Understanding Hepatic Encephalopathy

by National Institute of Health

Hepatic encephalopathy (HE) is a brain disorder caused by chronic liver failure, particularly in alcoholics with cirrhosis, which results in cognitive, psychiatric, and motor impairments. In these patients, the number of functional liver cells is reduced, and some blood is diverted around the liver before toxins are removed. As a result, toxins such as ammonia and manganese can accumulate in the blood and enter the brain, where they can damage nerve cells and supporting cells called astrocytes. Positron emission tomography analyses have determined that ammonia levels are elevated in the brains of HE patients; ammonia accumulation can alter the expression of various important brain genes. Magnetic resonance images show that manganese is deposited in a brain area called the globus pallidus; manganese deposits may be responsible for structural changes in the astrocytes that are characteristic of HE. Treatment of patients with HE involves measures to lower ammonia levels in the blood, medications to counteract ammonia's effects on brain cell function, devices to compensate for liver dysfunction, and liver transplantation.

The liver and the brain interact in numerous ways to ensure normal brain functioning. For example, the liver plays a key role in supplying nutrients to the brain, which cannot produce these compounds itself. The liver also removes toxic substances from the blood, including substances that have been generated in the brain and must be eliminated from the body, as well as compounds produced in other tissues that are harmful to the brain's nerve cells (neurotoxic). Thus, liver dysfunction can cause disturbances of brain function and even contribute to brain damage.

Liver dysfunction of varying severity is a frequent complication of chronic alcohol abuse. The most common and least severe form of alcoholic liver disease - fatty liver (steatosis) - is characterized by fat deposits in the primary liver cells (the hepatocytes). More serious stages of alcoholic liver disease include inflammation of liver tissue (hepatitis), scar tissue formation (fibrosis), and destruction of the normal liver architecture (cirrhosis). When the liver becomes fibrotic and cirrhotic, the number of functional hepatocytes decreases, and the liver loses its capacity to remove toxic substances from the blood. Moreover, during these disease stages some of the blood entering the liver through the portal vein cannot penetrate the diseased liver and is diverted directly into the general circulation; this phenomenon is known as portal-systemic shunting. Blood that bypasses the liver is not detoxified, and blood levels of toxic substances increase. Researchers have identified several toxins that normally are removed in the liver but are found in the circulation of patients with alcoholic cirrhosis, including ammonia, manganese, and chemicals called mercaptans, all of which readily enter the brain and are neurotoxic. Consequently, brain function in patients with severe alcoholic liver disease is compromised, resulting in a condition known as hepatic encephalopathy (HE) or portal-systemic encephalopathy. (The term "encephalopathy" refers to any abnormal condition in the structure or function of the brain, especially chronic, destructive, or degenerative conditions.)

This article describes the characteristics and diagnosis of HE and the changes in brain cell structure associated with this condition. The article also reviews imaging techniques that allow researchers to study changes in brain structure and function occurring in patients with HE and describes the contributions of ammonia and manganese to the development of HE, as elucidated by these techniques. Finally, the article explores some approaches currently used or being investigated for treating patients with HE resulting from alcoholic liver disease.

Characteristics and Diagnosis of Hepatic Encephalopathy

HE is a complex neuropsychiatric syndrome characterized by severe cognitive, psychiatric, and motor disturbances resulting from chronic liver failure, which in most cases in Western societies is caused by chronic alcohol abuse. As chronic liver failure develops and increases in severity, patients start to experience sleep disturbances, changes of mood and personality, and a shortened attention span. These symptoms are followed by psychiatric conditions such as anxiety and depression, as well as by motor problems, including motor incoordination and a type of flapping tremor of the hands called asterixis. Ultimately, patients no longer respond to external stimuli and may fall into a coma (hepatic coma), which can be fatal.

A fact largely overlooked in the literature on alcoholic brain disorders is that patients suffering from HE often have other alcohol-related brain disorders as well, such as Wernicke's encephalopathy and alcoholic cerebellar degeneration. These conditions are caused by alcohol-induced deficiencies in the vitamin thiamine and/or alcohol's direct toxic effects on the brain. It can be difficult to disentangle the contributions of concurrent alcohol-related brain disorders on the patient's cognitive functioning; however, when an alcoholic patient develops significant liver disease, HE becomes a major factor contributing to the cognitive dysfunction associated with chronic alcoholism. This is clearly illustrated by the results of studies involving neuropsychological tests, which demonstrated that alcoholic patients with cirrhosis had significantly lower scores in learning and memory tests than did alcoholics without cirrhosis.

HE is difficult to diagnose in alcoholic patients because no single clinical or laboratory test is sufficient to establish the diagnosis. Patients frequently are misdiagnosed, particularly in the early stages of HE, when symptoms occur that are common to a number of psychiatric disorders, such as euphoria, anxiety, depression, and sleep disorders. The following characteristics have been proposed as helpful in diagnosing HE in alcoholic cirrhotic patients:

• History of liver disease.
• A slowing of brain waves measured by electroencephalography (EEG).
• Impaired performance on neuropsychological tests assessing visuospatial and perceptual-motor control.
• Asterixis ("flapping tremor").
• Foul-smelling breath associated with liver disease (fetor hepaticus).
• Enhanced rate of breathing (hyperventilation).
• Elevated concentrations of ammonia in the serum after a period of fasting. (2 The serum is the clear portion of the blood that remains after blood cells, platelets, and blood-clotting molecules have been removed.)
• Reduced awareness or consciousness.

Although these signs and symptoms are useful tools for diagnosing HE, they also occur in brain disorders caused by metabolic disturbances and therefore are not specific to HE. Furthermore, whether - and to what extent - a patient displays each symptom may vary depending on fluctuations in the patient's medical and drug status or diet. For example, sedatives or meals high in protein frequently trigger episodes of HE in alcoholic patients with cirrhosis. Thus, an asymptomatic cirrhotic patient frequently begins to show signs of HE following ingestion of large amounts of protein, which is a source of ammonia. Also, small doses of sedatives may trigger overt encephalopathy in these patients.

In addition to patients' general medical status or diet, other factors can trigger or exacerbate HE. For example, alcoholic cirrhotic patients frequently experience elevated blood pressure in the portal vein transporting blood to the liver, which may lead to complications such as gastrointestinal bleeding and accumulation of fluid in the abdomen (a condition known as ascites). To treat these complications, physicians use a nonsurgical procedure known as transjugular intrahepatic stent shunt (TIPS), which redirects some of the blood flow around the liver. Following the procedure, blood bypasses the liver, as do the toxins contained in the blood (a process similar to the diversion of blood in patients with liver cirrhosis described in the introduction). Although TIPS leads to a lower blood pressure in the portal vein, thereby preventing gastrointestinal bleeding and ascites, it also can lead to HE because the blood is not detoxified. In fact, in up to 50 percent of patients treated with TIPS, the procedure results in new or worsening episodes of HE.

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.