Domino liver transplantation in maple syrup ... - Wiley Online Library

LIVER TRANSPLANTATION 12:876 – 882, 2006

SHORT REPORT

Domino Liver Transplantation in Maple Syrup Urine Disease Ajai Khanna,1 Marquis Hart,1 William L. Nyhan,2 Tarek Hassanein,3 Janice Panyard-Davis,2 and Bruce A. Barshop2 1 Department of Surgery, University of California, San Diego, La Jolla, CA, 2Department of Pediatrics, University of California, San Diego, La Jolla, CA, and 3Department of Medicine, University of California, San Diego, La Jolla, CA

Liver transplantation has been reported in a few cases of maple syrup urine disease (MSUD), but is controversial. Many patients with approved indications for liver transplantation die before grafts are available. A 25-yr-old man with MSUD underwent liver transplantation, and his liver was used as a domino graft for a 53-yr-old man with hepatocellular carcinoma who had low priority on the liver transplant waiting list and was unlikely to survive until routine organ procurement. Both transplants were performed as “piggy back” procedures, reconstructing the domino graft with caval segments from the cadaveric donor. Neither required veno-venous bypass. Whole body leucine oxidation was estimated by 13CO2 in breath after oral boluses of 13 L-[1- C]-leucine, before and after transplantation in both patients and a control subject. The surgical outcome was successful. The patient with MSUD had marked decreases in plasma branched-chain amino acids (BCAAs) and alloisoleucine (from 255 ⫾ 66 to 16 ⫾ 7 ␮mol/L), despite advancement of dietary protein from 6 to ⬎40 gm/day. The domino recipient maintained near-normal levels of plasma amino acids with no detectable alloisoleucine on unrestricted diet. Leucine oxidation increased in the patient with MSUD (from 2.2 to 5.6% recovered in 4 hours) and decreased in the recipient (from 9.7 to 6.2%). Neither patient demonstrated any apparent symptoms of MSUD over more than 7 months. In conclusion, liver transplantation substantially corrects whole body BCAA metabolism in MSUD and greatly attenuates the disease. Livers from patients with MSUD may be considered as domino grafts for patients who might otherwise not survive until transplantation. Liver Transpl 12:876 – 882, 2006. © 2006 AASLD. Received August 2, 2005; accepted January 18, 2006.

Maple syrup urine disease (MSUD; OMIM 248600) is an autosomal recessive disorder characterized by impaired activity of the branched-chain alpha-keto acid dehydrogenase (BCKADH; EC 1.2.4.4) complex (Fig. 1). The resulting accumulated branched-chain L-amino acids (BCAAs) and alpha-keto acids exert neurotoxic effects. The clinical course is typically punctuated by episodes of ketoacidosis, each potentially life-threatening. A very few cases are responsive to supplements of thiamine but, for most, treatment is limited to dietary management with strictly reduced quantities of protein and BCAAs as well as aggressive intervention during acute

episodes. The outcome is potentially favorable when the patients are kept on carefully supervised long-term therapy, but even with successful treatment late complications including brain damage or death are possible,1 and there is increasing awareness of chronic psychological burden in older patients with MSUD.2 Liver transplantation has been performed for several years in metabolic disorders that directly cause hepatic dysfunction, such as Wilson disease3 and tyrosinemia.4 More recently, as the methodology and success rates improved, liver transplantation has been performed in metabolic disorders which do not cause hepatic failure,

Abbreviations: MSUD, maple syrup urine disease; BCAA, branched chain amino acid. Supported by the UCSD General Clinical Research Center (M01 RR00827). There was no role of the study sponsor in study design, collection, analysis, or interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. None of the authors have any financial or personal relationships that could be construed as conflicts of interest. Address reprint requests to Bruce A. Barshop, M.D., Ph.D., Professor of Clinical Pediatrics, Division of Biochemical Genetics, Department of Pediatrics, UCSD School of Medicine, La Jolla, CA 92093-0830. Telephone: 619-543-5260; FAX: 619-543-3565; E-mail: [email protected] DOI 10.1002/lt.20744 Published online in Wiley InterScience (www.interscience.wiley.com).

