The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma
Monika Lewinska, PhD,
Alvaro Santos-Laso, PhD,
Enara Arretxe, PhD,
Cristina Alonso, PhD,
Ekaterina Zhuravleva, PhD,
Raul Jimenez-Agüero, MD, PhD,
Emma Eizaguirre, MD, PhD,
María Jesús Pareja, MD, PhD,
Manuel Romero-Gómez, MD, PhD,
Marco Arrese Jimenez, MD, PhD,
Malte P. Suppli, MD, PhD,
Filip K. Knop, MD, PhD,
Stine Karlsen Oversoe, MD, PhD,
Gerda Elisabeth Villadsen, MD, PhD,
Thomas Decaens, MD, PhD,
Flair Jose Carrilho, MD, PhD,
Claudia PMS de Oliveira, MD, PhD,
Bruno Sangro, MD, PhD,
Rocio I.R. Macias, MD, PhD,
Jesus M. Banales, PhD,
Jesper B. Andersen, PhD
Affiliations
Monika Lewinska, PhD
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark
Alvaro Santos-Laso, PhD
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
Enara Arretxe, PhD
OWL Metabolomics, Derio, Spain
Cristina Alonso, PhD
OWL Metabolomics, Derio, Spain
Ekaterina Zhuravleva, PhD
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark
Raul Jimenez-Agüero, MD, PhD
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
Emma Eizaguirre, MD, PhD
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
María Jesús Pareja, MD, PhD
Hospital Juan Ramón Jiménez - Huelva, Spain
Manuel Romero-Gómez, MD, PhD
UCM Digestive Diseases. Virgen del Rocío University Hospital. SeLiver group at the Institute of Biomedicine of Seville (IBIS). The University of Seville. Sevilla, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
Marco Arrese Jimenez, MD, PhD
Department of Gastroenterology, Escuela de Medicina, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
Malte P. Suppli, MD, PhD
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
Filip K. Knop, MD, PhD
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark
Stine Karlsen Oversoe, MD, PhD
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
Gerda Elisabeth Villadsen, MD, PhD
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
Thomas Decaens, MD, PhD
Université Grenoble Alpes, Grenoble, France; Department of Hepatology and Gastroenterology, CHU-Grenoble Alpes, France
Flair Jose Carrilho, MD, PhD
Department of Gastroenterology, Faculdade de Medicina da Universidade de São Paulo, Brazil
Claudia PMS de Oliveira, MD, PhD
Department of Gastroenterology, Faculdade de Medicina da Universidade de São Paulo, Brazil
Bruno Sangro, MD, PhD
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Liver Unit, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain
Rocio I.R. Macias, MD, PhD
Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM) group, IBSAL, University of Salamanca, Salamanca, Spain
Jesus M. Banales, PhD
Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Jesper B. Andersen, PhD
Biotech Research and Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Denmark; Corresponding author: Jesper B Andersen, Ole Maaløes Vej 5, Copenhagen N, DK-2200 Denmark. Phone: +45 35325834, FAX: +45 72620285
Background: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC. Methods: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score. Findings: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients’ metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum. Interpretation: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients. Funding: The funding sources for this study had no role in study design, data collection, data analyses, interpretation or writing of the report as it is presented herein.
