Mario Masarone1, Jacopo Troisi1,2,3,4, Andrea Aglitti1, Pietro Torre1, Angelo Colucci1,2, Marcello Dallio5, Alessandro Federico5, Clara Balsano6,7, Marcello Persico8. 1. Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy. 2. Theoreo srl, Via degli Ulivi 3, 84090, Montecorvino Pugliano, SA, Italy. 3. European Biomedical Research Institute of Salerno (EBRIS), Via S. de Renzi, 3, 84125, Salerno, SA, Italy. 4. Hosmotic srl, Via R. Bosco 178, 80069, Vico Equense, NA, Italy. 5. Hepatogastroenterology Division, University of Campania "Luigi Vanvitelli", Via S Pansini 5, 80131, Naples, Italy. 6. MESVA Department, University of L'Aquila, Piazza S. Salvatore Tommasi 1, 67100, Coppito, L'Aquila, Italy. 7. F. Balsano Foundation, Via Giovanni Battista Martini 6, 00198, Rome, Italy. 8. Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Via Salvador Allende, 84081, Baronissi, SA, Italy. mpersico@unisa.it.
Abstract
INTRODUCTION: Non-Alcoholic Fatty Liver Disease encompasses a spectrum of diseases ranging from simple steatosis to steatohepatitis (or NASH), up to cirrhosis and hepatocellular carcinoma (HCC). The challenge is to recognize the more severe and/or progressive pathology. A reliable non-invasive method does not exist. Untargeted metabolomics is a novel method to discover biomarkers and give insights on diseases pathophysiology. OBJECTIVES: We applied metabolomics to understand if simple steatosis, steatohepatitis and cirrhosis in NAFLD patients have peculiar metabolites profiles that can differentiate them among each-others and from controls. METHODS: Metabolomics signatures were obtained from 307 subjects from two separated enrollments. The first collected samples from 69 controls and 144 patients (78 steatosis, 23 NASH, 15 NASH-cirrhosis, 8 HCV-cirrhosis, 20 cryptogenic cirrhosis). The second, used as validation-set, enrolled 44 controls and 50 patients (34 steatosis, 10 NASH and 6 NASH-cirrhosis).The "Partial-Least-Square Discriminant-Analysis"(PLS-DA) was used to reveal class separation in metabolomics profiles between patients and controls and among each class of patients, and to reveal the metabolites contributing to class differentiation. RESULTS: Several metabolites were selected as relevant, in particular:Glycocholic acid, Taurocholic acid, Phenylalanine, branched-chain amino-acids increased at the increase of the severity of the disease from steatosis to NASH, NASH-cirrhosis, while glutathione decreased (p < 0.001 for each). Moreover, an ensemble machine learning (EML) model was built (comprehending 10 different mathematical models) to verify diagnostic performance, showing an accuracy > 80% in NAFLD clinical stages prediction. CONCLUSIONS: Metabolomics profiles of NAFLD patients could be a useful tool to non-invasively diagnose NAFLD and discriminate among the various stages of the disease, giving insights into its pathophysiology.
INTRODUCTION:Non-Alcoholic Fatty Liver Disease encompasses a spectrum of diseases ranging from simple steatosis to steatohepatitis (or NASH), up to cirrhosis and hepatocellular carcinoma (HCC). The challenge is to recognize the more severe and/or progressive pathology. A reliable non-invasive method does not exist. Untargeted metabolomics is a novel method to discover biomarkers and give insights on diseases pathophysiology. OBJECTIVES: We applied metabolomics to understand if simple steatosis, steatohepatitis and cirrhosis in NAFLD patients have peculiar metabolites profiles that can differentiate them among each-others and from controls. METHODS: Metabolomics signatures were obtained from 307 subjects from two separated enrollments. The first collected samples from 69 controls and 144 patients (78 steatosis, 23 NASH, 15 NASH-cirrhosis, 8 HCV-cirrhosis, 20 cryptogenic cirrhosis). The second, used as validation-set, enrolled 44 controls and 50 patients (34 steatosis, 10 NASH and 6 NASH-cirrhosis).The "Partial-Least-Square Discriminant-Analysis"(PLS-DA) was used to reveal class separation in metabolomics profiles between patients and controls and among each class of patients, and to reveal the metabolites contributing to class differentiation. RESULTS: Several metabolites were selected as relevant, in particular:Glycocholic acid, Taurocholic acid, Phenylalanine, branched-chain amino-acids increased at the increase of the severity of the disease from steatosis to NASH, NASH-cirrhosis, while glutathione decreased (p < 0.001 for each). Moreover, an ensemble machine learning (EML) model was built (comprehending 10 different mathematical models) to verify diagnostic performance, showing an accuracy > 80% in NAFLD clinical stages prediction. CONCLUSIONS: Metabolomics profiles of NAFLD patients could be a useful tool to non-invasively diagnose NAFLD and discriminate among the various stages of the disease, giving insights into its pathophysiology.
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