Research Article| Volume 68, ISSUE 4, P699-706, April 2018

Download started.


Impact of real-time metabolomics in liver transplantation: Graft evaluation and donor-recipient matching

Published:November 27, 2017DOI:


      • Real-time metabolomics by HR-MAS-NMR accurately predicts early allograft dysfunction.
      • Lactate and phosphocholine content are highly predictive biomarkers of early allograft dysfunction.
      • Livers from patients with sarcopenia and cirrhosis have low lactate and phosphocholine content.
      • Metabolic adaptation in these patients may lead to poor short-term outcomes.

      Background & Aims

      There is an emerging need to assess the metabolic state of liver allografts especially in the novel setting of machine perfusion preservation and donor in cardiac death (DCD) grafts. High-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS-NMR) could be a useful tool in this setting as it can extemporaneously provide untargeted metabolic profiling. The purpose of this study was to evaluate the potential value of HR-MAS-NMR metabolomic analysis of back-table biopsies for the prediction of early allograft dysfunction (EAD) and donor-recipient matching.


      The metabolic profiles of back-table biopsies obtained by HR-MAS-NMR, were compared according to the presence of EAD using partial least squares discriminant analysis. Network analysis was used to identify metabolites which changed significantly. The profiles were compared to native livers to identify metabolites for donor-recipient matching.


      The metabolic profiles were significantly different in grafts that caused EAD compared to those that did not. The constructed model can be used to predict the graft outcome with excellent accuracy. The metabolites showing the most significant differences were lactate level >8.3 mmol/g and phosphocholine content >0.646 mmol/g, which were significantly associated with graft dysfunction with an excellent accuracy (AUROClactates = 0.906; AUROCphosphocholine = 0.816). Native livers from patients with sarcopenia had low lactate and glycerophosphocholine content. In patients with sarcopenia, the risk of EAD was significantly higher when transplanting a graft with a high-risk graft metabolic score.


      This study underlines the cost of metabolic adaptation, identifying lactate and choline-derived metabolites as predictors of poor graft function in both native livers and liver grafts. HR-MAS-NMR seems a valid technique to evaluate graft quality and the consequences of cold ischemia on the graft. It could be used to assess the efficiency of graft resuscitation on machine perfusion in future studies.

      Lay summary

      Real-time metabolomic profiles of human grafts during back-table can accurately predict graft dysfunction. High lactate and phosphocholine content are highly predictive of graft dysfunction whereas low lactate and phosphocholine content characterize patients with sarcopenia. In these patients, the cost of metabolic adaptation may explain the poor outcomes.

