Clinical, Neuropsychological and Neurophysiological Indices and Predictors of Hepatic Encephalopathy (HE)

Chiara Formentin; Lisa Zarantonello; Chiara Mangini; Anna C. Frigo; Sara Montagnese; Carlo Merkel


Liver International. 2021;41(5):1070-1082. 

In This Article

Abstract and Introduction


Background and Aims: The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort.

Method: Four hundred and sixty-one patients with cirrhosis (59 ± 10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow-up information on mortality/HE-related hospitalization in 134/127 respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow-up in 124.

Results: Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow-up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk.

Conclusions: In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.


Hepatic encephalopathy (HE) is defined as a continuum of neuropsychiatric impairment caused by liver insufficiency and/or portal-systemic shunting, ranging from abnormalities detected on neurophysiological or neuropsychological testing to coma.[1–6]

The occurrence of overt HE marks a significant progression of the underlying disease, and it is associated with poorer prognosis[7,8] and a remarkable decrease in health-related quality of life.[9–12] Overt HE is associated with a 40% cumulative risk of recurrent overt HE at 1 year.[5,13] In addition, patients with minimal or covert HE have a significantly higher risk of developing overt HE.[14–17]

Previous studies have evaluated the impact of a clinical diagnosis of HE in terms of survival and subsequent overt HE episodes, over follow-up periods ranging from 90 days to 5 years.[9,14–16,18–24] Based on such studies, mortality and HE episodes are predicted by the severity of the underlying liver disease [Model for End-stage Liver Disease (MELD) and Child-Pugh score],[9,14–16,18–24] the presence of both overt[18] and covert HE,[14,16,18] and previous overt HE episodes.[7,21] Other variables, such as Critical Flicker Frequency,[20,22] bilirubin,[7] albumin,[7] potassium[7] and prothrombin[7] have also been associated with increased mortality over varying follow-up periods.

Nevertheless, most of these studies included only specific groups of patients with cirrhosis, such as patients undergoing transjugular intrahepatic portal-systemic shunt, inpatients hospitalized for HE, patients without overt HE history, patients with overt HE at the time of study or patients already on the waiting list for liver transplantation. Moreover, the diagnosis of HE was rarely based on standardized and/or homogeneous criteria. For example, only two studies used the complete Psychometric Hepatic Encephalopathy Score (PHES),[20,21] while in most of the others only subtests of this battery were administered.[14–16,24]

The aim of the present study was two-fold:

  • to describe a large cohort of consecutive patients with cirrhosis referred to a dedicated HE clinic in terms of demographic, clinical, laboratory, neuropsychological and neurophysiological indices, and to compare such indices between patients with and without previous overt HE episodes;

  • to test if the severity of liver disease and/or comprehensively evaluated neuropsychological/neurophysiological performance could predict mortality and/or the risk of HE-related hospitalizations over a 24-month follow-up period in a subgroup of the main cohort.