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Familial amyloidotic polyneuropathy as a model for orthotopic domino liver transplantation
PAPERS READ BY TITLE TRANSPLANTATION, 1 c01/001
1.51
SURGERY, ACUTE LIVER FAILURE
1
FAMILIAL AMYLOIDOTIC POLYNEUROPATHY AS A LIVER ORTHOTOPIC DOMINO MODEL FOR TRANSPLANTATION + l t. M. ProostinnB. M. Nakazato U. T%icX * Departments of Gastroenterology and *Abdominal Surgery, Medizinische Hochschule Hannover, 30623 Hannover, Germany, ‘Third Department of Internal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki 68-16, Japan
of Familial Arnyloidotic The primary cause Polyneuropathy is a variant transthyretin gene on chromosome 18. Progressive polynenropathy followed by fatal cardiac and renal failure usually manifest during middle age. Currently, liver transplantation is the only available therapeutic option. We performed liver transplantation in four patients with Familial Amyloidotic Polyneuropathy, two of them carrying the transthyretin-30 (TTR-30) mutant. Four patients aged older than 50 years received the explanted amyloidotic livers. This procedure is called Domino transplantation. We determined the serum half life of TTR-30 with 2.25 days using daily monitoring of TTR-30 levels. An affected amyloidotic patient had an increased serum concentration of lipoprotein(a) with 78 mg/dl before transplantation. The tumor patient, who received the organ from this affected patient, developed an almost identical sernm concentration of lipoprotein(a) after liver transplantation, confirming the liver as tbe primary site of synthesis of this apoprotein. In conclusion, once Domino liver transplantation is performed, the impact of liver dependent metaboblism of specific proteins of interest can be studied.
NEUTROPHIL ELASTASE AND NITRIC OXIDE (NO) DURING ISCHEMIA-REPERFUSION AND THEIR RELATIONSHIPS WITH slCAM-1 AND ANTIOXIDANTS. S. Battista. F. Bar, G. Menaozzi’, E. CerutV. M. SalizzonV. G. Cavalli”, M. Niara”, F. Biasi*, G. Poli’, G. Molino. Division of General Medicine A and ALiver Transplant Unit, San Giovanni Battista Hospital, Turin; *Dept. of Exp. Medicine and Oncology, University of Turin; “Clinical Chemistry Lab., G. Bosco Hospital, Turin; Italy. Reperfusion injury during liver transplantation (OLT) may be sustained by several factors including the release of free radicals and enzymes by infiltrating neutrophils. In order to assess the relationship among elastase, NO and slCAM-1, during and after OLT, serial blood samples were taken from 14 patients (11 males, mean age 48.3 years), 6 of whom received an antioxidant mixture up to the early reperfusion. Neutrophil elastase and slCAM-1 were measured by immunoenzymatic (Merck) and ELISA (Boehringer) assays, respectively; nitrite/nitrate were detected by the Griess reaction. Elastase increased 5 min after reperfusion, peaked at 120 min (328.5*140.1 ng/mL vs. 47.3k20.8 pre-OLT, and 372.7k196.5 vs 55.5k46.2; ~~0.05) and declined in the 5 days after OLT in both controls and treated (156.7i86.5 and 139.7&135.4). No changes in nitrite/nitrate intraoperative levels were found, and significantly elevated values were detected after OLT in controls only (12.9i8.5 uM/L vs. 5.5k2.1 at 120 min). slCAM-1 profile showed no significant changes during OLT and a great increase after OLT in both groups. The enhanced elastase release supports the early involvement of activated neutrophils, while local over-expression of ICAM- cannot be substantiated by the detection of soluble forms. Later elevated slCAM-1 might contribute to the observed decrease in elastase by blocking receptors on neutrophils. NO metabolites seem not to be a sensitive index of early NO peak as previously shown by electron paramagnetic resonance. Different effects of antioxidants on NO and slCAM-1 suggest independent regulation of these mediators.
