Mina Shaker, MD
Published: June 2014
Last Reviewed: August 2017
Hepatic encephalopathy (HE) describes a spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of unrelated neurologic and/or metabolic abnormalities. The term implies that altered brain function is due to metabolic abnormalities. The full reversibility of symptoms after improvement of liver function is considered to be direct proof of this causal relation.
An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels.1 Expression of encephalopathy is characterized by personality changes, intellectual impairment, and may advance to a depressed level of consciousness. In patients with cirrhosis, acute encephalopathy is most commonly associated with a precipitating factor, such as electrolyte disturbance, medications, gastrointestinal hemorrhage, or infection.2
Those with fulminant hepatic failure may experience altered mental status, severe cerebral edema and subsequent herniation of brain stem with fatal consequences. Detailed discussion of this entity is beyond the scope of this chapter.
HE may be clinically apparent in as many as one third of cirrhotic patients and, if rigorously tested, up to two thirds have some degree of mild or subclinical HE.
While the precise molecular mechanisms that result in these morphological changes in the brain are yet to be identified, many factors have been elucidated, especially the role of ammonia, false neurotransmitters, astrocyte swelling, inflammation, and oxidative stress.
Ammonia, a byproduct of the metabolism of nitrogen-containing compounds, is neurotoxic at elevated concentrations.3 The liver clears almost all of the portal vein ammonia, converting it into glutamine and urea preventing entry into the systemic circulation. However, glutamine is metabolized in mitochondria yielding glutamate and ammonia, and glutamine-derived ammonia may interfere with mitochondrial function leading to astrocytes dysfunction. The increase in blood ammonia in advanced liver disease is a consequence of impaired liver function and of shunting of blood around the liver. Muscle wasting, a common occurrence in these patients, also may contribute since muscle is an important site for extrahepatic ammonia removal.4
In addition to direct neurotoxicity, low-grade astrocyte swelling may contribute to brain dysfunction. The enzyme glutamine synthetase (present in the endoplasmic reticulum of astrocytes) is responsible for the conversion of and ammonia to glutamine.5 As glutamine acts as osmolyte, water moves inside the astrocyte causing low-grade cerebral edema and a predominantly neuroinhibitory state (that is, slowing of mental processes) is pathognomonic of HE, which is associated with chronic liver disease.6,7
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