Hepatic encephalopathy is a syndrome observed in patients with cirrhosis. Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of brain disease. [1, 2, 3] Hepatic encephalopathy is characterized by personality changes, intellectual impairment, and a depressed level of consciousness.  An important prerequisite for the syndrome is diversion of portal blood into the systemic circulation through portosystemic collateral vessels.  Hepatic encephalopathy is also described in patients without cirrhosis with either spontaneous or surgically created portosystemic shunts. The development of hepatic encephalopathy is explained, to some extent, by the effect of neurotoxic substances, which occurs in the setting of cirrhosis and portal hypertension.
Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. Symptoms may be debilitating in a significant number of patients. Overt hepatic encephalopathy occurs in about 30%-45% of patients with cirrhosis.  It is observed in 24%-53% of patients who undergo portosystemic shunt surgery.
The development of hepatic encephalopathy negatively impacts patient survival. The occurrence of encephalopathy severe enough to lead to hospitalization is associated with a survival probability of 42% at 1 year of follow-up and 23% at 3 years. 
Approximately 30% of patients dying of end-stage liver disease experience significant encephalopathy, approaching coma. 
The economic burden of hepatic encephalopathy is substantial. After ascites, hepatic encephalopathy is the second most common reason for hospitalization of cirrhotic patients in the United States.  Hepatic encephalopathy is also the most common, possibly preventable, cause for readmission.  The US national expenditures related to hospitalizations for hepatic encephalopathy have been estimated to range from about $1 billion per year to upwards of $7 billion per year. [6, 10] These costs may underestimate the true economic burden of hepatic encephalopathy, in terms of the condition’s negative impact on the employment and finances of patients and their caregivers. 
Hepatic encephalopathy, accompanying the acute onset of severe hepatic synthetic dysfunction, is the hallmark of acute liver failure (ALF). Symptoms of encephalopathy in ALF are graded using the same scale used to assess encephalopathy symptoms in cirrhosis. The encephalopathy of cirrhosis and ALF share many of the same pathogenic mechanisms. However, brain edema plays a much more prominent role in ALF than in cirrhosis. The brain edema of ALF is attributed to increased permeability of the blood-brain barrier, impaired osmoregulation within the brain, and increased cerebral blood flow. The resulting brain cell swelling and brain edema are potentially fatal. In contrast, brain edema is rarely reported in patients with cirrhosis. See Acute Liver Failure for more detailed information on the encephalopathy of ALF.
A nomenclature has been proposed for categorizing hepatic encephalopathy.  Type A hepatic encephalopathy describes encephalopathy associated with A cute liver failure. Type B hepatic encephalopathy describes encephalopathy associated with portal-systemic B ypass and no intrinsic hepatocellular disease. Type C hepatic encephalopathy describes encephalopathy associated with Cirrhosis and portal hypertension or portal-systemic shunts. Type C hepatic encephalopathy is, in turn, subcategorized as episodic, persistent, or minimal.
For patient education resources, see Digestive Disorders Center and Infections Center, as well as Cirrhosis.
A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with cirrhosis. Some investigators contend that hepatic encephalopathy is a disorder of astrocyte function. Astrocytes account for about one third of the cortical volume. They play a key role in the regulation of the blood-brain barrier. They are involved in maintaining electrolyte homeostasis and in providing nutrients and neurotransmitter precursors to the neurons. They also play a role in the detoxification of a number of chemicals, including ammonia. 
It is theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the brain in the setting of liver failure. These neurotoxic substances may then contribute to morphologic changes in the astrocytes. In cirrhosis, astrocytes may undergo Alzheimer type II astrocytosis. Here, astrocytes become swollen. They may develop a large pale nucleus, a prominent nucleolus, and margination of chromatin. In ALF, astrocytes may also become swollen. The other changes of Alzheimer type II astrocytosis are not seen in ALF. But, in contrast to cirrhosis, astrocyte swelling in ALF may be so marked as to produce brain edema. This may lead to increased intracranial pressure and, potentially, brain herniation.
In the late 1990s, authors from the University of Nebraska, using epidural catheters to measure intracranial pressure (ICP), reported elevated ICP in 12 patients with advanced cirrhosis and grade 4 hepatic coma over a 6-year period.  Cerebral edema was reported on computed tomography (CT) scans of the brain in 9 of the 12 patients. Several of the patients transiently responded to treatments that are typically associated with the management of cerebral edema in patients with ALF. Interventions included elevation of the head of the bed, hyperventilation, intravenous mannitol, and phenobarbital-induced coma.
In the author’s opinion, patients with worsening encephalopathy should undergo head CT scanning to rule out the possibility of an intracranial lesion, including hemorrhage. Certainly, cerebral edema, if discovered, should be aggressively managed. The true incidence of elevated ICP in patients with cirrhosis and severe hepatic encephalopathy remains to be determined.
Work focused on changes in gene expression in the brain has been conducted.  The genes coding for a wide array of transport proteins may be upregulated or downregulated in cirrhosis and ALF. As an example, the gene coding for the peripheral-type benzodiazepine receptor is upregulated in both cirrhosis and ALF. Such alterations in gene expression may ultimately result in impaired neurotransmission.
Hepatic encephalopathy may also be thought of as a disorder that is the end result of accumulated neurotoxic substances in the brain. Putative neurotoxins include short-chain fatty acids; mercaptans; false neurotransmitters, such as tyramine, octopamine, and beta-phenylethanolamines; manganese; ammonia; and gamma-aminobutyric acid (GABA).
Ammonia is produced in the gastrointestinal tract by the bacterial degradation of amines, amino acids, purines, and urea. Enterocytes also convert glutamine to glutamate and ammonia by the activity of glutaminase. 