© 2006 American Association for the Study of Liver Diseases.

DOMINO LIVER TRANSPLANTATION IN MSUD 877

Figure 1. Pathway of BCAA catabolism. Note that the branchedchain organic acids are derived from the BCAAs by deamination, and the site of the defect in MSUD is the dehydrogenase complex. The asymmetry of the ␤-carbon of isoleucine and the reversibility of the keto-enol interconversion gives rise to alloisoleucine, which is virtually pathognomonic for MSUD.

but in which the pathophysiology includes deficiency of an enzyme normally expressed exclusively in the liver, such as the urea cycle disorders, including ornithine transcarbamoylase deficiency, carbamyl phosphate synthetase deficiency, and citrullinemia.5 Even more recently, liver transplantation has been performed in metabolic disorders in which the enzyme activities are primarily or at least substantially present in liver, including propionic acidemia6 and methylmalonic acidemia.7 The outcome in propionic acidemia has generally been favorable, but there are concerns about outcomes in methylmalonic acidemia, with reports of late neurologic complications.8,9 Similarly, there have been reports of orthotopic liver transplantation for MSUD.10,11 In the initial patient, transplantation was carried out when liver failure developed after a hepatitis A infection.10 Although there was no effect on the already impaired intellectual function in that patient, dietary protein tolerance became normal, and there was no metabolic instability over more than 3 yr of follow-up. Three other patients with MSUD who received liver transplantation11 were found to have an increase in branched-chain alpha-keto acid dehydrogenase activity to at least the level of very mild MSUD variants; they no longer required protein restricted diets and had an apparently zero risk of metabolic decompensation during catabolic events. Nearly 18,000 patients are on the waiting list for liver transplantation in the United States, and fewer than 5,700 patients were transplanted in 2003.12 Strategies proposed to increase the availability of organs have included the use of partial and split grafts, and of nonheart beating and other “marginal” donors.13 Trans-

plantation of an organ removed from the prospective recipient of another organ (known as sequential organ transplantation, or “domino” transplantation) was first performed with heart transplantation in the late 1980s and early 1990s.14 Domino liver transplantation was first performed in the early 1990s, and it allowed the use of the liver from a recipient of liver transplant as a marginally qualified donor graft for another transplantation. The first types of domino donors were patients with familial amyloid polyneuropathy.15 Although recipients of these livers do express the abnormal transthyretin encoded in the hepatic graft,16 there is still considerable benefit to the recipients of these grafts, as it requires many years for adverse effects to manifest. In some cases, the recipient of the domino graft will express serious consequences of the disease afflicting the domino donor, as in the case of hyperoxaluria.17 In other cases, the recipient of the domino transplant seems to have enough of a delay in onset of symptoms, as in the case of familial amyloid polyneuropathy, or sufficiently attenuated symptoms, as in the case of familial hypercholesterolemia,18 to make domino transplantation worth considering in cases where the survival of the final recipient is questionable in the time frame for organ procurement through routine channels. We report here our experience with liver transplantation in a young man with MSUD, and the use of his liver to transplant to a man with hepatocellular carcinoma resulting from hepatitis C virus-induced cirrhosis. Both patients now tolerate a normal intake of protein with no evidence of metabolic imbalance.

