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Cyclosporine rechallenge after A previous neurotoxic reaction: A case report
HEPATOLOGY Vol. 22, No. 4, Pt. 2, 1995
AASLD A B S T R A C T S
1 5 3 7 CYCLOSPORINE RECHALLENGE AFTER A PREVIOUS NEUROTOXIC REACTION: A CASE REPORT. M Siciliano, D Tomasello, AM Ciammella and L Rossi, Istituto di Patologia Mcdica, Universith Cattolica del Sacro Cuore, Roma, Italy.
Case report: a 60 year-old woman affected by primary biliary cirrhosis underwent orthotopic liver transplantation in 1991 for hcpatocellular failure, intractable ascites with pleural effusion, recurrent infections and osteoporosis. On day 10 after transplantation, after five days of intravenous cyclosporine (100 mg i.v.b.i.d.), unresponsive coma developed. A lumbar puncture showeda normal liquoral pressure; ccrebrospinal fluid cell count and protein content were normal and no viruses or fungi were identified. Repeated EEGs were compatible with a severe toxic-metabo!ic encephalopathy and CT scan of tile head was negative. The observed neurological complications were ascribed to cyclosporine and the drag was discontinued. The immunosoppressive therapy was continued with azathioprine and prednisolone. After the withdrawal of cyclosporine therapy, the patient gradually recovered from coma and neurological examination on discharge was normal. In 1994 the patient was readmitted for D6 collapse and marked reduction in mineraldcnsity of all vertebrae. Cyclosporine (125 mg b.i.d, orally) was started and prednisolone was tapered two weeks after the beginning of the cyclosporine therapy, following a six month schedule. After cyclosporine re-administration, neurological examinations remained unremarkable and toxic effects did not appear. Discussion: nearly no doubt exists that the coma was a consequence of a toxic effect of cyclosporine. This neurologic s~cmptom began shortly after cyclosporin administration and gradually disappeared after withdrawal. Moreover, no other possible cause o f coma was identified. Hypomagnesemia, hypocalcemia, low total serum cholesterol levels during the post-operatfve period, high doses of steroids and other drugs, multiple organ failure and allograft rejection may arise the toxicity of cyclosporine, even when serum conentration is closely maintained in the therapeutic range. On the basis of the successful rechallenge with cyclosporin for the severe sequelae of chronic steroidal therapy, we think that some factors able'to influence cyclosporine neurotoxicity acted in our patient after transplantation. Conclusmn: we believe that in selected patients with a history of post-transplant cyclosporin toxicity, a rechallenge may be considered, expecially if the chronic steroidadministratinn caused severe side-effects.
1 5 3 9 FATE OF TRANSPLANTED HEPATIC ALLOGRAFTS FROM
OLDER CADAVERIC DONORS. R Sindhi. BW Shaw. TJ Pillen, D Mundv. AN Lananas. DL Sudan. IJ Fox. and TG Heffron. Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska. Purpose: To test the hypothesis that hepatic allografts from cadaveric donors aged 50 years or greater have a higher incidence of complications and lower graft survival after transplantation. Materials and Methods: Available records of 112 hepatic allografts obtained from cadaveric donors aged >50 years were reviewed for donor age, sex, cause of death, and cold ischemia time. Recipients UNOS status was used to assess recipient disease severity and recipient clinical records reviewed for complications. A control group of 36 random cadaveric hepatic aUograftsfrom donors aged 18-49 was selected where the recipients were comparable in age to those in the test group. Results: Univariate analysis revealed a significant donor age related decrease in graft survival (p=0.006). A multivariate analysis identified recipient UNOS status (p=0.0006), and donor age (0.010), as significant independent factors affecting graft survival. Donor age (p=0.016), and UNOS status (p=0.0162) were also independent factors affecting patient survival by multivariate analysis. Although cold isehemia time achieved statistical significance for patient survival (p=0.046), recipient age did not influence graft or patient survival in multivariate analyses of our study group. Donors aged > 50 years demonstrated an incidence of primary graft nonfunction of 13/112 and of hepatic artery thrombosis of 10/112 compared to 1/36 and 1136,respectively in allografts from younger donors. (The small sample size did not allow for statistical comparisons for these complications.) Conclusion: Althoughanografts from physiologicallyhealthy older donors > age 50 years can be used for transplantation with acceptable results their propensity toward lower graft survival and a potentially higher risk of PNF and HAT shouldbe recognized.
