Hepatic Encephalopathy : Neuroimaging, Part 2

by National Institute of Health

(Page 4 of 4)

Neuropharmacological Approaches

Other possible strategies for managing HE involve using neuroactive drugs to counteract ammonia's harmful effects on neurotransmitter systems in the brain. This treatment approach still is in its infancy, however, because researchers have not yet identified the precise nature of the neurotransmitter systems that either play a role in the development of HE or are affected by the condition. Some studies have reported occasional beneficial effects when the dopamine neurotransmitter system was stimulated by agents such as L-dopa or bromocriptine, but these approaches have not gained wide acceptance. Likewise, a compound called flumazenil that inhibits the actions of sedative agents (is a benzodiazepine antagonist) initially was reported to be beneficial, having an awakening effect on stuporous and comatose alcoholic cirrhotic patients. However, researchers now think that the beneficial action of flumazenil resulted from its activity as an antidote to the benzodiazepine medications frequently prescribed to alcoholic cirrhotic patients as part of an endoscopic evaluation or as a sedative. Thus, flumazenil may correct benzodiazepine-induced coma in these patients rather than treat HE per se.

Liver-Assist Devices

A great deal of attention currently is focused on the production of "artificial livers," or liver-assist devices. In general, these devices are composed of small columns filled with functional hepatocytes, a protein called albumin, or charcoal, or combinations thereof. The patient's plasma is circulated through the columns to remove toxins in a manner similar to dialysis treatment of patients with kidney failure. Initial studies using an albumin system yielded particularly promising results: Patients treated with this approach showed less ammonia circulating in the blood as well as amelioration of their HE symptoms.

Liver Transplantation

Liver transplantation is the ultimate treatment for alcoholic cirrhotic patients with end-stage chronic liver failure. In general, implantation of a new liver results in normalization of blood ammonia concentrations as well as in significant improvements in cognitive function in these patients, clearly confirming that HE is a major contributor to the cognitive dysfunction found in alcoholic patients with significant liver disease. Liver transplantation also eliminates the MRI signal hyperintensities that result from manganese deposits found in the brains of patients with HE. However, the MRI signal hyperintensities may take several months to resolve, suggesting that manganese is removed slowly from the brains of these patients.

Altered Gene Expression in the Brain Resulting From Alcoholic Liver Disease

One of the main causes of brain dysfunction in patients with hepatic encephalopathy is the accumulation of ammonia in the blood, which the patient's liver, damaged by alcoholic liver disease, cannot remove. Molecular biological techniques have allowed researchers new insights into how HE develops, including the specific effects of ammonia. These analyses have found that, among other effects, ammonia alters the expression of certain genes - that is, the rates at which the genetic information contained in DNA is converted into the final protein products encoded by those genes. Molecular approaches have enabled investigators to identify some of the genes affected in patients with HE. These genes code for key brain proteins that are essential to the cells' energy production, structure, and interactions with other cells, including the following proteins.

A specific type of monoamine oxidase called MAO-A, an enzyme responsible for the metabolism of neurotransmitters called monoamines. These compounds include the neurotransmitter serotonin, which is involved in the regulation of mood and sleep.

The mitochondrial (peripheral-type) benzodiazepine receptor, a receptor protein located on the membranes surrounding small cell structures called mitochondria, which serve as the cell's energy factories. This receptor helps facilitate the uptake of cholesterol into the mitochondria, which then is converted into a family of compounds known as neurosteroids. Neurosteroids can excite or inhibit other neighboring nerve cells, thereby influencing nerve signal transmission. The brains of patients with alcoholic liver disease show increased production of the neurosteroid allopregnanolone, a potent neuroinhibitory compound that could contribute to the development of HE in alcoholic liver disease. This increased production probably results from enhanced cholesterol uptake mediated by the benzodiazepine receptor.

A nerve cell-specific form of the enzyme nitric oxide synthase, which produces nitric oxide, a highly reactive molecule that plays a role in various cellular processes, including cell-to-cell communication and the widening (dilation) of blood vessels. Excess levels of nitric oxide, however, are toxic to the cells and can contribute to a cellular state called oxidative stress, which is characterized by the presence of excess free radicals and/or a lack of the compounds that remove these free radicals (antioxidants). Oxidative stress can cause cell damage and has been implicated in alcoholic liver disease. Increased expression of nitric oxide synthase in the brains of patients with chronic liver failure has been linked to excess nitric oxide production, which in turn leads to oxidative stress and cellular dysfunction.

A protein called glial fibrillary acidic protein, which is essential for maintaining the structure of astrocytes. Chronic liver failure or ammonia exposure results in decreased expression of GFAP, which is associated with the presence of Alzheimer type II astrocytes that are characteristic of HE.

Summary

HE is a major neuropsychiatric complication of alcoholic liver disease and an important contributor to the cognitive dysfunction found in chronic alcoholic patients. HE is caused in part by the accumulation in the brain of neurotoxic substances such as ammonia and manganese, which normally are removed by the hepatobiliary system. Increased brain concentrations of ammonia alter the expression of genes that encode important brain proteins responsible for regulating neurotransmitters; higher levels of ammonia also alter the structure of brain cells called astrocytes. Manganese deposited in basal ganglia structures (particularly the globus pallidus) in patients with alcoholic cirrhosis leads to impaired motor function and the appearance of distinct, abnormally intense signals, which can be detected by MRI. Prevention and treatment of HE in alcoholic cirrhotic patients continue to rely on strategies aimed at lowering blood ammonia concentrations. Current research is focused on identifying neurological and biochemical mechanisms underlying HE as well as pharmacotherapies that can address these mechanisms, and on creating liver-assist devices aimed at removing toxins from the blood. Liver transplantation is used in chronic alcoholic patients with end-stage liver failure.

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.