Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multi-center Inpatient Cirrhosis Cohort
Background and Aims
Grade 3-4 hepatic encephalopathy (advanced HE), also termed brain failure (BF), is an organ failure that defines acute-on chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be accurately predicted. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation.
Prospective inpatient cirrhosis cohorts (multi-center and 2-center validation) without BF underwent admission serum collection and inpatient follow-up. Serum metabolomics was analyzed to predict BF on random forest analysis (RFA) and logistic regression. A separate validation cohort was also recruited.
The multi-center cohort included 602 patients, of whom 144 developed BF (105 only BF) 3 days post-admission. Unadjusted RFA showed that higher admission microbially-derived metabolites and lower isoleucine, thyroxine and lysophospholipids were associated with BF development (AUC 0.87 all, 0.90 BF only). Logistic regression AUC with only clinical variables significantly improved with metabolites (0.65 to 0.75; p=0.005). Four metabolites that significantly added to BF 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=0.05). Validation cohort: prospectively included 81 patients, of whom 11 developed BF. Admission hospital laboratory thyroxine levels predicted BF development despite controlling for clinical variables with high specificity.
In a multi-center 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.