Lipidomics-based plasma signature of alcohol-related hepatitis linked to short-term mortality
Florent Artru,
Stephen Atkinson,
Francesca Trovato,
Luke D. Tyson,
Vishal C. Patel,
Nikhil Vergis,
Noora Kano,
Robert Goldin,
Alberto Quaglia,
Alexandros Pechlivanis,
Phillip Morgan,
Salma Mujib,
Anna Cavazza,
Ellen Jerome,
Marc Zentar,
Roosey Sheth,
Maura Morrison,
Evangelos Triantafyllou,
Elaine Holmes,
María Gómez-Romero,
Mark J. McPhail,
Mark Thursz
Affiliations
Florent Artru
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK; University of Rennes and Liver Department of Rennes University Hospital, Rennes, France
Stephen Atkinson
Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Francesca Trovato
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
Luke D. Tyson
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Vishal C. Patel
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK
Nikhil Vergis
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Noora Kano
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Robert Goldin
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Alberto Quaglia
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Alexandros Pechlivanis
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Phillip Morgan
Institute of Liver Studies, King’s College Hospital London, London, UK
Salma Mujib
Institute of Liver Studies, King’s College Hospital London, London, UK
Anna Cavazza
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
Ellen Jerome
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
Marc Zentar
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
Roosey Sheth
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Maura Morrison
Institute of Liver Studies, King’s College Hospital London, London, UK
Evangelos Triantafyllou
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
Elaine Holmes
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK
María Gómez-Romero
Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
Mark J. McPhail
Institute of Liver Studies, King’s College Hospital London, London, UK; Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; Corresponding authors. Addresses: Institute of Liver Studies, King’s College London, Denmark Hill, SE5 9RS, London, UK (M.J. McPhail); Division of Digestive Diseases, Imperial College South Kensington Campus, SW7 2BX, London, UK (M. Thursz).
Mark Thursz
Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary’s and Hammersmith Hospitals, Imperial College London, London, UK Imperial College London, London, UK; Corresponding authors. Addresses: Institute of Liver Studies, King’s College London, Denmark Hill, SE5 9RS, London, UK (M.J. McPhail); Division of Digestive Diseases, Imperial College South Kensington Campus, SW7 2BX, London, UK (M. Thursz).
Background & Aims: Severe alcohol-related hepatitis (sAH) is an inflammatory condition with high short-term mortality. Hypothesis-driven approaches have failed to identify effective treatments. Given the role of lipids as inflammatory mediators, this study aimed to identify lipidomic changes and lipid species associated with sAH and mortality risk. Methods: Untargeted lipidomics was performed on serum samples from two cohorts of patients with sAH and decompensated cirrhosis (DC). Principal component analysis and orthogonal partial least squares discriminant analysis were used to assess lipidome changes. Correlations were made with lipoproteins, lipid mediators, cytokines, cytokeratin fragments, and histological indices. Results: In the first part, 78 patients with sAH were matched on bilirubin levels with 23 patients with DC. Lipidomics identified a distinct sAH signature involving glycerophospholipids, including PC(34:2) (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.45–7.05, p = 0.01), PC(O–38:5) (OR 3.31, 95% CI 2.23–7.14, p = 0.002), PI(38:4) (OR 0.71, 95% CI 0.46–0.88, p = 0.02), and LPC(18:1) (OR 0.47, 95% CI 0.32–0.82, p = 0.01). These lipids demonstrated excellent discriminatory power between sAH and DC with areas under the receiver operating characteristic curve (AUROCs) between 0.87 and 0.88. In the second part, in 159 sAH patients, specific lipids, including carnitines CAR(2:0) (OR 2.51, 95% CI 1.25–4.96, p = 0.008) and CAR(16:1) (OR 2.21, 95% CI 1.09–7.48, p = 0.009), were linked to 90-day mortality. Acylcarnitines correlated with disease severity parameters such as model for end-stage liver disease, pro-inflammatory cytokines levels, and hepatocyte ballooning on pathology. Conclusions: Untargeted lipidomics identified a glycerophospholipid and sphingolipid signature distinguishing sAH from DC, implicating lipid species involved in liver regeneration and immune function. Acylcarnitine accumulation in patients with sAH and poor prognosis suggests mitochondrial dysfunction and warrants further investigation into therapeutic potential. Impact and implications: Lipids can act as mediators at the interface between the immune system and metabolism, potentially contributing to the pathogenesis and outcomes of patients with severe alcohol-related hepatitis, prompting us to investigate lipidomic changes in this population using untargeted approaches, compared with patients with decompensated cirrhosis. This study highlights a distinct lipidomic signature in patients with severe alcohol-related hepatitis compared with decompensated cirrhosis, primarily involving glycerophospholipids and sphingolipids. Specific lipid classes, such as acylcarnitines, suggest significant mitochondrial dysfunction and are associated with disease severity and short-term mortality in patients with severe alcohol-related hepatitis. These findings underscore the importance of targeted investigations into these lipid species, their pathways, and their links to disease severity and outcomes, particularly in this condition that currently lacks specific treatments.