1538
491A
DIFFERENTIAL DIAGNOSIS OF ISCHEMIC HEPATITIS, CHRONIC LIVER DISEASE AND EXTRAHEPATIC OBSTRUCTION IN CRITICALLY ILL: THE ROLE OF URINE BILE ACIDS. V Simko, S. Michael and C. Scott. Section of Gastroenterology, Brooklyn VA and SUNY Health Sciences Center at Brooklyn, N.Y. Hepatic perfusion injury (PI) frequently complicates the diagnosis in critically ill where a prompt decision is urgent. We studied 35 consecutive patients with total bilirubin (TBA) > 10 mg/DL and/or ALT > 700 l U l L The serum bile acids (SBA) and urine bile acids (UBA) assay was RIA (Beckton Dickinson). To correct for urine flow, UBA were expressed per g of creatinine. Normal SBA < 3.0 #M, UBA < 2.3 ,um/g. BA as well as AST, ALT, AP, GGT, TBA and prothrombin time were matched with verified diagnoses of PI (n= 8), hepatitis or cirrhosis (HE, n=14) and extrahepatic obstruction (EO, n=13). PI HE .1~0 J~ST 2895 (2684) a,b 713 (988) 685 (1580) ALT 2059 (1386) b 1002 (1505) 325 (694) AP 120 (55) b 214 (152) c 598 (394) GGT 129 (59) 244 (150 c 1582 (1259) TBA 1,4 (1.0) a,b 9.7(8.7) 15.0(6.5) UBA 7.0 (6.8) a,b 36:5 (32.4) 853 (99.4) _SBA 8.0 (7.7) a,b 111.7 (10&0) 132.7 (96.9) t-test81gnificalnt:a) PI va HE b) PI vs EO c) HE vs EO Using a multivariate discrirninant analysis, with final diagnosis as outcome variable, best predictor tests were selected to calculate multivariate predictor equations for PI, HE and EO: Test used in equation Per cent correct dia.qnosis HE vs EO UBA, GGT, AP 96 HE vs PI UBA, AST 77 EO vs Pl TBA 100 Conclusion: PI was typical with excessive AST and low UBA. In PI the TBA never exceeded 8.2 mg/DL. UBA in critical illness confirm the diagnostic value of random urine analysis.
1 5 4 0 IMPACT OF POSITIVE CROSSMATCH DUE TO IgG VERSUS IgM ANTIBODIES ON THE OUTCOME OF PRIMARY LIVER TRANSPLANTATION UNDER TACROLIMUS. AK S nqha, AB Jain, J Martell, JJ Funq, W irish, S Todo, J Reyes, TE Starzl. Dept. of Surgery, University of Pittsburgh Medical Center, Pittsburgh. Between Feb, 90 and June, 94, 1413 primary liver transplants (OLT) under pdmary tacrolimus immunosuppression were done at the University of Pittsburgh. Amos modified NIH technique with and without the addition of Dithiothreitol (DTT) to neutralize IgM antibodies was used for crossmatching. Of the 132 crossrnatch positive patients, 100 remained positive even after addition of DTT (IgG antibody positive) while 32 were rendered negative ( IgM antibody positive). The two groups were comparable with respect to mean age, indications for OLT, HLA mismatch, although IgG positive group had 35% higher prevalence of females. All the patients were retrospectively followed for the first three post-operative months after OLT for incidence and severity of rejection and a period of 4 to 56 months( mean 25.4 months) for graft and patient survival. 61% patients in the [gG positive group had at least 1 episode of rejection in the first 3 months after OLT as compared to 43.7% in the IgG positive group (p=0.086). 4% patients in the tgG positive group required retransplantation for organ rejection as compared to none in IgM positive group (p= 0.649). However the overall retransplantation rate was 10% in the IgG positive group as compared to 12.5% in the IgM positive group. Patient/graft survival is as shown below: Posttransplant months 3 6 12 24 36 48 p= Graft Survival IgG + 82 77 73.7 72.6 70.1 67 0.56 19M+ 78.1 75 68.3 68.3 64 64 Patient Survival IgG+ 88 83 79.7 78.5 76.7 73 0.49 I£1M+ 84.4 81.2 71.1 71.1 71.1 71.1 IgG crossmatch positive primary OLT has about 17.3% higher incidence of rejection and a 4% risk of graft loss due to irreversible rejection. (Prostagland El was not used in all the patients which has a beneficial effect). However long term patient and graft survival and retransplantation rates were similar to IgM positive group although slightly lower than our overall survival under tacrolimus.
