ReviewBrain edema in acute liver failure and chronic liver disease: Similarities and differences
Highlights
► Brain edema is a common feature in ALF and CLD. ► HE is inconsistently associated with the presence of brain edema. ► Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. ► The pathogenesis of HE is multifactorial causing an array of neurological symptoms.
Introduction
Loss of liver function occurs as a consequence of either acute liver failure (ALF) or chronic liver disease (CLD). ALF is defined as a rapid hepatocellular necrosis that leads to the severe deterioration of liver function, which occurs within hours up to 6 months after the onset of jaundice, and in the absence of a pre-existing liver disease (Lee, 2012). The most frequent cause of ALF is drug intoxication and hepatotoxicity (58%), with acetaminophen overdose being the most frequently observed (46%). Other etiologies include autoimmune hepatitis, acute viral hepatitis (A and B), drug-induced, with a large proportion (15%) remaining indeterminate. The mean survival rate (spontaneous liver regeneration) of patients with ALF is 45%, but this can vary significantly depending on the etiology of ALF. The highest recovery rate (55–65%) is reported in patients following acetaminophen overdose or hepatitis A infection (Lee, 2012).
CLD develops due to a chronic deterioration of liver function resulting from a persisting, long-term hepatic insult. After 10–20 years of continuous aggression, cirrhosis evolves, and is characterized by the progressive replacement of normal liver architecture by fibrosis, scar tissue and regenerative nodules (Fauci et al., 2011). The most common etiologies of cirrhosis are: (1) alcoholism, as 8–20% of long-term heavy drinkers develop cirrhosis (Sanyal et al., 2010), (2) chronic viral hepatitis, where approximately 30% of infected patients become cirrhotic (Rosen, 2011), and (3) the accumulation of fat deposits in the liver, which cause non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Given that obesity is on course of becoming a worldwide epidemic condition (in the USA, 66% of adults are overweight or obese; this is predicted to increase to 75% by 2015 (Wang and Beydoun, 2007)), the number of cases of NASH-related cirrhosis is expected to rise.
To date, the only curative treatment for patients with liver failure or disease is liver transplantation. Since the number of patients awaiting a liver transplantation surpasses the number of available livers (from both living and cadaveric donors), managing liver failure/disease-related complications remains the primary challenge.
Section snippets
Hepatic encephalopathy
Hepatic encephalopathy (HE), a major complication of both ALF and CLD, is a metabolic neuropsychiatric syndrome that comprises a spectrum of symptoms, ranging from mild cognition and attention deficits to coma and death. HE has been categorized into 3 types, based on the type of hepatic abnormality (Ferenci et al., 2002):
Brain edema in liver disease/failure
Brain edema is defined as an accumulation of water in the brain, which occurs in the setting of an osmotic gradient. It is commonly associated with HE in both ALF and CLD. Since the brain is contained within a non-compliant skull, an increase in brain volume can progressively result in an increase of intracranial pressure (ICP) and detrimentally lead to brain stem herniation and death.
Components involved in the development of brain edema in liver disease/failure
Brain edema can arise due to cytotoxic or vasogenic mechanisms, with the first occurring as a result of alterations in cellular metabolism, and the latter due to a physical breakdown of the BBB (Klatzo, 1967). The BBB is a physical and metabolic barrier that helps regulate brain homeostasis and protects the brain from endogenous and exogenous toxins arising from systemic circulation. The BBB is a multicellular vascular structure, composed of endothelial cells with tight intercellular junctions
Ammonia
The neurotoxic effects of ammonia have long been considered the main pathogenic factor in HE (Cooper and Plum, 1987). Ammonia is a neurotoxin whose homeostasis is maintained primarily by the liver. It is produced by a number of different metabolic reactions, with phosphate-activated glutaminase (PAG) being an important enzyme catalyzing the deamination of glutamine to glutamate. The gut is a primary source of ammonia production through ammonia-generating intestinal bacteria and PAG activity in
Role of brain edema in HE
In ALF, intracranial hypertension is the primary cause to brain stem herniation and death. Brain edema undoubtedly is linked to a rise of cerebral water in ALF, however aside from its physical contribution to brain volume and ICP, its role in the severe deterioration of neurological function remains unresolved. Brain edema in CLD patients is associated with MHE; not clinically obvious deterioration of neurological function. However, since patients with MHE have an 4-fold increased risk of
Conclusion
In summary, brain edema is present in both ALF and CLD, and a combination of multiple factors can lead to its development (vasogenic or cytotoxic). In ALF, a rapid development of brain edema contributes to an increase in ICP, which physically stresses the brain and causes sudden neurological deterioration. However, in CLD, during which an increase in ICP is rarely observed, the role of brain edema in the pathogenesis of HE remains elusive; brain edema (astrocyte swelling) can lead to
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