Cerebrospinal fluid metabolomics highlights dysregulation of energy metabolism in overt hepatic encephalopathy

Abstract

Background & aims: Hepatic encephalopathy (HE) is a neurological complication observed in patients with liver disease and/or porto-systemic shunt. The proportion of cirrhotic patients developing overt HE is about 20%, and 60-80% of cirrhotic patients exhibit mild cognitive impairment potentially related to minimal HE. However, the pathophysiological mechanisms of HE remain poorly understood. In this context, metabolomics was used to highlight dysfunction of metabolic pathways in cerebrospinal fluid (CSF) samples of patients suffering from HE.

Methods: CSF samples were collected in 27 control patients without any proven neurological disease and 14 patients with symptoms of HE. Plasma samples were obtained from control patients, and from cirrhotic patients with and without HE. Metabolomic analysis was performed using liquid chromatography coupled to high-resolution mass spectrometry.

Results: Concentrations of 73 CSF metabolites, including amino acids, acylcarnitines, bile acids and nucleosides, were altered in HE patients. Accumulation of acetylated compounds, which could be due to a defect of the Krebs cycle in HE patients, is reported for the first time. Furthermore, analysis of plasma samples showed that concentrations of metabolites involved in ammonia, amino-acid and energy metabolism are specifically and significantly increased in CSF samples of HE patients. Lastly, several drugs were detected in CSF samples and could partially explain worsening of neurological symptoms for some patients.

Conclusion: By enabling the simultaneous monitoring of a large set of metabolites in HE patients, CSF metabolomics highlighted alterations of metabolic pathways linked to energy metabolism that were not observed in plasma samples.

Lay summary: CSF metabolomics provides a global picture of altered metabolic pathways in CSF samples of HE patients and highlights alterations of metabolic pathways linked to energy metabolism that are not observed in plasma samples.

Keywords: Blood-brain barrier; Cerebrospinal fluid; Cirrhosis; Hepatic encephalopathy; High-resolution mass spectrometry; Liquid chromatography; Metabolomics.