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Metabolomic-Based Noninvasive Serum Test to Diagnose Nonalcoholic Steatohepatitis: Results from Discovery and Validation Cohorts

Hepatol Commun. 2018 May 4;2(7):807-820

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.



Use of a Metabolomic Approach to Non-Invasively Diagnose Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus

This study was an effort to determine whether existing OWL assay algorithms for NAFL and NASH were sufficient in diagnosing NASH in diabetics with controlled or uncontrolled glycemic control.
The study included 220 multi-ethnic diabetic patients whose diagnosis was NASH or NAFLD based on a combination of MRI or liver biopsy. The patients' serum samples were assayed in blinded fashion with the
current OWL assays for the diagnosis of NASH or NAFL. Interestingly, the test performed best in those T2DM patients who mirrored the patient profiles recorded in the discovery cohort. When compared to liver histologies, OWL assays performed sub-optimally in those diabetic patients who had either poor glycemic control or high insulin resistance. Among the Caucasian patients with good glycemic control (i.e., HbA1c <7.0%), the assay delivered an AUROC of 0.79. In that group of controlled diabetics with lower insulin resistance (i.e., HOMA-IR <3) and no cirrhosis, the blinded OWL test performance was even higher with an AUROC of 0.87 versus liver biopsy.

Diabetes, Obesity and Metabolism 2018;20(7):1702-1709



Deciphering non-alcoholic fatty liver disease through metabolomics

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disorders in industrialized countries. NAFLD develops in the absence of alcohol abuse and encompasses a wide spectrum of disorders ranging from benign fatty liver to non-alcoholic steatohepatitis (NASH). NASH often leads to fibrosis, cirrhosis and, finally, hepatocellular carcinoma. Therefore the earlier NAFLD is diagnosed, the better the patient's outlook. A tightly connected basic and applied research is essential to find the molecular mechanisms that accompany illness and to translate them into the clinic. From the simple starting point for triacylglycerol accumulation in the liver to the more complex implications of phospholipids in membrane biophysics, the influence of lipids may be the clue to understand NAFLD pathophysiology. Nowadays, it is achievable to diagnose non-invasively the initial symptoms to stop, revert or even prevent disease development. In this context, merging metabolomics with other techniques and the interpretation of the huge information obtained resembles the 'Rosetta stone' to decipher the pathological metabolic fluxes that must be targeted to find a cure. In the present review, we have tackled the application of metabolomics to find out the metabolic fluxes that underlie membrane integrity in NAFLD.

Biochem Soc Trans. 2014;42(5):1447-1452



Obesity-dependent metabolic signatures associated with nonalcoholic Fatty liver disease progression.

We studied 467 biopsied individuals with normal liver histology or diagnosed with NAFLD. Qualitative determinations of 540 serum metabolite variables were performed using UPLC-MS. The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values = 0.82/0.84).

Journal of Proteome Research 2012;11(4):2521-2532



Where Are We in the Search for Noninvasive Nonalcoholic Steatohepatitis Biomarkers?

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease associated with obesity and insulin resistance. Due to the rising prevalence of obesity and diabetes, NAFLD is presently the most common cause of liver disease in the Western world, both in adults and children. The prevalence of NAFLD in Western adults is between 20% and 30%. NAFLD associates with increased hepaticrelated mortality. NAFLD ranges from the simple accumulation of triacylglycerol (TAG) in the liver (hepatic steatosis) to nonalcoholic steatohepatitis (NASH), which is characterized by steatosis, hepatocyte ballooning, scattered inflammation, fibrosis, and necrosis.

Hepatology 2011;54(4):1115-1117



Liquid Chromatography-Mass Spectrometry (LC/MS)-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of non-alcoholic fatty liver disease.

This article describes a parallel animal model / human NAFLD exploratory metabolomics study, using ultra performance liquid chromatography-mass spectrometry (UPLC®-MS) to analyze 42 serum samples collected from non-diabetic, morbidly obese, biopsy-proven NAFLD patients, and 17 animals belonging to the glycine Nmethyltransferase knockout (GNMT-KO) NAFLD mouse model. Many of the altered metabolites observed could be associated with biochemical perturbations associated with liver dysfunction (e.g. reduced Creatine) and inflammation (e.g. eicosanoid signaling).

Journal of Proteome Research 2010;9(9):4501-4512.



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