.) were shown to be affected by membrane-proliferative glomendonephritis. 2/6 pts. developed a frank B-cell lymphoma I8 and 29 tn. after OLT, respectively. Clinical MC-related manifestations were generally relevant and frequently invalidating. This was particularly tlue for the patient in which MC was also evident before OLT, this patient died 62 m. after OLT due to renal impairment and multiorgan failure. All patients were HCV RNA positive. Semiquantitative analysis of HCV viremia (Amplicor HCV MonitorTM) performed in 4 pts. showed no significant differences with respect to viraemia levels detected in IO transplanted pts. without MC. Serological markers of EBV infection were negative in 4/4 pts. In two pts. in whom MC appeared aller OLT, molecular genetic analysis identified the t(14;lS) translocation in peripheral B cells. This study suggests that OLT may significantly worsen or manifest MC in HCVpositive pt.% In addition, malignant evolution of MC seems to be accelerated. Consequently, the possibility of MC should be taken into account in HCV+ OLT pts. both before and after intervention. This behaviour of HCV reinfection seems to be essentially related to a predisposition to LD in post-transplant pts probably on the basis of constitutional and/or HCV infection-induced conditions. These latter may possibly include anti-apoptotic mechanisms. High levels of viral replication generally observed after OLT may also play a role.
POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) IN LIVER RECIPIENTS. Z. Ben-An P. Amlot’. S. Lachmanan’, R. Tur-Kaspa, K. Rolles’, A.K. Burrouahs’ Liver Institute, Rabin Medical Center, Petah Tikva, Israel and ‘Hepatobil 8 Liver Transplantation Unit, Royal Free Hospital, London, UK. PTLD is a well recognized complication of organ transplantion but its significance in Orthotopic liver transplantation (OLT) needs to be ellucidated. Over a period of 9 years 7 adults (prevalence of 1.6%) mean age 53 years; liver allograft recipients developed PTLD, 1 to 36 months (m) post OLT (mean 6 m). Four patients (pts) received ATG/OKT3 for steroid resistant cellular rejection. Four pts had localized hepatic tumor, 2 had extralymphoreticular disease and 1 had spleen involvement, All tumors were B cell lymphomas. Three polymorhic, 3 monomorphic and 1 immunoblastic. Four pts had monoclonal and 3 had polyclonal tumors. All patients were seropositive for Epstein Barr virus (EBV) and had IgG anti-VCA. EBNA or EBER were demonstrated in all 6 tumors tested. lmmmunosuppressive therapy was decreased in all patients and the polyclonal tumors were treated either with acyclovir or excision. Monoclonal tumors were treated with systemic chemotherapy or in one case with monoclonal Ab’s (CD20). Mortality was 46% (all with monoclonal tumors). The median survival for the PTLD patients is 21 months (range 1 42 months). PTLD is presenting earlier post-OLT. EBV plays a special role in the pathogenesis combined with immunosuppressive therapy. The outcome is poor and newer therapeutic approaches are needed.