Use of Plasma Metabolomics and Lipidomics for the Diagnosis of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes
Authors: BRIL FERNANDO , KALAVALAPALLI SRILAXMI , DUFFIN KEVIN L. , HARTMAN MARK L. , CHEN YU , YANG QIAN , HAAS JOSEPH V. , MILLIGAN PAUL L. , ROTH KENNETH D. , CUSI KENNETH 
Published: June 2018

Nonalcoholic fatty liver disease (NAFLD) affects a significant number of patients with T2DM and places them at an increased risk of steatohepatitis (NASH) and cirrhosis. However, it is widely underdiagnosed due to lack of a simple, non-invasive test for its diagnosis. The aim of this study was to establish a plasma biomarker profile to identify NAFLD and NASH in patients with T2DM. We recruited 220 patients with T2DM (59±8 years; BMI: 33.6±4.8 kg/m2; A1c: 7.1±1.2%) and screened them for NAFLD by liver magnetic resonance spectroscopy (No NAFLD: n=76; NAFLD: n=144). If positive, a liver biopsy was performed (Isolated steatosis: n=73; NASH: n=71). All patients underwent untargeted plasma metabolomics and lipidomics. To account for multiple comparisons, a Bonferroni’s adjusted p-value&lt;0.000was considered significant. Twenty six metabolites (out of 618) were significantly different among groups: adenine, lactate, tyrosine, a lysophosphatidylethanolamine (LPE), 17 triglyceride (TG), 3 phosphtatidylinositol (PI), and 2 phosphatidyletanolamine (PE) subspecies. Of these, five were independently associated with the presence of NAFLD (tyrosine, lactate, 1 PI, and 2 TG subspecies). Their use allowed to successfully predict NAFLD (AUC = 0.88 [0.83-0.93]) with a sensitivity=83%, specificity=79%, PPV=88%, and NPV=71%. Age, gender, BMI, plasma glucose or insulin did not improve the model. However, adding plasma ALT resulted in a significant improvement in the discriminatory power: AUC = 0.91 [0.87-0.95], p=0.02. Eight metabolites were significantly different in patients with NASH vs. isolated steatosis, but only one LPE species (16:1) remained statistically significant in the multivariate analysis. However, this was of modest clinical value (AUC = 0.64 [0.55-0.73]).
Conclusion: Metabolomics/lipidomics may hold promise to non-invasively diagnose NAFLD in patients with T2DM, although its ability to identify those with NASH remains to be established.

Disclosure
F. Bril: None. S. Kalavalapalli: None. K.L. Duffin: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Pfizer Inc. M.L. Hartman: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Y. Chen: None. Q. Yang: None. J.V. Haas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. P.L. Milligan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. K.D. Roth: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc..