title: Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis.
abstract: OBJECTIVE
  Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival.
  
  
  METHODS
  Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC)).
  
  
  RESULTS
  (1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC.
  
  
  CONCLUSIONS
  Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death.
authors.affiliation: Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom; Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Mark J W
authors.initials: MJW
authors.lastname: McPhail
authors.affiliation: Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom.
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Shawcross
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lewis
authors.affiliation: Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom.
authors.forename: Iona
authors.initials: I
authors.lastname: Coltart
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Want
authors.affiliation: Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom; Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Charalambos G
authors.initials: CG
authors.lastname: Antoniades
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Kiril
authors.initials: K
authors.lastname: Veselkov
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Triantafyllou
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Oltin
authors.initials: O
authors.lastname: Pop
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Gomez-Romero
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Kyriakides
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Rabiya
authors.initials: R
authors.lastname: Zia
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Abeles
authors.affiliation: Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom.
authors.forename: Mary M E
authors.initials: MME
authors.lastname: Crossey
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Wayel
authors.initials: W
authors.lastname: Jassem
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: O'Grady
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Heaton
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Georg
authors.initials: G
authors.lastname: Auzinger
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Bernal
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Alberto
authors.initials: A
authors.lastname: Quaglia
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Muireann
authors.initials: M
authors.lastname: Coen
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE19 2RS, United Kingdom.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Wendon
authors.affiliation: Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London SW7 2AZ, United Kingdom. Electronic address: e.holmes@imperial.ac.uk.
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.affiliation: Division of Digestive Health, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 10th Floor QEQM Wing, St Mary's Hospital Campus, South Wharf Street, London NW1 2NY, United Kingdom.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016923:Cell Death; D016207:Cytokines / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000097:blood* / Q000401:mortality / Q000473:pathology; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines
keywords: Acute on chronic liver failure; Metabolic profiling; Metabolomics; Metabonomics; Outcome prediction; Personalised medicine