Multimodal Assessment of Covert Hepatic Encephalopathy and Its Outcome in a Prospective Cohort of Outpatients With Chronic Liver Disease

Background: Covert hepatic encephalopathy (CHE) is difficult to diagnose in patients (pts) with chronic liver disease (CLD), as other etiologies may cause neurocognitive impairment (NI). The aim of this study was to phenotype outpatients with CLD with a suspicion of CHE, and to assess the development of overt HE (OHE), liver-related rehospitalization (LRH) and liver transplantation (LT) free-survival (LTFS) during follow-up. Methods: Retrospective analysis of a prospective cohort of patients with CLD (March 2018-November 2022) referred to our outpatient clinics for suspicion of CHE. Exclusion criterion was previous LT. Multimodal work-up was performed in our multidisciplinary team: examination (hepatologist, neurologist), neuropsychological tests (neuropsychologist), biomarkers, electroencephalogram (EEG) and multimodal brainMRI with spectroscopy (MRIs). The diagnosis of CHE was made by an adjudication committee involving the aforementioned physicians. Pts were followed for OHE development, LRH and LTFS. Results: One hundred sixty-four patients were included: 77% cirrhosis (alcohol/MASH/virus in 62/54/16%, median MELD score 12[9-15]), 23% portosinusoïdal vascular liver disease. 70% had a previous history of HE, among them 98% had ammonia-lowering medications. Overall, 63% patients were diagnosed with CHE (PCHE+), and 37% with another diagnosis (PCHE-). PCHE+ had higher ammonia (P<0.001), lower score for animal naming test (P=0.005) or PHES (P=0.02), more CHE features on EEG (P=0.008) or on MRIs (P<0.001). 73% PCHE+ displayed also another cause of NI (anxio-depressive disorders (ADD) 23%, vascular leukopathy19%, alcohol sequalae 13%, neurodegenerative disorders5%, other20%, mixed causes in 21%). Among PCHE-, NI was related to: ADD/ vascular leukopathy/ alcohol sequalae/ other in 31%/15%/15%/18%; mixed causes in 30%. NI was not confirmed in 22%. Overall, during follow-up (25[12-44] months), PCHE+ developed more OHE (31% vs 18%, P=0.03), and had more LRH (71% vs 46%, P=0.01). At the end of follow-up, the LTFS was 39% and 61% in PCHE+ and PCHE- (P=0.06); the overall survival was not different (63% and 77%, respectively, P=0.2). Conclusion: Less than 2/3 of outpatients with CLD and suspicion of CHE were finally diagnosed with CHE, and among them 3/4 also displayed another cause of NI. Differential work-up must be performed in patients with suspicion of CHE, as a significant proportion of them present nonreversible causes of NI like vascular leukopathy or alcohol sequalae. CHE diagnosis was associated with a significantly higher rate of OHE development and LRH.