Hepatic Encephalopathy : Structural Brain Damage

by National Institute of Health

(Page 2 of 4)

HE associated with chronic liver failure (regardless of whether the liver disease is caused by alcohol or other factors) does not result in significant loss of nerve cells (neurons) in the brain or in other readily observable structural damage to the neurons. In contrast, liver failure causes significant changes to supporting brain cells called astrocytes. These large star-shaped cells are essential to the functioning of the central nervous system because they help maintain the proper composition of the fluid surrounding the neurons.

For example, astrocytes take up brain chemicals (neurotransmitters) that are released by the neurons and mediate nerve signal transmission between cells; astrocytes also take up minerals (potassium) generated and secreted during the brain's energy metabolism and remove neurotoxic substances. Some evidence suggests that a metabolic "cross-talk" (the release of substances by one cell type to stimulate another cell type) occurs between astrocytes and neurons which is essential to brain function.

In patients with HE, the astrocytes adopt a characteristic morphologic feature known as Alzheimer type II astrocytosis, named after the neuropathologist who also gave his name to the neuro-degenerative disease. These abnormal astrocytes, which usually are found in pairs or triplets, are characterized by their enlarged, glassy-looking nuclei. This glassy appearance is caused by the fact that the DNA and its associated proteins are not distributed throughout the nucleus but are confined to its edges. The nuclei of Alzheimer type II astrocytes also contain deposits of a molecule called glycogen, which serves as a storage form of the sugar glucose in cells but typically is not found in the nucleus; it is unknown whether these changes affect astrocyte function, however.

Neuroimaging Helps Elucidate the Mechanisms Leading to HE

Researchers have gained a better understanding of the mechanisms and consequences of alcoholic liver disease in the brain by using neuroimaging and spectroscopic techniques that allow them to study the metabolism and functions of specific brain regions in living patients. Two neuroimaging techniques used extensively in the study of HE in alcoholic cirrhotic patients are positron emission tomography (PET) and magnetic resonance imaging (MRI). Studies using these techniques have confirmed the contributions of two neurotoxic substances, ammonia and manganese, to the development of HE.

PET Establishes Ammonia's Role

PET is a technique used to examine the metabolic activity of various body regions, including the brain. For these analyses, patients are injected with a molecule called a ligand, which normally may be metabolized in the body. The ligand molecule is labeled by the addition of a radioactive atom. Using sophisticated machines to detect the radioactive molecules in various tissues, investigators can monitor the transport of ligand molecules and their breakdown in the tissues, and thereby can determine the metabolic activities of those tissues. For example, researchers can measure glucose uptake, which occurs in all cells in the process of generating the energy those cells need, by administering a radioactive form of glucose called 18F-fluorodeoxyglucose. Similarly, investigators can use radioactive water to monitor blood flow, radioactive ammonia to assess ammonia metabolism, and a wide range of radioactive compounds to study various molecules involved in the activities of neurotransmitters.

A variety of PET ligands have been used to assess the functions of various brain regions in patients with alcohol-induced cirrhosis. Studies using 18FDG have revealed that alcoholic cirrhotic patients with mild HE show decreases in glucose uptake in the region of the brain involved in controlling the "attention system" responsible for monitoring, for example, visual stimuli as well as in selecting appropriate responses to these stimuli (anterior cingulate cortex). These findings indicate that this brain region is less active in HE patients than in healthy people. Not surprisingly, the investigators also found that glucose utilization in the anterior cingulate cortex, as determined by 18FDG, correlated significantly with patients' performance on neuropsychological tests involving attention-demanding tasks (patients with reduced glucose utilization exhibited poorer performance). Reduced glucose utilization in patients with HE was accompanied by corresponding decreases in blood flow in those brain structures.

Other PET studies have assessed the levels of ammonia in the brain. As mentioned earlier, ammonia is one of the neurotoxic substances that the liver normally removes from the blood. PET analyses using radioactive ammonia in cirrhotic patients with mild HE have revealed significant increases in ammonia uptake and metabolism in the brain. These investigators found that, in particular, a measure of the extent to which ammonia can enter the brain from the general circulation3 - a variable called the permeability-surface area product (PS) - increases as cirrhotic patients start to develop HE. (3 The brain is largely separated from the general circulation by the blood-brain barrier, a property of the blood vessels in the brain that prevents the passage of many molecules from the blood into the brain tissue. As a result, only selected substances can enter the brain from the blood. This feature protects the brain cells from exposure to many toxic substances or disease-causing organisms; however, some molecules can pass the blood-brain barrier to a certain extent.) When the PS increases, a greater proportion of the ammonia present in the general circulation can enter the brain. Increases in the PS explain why severe HE can be found in alcoholic cirrhotic patients even if the ammonia levels in the blood are not greatly elevated: In these cases, a higher proportion of the ammonia in the blood can enter the brain and cause damage there. Studies have found that in patients with advanced stages of encephalopathy resulting from chronic liver failure, ammonia levels in the brain may increase more than twentyfold.

Ammonia is extremely toxic to the brain, affecting both neurons and astrocytes. For example, ammonia has deleterious effects on nerve signal transmission mediated by numerous neurotransmitter systems as well as on the brain's energy metabolism. In addition, ammonia can alter the expression4 of various genes encoding key brain proteins involved in the brain cells' energy production, structure, and cell-to-cell interactions. (4 The term "gene expression" refers to the entire process of converting the genetic information encoded in a gene into a protein product.) These alterations in gene expression may account for some of the changes in neurotransmitter activity and astrocyte structure observed in HE patients.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.