AASLD A B S T R A C T S
1 5 3 7 CYCLOSPORINE RECHALLENGE AFTER A PREVIOUS NEUROTOXIC REACTION: A CASE REPORT. M Siciliano, D Tomasello, AM Ciammella and L Rossi, Istituto di Patologia Mcdica, Universith Cattolica del Sacro Cuore, Roma, Italy.
Case report: a 60 year-old woman affected by primary biliary cirrhosis underwent orthotopic liver transplantation in 1991 for hcpatocellular failure, intractable ascites with pleural effusion, recurrent infections and osteoporosis. On day 10 after transplantation, after five days of intravenous cyclosporine (100 mg i.v.b.i.d.), unresponsive coma developed. A lumbar puncture showeda normal liquoral pressure; ccrebrospinal fluid cell count and protein content were normal and no viruses or fungi were identified. Repeated EEGs were compatible with a severe toxic-metabo!ic encephalopathy and CT scan of tile head was negative. The observed neurological complications were ascribed to cyclosporine and the drag was discontinued. The immunosoppressive therapy was continued with azathioprine and prednisolone. After the withdrawal of cyclosporine therapy, the patient gradually recovered from coma and neurological examination on discharge was normal. In 1994 the patient was readmitted for D6 collapse and marked reduction in mineraldcnsity of all vertebrae. Cyclosporine (125 mg b.i.d, orally) was started and prednisolone was tapered two weeks after the beginning of the cyclosporine therapy, following a six month schedule. After cyclosporine re-administration, neurological examinations remained unremarkable and toxic effects did not appear. Discussion: nearly no doubt exists that the coma was a consequence of a toxic effect of cyclosporine. This neurologic s~cmptom began shortly after cyclosporin administration and gradually disappeared after withdrawal. Moreover, no other possible cause o f coma was identified. Hypomagnesemia, hypocalcemia, low total serum cholesterol levels during the post-operatfve period, high doses of steroids and other drugs, multiple organ failure and allograft rejection may arise the toxicity of cyclosporine, even when serum conentration is closely maintained in the therapeutic range. On the basis of the successful rechallenge with cyclosporin for the severe sequelae of chronic steroidal therapy, we think that some factors able'to influence cyclosporine neurotoxicity acted in our patient after transplantation. Conclusmn: we believe that in selected patients with a history of post-transplant cyclosporin toxicity, a rechallenge may be considered, expecially if the chronic steroidadministratinn caused severe side-effects.
1 5 3 9 FATE OF TRANSPLANTED HEPATIC ALLOGRAFTS FROM
OLDER CADAVERIC DONORS. R Sindhi. BW Shaw. TJ Pillen, D Mundv. AN Lananas. DL Sudan. IJ Fox. and TG Heffron. Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska. Purpose: To test the hypothesis that hepatic allografts from cadaveric donors aged 50 years or greater have a higher incidence of complications and lower graft survival after transplantation. Materials and Methods: Available records of 112 hepatic allografts obtained from cadaveric donors aged >50 years were reviewed for donor age, sex, cause of death, and cold ischemia time. Recipients UNOS status was used to assess recipient disease severity and recipient clinical records reviewed for complications. A control group of 36 random cadaveric hepatic aUograftsfrom donors aged 18-49 was selected where the recipients were comparable in age to those in the test group. Results: Univariate analysis revealed a significant donor age related decrease in graft survival (p=0.006). A multivariate analysis identified recipient UNOS status (p=0.0006), and donor age (0.010), as significant independent factors affecting graft survival. Donor age (p=0.016), and UNOS status (p=0.0162) were also independent factors affecting patient survival by multivariate analysis. Although cold isehemia time achieved statistical significance for patient survival (p=0.046), recipient age did not influence graft or patient survival in multivariate analyses of our study group. Donors aged > 50 years demonstrated an incidence of primary graft nonfunction of 13/112 and of hepatic artery thrombosis of 10/112 compared to 1/36 and 1136,respectively in allografts from younger donors. (The small sample size did not allow for statistical comparisons for these complications.) Conclusion: Althoughanografts from physiologicallyhealthy older donors > age 50 years can be used for transplantation with acceptable results their propensity toward lower graft survival and a potentially higher risk of PNF and HAT shouldbe recognized.
