Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease worldwide and includes a broad spectrum of histologic phenotypes, ranging from simple hepatic steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). While liver biopsy is the reference gold standard for NAFLD diagnosis and staging, it has limitations due to its sampling variability, invasive nature, and high cost. Thus, there is a need for noninvasive biomarkers that are robust, reliable, and cost effective. In this study, we measured 540 lipids and amino acids in serum samples from biopsy-proven subjects with normal liver (NL), NAFL, and NASH. Using logistic regression analysis, we identified two panels of triglycerides that could first discriminate between NAFLD and NL and second between NASH and NAFL. These noninvasive tests were compared to blinded histology as a reference standard. We performed these tests in an original cohort of 467 patients with NAFLD (90 NL, 246 NAFL, and 131 NASH) that was subsequently validated in a separate cohort of 192 patients (7 NL, 109 NAFL, 76 NASH). The diagnostic performances of the validated tests showed an area under the receiver operating characteristic curve, sensitivity, and specificity of 0.88 ± 0.05, 0.94, and 0.57, respectively, for the discrimination between NAFLD and NL and 0.79 ± 0.04, 0.70, and 0.81, respectively, for the discrimination between NASH and NAFL. When the analysis was performed excluding patients with glucose levels >136 mg/dL, the area under the receiver operating characteristic curve for the discrimination between NASH and NAFL increased to 0.81 ± 0.04 with sensitivity and specificity of 0.73 and 0.80, respectively. Conclusion: The assessed noninvasive lipidomic serum tests distinguish between NAFLD and NL and between NASH and NAFL with high accuracy. (Hepatology Communications 2018;2:807-820).

Center of Investigation of Endocrinology and Clinical Nutrition Medicine School and Department of Endocrinology and Nutrition Clinic University Hospital University of Valladolid Valladolid Spain

CIC bioGUNE CIBERehd Bizkaia Technology Park Derio Bizkaia Spain

Department of Digestive Disease Clinic University Hospital University of Valladolid Valladolid Spain

Department of Digestive Disease Marqués de Valdecilla University Hospital Cantabaria University Research Institute Marqués de Valdecilla Santander Spain

Department of Liver and Gastrointestinal Diseases Biodonostia Research Institute Donostia University Hospital University of the Basque Country CIBERehd IKERBASQUE Donostia Spain

Department of Pathology University Hospital Príncipe de Asturias Alcalá University Madrid Spain

Department of Pathology University Hospitals Paris Nord Val de Seine Beaujon Hauts de Seine Clichy France

Division of Digestive and Liver Diseases Cedars Sinai Medical Center Los Angeles CA United States

Division of Gastroenterology and Hepatology Virginia Commonwealth University Medical Center Richmond VA United States

Division of Surgical Pathology Department of Pathology Virginia Commonwealth University Medical Center Richmond VA United States

Faculty General Hospital and the 1st Faculty of Medicine Charles University Prague Czech Republic

Faculty of Medicine and Health Science University Hospital Príncipe de Asturias Alcalá University Madrid Spain

Liver Unit Hospital Clinic CIBERehd IDIBAPS Barcelona Spain

OWL Metabolomics Bizkaia Technology Park Derio Spain

Surgery Department University Hospital Príncipe de Asturias Alcalá University Madrid Spain

Unit for the Clinical Management of Digestive Diseases and CIBERehd Valme University Hospital Seville Spain

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