Hepatic encephalopathy (HE) is a pathological condition defined by the spectrum of neuropsychiatric abnormalities which result from a liver dysfunction. It is known in the scientific community with a number of different names, such as portosystemic encephalopathy, liver encephalopathy or hepatic coma.
HE presentation can be classified based on the grading of its symptoms with the West Haven classification system. According to this system, there are five different grades of HE described as follows:
Grade 0: No detectable changes in the patient’s personality; minimal changes in memory, coordination, intellectual function and concentration.
Grade 1: Minimal lack of awareness; decreased attention capability; hypersomnia, insomnia, or inverted sleep pattern; depression usually accompanied by alternated moments of euphoria and irritability; slowed mental task performance (especially mathematical operations); mild confusion.
Grade 2: Marked personality changes usually accompanied by inappropriate behavior and slurred speech; heavily reduced mental task performance; recurrent/intermittent time disorientation; frequent lethargy/apathy.
Grade 4: Coma frequently accompanied by the absence of painful stimuli response.
In grade zero and one HE is also defined as “covert”, because of the minimal evidence of symptoms. By contrast, in the remaining three grades HE is defined as “overt” because of the marked evidence of these symptoms  . The 11th World Congress of Gastroenterology in Vienna (1998) decided to further classify HE based on the underlying cause , in a system which includes three types of disease: type A, associated with acute liver failure, type B, associated with portal-systemic shunting, and type C associated with cirrhosis.
Diagnosis of HE is very difficult, as diseases with similar symptoms are many and differential diagnoses is very frequent . Therefore, diagnosis of HE can only be made when the presence of a liver disorder or a portosystemic shunt has been confirmed with a liver function test or ideally a liver biopsy  .
Hemorrhage and seizures also have symptoms very similar to those of HE, but this conditions can be easily detected with CT scan of the brain or electroencephalography. The presence of HE can be further confirmed with other examinations such as chest X-ray, blood tests or urinalysis. In addition, there are a number of neurological tests    which might be very useful to diagnose the disorder, but they are not very frequently employed and the decision to use them should be based on the severity of the patient’s mental dysfunction.
Treatment for patients affected by HE depends on the its underlying cause, be it an acute liver failure (type A), a portal-systemic shunting (type B) or cirrhosis (type C). If necessity requires it, the physician might choose to send the patient to a specialist centre and receive the appropriate procedures, such as liver transplant or shunt occlusion. In regard to the treatments themselves, these can be divided in two groups, those which aim at decreasing intestinal ammonia production and those which aim at increasing ammonia clearance.
Among the treatments which aim at decreasing intestinal ammonia production there is the modification of diet. Risk of HE can be decreased in subjects affected with chronic liver disease by using a diet with adequate protein supply  , and the addition of suitable substances like lactulose can help treat the disorder when it occurs. In fact, the conversion of disaccharides lactulose to lactic acid causes gut lumen acidification and conversion of NH4 to NH3, which in turn inhibits ammoniagenic coliform bacteria and increases levels of nonammoniagenic lactobacilli. Ammoniagenic bacteria population can also be decreased by using a number of appropriate antibiotics, such as neomycin, metronizadole and especially rifaximin .
Among the treatments which aim at decreasing ammonia clearance there is the regimen with LOLA, a stable salt of the two constituent amino acids l-ornithine and l-aspartate. LOLA stimulates the urea cycle and both amino acids are substrates for glutamate transaminase, whose activity increases glutamate levels. Ammonia is then used to convert glutamate to glutamine through the activity of glutamine synthetase. The urea cycle can be further increased by zinc administration, as zinc improves the activity of ornithine transcarbamylase, one of the key enzymes of the urea cycle. Other substances with similar effects on ammonia clearance include sodium benzoate, sodium phenylbutyrate, sodium phenylacetate and glycerol phenylbutyrate   .
HE presents frequent complications which affect daily life activities, like deficits in working memory, psychomotor speed, attention, and response inhibition   . These effects significantly decrease the patients quality of life    and financial status, which in addition to the high rates of hospital admissions  make HE a serious burden for healthcare programs.
As previously mentioned, the major function of the liver is to break down the substances in the body and, if these are poisonous, make them harmless. When a liver dysfunction occurs, these toxins begin to build up in the bloodstream, until they reach particularly dangerous high concentrations. A classical example of poisonous compound is ammonia, produced in the body as a protein metabolism waste product. Other examples of putative neurotoxic substances include short-chain fatty acids, mercaptans, false neurotransmitters (like tyramine) or gamma-aminobutyric acid.
At present the exact cause of HE is unknown. A number of theories have been proposed to explain its development, and the scientific consensus in this regard appears to mainly support the idea of HE being a disorder of the astrocytes. Astrocytes are the characteristic star-shaped glial cells in the central nervous system collectively known as astroglia. They perform several supportive functions, including nutrients supply, biochemical support, ion-balance maintenance and repair. The neurotoxins which enter the brain contribute to several morphological changes in astrocytes, such as swelling and the appearance of large pale nuclei, that in the end lead to brain dysfunction. These physiological changes might even involve changes in gene expression, especially for those genes which code for transporter proteins.