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

878 KHANNA ET AL.

PATIENTS AND METHODS Patients Patient 1 was a 25-yr-old man with MSUD. He was diagnosed as an infant after a typical ketoacidotic episode. He was found to be thiamine-unresponsive, but there is no information about his specific mutation(s). He was well controlled for several years, and his intellectual function was within normal limits. However, his metabolic management was an increasing problem, and he had a series of 5 hospitalizations in 18 months prior to liver transplantation resulting from symptoms of ataxia and ketosis associated with plasma leucine concentrations reaching above 1,000 ␮mol/L. In order to maintain plasma leucine concentrations below 500 ␮mol/L, he required a very low protein diet (6 gm of whole protein/day plus 88.5 gm of amino acids from Ketonex formula; Ross Nutritionals, Columbus, OH). Patient 2 was a 51-yr-old man with hepatitis C-induced cirrhosis who had a 6 ⫻ 4 cm ⫻ 3.9 cm3 hepatocellular carcinoma in the right lobe of the liver. He was awaiting liver transplantation. To control his tumor he underwent right hepatic artery chemoembolization with cisplatinum, adriamycin, and mitomycin followed by laparoscopic radiofrequency ablation of the tumor. His liver functions were compensated, and his score according to the Model for End-Stage Liver Disease following local tumor control stood at 10.19 He had a low priority as a recipient for liver transplantation. According to the criteria set out by the United Network for Organ Sharing, our patient could not get extra points on his Model for End-Stage Liver Disease score due to the size of his tumor. Accordingly, our patient was offered the domino transplant. Approval of the Institutional Ethics Committee was obtained, and the patient was approved for the procedure in view of his disease severity and poor chances of survival without transplantation. He was fully informed about the experimental nature of this procedure and the possibility of developing clinical MSUD. The donor for patient 1 was an unrelated 30-yr-old woman who suffered brain death. Patient 3 was selected to act as a control; she was a 53-yr-old woman who, similar to patient 2, had hepatitis C-induced cirrhosis and hepatocellular carcinoma. She was studied before and after an independent orthotopic liver transplantation.

Methods Leucine oxidation was estimated in patients before and after liver transplantation using the oral bolus method, with 38 ␮mol/kg L-[1-13C]-leucine.20-22 For each subject, the first study was performed prior to transplantation, and the second study more than 3 weeks after surgery, under stable health conditions. After an overnight fast, an intravenous line was placed to allow for repeated blood sampling. A single 1-mL/kg dose of 38 ␮mol/mL L-[1-13C]-leucine solution (99% isotopically enriched; Cambridge Isotope Laboratories, Andover, MA) was administered orally. The patients remained in

bed at rest during the procedure. Prior to the ingestion of leucine, CO2 production (VCO2) was measured using an indirect calorimeter (Deltatrac II; Sensormedics, Yorba Linda, CA) in canopy mode. Breath samples were collected at 15-minute intervals over 3 hours; the subjects blew through small straws directly into autosampler vials that were immediately capped and crimped, and then analyzed within 2 days with an isotope ratio mass spectrometer (Dr. W. Paul Lee, UCLA-Harbor Medical Center). 13CO2/12CO2 was analyzed with gas chromatography-mass spectrometry (Finnegan MAT Delta IRMS coupled to a Hewlett-Packard 5890 gas chromatograph; Thermo-Finnigan, Waltham, MA). The sample vials containing breath samples were placed into an autosampler, and triplicate measurements of ⌬13C/12C were made using commercial grade CO2 gas as reference standard, with results expressed as the difference, positive or negative, of 13C/12C from the reference. From the measurements of atoms percent excess breath 13CO2 (APE13C) and the measured VCO2 (mL/minute), the rate of production of 13CO2 (F13CO2,␮mol/kg/minute) was calculated as F 13CO ⫽ 2

APE 13C ⫻ V CO2 w

冋

册

60 ⫻ 44.6 , 100 ⫻ 0.74

(1)

where w is the body weight (kg) and the constants 100, 60, and 44.6 convert from percentages, minutes to hours, and mL of CO2 to ␮mol, respectively, and 0.74 is used to compensate for the fraction of CO2 produced that is expired.23 The cumulative percent dose was estimated by trapezoidal integration. Plasma samples were analyzed on an automated amino acid analyzer (Model 6300, Beckman Instruments, Fullerton, CA). During the L-[1-13C]-leucine loads, blood samples were drawn every 30 minutes, placed on ice, and centrifuged within 15 minutes to isolate plasma, which was stored at ⫺20°C until analysis. Urine organic acids were analyzed by gas chromatography-mass spectrometry.24

Operative Procedure Upon notification of the donor liver availability, the domino donor and recipient were admitted to the hospital. Once the cadaver organ suitability was determined, the liver of patient 1 (MSUD patient /domino donor) was removed using the “piggy-back” method, conserving as much of hepatic veins, portal vein, and hepatic artery as possible. Particular attention was given to avoid narrowing the upper cava during hepatectomy. Venous outflow tract of the domino liver was reconstructed by lengthening the right, middle, and left hepatic veins using cadaveric inferior vena cava bifurcation at the common iliac veins. The domino liver was transplanted into the 51-yr-old male with hepatocellular carcinoma. Both recipients underwent a piggy-back type of implantation, a unique approach which allowed us to proceed without the use of veno-venous bypass in either case.25 Both patients had an excellent postoperative recovery and were discharged from the hospital within 10 days without any complications.