1538
491A
DIFFERENTIAL DIAGNOSIS OF ISCHEMIC HEPATITIS, CHRONIC LIVER DISEASE AND EXTRAHEPATIC OBSTRUCTION IN CRITICALLY ILL: THE ROLE OF URINE BILE ACIDS. V Simko, S. Michael and C. Scott. Section of Gastroenterology, Brooklyn VA and SUNY Health Sciences Center at Brooklyn, N.Y. Hepatic perfusion injury (PI) frequently complicates the diagnosis in critically ill where a prompt decision is urgent. We studied 35 consecutive patients with total bilirubin (TBA) > 10 mg/DL and/or ALT > 700 l U l L The serum bile acids (SBA) and urine bile acids (UBA) assay was RIA (Beckton Dickinson). To correct for urine flow, UBA were expressed per g of creatinine. Normal SBA < 3.0 #M, UBA < 2.3 ,um/g. BA as well as AST, ALT, AP, GGT, TBA and prothrombin time were matched with verified diagnoses of PI (n= 8), hepatitis or cirrhosis (HE, n=14) and extrahepatic obstruction (EO, n=13). PI HE .1~0 J~ST 2895 (2684) a,b 713 (988) 685 (1580) ALT 2059 (1386) b 1002 (1505) 325 (694) AP 120 (55) b 214 (152) c 598 (394) GGT 129 (59) 244 (150 c 1582 (1259) TBA 1,4 (1.0) a,b 9.7(8.7) 15.0(6.5) UBA 7.0 (6.8) a,b 36:5 (32.4) 853 (99.4) _SBA 8.0 (7.7) a,b 111.7 (10&0) 132.7 (96.9) t-test81gnificalnt:a) PI va HE b) PI vs EO c) HE vs EO Using a multivariate discrirninant analysis, with final diagnosis as outcome variable, best predictor tests were selected to calculate multivariate predictor equations for PI, HE and EO: Test used in equation Per cent correct dia.qnosis HE vs EO UBA, GGT, AP 96 HE vs PI UBA, AST 77 EO vs Pl TBA 100 Conclusion: PI was typical with excessive AST and low UBA. In PI the TBA never exceeded 8.2 mg/DL. UBA in critical illness confirm the diagnostic value of random urine analysis.
1 5 4 0 IMPACT OF POSITIVE CROSSMATCH DUE TO IgG VERSUS IgM ANTIBODIES ON THE OUTCOME OF PRIMARY LIVER TRANSPLANTATION UNDER TACROLIMUS. AK S nqha, AB Jain, J Martell, JJ Funq, W irish, S Todo, J Reyes, TE Starzl. Dept. of Surgery, University of Pittsburgh Medical Center, Pittsburgh. Between Feb, 90 and June, 94, 1413 primary liver transplants (OLT) under pdmary tacrolimus immunosuppression were done at the University of Pittsburgh. Amos modified NIH technique with and without the addition of Dithiothreitol (DTT) to neutralize IgM antibodies was used for crossmatching. Of the 132 crossrnatch positive patients, 100 remained positive even after addition of DTT (IgG antibody positive) while 32 were rendered negative ( IgM antibody positive). The two groups were comparable with respect to mean age, indications for OLT, HLA mismatch, although IgG positive group had 35% higher prevalence of females. All the patients were retrospectively followed for the first three post-operative months after OLT for incidence and severity of rejection and a period of 4 to 56 months( mean 25.4 months) for graft and patient survival. 61% patients in the [gG positive group had at least 1 episode of rejection in the first 3 months after OLT as compared to 43.7% in the IgG positive group (p=0.086). 4% patients in the tgG positive group required retransplantation for organ rejection as compared to none in IgM positive group (p= 0.649). However the overall retransplantation rate was 10% in the IgG positive group as compared to 12.5% in the IgM positive group. Patient/graft survival is as shown below: Posttransplant months 3 6 12 24 36 48 p= Graft Survival IgG + 82 77 73.7 72.6 70.1 67 0.56 19M+ 78.1 75 68.3 68.3 64 64 Patient Survival IgG+ 88 83 79.7 78.5 76.7 73 0.49 I£1M+ 84.4 81.2 71.1 71.1 71.1 71.1 IgG crossmatch positive primary OLT has about 17.3% higher incidence of rejection and a 4% risk of graft loss due to irreversible rejection. (Prostagland El was not used in all the patients which has a beneficial effect). However long term patient and graft survival and retransplantation rates were similar to IgM positive group although slightly lower than our overall survival under tacrolimus.