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Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways

Rachakonda, V and Gabbert, C and Raina, A and Bell, LN and Cooper, S and Malik, S and Behari, J (2014) Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways. PLoS ONE, 9 (12).

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Background and Objectives: While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods: This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results: Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Conclusion: Severe AAH is characterized by a distinct metabolic phenotype spanning multiple pathways. Metabolomics profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe AAH.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Rachakonda, V
Gabbert, C
Raina, A
Bell, LN
Cooper, S
Malik, S
Behari, Jjab31@pitt.eduJAB31
ContributionContributors NameEmailPitt UsernameORCID
Date: 2 December 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 12
DOI or Unique Handle: 10.1371/journal.pone.0113860
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Other ID: NLM PMC4252257
PubMed Central ID: PMC4252257
PubMed ID: 25461442
Date Deposited: 12 May 2015 19:04
Last Modified: 30 Mar 2021 13:56


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