Figure 2. Concentrations of amino acids in plasma before and after liver transplantation for (left panels) patient 1 (MSUD) and (right panels) patient 2. From top to bottom are shown: plasma alanine, valine, alloisoleucine, isoleucine, and leucine, with the daily intake of whole protein. For patient 1, values with error bars to the left of each panel show the average ⴞ SD for 20 measurements over 7 months preceding liver transplantation. Horizontal dashed lines indicate the normal ranges.

RESULTS Patient 1 was stable with no hint of metabolic imbalance, and dietary protein intake was gradually increased to the point at which he was receiving ⬎40 gm/day (Fig. 2). There was a drop in concentrations of BCAAs within the first day, and after 48 hours, the level of alloisoleucine was approximately normal. Prior to transplantation, the plasma alloisoleucine was 255 ⫾ 66 ␮mol/L (N ⫽ 21; alloisoleucine/isoleucine ratio 1.04), and afterward it decreased to 16 ⫾ 7 ␮mol/L (N ⫽ 28; ratio 0.15). The plasma concentrations of alanine increased, and the concentrations of BCAA decreased to near-normal levels (leucine from 544 ⫾ 233 to 209 ⫾ 37 ␮mol/L, isoleucine from 240 ⫾ 135 to 116 ⫾ 33 ␮mol/L, valine from 287 ⫾ 118 to 280 ⫾ 50 ␮mol/L; normal ranges are 75-175, 26-98, and 141-317 ␮mol/L, respectively) despite liberalization of diet to an extent which could never be considered previously. Urine organic acid analysis after transplantation (N ⫽ 9) showed no elevation of branched chain 2-hydroxy- or 2-oxo-acids. In patient 2, BCAA concentrations (Fig. 2) rose slightly, particularly valine, but the values were only slightly above normal limits on an unrestricted diet, and the concentration of alanine also rose moderately. Alloisoleucine was never detected in plasma, and urine organic acids (N ⫽ 11) remained normal. The responses of plasma amino acids with the leucine loads for patients 1 and 2 are shown in Figure 3. The basal concentrations in patient 1 were obviously re-

Figure 3. Concentrations of amino acids in plasma during 13 L-[1- C]-leucine loads. Top panels: patient 1 (MSUD), before (left) and after (right) receiving an orthotopic liver transplant. Bottom panels: patient 2, before (left) and after (right) receiving an orthotopic liver transplant from patient 1. The amount of leucine given was 38 ␮mol/kg (5 mg/kg).

duced postoperatively, and the increment in leucine after the load was greatly reduced and was transient, rather than sustained. Patient 2 showed a minimal increment in leucine preoperatively, but a small transient increase postoperatively.


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Figure 4. Breath 13CO2 following L-[1-13C]-leucine loads. Top panel: calculated apparent whole body oxidation of leucine, in ␮mol/kg/minute. Bottom panel: cumulative percent dose oxidized, with the normal range from Elsas et al.21 shown in stippling. Symbols: square, patient 1; circles, patient 2; and triangles, control patient 3. Filled symbols indicate results prior to liver transplantation, and empty symbols indicate results after liver transplantation.

As shown in Figure 4, apparent whole-body leucine oxidation increased substantially in patient 1 after transplantation (from 2.2 to 5.6% of the dose at 4 hours), and there was a decrement in leucine oxidation in patient 2 (from 9.7 to 6.2%). In control patient 3, the results before and after transplantation were virtually identical.

