|55 Kenosia Avenue
Danbury, CT 06810
Toll Free: 1.800.999.6673
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
NORD is very grateful to Roger F. Butterworth PhD, DSc, Professor of Medicine, University of Montreal, Director, Neuroscience Research Unit, Hopital St-Luc, Montreal, Canada, for assistance in the preparation of this report.
Hepatic encephalopathy is a brain disorder that develops in some individuals with liver disease. Hepatic encephalopathy is a complex disorder that encompasses a spectrum or continuum of disease that ranges from a subtle condition with no outward signs or symptoms to a severe form that can cause serious, life-threatening complications. Symptoms are related to progressive dysfunction of the brain and may include personality changes, intellectual impairment, impaired memory and loss of consciousness (coma). Hepatic encephalopathy can occur in individuals with acute or chronic liver (hepatic) disease or in individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present). A portosystemic shunt is an abnormal passageway that allows blood from the gastrointestinal tract to bypass the liver. They can be present at birth (congenital) or acquired during life. Hepatic encephalopathy is caused when toxins that are normally cleared from the body by the liver accumulate in the blood, eventually traveling to the brain. Many of the symptoms of hepatic encephalopathy are reversible when promptly detected and treated.
Hepatic encephalopathy encompasses a spectrum or continuum of disease and, consequently, the symptoms and severity of the disorder can vary widely from one person to another. The severity of hepatic encephalopathy can range from mild, barely discernable symptoms to serious, life-threatening complications. Hepatic encephalopathy may develop slowly over time in individuals with chronic liver disease or may occur episodically, worsening and then improving only to recur. An episode of hepatic encephalopathy is often triggered by certain conditions such as infection, gastrointestinal bleeding, constipation, certain drugs, surgery or an alcohol binge. Episodes of hepatic encephalopathy can develop rapidly and without warning, often necessitating hospitalization.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Many of the symptoms of hepatic encephalopathy are reversible when promptly identified and treated.
Hepatic encephalopathy is sometimes broken down into three subtypes: Type A, which is associated with acute liver failure; Type B, which is associated a portosystemic shunt (a shunt that bypasses the liver) with no existing liver disease present; and Type C, which is associated with scarring and poor function of the liver (cirrhosis), which often occurs with chronic liver disease.
While the symptoms are similar among these different subtypes of hepatic encephalopathy, individuals with acute liver failure are more likely to have swelling (edema) in the brain and increased pressure within the skull (intracranial hypertension), which can potentially cause life-threatening complications.
Researchers now believe that as many as 70 percent of individuals with cirrhosis development symptoms of hepatic encephalopathy. Many individuals only develop mild symptoms, so-called minimal hepatic encephalopathy (MHE).
MHE may not be associated with any obvious or outwardly noticeable signs or symptoms. However, there may be subtle or minimal changes in memory, concentration, and intellectual function. Coordination may also be affected and some affected individuals may take longer to respond to situations (increased reaction time). These symptoms, although termed "subtle", can still have significant consequences on daily life such as impairing a person's ability to drive a car.
Hepatic encephalopathy can be associated with more severe symptoms including reduced alertness, shortened attention span, disruptions in sleep patterns, mild confusion, slowing of the ability to perform mental tasks and mood or personality changes. More noticeable changes in memory, concentration or intellectual function than occur in MHE may also be seen. When affected individuals have obvious, outward signs and symptoms, the disorder may be referred to as overt hepatic encephalopathy.
Eventually, affected individuals may develop lethargy, slurred speech, confusion, significant delays in performing mental tasks, and regression of skills requiring the coordination of mental and physical activities (psychomotor retardation). Affected individuals may also develop obvious personality changes including inappropriate behavior or lack of restraint. Some individuals may slowly flap their hands up and down when attempting to hold their arms out, a condition known as asterixis.
In the most severe form of hepatic encephalopathy, affected individuals may develop marked confusion or disorientation, amnesia, greatly dulled or reduced consciousness (stupor) or loss of consciousness (coma). Additional severe and potentially life-threatening complications of cirrhosis include permanent nervous system damage, heart failure, kidney abnormalities including kidney failure, breathing (respiratory) abnormalities and blood poisoning (sepsis).
