PATHOGENESIS OF HEPATIC ENCEPHALOPATHY - 05/09/11
Resumen |
Hepatic encephalopathy (HE) or portal-systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatocellular failure and increased portal-systemic venous shunting.49 A normally functioning liver is necessary to maintain normal brain function. Theoretically, HE may occur as a consequence of (1) reduced synthesis by the failing liver of substances necessary for normal brain function, (2) synthesis by the failing liver of encephalopathogenic substances, and (3) reduced extraction and metabolism by the failing liver of encephalopathogenic substances or precursors of such substances.
Well-recognized factors which tend to precipitate encephalopathy in patients with chronic hepatocellular disease are listed in Table 1.49 They include a dietary protein load, constipation, and gastrointestinal hemorrhage, which can be classified as gut factors, and are consistent with the hypothesis that gut-derived nitrogenous constituents of portal venous blood contribute to HE. Such substances would probably be efficiently extracted and metabolized by the normal liver. If, however, their hepatic metabolism is impaired by hepatocellular failure or they bypass hepatocytes as a consequence of their passage through intrahepatic or extra-hepatic portal-systemic venous collateral channels, these substances would tend to accumulate in peripheral blood; if some are neuroactive and can traverse the blood-brain barrier, altered brain function may occur. The importance of gut factors in the pathogenesis of HE is also suggested by ameliorations of HE associated with evacuation of the bowel and dietary protein restriction.26 With the exception of sedative/hypnotic drugs the mechanisms by which well-recognized precipitating factors trigger encephalopathy in patients with chronic liver disease are poorly understood, and the elucidation of these mechanisms would provide new insights into the pathogenesis of HE. Any factor that increases portal-systemic shunting may precipitate or exacerbate HE.74 The onset of HE in the absence of an obvious precipitating factor may result from progression of the underlying liver disease with consequent deterioration of hepatocellular function. In patients with hepatocellular failure, encephalopathy is not necessarily due to HE, or to HE alone. Factors other than liver failure, such as uremia, hypoglycemia, and sedative or hypnotic drugs, may cause encephalopathy or may contribute to encephalopathy in such patients.
The occurrence of HE does not depend on the duration of hepatocellular disease or on the type of portal-systemic shunting, which may be congenital, caused by hepatic fibrogenesis, or iatrogenic (e.g., surgically-induced or transjugular intrahepatic portal systemic stent). In fulminant hepatic failure (FHF), HE complicates acute hepatocellular failure in the absence of vascular shunts, although increased portal-systemic shunting still occurs as a consequence of impaired hepatocellular function. In this article, the term liver failure implies both hepatocellular failure and increased portal-systemic shunting. The term PSE may be applied to encephalopathy associated with portal-systemic shunts (e.g., congenital shunts) in the absence of overt hepatocellular failure, but whether the term HE would also be applicable in this context is uncertain. For example, in contrast to patients with chronic liver failure, the encephalopathy that develops in dogs with an Eck fistula (a portalsystemic shunt) which are fed a standard diet can be prevented by giving a palatable nutritious diet that prevents weight loss and malnutrition but not hepatic atrophy.93
Hepatic encephalopathy is considered to be a reversible metabolic encephalopathy with a multi-factorial pathogenesis.49 Hepatic encephalopathy may progress from mild neuropsychiatric disturbances to coma over a period of hours, irrespective of therapy. Progression may stop at any stage, and HE may resolve spontaneously over a period of hours. Thus, a requirement for pathogenic mechanisms that contribute to HE is that they be rapidly reversible. This requirement would seem to preclude irreversible anatomical changes. The term HE should probably not be applied to rare neurodegenerative disorders associated with chronic liver disease and extensive portal-systemic shunting (e.g., nonWilsonian hepatocerebral degeneration) in which neurological deficits are persistent and irreversible. Cerebral edema and raised intracranial pressure occur in a large proportion of patients with FHF and, rarely, in patients with chronic liver failure. Different factors may contribute to HE and to cerebral edema associated with liver failure, and the management of these two complications of liver disease differs.49 Cerebral edema and raised intracranial pressure may be classified as complications of liver failure that are distinct from uncomplicated HE, and a discussion of their pathogenesis is outside the scope of this article.
Patients with cirrhosis, without overt encephalopathy on neurologic examination but with abnormal results of psychometric tests or impaired brain neuroelectrophysiologic function, may have subclinical HE.82 There is no general agreement concerning the definition of this entity or the criteria for diagnosing it. It is uncertain whether the mechanisms responsible for psychometric or neuroelectrophysiologic deficits in cirrhotic patients without overt encephalopathy are the same as those responsible for overt HE, and the potential reversibility of these deficits, with and without specific therapeutic intervention, requires further study.
Hepatic encephalopathy is characterized neurophysiologically by altered function of neurons. It is becoming increasingly apparent, however, that altered function of astrocytes and pathophysiologic interactions between astrocytes and neurons play important roles in the pathogenesis of HE.70, 71 Metabolic imbalances and increased concentrations of neurotoxins that occur in liver failure, may alter neuronal polarization, metabolism of neurotransmitters, sensitivity of neuronal receptors, and neuronal and astrocytic metabolism. Such changes may lead to the clinical manifestations of HE as a consequence of altered neurotransmission.10 Seizures, which are associated with a net increase in excitatory neurotransmission, rarely occur in patients with HE caused by chronic liver failure. Indeed, the manifestations of HE do not appear to be consequences of neuronal excitation and are more consistent with a global suppression of CNS function. This suppression is probably caused by a net increase in inhibitory neuro-transmission, which could occur as a consequence of increased neurotransmission mediated by inhibitory neurotransmitters, such as γ-aminobutyric acid (GABA) and glycine, or decreased neurotransmission mediated by excitatory neurotransmitters, such as glutamate and aspartate.31
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| Address reprint requests to E. Anthony Jones, MD, DSc, FRCP, Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam-ZO, The Netherlands, e-mail: E.A.Jones@AMC.UVA.NL |
Vol 4 - N° 2
P. 467-485 - mai 2000 Regresar al número
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