      Graphical abstract


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ghinolfi D.
        • Marti J.
        • De Simone P.
        • Lai Q.
        • Pezzai D.
        • Coletti L.
        • et al.
        Use of octogenarian donors for liver transplantation: a survival analysis.
        Am J Transplant. 2014; 14: 2062-2071
        • Dutkowski P.
        • Schlegel A.
        • Slankamenac K.
        • Oberkofler C.E.
        • Adam R.
        • Burroughs A.K.
        • et al.
        The use of fatty liver grafts in modern allocation systems; risk assessment by the balance of risk (BAR) score.
        Ann Surg. 2012; 256: 861-869
        • Chu M.J.
        • Dare A.J.
        • Phillips A.R.
        • Bartlett A.S.
        Donor hepatic steatosis and outcome after liver transplantation.
        J Gastrointest Surg. 2015; 19: 1713-1724
        • Burroughs A.K.
        • Sabin C.A.
        • Rolles K.
        • Delvart V.
        • Karam V.
        • Buckels J.
        • et al.
        3-Month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome.
        Lancet. 2006; 367: 225-232
        • Gruttadauria S.
        • Vizzini G.
        • Biondo D.
        • Mandalà L.
        • Volpes R.
        • Palazzo U.
        • et al.
        Critical use of Extended Criteria Donor Liver grafts in adult-to-adult whole liver transplantation: a single-center experience.
        Liver Transpl. 2008; 14: 220-227
        • Renz J.F.
        • Kin C.
        • Kinkhabwala M.
        • Jan D.
        • Varadarajan R.
        • Goldstein M.
        • et al.
        Utilization of Extended Donor Criteria Allografts maximizes donor use and patient access to liver transplantation.
        Ann Surg. 2005; 242: 556-563
        • Ghinolfi D.
        • De Simone P.
        • Lai Q.
        • Pezzati D.
        • Coletti L.
        • Balzano E.
        • et al.
        Risk analysis of ischemic-type biliary lesions after liver transplant using octogenarian donors.
        Liver Transpl. 2016; 22: 588-598
        • Ali J.M.
        • Davies S.E.
        • Brais R.J.
        • Randle L.V.
        • Klinck J.R.
        • Allison M.E.
        • et al.
        Analysis of ischemia/reperfusion injury in time-zero biopsies predicts allograft outcomes.
        Liver Transpl. 2015; 21: 487-499
        • Gaffey M.J.
        • Boyd J.C.
        • Traweek S.T.
        • Ali J.M.
        • Rezeig M.
        • Caldwell S.H.
        • et al.
        Predictive value of intraoperative biopsies and liver function tests for preservation injury in orthotopic liver transplantation.
        Hepatology. 1997; 25: 184-189
        • Dutkowski P.
        • Schlegel A.
        • Slankamenac M.C.
        • Oberkofler C.E.
        • Adam R.
        • Burroughs A.K.
        • et al.
        The use of fatty liver grafts in modern allocation systems: risk assessment by the balance of risk (BAR) Score.
        Ann Surg. 2012; 256: 861-869
        • Gabrielli M.
        • Moisan F.
        • Vidal M.
        • Duarte I.
        • Jiménez M.
        • Izquierdo G.
        • et al.
        Steatotic livers. Can we use them in OLTX ? Outcome data from a prospective baseline biopsy study.
        Ann Hepatol. 2012; 11: 891-898
        • El-Badry A.M.
        • Breitenstein S.
        • Jochum W.
        • Washington K.
        • Paradis V.
        • Rubbia-Brandt L.
        • et al.
        Assessment of hepatic steatosis by expert pathologists : the end of a gold standard.
        Ann Surg. 2009; 250: 691-697
        • Monbaliu D.
        • Liu Q.
        • Libbrecht L.
        • De Vos R.
        • Vekemans K.
        • Debbaut C.
        • et al.
        Preserving the morphology and evaluating the quality of liver grafts by hypothermic machine perfusion: a proof-of-concept studyusing discarded human livers.
        Liver Transpl. 2012; 18: 1495-1507
        • Bruinsma B.G.
        • Yeh H.
        • Ozer S.
        • Martins P.N.
        • Farmer A.
        • Wu W.
        • et al.
        Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation.
        Am J Transpl. 2014; 14: 1400-1409
        • Op den Dries S.
        • Karimian N.
        • Sutton M.E.
        • Westerkamp A.C.
        • Nijsten M.W.
        • Gouw A.S.
        • et al.
        Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers.
        Am J Transpl. 2013; 13: 1327-1335
        • Moers C.
        • Smits J.M.
        • Maathuis M.H.
        • Treckmann J.
        • van Gelder F.
        • Napieralski B.P.
        • et al.
        Machine perfusion or cold storage in deceased-donor kidney transplantation.
        N Eng J Med. 2009; 360: 7-19
        • Graham J.A.
        • Guarrera J.V.
        Resuscitation of marginal liver allografts for transplantation with machine perfusion technology.
        J Hepatol. 2014; 61: 418-431
        • Okamura Y.
        • Hata K.
        • Tanaka H.
        • Hirao H.
        • Kubota T.
        • Inamoto O.
        • et al.
        Impact of subnormothermic machine perfusion preservation in severely steatotic rat livers: a detailed assessment in isolated setting.
        Am J Transpl. 2017; 17: 1204-1215
        • Duarte I.F.
        • Stanley E.G.
        • Holmes E.
        • Lindon J.C.
        • Gil A.M.
        • Tanq H.
        • et al.
        Metabolic assessment of Human Liver Transplants from biospy samples at the donor and recipient stages using High-resolution Magic angle Spinning 1H NMR spectroscopy.
        Ann Chem. 2005; 77: 5570-5578
        • Cortes M.
        • Pareja E.
        • Garcia-Canaveras J.C.
        • Donato M.T.
        • Montero S.
        • Mir J.
        • et al.
        Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.
        J Hepatol. 2014; 61: 564-574
        • Memeo R.
        • Le Roy B.
        • Pittau G.