Normally, ammonia is detoxified in the liver by conversion to urea by the Krebs-Henseleit cycle. Ammonia is also consumed in the conversion of glutamate to glutamine, a reaction that depends upon the activity of glutamine synthetase. Two factors contribute to the hyperammonemia that is seen in cirrhosis. First, there is a decrease in the mass of functioning hepatocytes, resulting in fewer opportunities for ammonia to be detoxified by the above processes. Secondly, portosystemic shunting may divert ammonia-containing blood away from the liver to the systemic circulation.
Normal skeletal muscle cells do not possess the enzymatic machinery of the urea cycle but do contain glutamine synthetase. Glutamine synthetase activity in muscle actually increases in the setting of cirrhosis and portosystemic shunting. Thus, the skeletal muscle is an important site for ammonia metabolism in cirrhosis. However, the muscle wasting that is observed in patients with advanced cirrhosis may potentiate hyperammonemia.
The kidneys express glutaminase and, to some extent, play a role in ammonia production. However, the kidneys also express glutamine synthetase and play a key role in ammonia metabolism and excretion. 
Brain astrocytes also possess glutamine synthetase. However, the brain is not able to increase glutamine synthetase activity in the setting of hyperammonemia. Thus, the brain remains vulnerable to the effects of hyperammonemia.
Ammonia has multiple neurotoxic effects. It can alter the transit of amino acids, water, and electrolytes across astrocytes and neurons. It can impair amino acid metabolism and energy utilization in the brain. Ammonia can also inhibit the generation of excitatory and inhibitory postsynaptic potentials. Inflammation (eg, systemic, neuroinflammation, endotoxemia) in conjunction with ammonia also appears to play a role in hepatic encephalopathy in patients with cirrhosis, which may indicate that different types of anti-inflammatory therapy be a potential therapeutic approach. 
Additional support for the ammonia hypothesis comes from the clinical observation that treatments that decrease blood ammonia levels can improve hepatic encephalopathy symptoms. 
One argument against the ammonia hypothesis is the observation that approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence for encephalopathy. Also, ammonia does not induce the classic electroencephalographic (EEG) changes associated with hepatic encephalopathy when it is administered to patients with cirrhosis.
GABA is a neuroinhibitory substance produced in the gastrointestinal tract. Of all brain nerve endings, 24%-45% may be GABAergic. For over 20 years, it was postulated that hepatic encephalopathy was the result of increased GABAergic tone in the brain.  However, experimental work is changing perceptions regarding the activity of the GABA receptor complex in cirrhosis. [15, 19]
The GABA receptor complex contains binding sites for GABA, benzodiazepines, and barbiturates. It was believed that there were increased levels of GABA and endogenous benzodiazepines in plasma. These chemicals would then cross an extrapermeable blood-brain barrier. Binding of GABA and benzodiazepines to a supersensitive neuronal GABA receptor complex permitted the influx of chloride ions into the postsynaptic neurons, leading to the generation of an inhibitory postsynaptic potential.
However, experimental work has demonstrated that there is no change in the brain GABA or benzodiazepine levels. Similarly, there is no change in the sensitivity of the receptors of the GABA receptor complex. 
Previously, it was believed that the administration of flumazenil, a benzodiazepine receptor antagonist, could improve mental function in patients with hepatic encephalopathy. It now appears that flumazenil improves mental function in only a small percentage of patients with cirrhosis.
The neuronal GABA receptor complex contains a binding site for neurosteroids. Some investigators contend that neurosteroids play a key role in hepatic encephalopathy. 
In experimental models, neurotoxins, like ammonia and manganese, increase the production of the peripheral-type benzodiazepine receptor (PTBR) in astrocytes.  PTBR, in turn, stimulates the conversion of cholesterol to pregnenolone to neurosteroids. Neurosteroids are then released from the astrocytes. They are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission.
One study compared the levels of various chemicals in the autopsied brain tissues from patients with cirrhosis who had either died in hepatic coma or died without evidence of hepatic encephalopathy. Elevated levels of allopregnanolone, the neuroactive metabolite of pregnenolone, were found in the brain tissue of patients who died in hepatic coma.  Brain levels of benzodiazepine receptor ligands were not significantly elevated in patients with or without coma. This work further bolsters the role of neurosteroids in hepatic encephalopathy.
Reversibility of hepatic encephalopathy
Classically, hepatic encephalopathy was regarded as a reversible condition. Patients appeared to improve with either drug therapy (eg, lactulose or rifaximin) or liver transplantation. However, a recent study assessed cirrhotic patients who had apparently recovered from an episode of overt hepatic encephalopathy. After careful psychometric testing, it was discovered that these clinically improved patients had residual cognitive impairment compared with cirrhotic patients with either minimal hepatic encephalopathy or no encephalopathy. 
In 2009, Sotil et al evaluated 39 patients who had undergone liver transplantation about 1.5 years before the study. The 25 patients who had hepatic encephalopathy prior to transplantation, on the whole, performed worse on psychometric testing than the 14 patients with no history of overt encephalopathy prior to transplantation. 
In 2011, Garcia-Martinez et al assessed the cognitive function in 52 patients who had undergone liver transplantation. Global cognitive function after transplantation was worse in patients with a history of alcohol-induced cirrhosis, patients with diabetes, and patients with a history of hepatic encephalopathy prior to transplantation. Furthermore, the brain volume (as assessed by magnetic resonance imaging [MRI]) after transplantation was smaller in patients with a history of hepatic encephalopathy prior to transplantation than in patients with no overt encephalopathy.  These are provocative findings that require additional investigation.