1 co1/003
ACUTE
1 LIVER
FAILURE
IN CHILDREN
E.D.Pfister. M.Melter, B.Rodeck, R.Kardorff, J.H.H.Ehrich Children’s Hospital, Medical School Hannover, Germany Introduction: Acute liver failure (ALF) is defined by acute onset of severely impaired liver function (PI < 40%, CHE < 2,5 kU/l) in patients with no recognized chronic liver disease. ALF is unusual in pediatric patients and little is known about parameters predicting the outcome of ALF in children. Patients: Fifty children with ALF aged 1 month to 16,5 years -ma,2 years- (30 girls, 20 boys) were admitted to our center between 1st Jan 1986 and 3 1st Dee 1996. Results: ALF was caused by metabolic disorders (n=6), drugs (nmfections (n=4), Reye-like syndrome (n=4), toxins (n=3), autoimmune hepatitis (n=2), acute Budd-Chiari syndrome (n=2) and miscellaneous (n=5) , No etiological agent was found in I9 (38%) cases. OLT was performed in I9 patients, auxiliary partial OLT (APOLT) in 2 patients. 47 (94%) children developed hepatic encephalopathy (HE) . Progression of HE to grade 3 or more was observed in 29 patients. Aplastic anemia developed in 5 children with ALF of unknown etiology, 3 of them recovered (2 after OLT) and 2 died (1 after APOLT) . 17 (34%) patients died, 7 of them without OLT 0 - 2 month after the initial symptoms of ALF. 10 Patients died 0 - 18 month after OLT. Summary_: ALF was associated with poor prognosis. High mortality rate was improved by OLT. The two year survival rate for emergency OLT was -50%.
GRANULOCYTE COLONY-STIMULATING FACTOR (G CSF) ENHANCES SUPEROXIDE PRODUCTION IN ACUTE LIVER FAILURE (ALF): AN IN WO EFFECT. M. Clauoerkm.1. Wendax N. Roland~. Institute of Liver Studies, King’s College School of Medicineand Dentistry.Lcw.&n,UK. The in vitro ability ofG-CSF to improveneutrophilsuperoxide productias has beenpreviously demmstrated in ALF patients&f 1). However, the effect ut neutmphil fbncticn ofG-CSF administraticn tothese patients is unknown. Therefore GCSF was given to three groups of ALF patients (n=6) as a daily IV infusion at three different dosages (25,SO and 100 mcg/m3. and superoxide production was assessedbefore and at 24 and 96 hours. ResuHl GCSF mcg/m’ Hoursafter G-CSF infusion 0 hr. 24 br % hr. 25 221458.1) 267.9(62.7) 382.7(40.6) 50 308.1(17.2) 339.3(56.3) 592.q9a.7) 100 231.5(65.2) 225.q52.6) 317.5(82.5) GCSF significantly enhanced superoxide prod&at at % hr @
1.51
SURGERY, ACUTE LIVER FAILURE
1
FAMILIAL AMYLOIDOTIC POLYNEUROPATHY AS A LIVER ORTHOTOPIC DOMINO MODEL FOR TRANSPLANTATION + l t. M. ProostinnB. M. Nakazato U. T%icX * Departments of Gastroenterology and *Abdominal Surgery, Medizinische Hochschule Hannover, 30623 Hannover, Germany, ‘Third Department of Internal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki 68-16, Japan
of Familial Arnyloidotic The primary cause Polyneuropathy is a variant transthyretin gene on chromosome 18. Progressive polynenropathy followed by fatal cardiac and renal failure usually manifest during middle age. Currently, liver transplantation is the only available therapeutic option. We performed liver transplantation in four patients with Familial Amyloidotic Polyneuropathy, two of them carrying the transthyretin-30 (TTR-30) mutant. Four patients aged older than 50 years received the explanted amyloidotic livers. This procedure is called Domino transplantation. We determined the serum half life of TTR-30 with 2.25 days using daily monitoring of TTR-30 levels. An affected amyloidotic patient had an increased serum concentration of lipoprotein(a) with 78 mg/dl before transplantation. The tumor patient, who received the organ from this affected patient, developed an almost identical sernm concentration of lipoprotein(a) after liver transplantation, confirming the liver as tbe primary site of synthesis of this apoprotein. In conclusion, once Domino liver transplantation is performed, the impact of liver dependent metaboblism of specific proteins of interest can be studied.
