Plasma Neurofilament Light Chain as a Novel Potential Biomarker for the Stratification and Risk Profiling of Hepatic Encephalopathy in Cirrhosis

Background: Hepatic encephalopathy (HE) is a debilitating and complex neuropsychiatric complication associated with cirrhosis, yet current diagnostic and grading approaches are limited and non-specific. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein previously utilised as a biomarker for various neurological disorders as its levels increase in cerebrospinal fluid and blood proportionally to the degree of axonal damage. In this study we used plasma samples from patients with varying severities of cirrhosis and HE to investigate the utility of NfL as a diagnostic and predictive tool for HE. Methods: Cirrhosis patients were classified according to disease severity as stable cirrhosis (SC, n=34), decompensated cirrhosis (DC, n=55) and acute-on-chronic liver failure (ACLF, n=43) and compared to 19 healthy controls (HC). The clinical West Haven criteria were used to grade HE severity at the time of blood sampling (grade 0: no abnormalities/symptoms, grade 1/2: mild behavioural and cognitive alterations, grade 3/4: severe symptoms including coma). Plasma NfL levels were measured using the MSD R-PLEX Human assay. Results: Mean plasma NfL concentration progressively increased with cirrhosis severity and was significantly higher in all groups, except from SC when compared to HC. NfL was also higher in all HE groups (grade 0, 1/2, 3/4) compared with HC (Figure 1). NfL levels could discriminate HE grade 0 and grade 1/2, which is clinically challenging to differentiate due to subtlety in symptoms. Furthermore, in cirrhosis patients with HE grade 0, NfL levels were higher in those who experienced a HE episode up to 6 months after sampling compared to patients who did not (Figure 2). At 30, 90 and 180 days follow up post sampling, spontaneous survivors had lower plasma NfL concentration compared to non survivors. Correlation analysis also revealed that plasma NfL is closely associated with disease severity and IL-6 in cirrhosis patients, but not with age or blood ammonia. Conclusions: Plasma NfL levels have biomarker potential for the diagnosis and grading of HE in cirrhosis patients and may have predictive value for risk of future HE occurrence, as well as survival outcome.Figure 1.: Plasma NfL concentration in cirrhosis patients with varying HE grades (grade 0: n=93, grade 1/2: n=28, grade 3/4: n=13) and healthy controls (HC, n=19). A p value of <0.05 indicates significance level.Figure 2.: Plasma NfL concentration in cirrhosis patients with HE grade 0 at sampling who experienced a HE episode up to 90 (2a: no future HE=62, future HE=10) and 180 days (2b: no future HE=45, future HE=11) post-sampling. A p value of <0.05 indicates significance level.