Hepatic Encephalopathy : Neuroimaging

by National Institute of Health

(Page 3 of 4)

Ammonia normally is removed from the blood in the liver by a series of chemical reactions called the urea cycle. During these sequential reactions, ammonia is converted into urea, which is excreted in the urine. The brain, however, lacks an effective urea cycle and therefore has only a limited capacity to remove any ammonia that enters the tissue from the blood 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 combines a molecule of the amino acid glutamate with a molecule of ammonia to form the amino acid glutamine. The relevance of this reaction was confirmed in neuroimaging analyses measuring glutamine levels in the brains of alcoholic patients with HE. These studies found that the amounts of glutamine formed in the brain correlated with the severity of HE, confirming that the brain is exposed to elevated levels of ammonia. However, glutamine synthetase is present only in astrocytes, not in neurons, and cannot remove all the ammonia that enters the brain. As a result, neurons are virtually defenseless against increased ammonia concentrations and therefore are most likely to exhibit impaired function indicative of ammonia-related damage.

MRI Identifies Signal Hyperintensities That May Result From Manganese Deposits

MRI technology is based on the fact that when the body is exposed to radio waves in the presence of a strong magnetic field, the nuclei of certain atoms emit signals as they align and realign in the magnetic field. These signals can be detected by a scanning device and converted into three-dimensional images of specific structures of the body (brain structures). MRI scanners generally form images based on signals emitted by hydrogen atoms, the most abundant element in biological tissues. Because most of the hydrogen in the body is in the form of water, MRI images differentiate brain structures based on their water content. However, elements other than hydrogen, including manganese, also can emit signals that are detected by MRI, as discussed below.

When MRI analyses are performed on alcoholics with cirrhosis, more than 80 percent of the patients show regions of abnormally high signal intensity (signal hyperintensities) in both the right and left halves of the brain and concentrated in an area that is involved in the control of motor function (the globus pallidus). The elevation in intensity of these signals correlates with the presence of certain signs and symptoms of impaired motor function that are found, for example, in patients with Parkinson's disease (rigidity, abnormally diminished motor activity, and tremors) and also are present in HE patients. However, the intensity of the MRI images does not correlate with the patients' performance on tests assessing global encephalopathy and cognitive functioning.

ncreasing evidence suggests that the intense MRI signals in the globus pallidus of cirrhotic alcoholics are caused by deposits of a paramagnetic substance, probably manganese, in that region. Manganese normally is eliminated by the joint actions of the liver, gallbladder, and bile ducts (the hepatobiliary system). In patients with chronic liver failure, manganese concentrations in the blood increase, and the metal can enter the brain and be deposited in the globus pallidus and associated brain structures. Studies using brain tissue from alcoholic cirrhotic patients who died from HE revealed up to seven times more manganese in the globus pallidus compared with normal levels.

Manganese is known to be neurotoxic, particularly affecting the actions of certain proteins (receptors) that interact with the neurotransmitter dopamine. Consistent with this finding, researchers found altered dopamine receptors in the brains of alcoholic cirrhotic patients who died in a hepatic coma. In addition, manganese induces Alzheimer type II changes in astrocytes. Taken together, these observations suggest that deposits of manganese in the globus pallidus resulting from chronic liver failure probably cause the motor symptoms and structural changes of astrocytes that are characteristic of HE.

Amounts of other metals whose chemical properties are similar to those of manganese are not substantially elevated in the brains of patients with chronic liver failure, ruling out those metals as causes of HE and its symptoms.

Management of Patients With HE

Researchers and clinicians are exploring a variety of approaches for preventing HE in patients with alcohol-induced chronic liver failure or for ameliorating its consequences. These approaches involve strategies to lower the levels of ammonia in the blood, medications to counteract ammonia's neurotoxic effects, devices to improve liver function, and liver transplantation.

Ammonia-Lowering Strategies

In patients with cirrhosis, HE is frequently triggered by conditions that cause an increase in circulating ammonia, including gastrointestinal bleeding or a diet that contains high amounts of protein (which generates ammonia when broken down). Because levels of ammonia in the blood and brain are elevated in these patients, the most popular strategies currently used to manage and treat HE involve reducing ammonia production or increasing ammonia metabolism (the conversion of ammonia into harmless molecules) outside the brain.

Traditional ammonia-lowering strategies include the use of certain sugar molecules that are not absorbed into the body (lactulose) or certain antibiotics (neomycin), both of which reduce the production of ammonia in the gastrointestinal tract. To increase ammonia metabolism, one can administer an agent called L-ornithine L-aspartate to patients, which enhances the natural process by which ammonia is incorporated into the amino acid glutamine in the skeletal muscle; this agent also optimizes the residual urea synthesis in the patient's cirrhotic liver. An earlier approach to lowering ammonia levels - that is, seriously limiting the protein intake of patients with alcoholic cirrhosis - is no longer recommended because it can lead to a reduction in the patient's muscle mass. Maintaining muscle mass is important because, as mentioned above, a chemical reaction that removes free ammonia from the blood by incorporating it into glutamine can occur in the skeletal muscle.

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.