Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Apr 8, 2016; 8(10): 499-508
Published online Apr 8, 2016. doi: 10.4254/wjh.v8.i10.499
Metabolomics studies identify novel diagnostic and prognostic indicators in patients with alcoholic hepatitis
Mona Ascha, Zeneng Wang, Mustafa S Ascha, Raed Dweik, Nizar N Zein, David Grove, J Mark Brown, Stephanie Marshall, Rocio Lopez, Ibrahim A Hanouneh
Mona Ascha, Mustafa S Ascha, Nizar N Zein, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, United States
Zeneng Wang, J Mark Brown, Stephanie Marshall, Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
Raed Dweik, David Grove, Department of Pulmonary, Allergy, and Critical Care Medicine/Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, United States
Rocio Lopez, Department of Quantitative Health Science, Cleveland Clinic, Cleveland, OH 44195, United States
Ibrahim A Hanouneh, Minnesota Gastroenterology, Minneapolis, Minnesota, PA 55414, United States
Author contributions: Ascha M, Ascha MS and Hanouneh IA performed the writing and critical revision of the manuscript; Wang Z, Dweik R, Grove D, Brown JM and Marshall S performed the majority of data collection; Zein NN and Hanouneh IA conceived and implemented the design of the project; Lopez R performed the statistical analysis.
Supported by In part by NIH grant R01 HL122283 (Brown JM).
Institutional review board statement: The study was reviewed and approved by the Cleveland Clinic Foundation Institutional Review Board.
Institutional animal care and use committee statement: No animals were involved in this study.
Conflict-of-interest statement: The authors have no conflict of interest to report.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at mxa256@case.edu. Participants gave informed consent for data sharing.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ibrahim A Hanouneh, MD, Minnesota Gastroenterology, P.O. Box 14909, Minneapolis, Minnesota, PA 55414, United States. ibrahim.hanouneh@mngastro.com
Telephone: +1-612-8711145 Fax: +1-612-8705491
Received: September 12, 2015
Peer-review started: September 16, 2015
First decision: October 28, 2015
Revised: January 22, 2016
Accepted: March 9, 2016
Article in press: March 14, 2016
Published online: April 8, 2016
Processing time: 199 Days and 18.8 Hours
Abstract

AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis (AH).

METHODS: We prospectively recruited patients with cirrhosis from AH (n = 23) and those with cirrhosis with acute decompensation (AD) from etiologies other than alcohol (n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis. Logistic regression analysis was performed to build a predictive model for AH based on clinical characteristics. A survival analysis was used to construct Kaplan Meier curves evaluating transplant-free survival.

RESULTS: A comparison of model for end-stage liver disease (MELD)-adjusted metabolomics levels between cirrhosis patients who had AD or AH showed that patients with AH had significantly higher levels of betaine, and lower creatinine, phenylalanine, homocitrulline, citrulline, tyrosine, octenoyl-carnitine, and symmetric dimethylarginine. When considering combined levels, betaine and citrulline were highly accurate predictors for differentiation between AH and AD (area under receiver operating characteristics curve = 0.84). The plasma levels of carnitine [0.54 (0.18, 0.91); P = 0.005], homocitrulline [0.66 (0.34, 0.99); P < 0.001] and pentanoyl-carnitine [0.53 (0.16, 0.90); P = 0.007] correlated with MELD scores in patients diagnosed with AH. Increased levels of many biomarkers (carnitine P = 0.005, butyrobetaine P = 0.32, homocitrulline P = 0.002, leucine P = 0.027, valine P = 0.024, phenylalanine P = 0.037, tyrosine P = 0.012, acetyl-carnitine P = 0.006, propionyl-carnitine P = 0.03, butyryl-carnitine P = 0.03, trimethyl-lisine P = 0.034, pentanoyl-carnitine P = 0.03, hexanoyl-carnitine P = 0.026) were associated with increased mortality in patients with AH.

CONCLUSION: Metabolomics plasma analyte levels might be used to diagnose of AH or help predict patient prognoses.

Keywords: Metabolomics; Biomarkers; Liver disease; Model for end-stage liver disease; Cirrhosis; Alcoholic hepatitis; Liver biopsy

Core tip: The model for end-stage liver disease score, which is commonly used to predict outcomes in patients who have liver disease, is far from perfect. We report results from a study that uses metabolomics biomarkers as a means for assessing diagnosis and prognosis in patients who have liver disease. Plasma analytes from fasted subjects have provided information regarding 3 and 6 mo transplant free survival. This study is one of the first to employ the novel metabolomics approach as it relates to patient outcomes. These results can pave the way for future research that can enhance the way we assess patients with liver disease.