DISCUSSION In the earliest reports, orthotopic liver transplantation in MSUD was for nonmetabolic reasons; both of the first patients had hepatic failure, 1 from hepatitis A10 and the other from hypervitaminosis A.26 A third patient27 was transplanted at the request of parents concerned about delayed psychomotor development and frequent metabolic decompensation. Those patients remained metabolically and neurologically stable at report, for 8 yr in 1 case.11 None of those patients had ketoacidosis following transplantation, and that has also been our experience with 2 infants with MSUD treated with liver transplantation. These observations provide an argument for liver transplantation in this disease in which death and/or mental retardation is common, even in patients ascertained presymptomatically through newborn screening. The concentration of alloisoleucine is considered to be the most sensitive and specific marker for the diagnosis and treatment control of patients with MSUD.22

The rapid correction of the hyperalloisoleucinemia in our patient with MSUD was rewarding. Wendel et al.11 emphasized that transplantation does not lead to complete correction of the metabolism of branched chain amino acids. In their patient, BCAA concentrations were consistently elevated 2- to 3-fold. The concentrations of alloisoleucine were 13-19 ␮mol/L, and the alloisoleucine/leucine ratio remained above normal. The homeostasis of BCAA was not completely normal after liver transplantation, but BCAA concentrations in our patient were reduced to the upper end of the normal range, and the level of alloisoleucine was similar to that previously reported.10 It represented a significant improvement and was similar to that observed naturally in patients with mild variant forms of MSUD.22 Inasmuch as the recipient of the domino organ has maintained near-normal levels of plasma amino acids and normal levels of urine branched-chain keto acids and hydroxy acids, it is clear that he did not develop MSUD. Considerable thought was given to that possibility. Branched-chain alpha-keto acid dehydrogenase is expressed widely, with a minority of the body’s distribution being hepatic,28 so we reasoned that the metabolic effects in the domino recipient would be at least substantially attenuated. The domino recipient maintained normal extrahepatic oxidation of leucine. Both recipients were very satisfied with the outcomes. Leucine is an abundant amino acid in muscle protein, and its turnover is very active. Constant infusions of stable isotopes in children with MSUD show normal rates of leucine uptake into protein synthesis, but markedly decreased rates of leucine oxidation,29 whereas apparent rates of oxidation were surprisingly near normal in the case of 2H5-phenylalanine in phenylketonuria and 1-13C-propionate in propionic acidemia or methylmalonic acidemia.30 In MSUD, the apparent rate of leucine oxidation from L-[1-13C]-leucine infusion clearly distinguished subjects with MSUD (with observed rates near 0) as compared to normal subjects,30 although detectable rates were observed in 1 (16% of control) out of 4,29 in 3 (8-24% of control) out of 7,31 and in 1 (5% of control) out of 2 patients.30 Similar estimates of in vivo oxidation rates in patients with MSUD were made32 using L-[1-13C]-leucine with both primed continuous infusion and oral bolus. The oral bolus method is simpler to perform and less invasive; although the results do not readily permit quantitation of flux rates, they have been used to reflect whole body leucine oxidation and were shown to be practical in distinguishing patients with MSUD,20 and in some cases heterozygotes from normals. Another study of the bolus L-[1-13C]-leucine method33 found no measurable 13 CO2 generation in any of the 3 patients with MSUD, permitting clear distinction from control subjects and from obligate heterozygotes. It is true that results of oral bolus oxidation studies may be affected by the dilution of tracer by the endogenous, unlabeled compound, and thus the apparent increase in 13CO2 generation could, at least in part, simply reflect a smaller leucine pool. However, the decreased increment in leucine in patient 1, and increased increment in patient 2 after liver