Hepatic encephalopathy occurs in individuals with liver disease when toxins that are normally cleared in the liver accumulate in the blood eventually traveling to and damaging the brain. The exact underlying mechanisms by which hepatic encephalopathy develops in individuals with liver disease are not fully understood.
Researchers believe that high blood pressure of the main vein of the liver (portal hypertension) results in blood bypassing the liver. Normally, blood travels through the portal vein and enters the liver where toxins are removed or filtered from the blood (detoxification). By bypassing the liver, unfiltered blood ends up circulating throughout the body eventually reaching the brain where certain toxics damage brain tissue.
Although the exact underlying process by which hepatic encephalopathy develops is unknown, high levels of substances produced by the digestive breakdown of proteins, such as ammonia, are believed to play a major role. Ammonia is elevated in individuals with acute and chronic liver disease and is known to affect the brain in other disorders such as Reye syndrome and certain metabolic disorders. Ammonia is normally converted to urea in the liver and cleared out of the body through the urine. Ammonia is highly toxic to the brain. Although ammonia is generally accepted to a play a role in hepatic encephalopathy, some individuals with elevated ammonia levels do not develop symptoms, suggesting that additional factors play a role in the development of the disorder.
Additional factors that have been explored as potentially playing a role in the development of hepatic encephalopathy include manganese toxicity and impaired function of certain central nervous system cells called astrocytes, which play a role in regulating the blood-brain barrier and also help to detoxify certain chemicals including ammonia; dysfunction of the blood-brain barrier, which prevents dangerous substances from reaching the brain; amino acid imbalances; short chain fatty acids; infection; inflammation; and increased activity of GABA, an inhibitory neurotransmitter in the central nervous system. More research is necessary to determine the exact, underlying factors that ultimately cause the development of hepatic encephalopathy and its associated symptoms.
As briefly discussed above, in individuals with chronic liver disease, episodes of hepatic encephalopathy may be triggered by certain events or occurrences such as low levels of oxygen in the body, dehydration, constipation, gastrointestinal bleeding, an alcohol binge, infection, kidney abnormalities and the use of certain drugs especially those that act on the central nervous system such as tranquilizers and other sleep medications, antidepressants, and antipsychotics. In some cases, surgery can precipitate an episode of hepatic encephalopathy. Gastrointestinal bleeding is the most common precipitating event associated with hepatic encephalopathy, most likely because individuals with cirrhosis are at a greater risk of gastrointestinal bleeding than the general population.
The exact incidence of hepatic encephalopathy in the general population is unknown. It affects males and females in equal numbers and can occur in individuals of any age who have acute or chronic liver disease. Approximately 24-53 percent of individuals whose liver is bypassed by a portosystemic shunt (with no liver disease present) develop hepatic encephalopathy.
Hepatic encephalopathy is most often associated with cirrhosis, which is estimated to affect 5.5 million people in the United States. Approximately 70 percent of individuals with cirrhosis may develop symptoms of hepatic encephalopathy. Because some mild cases of hepatic encephalopathy may go undiagnosed, it is difficult to determine the true frequency in the general population.
Symptoms of the following disorders can be similar to those of hepatic encephalopathy. Comparisons may be useful for a differential diagnosis.
There are a wide variety of disorders and conditions that can cause altered mental status similar to that seen in individuals with hepatic encephalopathy. Such disorders and conditions can include intracranial tumors or lesions, infections of the brain including meningitis or encephalitis, psychiatric illnesses, metabolic disorders, toxic encephalopathy such as from excessive alcohol intake, Wernicke-Korsakoff syndrome, Reye syndrome, and other disorders such as the urea cycle disorders that cause high levels of ammonia in the blood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of hepatic encephalopathy may be suspected in some individuals with liver disease based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests that are used to rule out other conditions. Such tests may include a complete blood count, liver function tests, tests that evaluate serum ammonia levels, and an electroencephalogram, which is a test that measures the electrical activity of the brain, may be useful in detecting encephalopathy. Specialized imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans may be used to rule out other conditions affecting the brain such as tumors.
