4.8 Article

Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis

期刊

JOURNAL OF HEPATOLOGY
卷 64, 期 5, 页码 1058-1067

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2016.01.003

关键词

Metabonomics; Metabolomics; Metabolic profiling; Personalised medicine; Outcome prediction; Acute on chronic liver failure

资金

  1. Wellcome Trust, London, United Kingdom [090542]
  2. HEFCE
  3. Waters Corporation
  4. Medical Research Council (MRC) Centre for Transplantation, King's College London, UK - MRC grant [MR/J006742/1]
  5. National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London
  6. MRC [MR/K010514/1] Funding Source: UKRI
  7. Medical Research Council [MR/K010514/1, 1583052, MR/J006742/1] Funding Source: researchfish
  8. Rosetrees Trust [M439-F1-CD2, M439, M228-F1] Funding Source: researchfish

向作者/读者索取更多资源

Background & Aims: 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 H-1 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: 1H 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 down regulated 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. Conclusion: 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. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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