ReviewPathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies
Introduction
Hepatic encephalopathy (HE) is a major neuropsychiatric complication of both acute and chronic liver failure. Symptoms of HE include attentional deficits, alterations of sleep patterns and muscular incoordination progressing to stupor and coma. HE in acute liver failure may include seizures. Despite several decades of intensive scientific research, the precise causes of HE are still unknown. Attention has been focussed on two major areas, namely the role of blood-borne neurotoxins (particularly ammonia [1]) and the key role of the astrocyte [2].
One impediment in the search for pathophysiologic mechanisms in HE has resulted from the lack of standardization of terminology used to define the syndrome, both clinically and experimentally. Terms such as ‘chronic HE’ were commonly used to describe HE in chronic liver failure and it was frequently unclear whether ‘acute HE’ referred to acute liver failure or to acute decompensation in a patient with chronic liver failure. Fortunately, the year 2002 saw the publication of the final report [3] of a working party whose task was to better define HE from the standpoint of the standardization of clinical diagnosis. It was concluded that “HE reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease. A multiaxial definition of HE is required that defines both the type of hepatic abnormality and the duration/characteristics of neurologic manifestations in chronic liver disease”. Three types of hepatic abnormality were defined, namely:
- Type A:
HE associated with acute liver failure
- Type B:
HE associated with portal-systemic bypass with no intrinsic hepatocellular disease
- Type C:
HE associated with cirrhosis and portal hypertension or portal-systemic shunts
Section snippets
The astrocyte in HE
Results of neuropathological and biochemical studies together with the clinical observation of substantial recovery of central nervous system function following liver transplantation indicate that HE is not the consequence of extensive neuronal cell death. On the other hand, morphological changes of astrocytes are commonplace in liver failure. The nature of these astrocytic changes is dependent upon the type of liver failure (acute versus chronic) as well as the severity of HE [4]. In acute
Pathogenesis of HE: imaging and spectroscopic studies
Advances in neuroimaging and spectroscopic techniques continue to provide new insights into pathophysiologic mechanisms in HE (Table 1).
Altered expression of genes coding for key brain proteins
The advent of modern molecular biological techniques has provided new impetus for the study of molecular mechanisms implicated in the pathogenesis of HE. Using postmortem material from cirrhotic patients who died in hepatic coma or brain tissue from experimental animals with acute or chronic liver failure, alterations in the expression of a number of genes coding for important brain proteins (enzymes, transporters, receptors, structural proteins) have been identified (summarized in Table 3).
Therapeutic implications
Since HE is often precipitated by ammoniagenic conditions such as an oral protein load, constipation or a gastrointestinal hemorrhage, and given the new evidence from non-invasive studies that brain ammonia and its detoxification product glutamine accumulate in brain in liver failure, the major treatment strategy still focuses on lowering of circulating ammonia. This is currently achieved either by agents such as lactulose or antibiotics aimed at reducing gut ammonia production or agents such
Acknowledgements
Studies from the author's research unit are funded by grants from the Canadian Institutes of Health Research and the The Canadian Liver Foundation.
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