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Multivariate metabotyping of plasma accurately predicts survival in patients with decompensated cirrhosis.

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Mark McPhail, Deborah Lindsay Shawcross, Matthew R. Lewis, Iona Coltart, Elizabeth J Want, Charalambos G Antoniades, Kiril Veselkov, Evangelos Triantafyllou, Vishal C. Patel, Oltin T Pop, Maria Gomez-Romero, Michael Kyriakides, Rabiya Zia, Robin Daniel Abeles, Mary M E Crossey, Wayel Jassem, John O'Grady, Nigel Heaton, Georg Auzinger, William Bernal & 6 more Alberto Quaglia, Muireann Coen, Jeremy K. Nicholson, Julia Alexis Wendon, Elaine Holmes, Simon D. Taylor-Robinson

Original languageEnglish
Pages (from-to)1058-1067
JournalJournal of Hepatology
Volume64
Issue number5
Early online date18 Jan 2016
DOIs
Accepted/In press6 Jan 2015
E-pub ahead of print18 Jan 2016
PublishedMay 2016

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Abstract

BACKGROUND AND 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: 248 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 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.

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