Hepatic Encephalopathy, Part 2

Complication of Alcoholic Liver Disease
by National Institute of Health

(Page 2 of 2)

The brain has only a limited capacity to remove any ammonia coming in because of the increased PS. The only way to eliminate any ammonia that has reached the brain cells is through a reaction mediated by an enzyme called glutamine synthetase, which is found in the astrocytes. This enzyme combines a molecule of the amino acid glutamate with a molecule of ammonia to form the amino acid glutamine. In patients with HE, the amounts of glutamine formed in the brain are correlated with the severity of the disease, indicating that the brain is exposed to increasing levels of ammonia as the disease progresses.

Ammonia adversely affects both neurons and astrocytes. Because the enzyme that eliminates ammonia in the brain is present only in astrocytes, neurons are virtually defenseless against increased ammonia concentrations and therefore are likely to suffer ammonia-related damage. For example, ammonia has deleterious effects on nerve signal transmission that is mediated by numerous neurotransmitter systems and impairs the brain's energy metabolism. In addition, ammonia can alter the expression1 of various genes that encode key brain proteins involved in the brain cells' energy production, structure, and cell-to-cell interactions. (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.

The Role of Manganese. Researchers also have used magnetic resonance imaging (MRI) to analyze changes in the brains of alcoholics. This technique generates images based on differences between tissues in water content as well as in the content of other molecules that respond to a magnetic field. MRI analyses have found that more than 80 percent of alcoholics with cirrhosis show regions of abnormally high signal intensity (signal hyperintensities), primarily in a brain area called the globus pallidus, which is involved in control of motor function. The intensity of these signals correlates with the presence of certain signs and symptoms of impaired motor function but not with the patients' performance on tests assessing global encephalopathy and cognitive functioning.

Additional analyses have determined that hyperintense MRI signals in the globus pallidus are probably caused by manganese deposits in that region. Indeed, studies using brain tissue from alcoholic cirrhotic patients who died from HE have revealed manganese levels in the globus pallidus that were up to seven times higher than manganese levels in subjects without cirrhosis. Manganese normally is eliminated by the joint actions of the liver, gallbladder, and bile ducts (the hepatobiliary system), but patients with chronic liver failure have elevated manganese concentrations in the blood. As a result, the metal can enter the brain and be deposited in the globus pallidus and associated brain structures, where it particularly affects the actions of certain proteins (receptors) that interact with the neurotransmitter dopamine. This effect is demonstrated by the fact that dopamine receptors are altered in the brains of alcoholic cirrhotic patients who died in a hepatic coma. In addition, manganese induces Alzheimer type II changes that interfere with the functioning of astrocytes. Thus, manganese deposits in the globus pallidus may account for both the motor symptoms and the structural changes in astrocytes that are characteristic of HE.

Treatment of Patients With HE

Researchers and clinicians are exploring various approaches to preventing HE in patients with alcohol-induced chronic liver failure or to ameliorating its consequences. These approaches include the following.

Strategies to lower ammonia levels. One approach - administering certain sugar molecules (lactulose) or antibiotics (neomycin) - reduces the production of ammonia in the gastrointestinal tract. Other strategies are intended to increase the conversion of ammonia into harmless molecules outside the brain - for example, by treating the patients with an agent called L-ornithine L-aspartate, which helps to incorporate ammonia into the amino acid glutamine in the skeletal muscle - and to bolster the residual ability of the patient's cirrhotic liver to eliminate ammonia as urea.

Neuropharmacological strategies. These approaches involve using neuroactive drugs to counteract ammonia's harmful effects on neurotransmitter systems in the brain. This type of treatment is in its infancy, however, because researchers have not yet identified the precise nature of the neurotransmitter systems that contribute to the development of HE or are affected by the condition.

Liver-assist devices. These machines, or "artificial livers," are dialysis systems composed of columns that are filled with hepatocytes, a protein called albumin, charcoal, or combinations thereof. The patient's blood is circulated through these columns to remove the toxins. In initial studies, patients treated with an albumin-based system showed lower amounts of ammonia circulating in the blood as well as improvements in the severity of their encephalopathy.

Liver transplantation. This approach is widely used in alcoholic cirrhotic patients with end-stage chronic liver failure. In general, implantation of a new liver results in significant improvements in cognitive function in these patients and corrects the excessive ammonia levels as well as the MRI signal hyperintensities that result from manganese deposits found in patients with HE.

Summary

HE is a serious complication of alcoholic liver disease that contributes to cognitive dysfunction in chronic alcoholic patients. In patients with HE, the damaged liver can no longer remove neurotoxic substances such as ammonia and manganese from the blood. As a result, these molecules may enter the brain, where they can exert a variety of harmful effects that interfere with normal neurotransmitter activity, impair motor functions, and cause structural alterations in the astrocytes. To prevent or treat HE in alcoholic patients with cirrhosis, physicians currently rely primarily on strategies to lower blood ammonia concentrations as well as on liver transplantation in patients with end-stage liver disease; new approaches also are also being investigated.

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.