        • Ntona E.
        N. de'Angelis. Personal experience with 150 isolated procurements of liver allografts: two different techniques.
        Prog transplant. 2015; 25: 287-288
        • European Association for the study of the liver
        EASL clinical practice guidelines: liver transplantation.
        J Hepatol. 2016; 64: 433-485
        • Olthoff K.M.
        • Kulik L.
        • Samstein B.
        • Kaminski M.
        • Abecassis M.
        • Emond J.
        • et al.
        Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors.
        Liver Transpl. 2010; 16: 943-949
        • Golse N.
        • Bucur P.O.
        • Ciacio O.
        • Pittau G.
        • Sa Cunha A.
        • Adam R.
        • et al.
        A new definition of sarcopenia in patients undergoing liver transplantation.
        Liver Transpl. 2017; 23: 143-154
        • Cicek A.E.
        • Bederman I.
        • Henderson L.
        • Drumm M.L.
        • Ozsoyoglu G.
        ADEMA: an algorithm to determine expected metabolite level alterations using mutual information.
        PLoS Comput Biol. 2013; 9: e1002859
        • Selway Z.Z.
        Metabolism at a glance.
        3rd ed. Blackwell Publishing, Malden, MI2014
        • Dutkowski P.
        • Oberkofler C.E.
        • Slankamenac K.
        • Puhan M.A.
        • Schadde E.
        • Müllhaupt B.
        • et al.
        Are there better guidelines for allocation in liver transplantation? A novel score targeting justice and utility in the Model for End-stage liver disease era.
        Ann Surg. 2011; 254: 745-753
        • van Golen R.F.
        • van Gulik T.M.
        • Heger M.
        Mechanistic overview of reactive species-induced degradation of the endothelial glycocalyx during hepatic ischemia/reperfusion injury.
        Free Radic Biol Med. 2012; 52: 1382-1402
        • Land W.G.
        • Agostinis P.
        • Gasser S.
        • Garg A.D.
        • Linkermann A.
        Transplantation and Damage-Associated Molecular Patterns (DAMPs).
        Am J Transplant. 2016; 16: 3322-3337
        • Jaeschke H.
        Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning.
        Am J Physiol Gastrointest Liver Physiol. 2003; 284: G15-G26
        • Defamie V.
        • Cursio R.
        • Le Brigand K.
        • Moreilhon C.
        • Saint-Paul M.C.
        • Laurens M.
        • et al.
        Gene expression profiling of human liver transplants identifies an early transcriptional signature associated with initial poor graft function.
        Am J Transplant. 2008; 8: 1221-1236
        • Wu J.F.
        • Wu R.Y.
        • Chen J.
        • Ou-Yang B.
        • Guan X.D.
        Early lactate clearance is a reliable predictor of initial poor graft function after orthotopic liver transplantation.
        Hepatobiliary Pancreat Dis Int. 2011; 10: 587-592
        • Sarfaraz M.O.
        • Myers R.P.
        • Coffin C.S.
        • Gao Z.H.
        • Shaheen A.A.
        • Crotty P.M.
        • et al.
        A quantitative metabolomics profiling approach for the non invasive assessment of liver histology in patients with chronic hepatitis C.
        Clin Trans Med. 2016; 5: 33
        • Cheng S.
        • Rhee E.P.
        • Larson M.G.
        • Lewis G.D.
        • McCabe E.L.
        • Shen D.
        • et al.
        Metabolite Profiling identifies Pathways associated with metabolic risk in humans.
        Circulation. 2012; 125: 2222-2231
        • Lindell S.L.
        • Klahn S.L.
        • Piazza T.M.
        • Mangino M.J.
        • Torrealba J.R.
        • Southard J.H.
        • et al.
        Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype.
        Am J Physiol Gastrointest Liver Physiol. 2005; 288: 473-480
        • Abrahám I.
        • Juhász G.
        • Kékesi K.A.
        • Kovács K.J.
        Corticosterone peak is responsible for stress induced elevation of glutamate in the hippocampus.
        Stress. 1998; 2: 171-181
        • Lemasters J.J.
        • DiGuiseppi J.
        • Nieminen A.L.
        • Herman B.
        Blebbing, free Ca2+ and mitochondrial membrane potential preceding cell death in hepatocytes.
        Nature. 1987; 325: 78-81
        • Hartmann P.
        • Fet N.
        • Garab D.
        • Szabó A.
        • Kaszaki J.
        • Srinivasan P.K.
        • et al.
        L-alpha-GPC reduces the microcirculatory dysfunction and nicotinamide adenine dinucleotide phosphate-oxidase type 4 induction after partial hepatic ischemia in rats.
        J Surg Res. 2014; 189: 32-40
        • Lau J.K.
        • Zhang X.
        • Yu J.
        Animal models of non –alcoholic fatty liver disease: current perspectives and recent advances.
        J Pathol. 2017; 241: 36-44
        • van der Veen J.N.
        • Lingrell S.
        • Gao X.
        • Quiroga A.D.
        • Takawale A.
        • Armstrong E.A.
        • et al.
        Pioglitazone attenuates hepatic inflammation and fibrosis in phosphatidylethanolamine-N-mehtyl-transferase-deficient mice.
        Am J Physiol Gastrointest Liver Physiol. 2016; 310: G526-G538
        • Hrydziuszko O.
        • Perera M.T.
        • Laing R.
        • Kirwan J.
        • Silva M.A.
        • Richards D.A.
        • et al.
        Mass spectroscopy based metabolomics comparison of liver grafts from donors after circulatory death (DCD) and donors after brain death (DBD) used in human orthotopic liver transplantation.
        PLoS One. 2016; 11: e0165884
        • Benhamed M.A.
        • Santelmo N.
        • Elbayed K.
        • Frossard N.
        • Noll E.
        • Canuet M.
        • et al.
        The assessment of the quality of the graft in animal model for lung transplantation using the metabolomics 1H high-resolution magic angle spinning NMR spectroscopy.
        Magn Res Med. 2012; 68: 1026-1038