Hepatic Encephalopathy Is Associated With a Poorer Prognosis Than Non Hepatic Encephalopathy in Cirrhotic Patients

Background: Survival dramatically decreases after a first episode of overt hepatic encephalopathy (HE) in cirrhotic patients (pts) and recent data suggest that hyerperammonemia is associated with a worse prognosis at short and long term. Some patients display clinical encephalopathy without hyperammonemia (non hepatic encephalopathy - nHE), prompting to seek for differential diagnoses of encephalopathy. No study compared the prognosis of HE with that of nHE. Methods: We conducted a retrospective observational study in 2 different cohorts of patients hospitalized in our ICU of Hepatology between February 2014 and October 2016, and January 2019 and August 2021. All patients had one blood ammonia (NH3) measurement at admission. Hyperammonemia was defined by NH3 > 50 µmol/L. Pts were divided into 4 groups: HE (encephalopathy and NH3 > 50 µmol/L: group 1), nHE (encephalopathy and NH3 ≤ 50 µmol/L, group 2), and 2 control groups: no encephalopathy and NH3 ≤ 50 µmol/L (group 3), no encephalopathy and NH3 > 50 µmol/L (group 4). The primary endpoint was one-year transplant-free survival. Results: 533 patients were included (group 1 = 169 pts, group 2 = 77 pts, group 3 = 126 pts, group 4 = 161 pts). 31% of patients with encephalopathy displaid nHE. The main etiologies of cirrhosis were alcohol (68%), MAFLD (37%) and HBV/HCV infections (20%) without difference between groups. Pts in group 1 and 2 had significantly more history of encephalopathy and more severe cirrhosis with higher MELD and CLIF-OF scores than in group 3 and 4. nHE patients were more exposed to medications than HE pts. One-year transplant-free survival was significantly lower in patients with HE at admission than those with nHE or without encephalopathy (Figure 1). In multivariate analysis, the presence of HE, but not that of nHE, was independently associated with a lower one year transplant-free survival (HR 1.91, 95%CI 1.34 – 2.73) (Table 1). Conclusion: nHE is frequent in cirrhotic patients presenting encephalopathy and accounts probably for drug-induced encephalopathy. nHE prognosis is not different from that of patients without encephalopathy. HE, but not nHE is independently associated with a lower transplant-free survival in cirrhotic patients admitted to ICU.Figure 1.: Adjusted survival curve representing the probability of death and/or liver transplantation at 1 year depending on the presence or absence of encephalopathy and the presence or absence of hyperammonemia with a cut-off defined at 50 µmol/L. Table 1. - Factors associated with transplat-free survival at one year after analysis by Cox regression model Parameters Alive Dead or transplant Univariate analysis Multivariate analysis N = 247 N = 286 HR [95CI] P-value HR [95CI] P-value Ammonia level and encephalopathy Group 1 54 (21.9) 115 (40.2) 2.34 [1.67-3.26] <0.001 1.91 [1.34-2.73 ] <0.001 Group 2 24 (9.7) 53 (18.5) 2.54 [1.72-3.75] <0.001 1.46 [0.97-2.20 ] 0.069 Group 3 77 (31.2) 49 (17.1) 1 (ref) - 1 (ref) 1 (ref) Group 4 92 (37.2) 69 (24.1) 1.17 [0.81-1.69 ] 0.401 1.20 [0.82-1.76 ] 0.346 Age, years 57.5 (11.0) 58.9 (11.3) 1.01 [1.00-1.02 ] 0.163 1.02 [1.01-1.04 ] <0.001 Sex Men vs women 185 (74.9) 202 (70.6) 0.90 [0.70-1.17 ] 0.439 0.99 [0.75-1.30 ] 0.936 Sodium, mmol/L 136.0 (9.9) 133.8 (9.1) 0.99 [0.98-1.00 ] 0.002 0.99 [0.98-1.00 ] 0.006 Albumin, g/L 27.8 (6.4) 27.1 (6.8) 0.99 [0.97-1.01] 0.211 0.99 [0.97-1.01 ] 0.217 Creatinine, µmol/L By 10 µmol/L 10.3 (9.5) 12.3 (9.1) 1.01 [1.00-1.02 ] 0.005 1.01 [1.00-1.02 ] 0.065 Prothrombin time ratio, % 53.8 (15.1) 42.2 (16.6) 0.96 [0.95-0.97] <0.001 0.97 [0.96-0.98 ] < 0.001 Total bilirubin, µmol/L 77.6 (99.1) 168.8 (178.8) 1.00 [1.00 - 1.00] <0.001 1.00 [1.00-1.00 ] < 0.001 Infection Yes vs no 79 (32.0) 183 (64.0) 2.46 [1.93-3.13 ] <0.001 1.67 [1.28-2.19 ] < 0.001 Hepatocellular carcinoma Yes vs no 27 (10.9) 60 (21.1) 1.47 [1.10-1.95 ] 0.008 1.42 [1.04-1.95 ] 0.027 Hemodynamic failure Yes vs no 13 ( 5.3) 17 ( 5.9) 1.32 [0.81-2.15] 0.269 0.95 [0.53-1.72 ] 0.876 Respiratory failure Yes vs no 11 ( 4.5) 10 ( 3.5) 0.99 [0.53-1.86] 0.980 1.26 [0.63-2.50 ] 0.518 Group 1: hepatic encephalopathy, Group 2 : non hepatic encephalopathy, Group 3 : no encephalopathy and ammonemia < 50 µmol/L, Group 4 : non encephalopathy and ammonemia > 50 µmol/L.