The specific therapies used to treat hepatic encephalopathy may vary depending upon numerous factors including whether there is a triggering event, the presence or absence of certain symptoms, the severity of the disorder and the severity of the underlying liver disease, an individual's age and general health and other factors. An episode of hepatic encephalopathy can be a medical emergency that requires an emergency room visit or hospitalization.
Initial therapies may be aimed at identifying and removing a triggering event such as infection, gastrointestinal bleeding, certain drugs or kidney dysfunction. Such therapies may include medications to treat infections, medications or procedures to alleviate or control bleeding, stopping the use of medications that can trigger an episode and any appropriate therapy for kidney issues.
Additional treatment for individuals with hepatic encephalopathy is usually aimed at lowering the levels of ammonia and other toxins in the blood. Since such toxins originally arise in the gut, therapies are directed toward the gastrointestinal system. Such therapies may include, using synthetic sugars such as lactulose, which speeds up the passage of food through the gastrointestinal tract and inhibits the absorption of toxins by the intestines and antibiotics, which act on bacteria in the colon. Lactulose and antibiotics may be used in conjunction.
In 2010, the Food and Drug Administration (FDA) approved the use of rifaximin (Xifaxan®) to reduce the risk of overt hepatic encephalopathy in individuals 18 and older. Xifaxan reduces the risk of overt hepatic encephalopathy and reduces the number of hospitalizations due to hepatic encephalopathy. Xifaxan is thought to act on microorganisms found in the digestive tracts of humans (gut flora). For more information on Xifaxan, contact:
Salix Pharmaceuticals Corporate Headquarters
1700 Perimeter Park Drive
Morrisville, NC 27560-8404
For product information, adverse event reports, and product complaint reports, please contact:
Salix Product Information Call Center
The symptoms of hepatic encephalopathy are often reversible when promptly identified and treated. However, individuals with chronic liver disease are at risk for a recurrence of hepatic encephalopathy and should be periodically monitored by a physician.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Dancygier H. Ed. Clinical Hepatology: Principles and Practice of Hepatobiliary Disease. 2nd ed. Springer-Verlag Berlin Hiedelberg. New York, NY. 2010:1005-1016.
Rowland LP. Ed. Merritt's Neurology. 10th ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2000:876-878.
Butterworth RF. Editorial: rifaximin and minimal hepatic encephalopathy. Am J Gastroenterol. 2011;106:317-318.
Spiegel DR, Surkin K. A possible case of minimal hepatic encephalopathy treated successfully with lactulose. J Neuropsychiatry Clin Neurosci. 2011;23:E1.
Seyan AS, Hughes RD, Shawcross DL. Change face of hepatic encephalopathy: role of inflammation and oxidative stress. World J Gastroenterol. 2010;16:3347-3357.
Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071-1081.
Jalan R. Rifaximin in hepatic encephalopathy: more than just a non-absorbable antibiotic? J Hepatol. 2010;53:580-582.
Foerster BR, Conklin LS, Petrou M, Barker PB, Schwarz KB. Minimal hepatic encephalopathy in children: evaluation with proton MR spectroscopy. AJNR Am J Neuroradiol. 2009;301610-1613.
DiMartini A, Chopra K. The importance of hepatic encephalopathy: pre-transplant and post-transplant. Liver Transpl. 2009;15:121-123.
Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy - definition, nomenclature, diagnosis and qualification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716-721.
Blei AT, Cordoba J. Hepatic encephalopathy. Am J Gastroenterol. 2001;96:1968-1976.
FROM THE INTERNET
Wolf DC. Hepatic Encephalopathy. Emedicine Journal, February 14, 2011. Available at: http://emedicine.medscape.com/article/186101-overview Accessed February 14, 2011.
Cohen S. Hepatic Encephalopathy. The Merck Manuals Online Medical Library. August 2006. Available at: http://www.merckmanuals.com/home/sec10/ch135/ch135f.html Accessed February 14, 2011.
Report last updated: 2011/04/18 00:00:00 GMT+0