transplantation (Fig. 3) suggest that the phenomenon does reflect leucine removal and not simply an artifact of dilution. It is also likely that changes in 13CO2 evolution after an oral L-1-[13C]-leucine bolus overestimate changes in whole body leucine oxidation. Complete replacement of the liver might only be expected to change the body’s enzyme content by 10%,28 yet the change in appearance of 13CO2 was much greater (Fig. 4), probably a consequence of an emphasized role of the liver in handling an enteral leucine bolus. There have been no previous studies of leucine metabolism in individual patients, with or without MSUD, before and after liver transplantation. Cirrhotic patients after liver transplantation were found to have normal leucine oxidation.34 Our control patient 3 displayed normal oxidation, unchanged after transplantation. In vivo leucine oxidation has been studied in 1 MSUD patient after orthotopic liver transplantation.21 After transplantation, she received an unrestricted diet, and plasma concentrations of branched chain amino and 2-oxo acids were stable, yet at moderately increased levels (2- to 3-fold of control), and alloisoleucine concentrations remained remarkably elevated (⬎5-fold of control). In an oral L-[1-13C]-leucine load (38 ␮mol/ kg), 19.5% of the tracer dose applied was recovered in exhaled 13CO2, vs. 18.9 ⫾ 3.6% in healthy subjects. Recovery of 13CO2 in our patients was somewhat lower, but those results21 were extrapolated to infinity, and our results (Fig. 4) did correlate well with other data reported over 3 hours.20 In our MSUD patient, the cumulative recovered dose at 180 minutes increased from 2.2 to 5.6%. The recipient of his liver had a baseline apparent whole-body leucine oxidation rate in the lownormal range (9.7%) and ended up at approximately the same level (6.2%) as in the MSUD patient posttransplantation. Thus, the result in both patients was a moderate impairment of BCAA metabolism that so far appears to be clinically tolerable. It is interesting that alloisoleucine accumulation was only seen in the patient with persisting extrahepatic branched-chain alpha-keto acid dehydrogenase deficiency. Domino liver transplantation from patients with MSUD is feasible, and it may be feasible with other metabolic diseases as well. It is a useful approach to the treatment of metabolic disease, and in judiciously selected conditions it may provide precious resource for liver transplantation.

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ACKNOWLEDGMENTS We thank Dr. W. Paul Lee and Ms. Shu Lim of the Biomedical Mass Spectrometry Facility at the HarborUCLA GCRC (M01-RR00425) for performing the isotope ratio mass spectrometry of breath samples.

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REFERENCES 1. Chuang DT, Shih VE, Scriver CR. Maple syrup urine disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, vol 2. New York: McGraw-Hill, 2002:1971-2005. 2. Strauss KA, Morton DH. Branched-chain ketoacyl dehy-

21.

22.

drogenase deficiency: maple syrup disease. Curr Treat Options Neurol 2003;5:329-341. Bellary S, Hassanein T, Van Thiel DH. Liver transplantation for Wilson’s disease. J Hepatol 1995;23:373-381. Blanchard H, Bensoussan AL, Weber A, Gauthier M, Lacroix J, Charest J, et al. Pediatric liver transplantation: the Montreal experience. J Pediatr Surg 1989;24:1009-1012. Todo S, Starzl TE, Tzakis A, Benkov KJ, Kalousek F, Saheki T, et al. Orthotopic liver transplantation for urea cycle enzyme deficiency. Hepatology 1992;15:419-422. Yorifuji T, Muroi J, Uematsu A, Nakahata T, Egawa H, Tanaka K. Living-related liver transplantation for neonatalonset propionic acidemia. J Pediatr 2000;137:572-574. van’t Hoff WG, Dixon M, Taylor J, Mistry P, Rolles K, Rees L, Leonard JV. Combined liver-kidney transplantation in methylmalonic acidemia. J Pediatr 1998;132:1043-1044. Chakrapani A, Sivakumar P, McKiernan PJ, Leonard JV. Metabolic stroke in methylmalonic acidemia five years after liver transplantation. J Pediatr 2002;140:261-263. Nyhan WL, Gargus JJ, Boyle K, Selby R, Koch R. Progressive neurologic disability in methylmalonic acidemia despite transplantation of the liver. Eur J Pediatr 2002;161: 377-379. Netter JC, Cossarizza G, Narcy C, Hubert P, Ogier H, Revillon Y, et al. Mid-term outcome of 2 cases with maple syrup urine disease: role of liver transplantation in the treatment. Arch Pediatr 1994;1:730-734. Wendel U, Saudubray JM, Bodner A, Schadewaldt P. Liver transplantation in maple syrup urine disease. Eur J Pediatr 1999;158(Suppl 2):S60 –S64. Organ Procurement and Transplantation Network. http://www.optn.org/, 2004. Mor E, Klintmalm GB, Gonwa TA, Solomon H, Holman MJ, Gibbs JF, et al. The use of marginal donors for liver transplantation. A retrospective study of 365 liver donors. Transplantation 1992;53:383-386. Yacoub MH, Banner NR, Khaghani A, Fitzgerald M, Madden B, Tsang V, et al. Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation. J Heart Transplant 1990;9:459-466; discussion 466-457. Azoulay D, Samuel D, Castaing D, Adam R, Adams D, Said G, Bismuth H. Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy. J Am Coll Surg 1999;189:584-593. Terazaki H, Ando Y, Nakamura M, et al. Variant transthyretin in blood circulation can transverse the blood-cerebrospinal barrier: qualitative analyses of transthyretin metabolism in sequential liver transplantation. Transplantation 2001;72:296-299. Donckier V, El Nakadi I, Closset J, Ickx B, Louis H, Le Moine O, et al. Domino hepatic transplantation using the liver from a patient with primary hyperoxaluria. Transplantation 2001;71:1346-1348. Popescu I, Simionescu M, Tulbure D, Sima A, Catana C, Niculescu L, et al. Homozygous familial hypercholesterolemia: specific indication for domino liver transplantation. Transplantation 2003;76:1345-1350. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33: 464-470. 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. 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. Schadewaldt P, Bodner-Leidecker A, Hammen HW, Wen-


