Domino Hepatic Transplantation in Maple Syrup Urine Disease
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《新英格兰医药杂志》
To the Editor: Orthotopic liver transplantation has been performed in at least 10 patients who have maple syrup urine disease (MSUD).1,2,3,4 In the first patients, transplantation was for nonmetabolic reasons (hepatic failure with hepatitis A1 and hypervitaminosis A2). In all patients, there was marked improvement in dietary protein tolerance and no evidence of any decompensation episodes during follow-up extending 10 years.3 Because the long-term outcome and effect on neurologic development remain to be identified, orthotopic liver transplantation remains a controversial therapy.1 With recent reports of success, it has been established as an option for patients with MSUD whose condition fails to respond to medical management. Many patients with approved indications for orthotopic liver transplantation die before grafts become available (in 2004, approximately 18,000 patients were on the waiting list for transplants, 6168 of whom received them).
We performed an orthotopic liver transplantation in a 25-year-old man (Patient 1) with MSUD and frequent episodes of decompensation, including six hospitalizations over 18 months for ataxia and plasma levels of leucine higher than 1000 μmol per liter (13 mg per deciliter). We used his liver as a domino graft (the use of an explanted liver from a patient with a metabolic disease as a graft in another patient in need of a transplant) in a 53-year-old man (Patient 2) with hepatitis C and hepatocellular carcinoma, who had low priority on the transplant waiting list and was unlikely to survive until routine procurement. Both transplantations were performed "piggyback," with the domino graft reconstructed with caval segments from a cadaveric donor; accordingly, neither patient required venovenous bypass. Plasma levels of amino acids (Table 1) and apparent whole-body leucine oxidation levels5 (low levels indicating MSUD) were measured before and after transplantation in both patients and in a control (Patient 3), a 47-year-old woman who had hepatitis C and hepatocellular carcinoma but who was eligible for transplantation through the usual channels.
Table 1. Plasma Levels of Amino Acids before and after Liver Transplantation.
Surgical outcomes were good. Patient 1 had marked decreases in plasma levels of branched-chain amino acids and alloisoleucine (Table 1), despite increased dietary protein from 6 g to more than 40 g per day. Patient 2 maintained near-normal amino acid levels with no detectable alloisoleucine on an unrestricted diet, reflecting the role of extrahepatic metabolism of branched-chain amino acids. Leucine oxidation (unchanged in Patient 3) increased in Patient 1 and decreased in Patient 2; after transplantation, both patients had levels of whole-body leucine oxidation expected in patients with heterozygosity for MSUD. Both patients have tolerated normal protein intake without any symptoms of MSUD for more than 12 months.
We conclude that liver transplantation substantially corrects whole-body branched-chain amino acid metabolism in patients with MSUD and greatly attenuates the disease. Livers from patients with MSUD may be considered as domino grafts for patients who have low priority on the transplant waiting list and who are likely to die without a transplant.
Bruce A. Barshop, M.D., Ph.D.
Ajai Khanna, M.D., Ph.D.
University of California, San Diego
La Jolla, CA 92093
akhanna@ucsd.edu
References
Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease. Eur J Pediatr 1999;158:Suppl 2:S60-S64.
Kaplan P, Mazur AM, Smith R, et al. Transplantation for maple syrup urine disease (MSUD) and methylmalonic acidopathy (MMA). J Inherit Metab Dis 1997;20:Suppl 1:37-37.
Bodner-Leidecker A, Wendel U, Saudubray JM, Schadewaldt P. Branched-chain L-amino acid metabolism in classical maple syrup urine disease after orthotopic liver transplantation. J Inherit Metab Dis 2000;23:805-818.
Mazariegos G, Morton H, Strauss K, et al. Liver transplantation for maple syrup urine disease: protocol and preliminary results. Pediatr Transplant 2005;9:Suppl 6:49-49.
Elsas LJ, Ellerine NP, Klein PD. Practical methods to estimate whole body leucine oxidation in maple syrup urine disease. Pediatr Res 1993;33:445-451.
We performed an orthotopic liver transplantation in a 25-year-old man (Patient 1) with MSUD and frequent episodes of decompensation, including six hospitalizations over 18 months for ataxia and plasma levels of leucine higher than 1000 μmol per liter (13 mg per deciliter). We used his liver as a domino graft (the use of an explanted liver from a patient with a metabolic disease as a graft in another patient in need of a transplant) in a 53-year-old man (Patient 2) with hepatitis C and hepatocellular carcinoma, who had low priority on the transplant waiting list and was unlikely to survive until routine procurement. Both transplantations were performed "piggyback," with the domino graft reconstructed with caval segments from a cadaveric donor; accordingly, neither patient required venovenous bypass. Plasma levels of amino acids (Table 1) and apparent whole-body leucine oxidation levels5 (low levels indicating MSUD) were measured before and after transplantation in both patients and in a control (Patient 3), a 47-year-old woman who had hepatitis C and hepatocellular carcinoma but who was eligible for transplantation through the usual channels.
Table 1. Plasma Levels of Amino Acids before and after Liver Transplantation.
Surgical outcomes were good. Patient 1 had marked decreases in plasma levels of branched-chain amino acids and alloisoleucine (Table 1), despite increased dietary protein from 6 g to more than 40 g per day. Patient 2 maintained near-normal amino acid levels with no detectable alloisoleucine on an unrestricted diet, reflecting the role of extrahepatic metabolism of branched-chain amino acids. Leucine oxidation (unchanged in Patient 3) increased in Patient 1 and decreased in Patient 2; after transplantation, both patients had levels of whole-body leucine oxidation expected in patients with heterozygosity for MSUD. Both patients have tolerated normal protein intake without any symptoms of MSUD for more than 12 months.
We conclude that liver transplantation substantially corrects whole-body branched-chain amino acid metabolism in patients with MSUD and greatly attenuates the disease. Livers from patients with MSUD may be considered as domino grafts for patients who have low priority on the transplant waiting list and who are likely to die without a transplant.
Bruce A. Barshop, M.D., Ph.D.
Ajai Khanna, M.D., Ph.D.
University of California, San Diego
La Jolla, CA 92093
akhanna@ucsd.edu
References
Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease. Eur J Pediatr 1999;158:Suppl 2:S60-S64.
Kaplan P, Mazur AM, Smith R, et al. Transplantation for maple syrup urine disease (MSUD) and methylmalonic acidopathy (MMA). J Inherit Metab Dis 1997;20:Suppl 1:37-37.
Bodner-Leidecker A, Wendel U, Saudubray JM, Schadewaldt P. Branched-chain L-amino acid metabolism in classical maple syrup urine disease after orthotopic liver transplantation. J Inherit Metab Dis 2000;23:805-818.
Mazariegos G, Morton H, Strauss K, et al. Liver transplantation for maple syrup urine disease: protocol and preliminary results. Pediatr Transplant 2005;9:Suppl 6:49-49.
Elsas LJ, Ellerine NP, Klein PD. Practical methods to estimate whole body leucine oxidation in maple syrup urine disease. Pediatr Res 1993;33:445-451.