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Abstract Details
Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multicenter Inpatient Cirrhosis Cohort
1Department of Medicine, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, Richmond, Virginia. Electronic address: jasmohan.bajaj@vcuhealth.org.
2Department of Medicine, University of Alberta, Edmonton, Canada.
3Department of Medicine, Dallas Veterans Affairs Medical Center, Dallas, Texas.
4Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
5Department of Medicine, Yale University Medical Center, New Haven, Connecticut.
6Department of Medicine, Mercy Medical Center, Baltimore, Maryland.
7Department of Medicine, University of California San Francisco, San Francisco, California.
8Department of Medicine, Emory University Medical Center, Atlanta, Georgia.
9Department of Medicine, Mayo Clinic Arizona, Phoenix, Arizona.
10Department of Medicine, University of Toronto, Toronto, Canada.
11Department of Medicine, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, Richmond, Virginia.
12Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota.
Abstract
Background & aims: Grades 3 to 4 hepatic encephalopathy (advanced HE), also termed brain failure, is an organ failure that defines acute-on-chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be predicted accurately. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation.
Methods: Prospective inpatient cirrhosis cohorts (multicenter and 2-center validation) without brain failure underwent admission serum collection and inpatient follow-up evaluation. Serum metabolomics were analyzed to predict brain failure on random forest analysis and logistic regression. A separate validation cohort also was recruited.
Results: The multicenter cohort included 602 patients, of whom 144 developed brain failure (105 only brain failure) 3 days after admission. Unadjusted random forest analysis showed that higher admission microbially derived metabolites and lower isoleucine, thyroxine, and lysophospholipids were associated with brain failure development (area under the curve, 0.87 all; 0.90 brain failure only). Logistic regression area under the curve with only clinical variables significantly improved with metabolites (95% CI 0.65-0.75; P = .005). Four metabolites that significantly added to brain failure prediction were low thyroxine and maltose and high methyl-4-hydroxybenzoate sulfate and 3-4 dihydroxy butyrate. Thyroxine alone also significantly added to the model (P = .05). The validation cohort including 81 prospectively enrolled patients, of whom 11 developed brain failure. Admission hospital laboratory thyroxine levels predicted brain failure development despite controlling for clinical variables with high specificity.
Conclusions: In a multicenter inpatient cohort, admission serum metabolites, including thyroxine, predicted advanced HE development independent of clinical factors. Admission low local laboratory thyroxine levels were validated as a predictor of advanced HE development in a separate cohort.