882 KHANNA ET AL.

23.

24.

25.

26.

27.

28.

del U. Whole-body L-leucine oxidation in patients with variant form of maple syrup urine disease. Pediatr Res 2001;49:627-635. Hoerr RA, Yu YM, Wagner DA, Burke JF, Young VR. Recovery of 13C in breath from NaH13CO3 infused by gut and vein: effect of feeding. Am J Physiol 1989;257(Pt 1): E426 –E438. Hoffmann G, Aramaki S, Blum-Hoffmann E, Nyhan WL, Sweetman L. Quantitative analysis for organic acids in biological samples: batch isolation followed by gas chromatographic-mass spectrometric analysis. 1989;35:587. Pacheco-Moreira LF, de Oliveira ME, Balbi E, et al. A new technical option for domino liver transplantation. Liver Transpl 2003;9:632-633. 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. Merinero B, Perez-Cerda C, Sanz P, Font LM, Garcia MJ, Martinez Pardo M, et al. Liver transplantation (LT) in a Spanish MSUD patient. 32nd Annual Symposium, Society for the Study of Inborn Errors of Metabolism, 1994, Edinburgh. 64. Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM. A molecular model of human

29.

30.

31.

32.

33.

34.

branched-chain amino acid metabolism. Am J Clin Nutr 1998;68:72-81. Thompson GN, Bresson JL, Pacy PJ, Bonnefont JP, Walter JH, Leonard JV, et al. Protein and leucine metabolism in maple syrup urine disease. Am J Physiol 1990; 258(Pt 1):E654 –E660. Thompson GN, Walter JH, Leonard JV, Halliday D. In vivo enzyme activity in inborn errors of metabolism. Metabolism 1990;39:799-807. Thompson GN, Francis DE, Halliday D. Acute illness in maple syrup urine disease: dynamics of protein metabolism and implications for management. J Pediatr 1991; 119(Pt 1):35-41. Schadewaldt P, Wendel U. Metabolism of branched-chain amino acids in maple syrup urine disease. Eur J Pediatr 1997;156(Suppl 1):S62–S66. Schadewaldt P, Bodner A, Brosicke H, Hammen HW, Wendel U. Assessment of whole body L-leucine oxidation by noninvasive L-[1-13C]leucine breath tests: a reappraisal in patients with maple syrup urine disease, obligate heterozygotes, and healthy subjects. Pediatr Res 1998;43: 592-600. Luzi L, Regalia E, Pulvirenti A, Piceni Sereni L, Spessot M, Romito R, et al. Post-absorptive and insulin-mediated muscle protein metabolism in liver-transplanted patients. Acta Diabetol 2002;39:203-208.
