Pathogenesis of Hepatic Encephalopathy in Acute Liver Failure

Javier Vaquero, MD, Chuhan Chung, MD, Michael E. Cahill, BA, Andres T. Blei, MD


Semin Liver Dis. 2003;23(3) 

In This Article

A Clinical Overview: Comparison of HE in ALF and Cirrhosis

Encephalopathy in ALF shares features and exhibits differences with the encephalopathy of cirrhosis. Five aspects deserve specific consideration.

Grading of HE

The West Haven criteria, designed for clinical studies in cirrhosis,[3] have also been used in patients with ALF. However, the precise characteristics of each stage often overlap, and differences between stages I and II or between II and III can be blurred. Certain clinical features of ALF are not well-represented in this classification, especially severe agitation, which can be an initial neurological symptom in ALF and pose serious problems in management (including the need to sedate the patient with loss of neurological end points for follow-up). An excitatory behavioral phase is consistent with robust experimental findings of an increased extracellular brain glutamate in this condition.[4]

Once stage IV encephalopathy is reached, the Glasgow coma scale, initially developed for patients with neurotrauma,[5] provides a numerical continuous score from 3 (worst) to 15 (best). Although it has not been formally evaluated in metabolic encephalopathies, it is better suited for examining patients in stages III and IV encephalopathy than the West Haven criteria, as was recently shown.[6]

Precipitating Factors

The pathogenic role of precipitating factors, well-recognized in the encephalopathy of cirrhosis, is often overlooked in ALF. Patients with acute liver failure may develop encephalopathy from the use of sedatives, as disturbances of sleep or agitation may be an early prodrome and are often medicated prior to arrival at a specialized center. Gastrointestinal hemorrhage, uremia, and electrolyte disturbances need to be ruled out. Infection, however, is the key precipitant to consider; the role of infection is discussed in the next section.


Seizures have traditionally been viewed as a rare event in hepatic encephalopathy. A retrospective review of electroencephalogram tracings in 94 patients with cirrhosis described epileptiform abnormalities in 14% of subjects with deep encephalopathy who did not receive a liver transplant.[7]

Seizure activity has been reported in previous clinical series of ALF[8] and is a well-recognized complication of acute hyperammonemia in urea-cycle disorders.[9] In a recent controlled trial, subclinical seizure activity was detected in 10 of 22 patients enrolled as controls in a trial of prophylactic phenytoin in ALF.[10] Measurements of low oxygen saturation in the jugular vein led to the conclusion that poor cerebral perfusion and tissue anoxia were potential determinants of seizure development. At autopsy, patients in the nontreated group had greater evidence of cerebral edema. The high frequency of subclinical seizures reported in this series awaits confirmation from other centers.

Brain Edema

Death from intracranial hypertension has now been reported in patients with cirrhosis and deep hepatic encephalopathy in the setting of acute-on-chronic liver failure.[11,12] The magnetization transfer ratio, an indirect reflection of brain water content on spectroscopy, was clearly abnormal in patients with cirrhosis,[13] suggesting low-grade brain edema. The paradigm has shifted, with an increasing realization that a disturbance in brain water regulation is central to the process responsible for hepatic encephalopathy.[14,15] Nonetheless, a neurological death is a rare event in patients with cirrhosis.

Cerebral Perfusion

In cirrhosis, a reduction in cerebral blood flow has been described in patients with overt[16] and minimal[17] encepha lopathy. A hyperdynamic circulatory state is a characteristic finding in liver failure, and the response of the cerebral circulation needs to be considered in this context. Recently, Guevara and colleagues[18] postulated a direct relation between the reduction in cerebral and renal blood flow in patients with cirrhosis and ascites. The decrease in perfusion of both territories was viewed as a response to systemic arterial vasodilatation, a sequence well-accepted for the renal vasoconstriction of cirrhosis.[19] The absence of signs of encephalopathy in these patients adds further credence to the view that the cerebral circulation also reacts to the generalized hemodynamic disturbance of liver failure.[20] In ALF, an initial reduction of cerebral blood flow (CBF) may reflect similar mechanisms.[21] However, a rise in CBF is prominently seen in patients with overt brain edema.[22]