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.