NEUTROPHIL ELASTASE AND NITRIC OXIDE (NO) DURING ISCHEMIA-REPERFUSION AND THEIR RELATIONSHIPS WITH slCAM-1 AND ANTIOXIDANTS. S. Battista. F. Bar, G. Menaozzi’, E. CerutV. M. SalizzonV. G. Cavalli”, M. Niara”, F. Biasi*, G. Poli’, G. Molino. Division of General Medicine A and ALiver Transplant Unit, San Giovanni Battista Hospital, Turin; *Dept. of Exp. Medicine and Oncology, University of Turin; “Clinical Chemistry Lab., G. Bosco Hospital, Turin; Italy. Reperfusion injury during liver transplantation (OLT) may be sustained by several factors including the release of free radicals and enzymes by infiltrating neutrophils. In order to assess the relationship among elastase, NO and slCAM-1, during and after OLT, serial blood samples were taken from 14 patients (11 males, mean age 48.3 years), 6 of whom received an antioxidant mixture up to the early reperfusion. Neutrophil elastase and slCAM-1 were measured by immunoenzymatic (Merck) and ELISA (Boehringer) assays, respectively; nitrite/nitrate were detected by the Griess reaction. Elastase increased 5 min after reperfusion, peaked at 120 min (328.5*140.1 ng/mL vs. 47.3k20.8 pre-OLT, and 372.7k196.5 vs 55.5k46.2; ~~0.05) and declined in the 5 days after OLT in both controls and treated (156.7i86.5 and 139.7&135.4). No changes in nitrite/nitrate intraoperative levels were found, and significantly elevated values were detected after OLT in controls only (12.9i8.5 uM/L vs. 5.5k2.1 at 120 min). slCAM-1 profile showed no significant changes during OLT and a great increase after OLT in both groups. The enhanced elastase release supports the early involvement of activated neutrophils, while local over-expression of ICAM- cannot be substantiated by the detection of soluble forms. Later elevated slCAM-1 might contribute to the observed decrease in elastase by blocking receptors on neutrophils. NO metabolites seem not to be a sensitive index of early NO peak as previously shown by electron paramagnetic resonance. Different effects of antioxidants on NO and slCAM-1 suggest independent regulation of these mediators.
1 co1/003
ACUTE
1 LIVER
FAILURE
IN CHILDREN
E.D.Pfister. M.Melter, B.Rodeck, R.Kardorff, J.H.H.Ehrich Children’s Hospital, Medical School Hannover, Germany Introduction: Acute liver failure (ALF) is defined by acute onset of severely impaired liver function (PI < 40%, CHE < 2,5 kU/l) in patients with no recognized chronic liver disease. ALF is unusual in pediatric patients and little is known about parameters predicting the outcome of ALF in children. Patients: Fifty children with ALF aged 1 month to 16,5 years -ma,2 years- (30 girls, 20 boys) were admitted to our center between 1st Jan 1986 and 3 1st Dee 1996. Results: ALF was caused by metabolic disorders (n=6), drugs (nmfections (n=4), Reye-like syndrome (n=4), toxins (n=3), autoimmune hepatitis (n=2), acute Budd-Chiari syndrome (n=2) and miscellaneous (n=5) , No etiological agent was found in I9 (38%) cases. OLT was performed in I9 patients, auxiliary partial OLT (APOLT) in 2 patients. 47 (94%) children developed hepatic encephalopathy (HE) . Progression of HE to grade 3 or more was observed in 29 patients. Aplastic anemia developed in 5 children with ALF of unknown etiology, 3 of them recovered (2 after OLT) and 2 died (1 after APOLT) . 17 (34%) patients died, 7 of them without OLT 0 - 2 month after the initial symptoms of ALF. 10 Patients died 0 - 18 month after OLT. Summary_: ALF was associated with poor prognosis. High mortality rate was improved by OLT. The two year survival rate for emergency OLT was -50%.
GRANULOCYTE COLONY-STIMULATING FACTOR (G CSF) ENHANCES SUPEROXIDE PRODUCTION IN ACUTE LIVER FAILURE (ALF): AN IN WO EFFECT. M. Clauoerkm.1. Wendax N. Roland~. Institute of Liver Studies, King’s College School of Medicineand Dentistry.Lcw.&n,UK. The in vitro ability ofG-CSF to improveneutrophilsuperoxide productias has beenpreviously demmstrated in ALF patients&f 1). However, the effect ut neutmphil fbncticn ofG-CSF administraticn tothese patients is unknown. Therefore GCSF was given to three groups of ALF patients (n=6) as a daily IV infusion at three different dosages (25,SO and 100 mcg/m3. and superoxide production was assessedbefore and at 24 and 96 hours. ResuHl GCSF mcg/m’ Hoursafter G-CSF infusion 0 hr. 24 br % hr. 25 221458.1) 267.9(62.7) 382.7(40.6) 50 308.1(17.2) 339.3(56.3) 592.q9a.7) 100 231.5(65.2) 225.q52.6) 317.5(82.5) GCSF significantly enhanced superoxide prod&at at % hr @