Hepatic Encephalopathy

Complication of Alcoholic Liver Disease
by National Institute of Health

Alcohol's harmful effects on liver cells not only interfere not only with the normal functioning of the liver but also impact distant organs, including the brain. Prolonged liver dysfunction resulting from excessive alcohol consumption can lead to the development of a serious and potentially fatal brain disorder known as hepatic encephalopathy (HE). Patients with HE suffer from sleep disturbances, changes of mood and personality, severe cognitive effects (a shortened attention span), psychiatric conditions such as anxiety and depression, as well as motor disturbances, including motor incoordination and a type of flapping tremor of the hands called asterixis. In the most serious cases, the patients no longer respond to external stimuli and may fall into a coma (hepatic coma), which can be fatal.

Analyses of brain tissue of HE patients found characteristic changes in the structure of supporting cells known as astrocytes rather than obvious destruction of nerve cells (neurons). Astrocytes are large star-shaped cells, distributed throughout the brain, that help maintain the proper composition of the fluid surrounding the neurons. For example, astrocytes take up brain chemicals (neurotransmitters) that are released by neurons, and minerals such as potassium, which are generated and secreted during the brain's energy metabolism. In addition, astrocytes eliminate some substances that are toxic to neurons (neurotoxic). The proper functioning of the astrocytes and their interactions with the neurons are essential to brain function. Patients with HE frequently have pairs and triplets of abnormal astrocytes with a characteristic structure known as Alzheimer type II astrocytosis, in which the astrocytes' nuclei are enlarged and glassy-looking. This glassy appearance is caused by the fact that the DNA and its associated proteins are confined to the edges of the nuclei, rather than distributed throughout them. Alzheimer type II astrocytes also exhibit other physiological and functional abnormalities.

Diagnosing HE in alcoholic patients is difficult because no single clinical or laboratory test can conclusively establish the diagnosis. Patients frequently are misdiagnosed, particularly in the early stages of HE, when symptoms such as euphoria, anxiety, depression, and sleep disorders occur that are common to a number of psychiatric conditions. In addition, whether - and to what extent - a patient shows each of these symptoms depends on fluctuations in the patient's medical status or diet. Diagnosis also is hindered because HE can be triggered or exacerbated by a medical procedure known as the transjugular intrahepatic stent shunt (TIPS), which commonly is used to treat alcoholic patients who experience elevated blood pressure in the portal vein that transports blood to the liver. By redirecting blood flow around the liver, the TIPS procedure is intended to alleviate this condition and prevent complications such as gastrointestinal bleeding and accumulation of fluid in the abdomen.

Relationships Between the Liver and the Brain

Normal brain functioning depends on several aspects of normal liver functioning. For example, the liver supplies certain nutrients to the brain that the brain itself cannot produce. The liver also cleanses the blood of substances that could damage brain cells (neurotoxins). Although the brain is protected from many neurotoxic substances by the blood-brain barrier - a property of blood vessels in the brain that prevents passage of many compounds from the blood into the brain tissue - certain neurotoxins can penetrate that barrier. These substances - which include ammonia, manganese, and other chemicals - can enter the brain at least to some extent unless they are effectively removed from the blood by the liver.

In patients with fibrosis or cirrhosis (whether caused by excessive alcohol consumption or factors such as viruses or toxins), the liver loses its capacity to remove toxic substances from the blood because the number of functional liver cells (hepatocytes) has decreased. Moreover, in these patients some of the blood that normally flows through the portal vein into the liver for cleansing is diverted directly into the general circulation without first passing through the liver, a phenomenon known as portal-systemic shunting. As a result, the shunted blood is not detoxified and blood levels of toxic substances rise. Persistently elevated neurotoxin levels damage brain cells and the patients begin to develop HE. In fact, studies involving neuropsychological tests have found that although alcohol's direct effects on the brain also cause cognitive deficits and brain damage in alcoholics, HE is a major contributing factor to cognitive dysfunction in alcoholics with severe liver disease. In these studies, alcoholic patients with cirrhosis had significantly lower scores on learning and memory tests than did alcoholics without cirrhosis, indicating that liver dysfunction is associated with more extensive brain dysfunction in these patients.

Mechanisms Leading to HE

Researchers have gained a better understanding of the mechanisms leading to HE in patients with alcoholic liver disease by using neuroimaging and spectroscopic techniques that permit them to study the metabolism and functions of specific brain regions in living patients. These studies have confirmed the contributions of at least two neurotoxic substances, ammonia and manganese, to the development of HE.

The Role of Ammonia. Some of these investigations employed positron emission tomography (PET), a technique used to examine the metabolic activity of various body regions, including the brain, by monitoring the transport and breakdown of radioactively labeled molecules using sophisticated detection devices. Some PET studies of alcoholic patients have assessed ammonia uptake and metabolism in the brain. In cirrhotic patients with mild HE, PET analyses using radioactive ammonia have revealed significant increases in the amount of ammonia taken up and metabolized in the brain. In particular, a variable called the permeability-surface area product (PS), a measure of how much ammonia can enter the brain from the general circulation, increases as cirrhotic patients start to develop HE. When the PS increases, a greater proportion of the ammonia in the general circulation can enter the brain.

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.