TY - JOUR

T1 - The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma

T2 - Diagnosis of NAFLD-HCC utilising serum lipidomics

AU - Lewinska, Monika

AU - Santos-Laso, Alvaro

AU - Arretxe, Enara

AU - Alonso, Cristina

AU - Zhuravleva, Ekaterina

AU - Jimenez-Agüero, Raul

AU - Eizaguirre, Emma

AU - Pareja, María Jesús

AU - Romero-Gómez, Manuel

AU - Jimenez, Marco Arrese

AU - Suppli, Malte P.

AU - Knop, Filip K.

AU - Oversoe, Stine Karlsen

AU - Villadsen, Gerda Elisabeth

AU - Decaens, Thomas

AU - Carrilho, Flair Jose

AU - de Oliveira, Claudia PMS

AU - Sangro, Bruno

AU - Macias, Rocio I.R.

AU - Banales, Jesus M.

AU - Andersen, Jesper B.

N1 - Publisher Copyright: © 2021 The Author(s)

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - biomarker discovery

KW - HCC

KW - lipidomics

KW - metabolomics

KW - NAFLD

U2 - 10.1016/j.ebiom.2021.103661

DO - 10.1016/j.ebiom.2021.103661

M3 - Journal article

C2 - 34740106

AN - SCOPUS:85118179518

VL - 73

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 103661

ER -