Multivariate metabotyping of plasma predicts survival in patients with decompensated cirrhosis

Mark Mcphail ,Evangelos Triantafyllou,Muireann Coen,Iona Coltart,Matthew R Lewis,John O’Grady,Wayel Jassem,Elaine Holmes,Elizabeth J Want,William Bernal,Alberto Quaglia,Nigel Heaton,Michael Kyriakides,Jeremy K Nicholson,Debbie L Shawcross,Rabiya Zia,Mary M.E Crossey,Oltin T Pop ,R.d Abeles ,Julia Wendon ,G Auzinger ,María José Gómez-Romero ,Charalambos Antoniades ,Kirill Veselkov ,Vishal C Patel ,Simon D Taylor-Robinson

doi:10.1016/j.jhep.2016.01.003

Mark Mcphail , Evangelos Triantafyllou + Show 24 more

Open Access

https://doi.org/10.1016/j.jhep.2016.01.003

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Abstract

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. 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)). (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. 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.

Highlights

The global incidence of cirrhosis is rising rapidly, owing to an increased prevalence of alcohol-related liver disease, nonalcoholic fatty liver disease, and viral hepatitis [1]
Of the identified lipids on UPLC-MS, LPC (16:0) was negatively correlated with M30 (r = À0.30, p = 0.010) and M65 (r = À0.39, p = 0.002) levels and predicted hospital survival (AUROC 0.76, p
M65 levels performed less well at outcome prediction (AUROC 0.66 p = 0.02)

Summary

Introduction

The global incidence of cirrhosis is rising rapidly, owing to an increased prevalence of alcohol-related liver disease, nonalcoholic fatty liver disease, and viral hepatitis [1]. Patients with cirrhosis are prone to decompensation, requiring hospital treatment and can progress to acute on chronic liver failure (ACLF) [2], which requires admission to intensive care with an associated high short-term mortality and significant economic cost [3]. The performance of MELD for outcome prediction is best in patients with stable cirrhosis, but is less accurate for patients with acute on chronic liver failure (ACLF) [5]. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities.

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Conclusion