The majority of the epidemiological data comes from the subjects affected by advanced liver diseases. When it comes to understanding the origin of HE, it is often difficult to assess the burden of a chronic liver disease, as this often has an insidious onset and a long period of latency. Therefore, most patients start seeking for medical assistance when the disease is well on its way to reaching its full development.
HE can appear in patients in both a mild form known as minimal hepatic encephalitis (MHE) and a fully symptomatic overt form know as over hepatic encephalopathy (OHE). Data about the incidence and prevalence of HE is still insufficient. Anyway, according to some studies carried out in the United States, of the 150,000 individuals which are annually diagnosed with chronic liver diseases, cirrhosis accounts for 20% of the cases while chronic hepatitis C accounts for almost two-thirds . Furthermore, while the prevalence of hepatitis C is decreasing, that of cirrhosis is expected to increase in the next two decades .
It is believed that most of the patients affected by cirrhosis will develop some degree of HE at some point of the course of their liver disease. According to recent data, it appears that MHE occurs in up to 80% of the cirrhotic patients, while OHE occurs in up to 45% of the cases. OHE also appears in up to 50% of the patient with surgical complications and sometime as complication of an acute liver failure . After the first episode of OHE, the probability to survive is 42% in the first year of follow-up and 23% in the third .
One of the most important theories used to explain why liver dysfunction and portosystemic shunting lead to HE is the theory of the nitrogen-containing compounds. Nitrogen-containing compounds come from the gastrointestinal system through the portal vein. After getting into the liver, 80-90% of them will then be metabolized through the urea cycle and excreted through the urogenital system. In all the subtypes of HE the nitrogen-compounds disposal mechanism is impaired, either because hepatocytes are no longer capable of metabolizing these substances or because the shunt that bypasses the liver leads the nitrogen-rich compounds right into the systemic circulation. The shunt can be the product of either a collateral circulation or of a surgery.
One of the most important nitrogen-rich compounds is ammonia (NH3), a substance which crosses the blood-brain barrier and is absorbed by astrocytes. Astrocytes use ammonia to synthesize glutamine from glutamate, through the activity of the glutamine synthetase. However, in contrast to what happens in other types of cells, such as skeletal muscles and kidney cells, astrocytes are not capable of increasing the glutamine synthetase activity in the setting of hyperammonemia, making the brain extremely vulnerable to the high ammonia concentrations. The high ammonia concentration has multiple neurotoxic effects, like altered transits of amino acids, water and other electrolytes across astrocytes and neurons, in addition to reduced amino acid metabolism, modified energy utilization, and impaired capacity to generate excitatory and inhibitory postsynaptic potentials.
Another important hypothesis used to explain why liver dysfunction and portosystemic shunting lead to HE is the GABA theory. GABA is a neuroinhibitory substance produced in the gastrointestinal tract and found in around 25% of the brain nerve endings. It is believed that the increased GABA plasma levels during HE would cause an influx of chloride ions into the postsynaptic neurons and the subsequent generation of inhibitory potentials. However, experimental data shows no change in the brain GABA levels or in the sensitivity of GABA receptor complex in subjects affected by HE .
Since HE often comes as a complication of a liver disease, the best way to prevent it is to take steps to prevent the liver disease itself. These include avoiding alcohol and high-fat food consumption, losing weight in excess and steps to prevent viral hepatitis, like frequent hand washing and having no contact with infected subjects.
This physiological dysfunction prevents the liver from breaking down and removing several toxic substances which begin to flow freely around the body. The main features of hepatic encephalopahty (HE) include intellectual impairment, personality changes and severely reduced consciousness levels, possibly due to the presence of substances with neurotoxic effects. HE usually occurs in subjects affected by liver cirrhosis and in those with either spontaneous or surgically created vascular shunts.
Hepatic encephalopathy (HE) is a pathological condition defined by the spectrum of neuropsychiatric abnormalities which result from a liver dysfunction. This physiological dysfunction prevents liver from breaking down and removing several toxic substances, which begin to flow freely around the body. A classical example of poisonous compound is ammonia, produced in the body as protein metabolism waste product. Ammonia has a number of toxic effects over the brain, which ultimately cause the typical neural impairments of HE. The disease can be classified using a number of systems, the most used of which recognizes three types of HE according to the underlying cause: type A, associated with acute liver failure, type B, associated with portal-systemic shunting, and type C, associated with cirrhosis.
Treatment of HE is largely based on the integration in the diet of substances which can affect ammonia intestinal production and ammonia clearance. Since it often comes as a complication of a liver disease, the best way to prevent HE is to take steps to prevent the liver disease itself, such as avoiding alcohol consumption and having no contact with subjects affected by viral hepatitis.