Abstract 3122: Metabolic dysregulation and risk of non-alcoholic fatty liver disease in Mexican adults
Authors: Flores Yvonne N. , Sanchez Gerardo J. , ten Hoeve Johanna , Amoon Aryana T. , Graeber Thomas , Glenn Beth A. , May Folasade P. , Durazo Francisco , Zhang Zuo-Feng , Salmerón Jorge , Pollock Brad H. , Bastani Roshan 
Published: September 2020

Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and the fastest growing cause of cirrhosis in the United States (U.S.). This is very concerning because NAFLD-related cirrhosis is associated with hepatocellular carcinoma (HCC), the most common form of liver cancer. Latinos have the highest prevalence of NAFLD in the U.S., and the second highest incidence of and mortality from liver cancer, after American Indians. Known risk factors for NAFLD include obesity, metabolic syndrome, diabetes, and insulin resistance. Less is known about how specific metabolites may contribute to increased liver cancer susceptibility among Latinos despite the disproportionate burden of disease in this population.
Methods: Using existing clinical data and biospecimens obtained from a longitudinal study in Mexico, we examined the association between metabolic dysregulation and NAFLD in a sample of Mexican adults. A nested case-control analysis was conducted using 100 cases of NAFLD and 100 healthy controls. Risk of NAFLD was assessed using metabolic markers supplemented by clinical data. NAFLD cases were clinically confirmed by a hepatologist using elevated liver enzyme tests (ALT &gt;40 UI/L or AST &gt;40 UI/L) and ultrasound of the liver, after excluding heavy or binge drinking (&gt;2 drinks per day for males, &gt;1 drink per day for females). 159 targeted metabolites were detected with a Thermo Scientific Q Exactive mass spectrometer run with polarity switching on full scan mode with a 65-975 m/z range. TraceFinder Software 4.1 (Thermo Scientific) was used to quantify metabolites using retention time and accurate mass measurements (&lt; 5 ppm). Data analysis was carried out using in-house R scripts. Principal component analysis was constructed from metabolites identified as significant (p&lt;0.05) using a Multiple Analysis of Covariance comparing the healthiest controls in our cohort (without diabetes or metabolic syndrome, n=46) to the least healthy cases (with diabetes and metabolic syndrome, n=24).
Results: Out of 159 metabolites assessed, we found 25 metabolites to be significantly different between the groups after adjusting for age and sex. After further Bonferroni correction for multiple comparisons, eight were significantly increased in cases: Aconitate, Gluconic Acid, Glucose, Hexose Phosphate, Malate, and Phosphate; while two had significantly lower levels: Guanine and Inosine. Our findings indicate distinguishable changes in the serum metabolites of patients with NAFLD, which appear to be associated with more metabolic dysregulation.
Conclusions: Our results support the use of mass spectrometry-based metabolomics as an appropriate tool to identify serum metabolite signatures associated with NAFLD disease progression. This tool may be useful in developing targeted liver cancer prevention strategies. These findings should be validated in larger studies that examine the trafficking of these identified prognostic metabolites through the liver.
Citation Format: Yvonne N. Flores, Gerardo J. Sanchez, Johanna ten Hoeve, Aryana T. Amoon, Thomas Graeber, Beth A. Glenn, Folasade P. May, Francisco Durazo, Zuo-Feng Zhang, Jorge Salmerón, Brad H. Pollock, Roshan Bastani. Metabolic dysregulation and risk of non-alcoholic fatty liver disease in Mexican adults [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3122.