Neurofilament Light Chain in Cerebrospinal Fluid and Blood Identifies Patients With Minimal and Overt Hepatic Encephalopathy

BACKGROUND: Minimal hepatic encephalopathy (MHE) is an underdiagnosed complication of liver cirrhosis, associated with progression to overt hepatic encephalopathy (HE). The Portosystemic Hepatic Encephalopathy Score (PHES) is the recommended diagnostic standard, but its use is hindered by resource constraints and limited accuracy. Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are released during neuroaxonal and astrocyte injury and may serve as HE-biomarkers. We investigated NfL and GFAP in cerebrospinal fluid (CSF) and serum across the spectrum of HE and assessed their correlation and diagnostic performance. METHODS: In this cross-sectional study, 35 patients with cirrhosis and 14 healthy controls (HC) were included. MHE was defined as PHES < -4, and overt HE was graded according to the West Haven Criteria. NfL and GFAP were quantified in CSF and serum using single-molecule array technology. RESULTS: NfL concentrations in CSF and serum increased stepwise from HC to unimpaired patients, MHE, and overt HE (p < 0.0001). CSF- and serum NfL were strongly correlated (rho = 0.888, p < 0.0001), and CSF and serum NfL discriminated MHE and overt HE from unimpaired patients and HC, with AUROCs of 0.877-0.902 and 0.930-0.951, respectively. GFAP showed moderate correlation between CSF and serum (rho = 0.496, p < 0.0004) and discriminatory value in CSF (AUROCs of 0.777-0.800); however, to a lesser extent than NfL. CONCLUSION: Neuroaxonal injury is detectable in HE by NfL in both CSF and serum. The strong CSF and serum correlation suggests that serum NfL may serve as a minimally invasive biomarker of MHE and overt HE.