Hepatic Encephalopathy is the Key Driver of Symptom Burden in a Longitudinal Cohort of Patients with Advanced Chronic Liver Disease: PAL-LIVER sub-study

Background: Cirrhosis is a chronic illness with high morbidity, marked by persistent physical and psychological symptoms that impact patients and their caregivers. Longitudinal data on symptom trajectories and their determinants, particularly hepatic encephalopathy (HE), are limited. Methods: We conducted a secondary analysis of PAL-LIVER, a 19-site cluster-randomized trial comparing hepatologist-led and consultative palliative care for patients with decompensated cirrhosis and/or hepatocellular carcinoma. Patients and caregivers completed assessments at baseline and multiple intervals up to 12 months (patients: modified ESAS-13, PHQ-9, Distress Thermometer; caregivers: Zarit Burden Interview-12). Latent class growth analysis identified subgroups with persistently high or low burden for each symptom. Multivariable models evaluated associations between HE and symptom/caregiver burden, adjusting for demographics, disease severity, and comorbidities. Results: 935 patients were enrolled, 823 with HE information, 368 of whom had HE at baseline. Symptom burden trajectories remained stable over 12 months. HE was the primary independent predictor of high overall symptom burden (ESAS OR 1.83, 95%CI 1.38–2.41), depression (PHQ-9 OR 1.93, 95%CI 1.44–2.60), and greater caregiver burden (ZBI-12 OR 1.53, 95%CI 1.02–2.30). Alcohol-related liver disease and female sex were also associated with higher symptom burden. Caregiver burden remained generally low and stable. Conclusions: Symptom burden in cirrhosis is generally stable but remain high among certain subgroups, especially those with HE. HE is the strongest and most consistent determinant of physical, psychological, and caregiver burden in cirrhosis. These findings highlight the urgent need for novel, HE-targeted interventions and comprehensive symptom management strategies particularly for women and those with alcohol-related liver disease.